Sharon Worcester

ATLANTA – The incidence of hepatitis C infection is increasing among adolescents and young adults in Pennsylvania, just as it has in other areas in the United States, according to surveillance data for 2003 through 2010.

During that 7-year period, the number of reports of newly recognized confirmed or probable cases of hepatitis C past or present infection among those aged 15-34 years increased from 1,384 to 2,393, representing a near doubling of the rate of cases (from 43 to 72) per 100,000 population, Dr. Sameh W. Boktor reported in a poster at the International Conference on Emerging Infectious Diseases.

The rates in other age groups, however, declined during this time period.

For example, the overall rate of newly reported cases for all age groups combined declined from 85 to 72 per 100,000 population, and the rate of cases among those aged 45-64 years declined from 185 to 142 per 100,000 population, said Dr. Boktor of the Pennsylvania Department of Health, Harrisburg.

The increases in the adolescent and young adult age groups are likely caused by high-risk behaviors, such as intravenous drug use and unprotected sex between men – and, to a lesser degree – unprotected heterosexual sex.

"We know high-risk behaviors are common in this age group," Dr. Boktor said, noting that evidence suggests such high-risk behaviors are increasing among residents in rural areas, and the increases in cases of hepatitis C among adolescents and young adults in this study were greater in rural areas, compared with two large urban centers.

This finding, however, should be interpreted with caution because of the small population in rural counties; targeted studies may shed more light on this apparent trend.

The data for this study were derived mainly from laboratories via electronic reporting. Age-specific rates of reported cases were calculated and compared over time, as were demographic and spatial characteristic, Dr. Boktor said.

The findings, which are similar to those from Massachusetts and other areas, are of concern, because hepatitis C infection is the leading cause of advanced liver cirrhosis and liver cancer in the United States. They indicate a need for increased attention to prevention in the adolescent and young adult population.

"We need to work more on characterizing risk factors, and we need to work more on developing effective prevention strategies in this very productive age group," Dr. Boktor said.

He noted that these findings "almost certainly underestimate the real impact of viral hepatitis," because they reflect only those patients with access to testing, and whose results are reported.

Dr. Boktor said he had no relevant financial disclosures.

ATLANTA – The incidence of hepatitis C infection is increasing among adolescents and young adults in Pennsylvania, just as it has in other areas in the United States, according to surveillance data for 2003 through 2010.

During that 7-year period, the number of reports of newly recognized confirmed or probable cases of hepatitis C past or present infection among those aged 15-34 years increased from 1,384 to 2,393, representing a near doubling of the rate of cases (from 43 to 72) per 100,000 population, Dr. Sameh W. Boktor reported in a poster at the International Conference on Emerging Infectious Diseases.

The rates in other age groups, however, declined during this time period.

For example, the overall rate of newly reported cases for all age groups combined declined from 85 to 72 per 100,000 population, and the rate of cases among those aged 45-64 years declined from 185 to 142 per 100,000 population, said Dr. Boktor of the Pennsylvania Department of Health, Harrisburg.

The increases in the adolescent and young adult age groups are likely caused by high-risk behaviors, such as intravenous drug use and unprotected sex between men – and, to a lesser degree – unprotected heterosexual sex.

"We know high-risk behaviors are common in this age group," Dr. Boktor said, noting that evidence suggests such high-risk behaviors are increasing among residents in rural areas, and the increases in cases of hepatitis C among adolescents and young adults in this study were greater in rural areas, compared with two large urban centers.

This finding, however, should be interpreted with caution because of the small population in rural counties; targeted studies may shed more light on this apparent trend.

The data for this study were derived mainly from laboratories via electronic reporting. Age-specific rates of reported cases were calculated and compared over time, as were demographic and spatial characteristic, Dr. Boktor said.

The findings, which are similar to those from Massachusetts and other areas, are of concern, because hepatitis C infection is the leading cause of advanced liver cirrhosis and liver cancer in the United States. They indicate a need for increased attention to prevention in the adolescent and young adult population.

"We need to work more on characterizing risk factors, and we need to work more on developing effective prevention strategies in this very productive age group," Dr. Boktor said.

He noted that these findings "almost certainly underestimate the real impact of viral hepatitis," because they reflect only those patients with access to testing, and whose results are reported.

Dr. Boktor said he had no relevant financial disclosures.

ATLANTA – The incidence of hepatitis C infection is increasing among adolescents and young adults in Pennsylvania, just as it has in other areas in the United States, according to surveillance data for 2003 through 2010.

During that 7-year period, the number of reports of newly recognized confirmed or probable cases of hepatitis C past or present infection among those aged 15-34 years increased from 1,384 to 2,393, representing a near doubling of the rate of cases (from 43 to 72) per 100,000 population, Dr. Sameh W. Boktor reported in a poster at the International Conference on Emerging Infectious Diseases.

The rates in other age groups, however, declined during this time period.

For example, the overall rate of newly reported cases for all age groups combined declined from 85 to 72 per 100,000 population, and the rate of cases among those aged 45-64 years declined from 185 to 142 per 100,000 population, said Dr. Boktor of the Pennsylvania Department of Health, Harrisburg.

The increases in the adolescent and young adult age groups are likely caused by high-risk behaviors, such as intravenous drug use and unprotected sex between men – and, to a lesser degree – unprotected heterosexual sex.

"We know high-risk behaviors are common in this age group," Dr. Boktor said, noting that evidence suggests such high-risk behaviors are increasing among residents in rural areas, and the increases in cases of hepatitis C among adolescents and young adults in this study were greater in rural areas, compared with two large urban centers.

This finding, however, should be interpreted with caution because of the small population in rural counties; targeted studies may shed more light on this apparent trend.

The data for this study were derived mainly from laboratories via electronic reporting. Age-specific rates of reported cases were calculated and compared over time, as were demographic and spatial characteristic, Dr. Boktor said.

The findings, which are similar to those from Massachusetts and other areas, are of concern, because hepatitis C infection is the leading cause of advanced liver cirrhosis and liver cancer in the United States. They indicate a need for increased attention to prevention in the adolescent and young adult population.

"We need to work more on characterizing risk factors, and we need to work more on developing effective prevention strategies in this very productive age group," Dr. Boktor said.

He noted that these findings "almost certainly underestimate the real impact of viral hepatitis," because they reflect only those patients with access to testing, and whose results are reported.

Dr. Boktor said he had no relevant financial disclosures.

Unexplained shoulder pain and abnormal ultrasound findings of those large joints are part of provisional criteria published on polymyalgia rheumatica.

To be diagnosed with polymyalgia rheumatica (PMR) under the criteria proposed jointly by the American College of Rheumatology and the European League Against Rheumatism, patients should be at least 50 years old, have morning stiffness lasting at least 45 minutes, new hip pain, and elevated C-reactive protein and/or erythrocyte sedimentation rate.

ACR and EULAR based their criteria on findings from a prospective, international, multicenter cohort study, are published in the April issue of Arthritis & Rheumatism.

Additional validation in an external data set is required, and the criteria should not be used for diagnostic purposes, but they do have value for identifying the most appropriate patients for enrollment in clinical trials, and thus could pave the way for new therapeutic approaches and novel treatments for the inflammatory disease, Dr. Bhaskar Dasgupta of Southend University Hospital, Westcliff-on-Sea, U.K. and his colleagues reported (Arthritis Rheum. 2012 April;64:943-54).

PMR is a common condition, but its clinical management varies widely, due largely to considerable uncertainty with respect to diagnosis, disease course, and management, according to Dr. Eric L. Matteson, the study’s senior author, who noted in an interview that a lack of classification criteria has hampered development of rational therapeutic approaches because of difficulties in grouping together appropriate patients for enrollment in clinical studies.

"We have no good, established, and in any way validated criteria for classifying patients with having PMR. All previous criteria were based mainly on expert opinion, so what we did here was look at expert opinion about components of the disease that would help us classify a patient as having PMR, then tested to see which of the features in patients who appear to have PMR by expert diagnosis at the outset were most effective in identifying, for classification purposes, patients as having PMR after they were followed for 6 months," said Dr. Matteson, chair of rheumatology at the Mayo Clinic in Rochester, Minn.

The criteria were based on the findings of a criteria development work group convened in 2005 in response to an ACR/EULAR initiative. The group performed a systematic literature review, and through a multiphase process, identified candidate classification criteria, which were ultimately investigated in the 6-month prospective cohort study of 125 patients with new-onset PMR and 169 comparison patients with conditions mimicking PMR.

A scoring algorithm was developed based on four criteria: morning stiffness for greater than 45 minutes (2 points); hip pain/limited range of motion (1 point), absence of rheumatoid factor (RF) and/or anticitrullinated protein antibody (2 points), and absence of peripheral joint pain (1 point).

"A score of 4 or higher had 68% sensitivity and 78% specificity for discriminating all comparison subjects from PMR. The specificity was higher (88%) for discriminating shoulder conditions from PMR and lower (65%) for discriminating RA from PMR. The C statistic for the scoring algorithm was 81%," the investigators said.

The absence of peripheral synovitis or positive RF serology increased the likelihood of PMR.

Additionally, ultrasound was found to significantly improve the specificity of the clinical criteria, improving the C statistic to 82% when added to the scoring algorithm.

"Patients with PMR were more likely to have abnormal ultrasound findings in the shoulder (particularly subdeltoid bursitis and biceps tenosynovitis), and somewhat more likely to have abnormal findings in the hips than [do] comparison subjects as a group," the investigators said, adding that PMR could not be distinguished from RA on the basis of ultrasound, but could be distinguished from non-RA shoulder conditions and subjects without shoulder conditions.

Adding ultrasound to the scoring algorithm improved the C statistic of 82%.

The ultrasound finding mark the first time this technology has been systematically utilized in a longitudinal study for this purpose, Dr. Matteson said, adding that there are, indeed, typical findings on ultrasound in PMR, and although ultrasound alone can’t be used to identify PMR as opposed to RA, the findings can be helpful for classification of patients with PMR.

He also noted that the ultrasound features seen in PMR at the outset improved with treatment.

Patients and controls in the study were recruited from 21 community-based and academic rheumatology clinics in 10 European countries and the United States. All were aged 50 years or older, had new-onset bilateral shoulder pain, and no corticosteroid treatment within 12 weeks before the study. Patients had received a diagnosis of PMR, and corticosteroid treatment was initiated after enrollment.

The non-PMR comparison cohort included subjects with a variety of conditions that need to be distinguished from PMR, in both primary and secondary care, the investigators said.

Initial diagnoses in this group of patients included new-onset RA, connective tissue disease, various shoulder conditions, fibromyalgia, and generalized osteoarthritis, among others, they noted.

"Newer concepts of PMR are revealed by this and other recent studies – heterogeneity at presentation and course, lack of uniform responsiveness to low-dose steroids, and overlap with inflammatory arthritis. However, we feel that at present these classification criteria provide a basic framework for developing clinical trials of novel therapies in PMR," the investigators said, adding that C statistic of 81%, for the algorithm (82% when ultrasound is included), "exceeds the threshold of 80% that is conventionally considered to be useful in clinical decision-making."

"In our view, this approach can now be used to test eligibility for trials with newer therapies in PMR," they said.

The next steps are to validate the classification criteria in another group of patients and to identify better biomarkers for diagnosis and assessment of disease activity and disease damage, Dr. Matteson noted.

The provisional classification criteria are also published simultaneously in the April issue of Annals of the Rheumatic Diseases.

This work was supported by the ACR, EULAR, and the Mayo Foundation, as well as by Biobanque de Picardie in Amiens, France, and by the Ministero de Ciencia y Tecnologia, Spain. Numerous study authors reported various disclosures. Details are included in the full text of the article.

Unexplained shoulder pain and abnormal ultrasound findings of those large joints are part of provisional criteria published on polymyalgia rheumatica.

To be diagnosed with polymyalgia rheumatica (PMR) under the criteria proposed jointly by the American College of Rheumatology and the European League Against Rheumatism, patients should be at least 50 years old, have morning stiffness lasting at least 45 minutes, new hip pain, and elevated C-reactive protein and/or erythrocyte sedimentation rate.

ACR and EULAR based their criteria on findings from a prospective, international, multicenter cohort study, are published in the April issue of Arthritis & Rheumatism.

Additional validation in an external data set is required, and the criteria should not be used for diagnostic purposes, but they do have value for identifying the most appropriate patients for enrollment in clinical trials, and thus could pave the way for new therapeutic approaches and novel treatments for the inflammatory disease, Dr. Bhaskar Dasgupta of Southend University Hospital, Westcliff-on-Sea, U.K. and his colleagues reported (Arthritis Rheum. 2012 April;64:943-54).

PMR is a common condition, but its clinical management varies widely, due largely to considerable uncertainty with respect to diagnosis, disease course, and management, according to Dr. Eric L. Matteson, the study’s senior author, who noted in an interview that a lack of classification criteria has hampered development of rational therapeutic approaches because of difficulties in grouping together appropriate patients for enrollment in clinical studies.

"We have no good, established, and in any way validated criteria for classifying patients with having PMR. All previous criteria were based mainly on expert opinion, so what we did here was look at expert opinion about components of the disease that would help us classify a patient as having PMR, then tested to see which of the features in patients who appear to have PMR by expert diagnosis at the outset were most effective in identifying, for classification purposes, patients as having PMR after they were followed for 6 months," said Dr. Matteson, chair of rheumatology at the Mayo Clinic in Rochester, Minn.

The criteria were based on the findings of a criteria development work group convened in 2005 in response to an ACR/EULAR initiative. The group performed a systematic literature review, and through a multiphase process, identified candidate classification criteria, which were ultimately investigated in the 6-month prospective cohort study of 125 patients with new-onset PMR and 169 comparison patients with conditions mimicking PMR.

A scoring algorithm was developed based on four criteria: morning stiffness for greater than 45 minutes (2 points); hip pain/limited range of motion (1 point), absence of rheumatoid factor (RF) and/or anticitrullinated protein antibody (2 points), and absence of peripheral joint pain (1 point).

"A score of 4 or higher had 68% sensitivity and 78% specificity for discriminating all comparison subjects from PMR. The specificity was higher (88%) for discriminating shoulder conditions from PMR and lower (65%) for discriminating RA from PMR. The C statistic for the scoring algorithm was 81%," the investigators said.

The absence of peripheral synovitis or positive RF serology increased the likelihood of PMR.

Additionally, ultrasound was found to significantly improve the specificity of the clinical criteria, improving the C statistic to 82% when added to the scoring algorithm.

"Patients with PMR were more likely to have abnormal ultrasound findings in the shoulder (particularly subdeltoid bursitis and biceps tenosynovitis), and somewhat more likely to have abnormal findings in the hips than [do] comparison subjects as a group," the investigators said, adding that PMR could not be distinguished from RA on the basis of ultrasound, but could be distinguished from non-RA shoulder conditions and subjects without shoulder conditions.

Adding ultrasound to the scoring algorithm improved the C statistic of 82%.

The ultrasound finding mark the first time this technology has been systematically utilized in a longitudinal study for this purpose, Dr. Matteson said, adding that there are, indeed, typical findings on ultrasound in PMR, and although ultrasound alone can’t be used to identify PMR as opposed to RA, the findings can be helpful for classification of patients with PMR.

He also noted that the ultrasound features seen in PMR at the outset improved with treatment.

Patients and controls in the study were recruited from 21 community-based and academic rheumatology clinics in 10 European countries and the United States. All were aged 50 years or older, had new-onset bilateral shoulder pain, and no corticosteroid treatment within 12 weeks before the study. Patients had received a diagnosis of PMR, and corticosteroid treatment was initiated after enrollment.

The non-PMR comparison cohort included subjects with a variety of conditions that need to be distinguished from PMR, in both primary and secondary care, the investigators said.

Initial diagnoses in this group of patients included new-onset RA, connective tissue disease, various shoulder conditions, fibromyalgia, and generalized osteoarthritis, among others, they noted.

"Newer concepts of PMR are revealed by this and other recent studies – heterogeneity at presentation and course, lack of uniform responsiveness to low-dose steroids, and overlap with inflammatory arthritis. However, we feel that at present these classification criteria provide a basic framework for developing clinical trials of novel therapies in PMR," the investigators said, adding that C statistic of 81%, for the algorithm (82% when ultrasound is included), "exceeds the threshold of 80% that is conventionally considered to be useful in clinical decision-making."

"In our view, this approach can now be used to test eligibility for trials with newer therapies in PMR," they said.

The next steps are to validate the classification criteria in another group of patients and to identify better biomarkers for diagnosis and assessment of disease activity and disease damage, Dr. Matteson noted.

The provisional classification criteria are also published simultaneously in the April issue of Annals of the Rheumatic Diseases.

This work was supported by the ACR, EULAR, and the Mayo Foundation, as well as by Biobanque de Picardie in Amiens, France, and by the Ministero de Ciencia y Tecnologia, Spain. Numerous study authors reported various disclosures. Details are included in the full text of the article.

Unexplained shoulder pain and abnormal ultrasound findings of those large joints are part of provisional criteria published on polymyalgia rheumatica.

To be diagnosed with polymyalgia rheumatica (PMR) under the criteria proposed jointly by the American College of Rheumatology and the European League Against Rheumatism, patients should be at least 50 years old, have morning stiffness lasting at least 45 minutes, new hip pain, and elevated C-reactive protein and/or erythrocyte sedimentation rate.

ACR and EULAR based their criteria on findings from a prospective, international, multicenter cohort study, are published in the April issue of Arthritis & Rheumatism.

Additional validation in an external data set is required, and the criteria should not be used for diagnostic purposes, but they do have value for identifying the most appropriate patients for enrollment in clinical trials, and thus could pave the way for new therapeutic approaches and novel treatments for the inflammatory disease, Dr. Bhaskar Dasgupta of Southend University Hospital, Westcliff-on-Sea, U.K. and his colleagues reported (Arthritis Rheum. 2012 April;64:943-54).

PMR is a common condition, but its clinical management varies widely, due largely to considerable uncertainty with respect to diagnosis, disease course, and management, according to Dr. Eric L. Matteson, the study’s senior author, who noted in an interview that a lack of classification criteria has hampered development of rational therapeutic approaches because of difficulties in grouping together appropriate patients for enrollment in clinical studies.

"We have no good, established, and in any way validated criteria for classifying patients with having PMR. All previous criteria were based mainly on expert opinion, so what we did here was look at expert opinion about components of the disease that would help us classify a patient as having PMR, then tested to see which of the features in patients who appear to have PMR by expert diagnosis at the outset were most effective in identifying, for classification purposes, patients as having PMR after they were followed for 6 months," said Dr. Matteson, chair of rheumatology at the Mayo Clinic in Rochester, Minn.

The criteria were based on the findings of a criteria development work group convened in 2005 in response to an ACR/EULAR initiative. The group performed a systematic literature review, and through a multiphase process, identified candidate classification criteria, which were ultimately investigated in the 6-month prospective cohort study of 125 patients with new-onset PMR and 169 comparison patients with conditions mimicking PMR.

A scoring algorithm was developed based on four criteria: morning stiffness for greater than 45 minutes (2 points); hip pain/limited range of motion (1 point), absence of rheumatoid factor (RF) and/or anticitrullinated protein antibody (2 points), and absence of peripheral joint pain (1 point).

"A score of 4 or higher had 68% sensitivity and 78% specificity for discriminating all comparison subjects from PMR. The specificity was higher (88%) for discriminating shoulder conditions from PMR and lower (65%) for discriminating RA from PMR. The C statistic for the scoring algorithm was 81%," the investigators said.

The absence of peripheral synovitis or positive RF serology increased the likelihood of PMR.

Additionally, ultrasound was found to significantly improve the specificity of the clinical criteria, improving the C statistic to 82% when added to the scoring algorithm.

"Patients with PMR were more likely to have abnormal ultrasound findings in the shoulder (particularly subdeltoid bursitis and biceps tenosynovitis), and somewhat more likely to have abnormal findings in the hips than [do] comparison subjects as a group," the investigators said, adding that PMR could not be distinguished from RA on the basis of ultrasound, but could be distinguished from non-RA shoulder conditions and subjects without shoulder conditions.

Adding ultrasound to the scoring algorithm improved the C statistic of 82%.

The ultrasound finding mark the first time this technology has been systematically utilized in a longitudinal study for this purpose, Dr. Matteson said, adding that there are, indeed, typical findings on ultrasound in PMR, and although ultrasound alone can’t be used to identify PMR as opposed to RA, the findings can be helpful for classification of patients with PMR.

He also noted that the ultrasound features seen in PMR at the outset improved with treatment.

Patients and controls in the study were recruited from 21 community-based and academic rheumatology clinics in 10 European countries and the United States. All were aged 50 years or older, had new-onset bilateral shoulder pain, and no corticosteroid treatment within 12 weeks before the study. Patients had received a diagnosis of PMR, and corticosteroid treatment was initiated after enrollment.

The non-PMR comparison cohort included subjects with a variety of conditions that need to be distinguished from PMR, in both primary and secondary care, the investigators said.

Initial diagnoses in this group of patients included new-onset RA, connective tissue disease, various shoulder conditions, fibromyalgia, and generalized osteoarthritis, among others, they noted.

"Newer concepts of PMR are revealed by this and other recent studies – heterogeneity at presentation and course, lack of uniform responsiveness to low-dose steroids, and overlap with inflammatory arthritis. However, we feel that at present these classification criteria provide a basic framework for developing clinical trials of novel therapies in PMR," the investigators said, adding that C statistic of 81%, for the algorithm (82% when ultrasound is included), "exceeds the threshold of 80% that is conventionally considered to be useful in clinical decision-making."

"In our view, this approach can now be used to test eligibility for trials with newer therapies in PMR," they said.

The next steps are to validate the classification criteria in another group of patients and to identify better biomarkers for diagnosis and assessment of disease activity and disease damage, Dr. Matteson noted.

The provisional classification criteria are also published simultaneously in the April issue of Annals of the Rheumatic Diseases.

This work was supported by the ACR, EULAR, and the Mayo Foundation, as well as by Biobanque de Picardie in Amiens, France, and by the Ministero de Ciencia y Tecnologia, Spain. Numerous study authors reported various disclosures. Details are included in the full text of the article.

Sleep-disordered breathing in infancy and early childhood increases the likelihood of problematic behavior in later childhood, findings from a large, population-based, longitudinal study suggest.

The findings, based on an analysis of data from more than 11,000 participants in the Avon Longitudinal Study of Parents and Children, underscore the importance of addressing sleep-disordered breathing symptoms as early as the first year of life, Karen Bonuck, Ph.D., of the Albert Einstein College of Medicine, N.Y., and her colleagues reported online in the March 5 issue of Pediatrics.

Parental reports on children’s snoring, mouth breathing, and observed apnea identified five early and five late symptom trajectories, or clusters, among the children in the study. The early clusters included those with symptoms arising between 6 and 42 months of age, and the later clusters included those with symptoms between 6 and 69 months of age. The later clusters represented extensions of early clusters.

© Mykola Velychko - Fotolia.com

After researchers controlled for 15 possible confounders, including factors such as fish intake, Family Adversity index, mother and home score, smoking and alcohol use during pregnancy, and race, these clusters predicted approximately 20%-60% increased odds of problematic behaviors at age 4 years, and approximately 40%-100% increased odds of problematic behaviors at age 7 years, as measured using the Strength and Difficulties Questionnaire (SDQ). Behavioral problems assessed included hyperactivity, conduct problems, peer difficulties, and emotional difficulties (Pediatrics 2012 March 5 [doi: 10.1542/peds.2011-1402]).

The strongest and most persistent associations were for a "worst case" cluster of patients in the early symptoms cluster, whose symptoms peaked at 30 months and persisted. The associations between symptoms and SDQ scores in this group were comparable at 4 and 7 years (odds ratios, 1.49 and 1.72, respectively).

However, a "worst case" cluster in the later symptom group, which had peak symptoms at 30 months that abated thereafter, also had increased odds of hyperactivity (OR, 1.85), conduct problems (OR, 1.60), and peer difficulties at age 7 years (OR, 1.37), according to SDQ subscale analyses.

Also, a "late symptom" cluster, with symptoms that increased after 30 months was associated with increased odds of emotional difficulties at 7 years (OR, 1.65) and hyperactivity at age 7 years (OR, 1.88).

"Even very early symptom peaks at 6 and 18 months are associated with [approximately] 40% and 50%, respectively, increased behavioral morbidity at 7 years of age," the investigators said, noting that this may be because of the "increased vulnerability to sleep-disordered breathing effects during this early critical period of brain development, when there is the greatest need for sleep."

Of note, the effects of sleep disordered breathing exceeded those of maternal smoking, maternal education, and paternal employment in multivariate analysis, and only male gender and not being the second or later-born child had greater adverse effects, they said.

Additionally, greater family adversity was associated with poorer behavioral outcomes, and higher home environment scores were associated with improved outcomes.

Sleep-disordered breathing, which can range from mouth breathing to snoring to obstructive sleep apnea, typically peaks between ages 2 and 6 years, but also can occur in younger children. It also is known to be associated with neurobehavioral morbidity, and although understanding how and when symptom patterns in early life affect neurobehavioral outcomes has important clinical implications, existing studies are primarily cross-sectional and generally of insufficient quality, the investigators said.

The findings are important because, depending on how you define sleep-disordered breathing, levels of snoring can range from 5% to 10%-20%, while apnea levels are about 1%-2%, Dr. Bonuck said in an interview.

"What prompted this study was a desire to examine sleep-disordered breathing in a population, rather than selected samples of, let’s say, children who had adenotonsillectomy or who had a sleep study, and to do so over time. Certainly there are a spate of studies examining associations between sleep-disordered breathing, but few followed this many children for as long a period of time," she said.

By pinpointing the sleep-disordered breathing profile of those with the worst emotional/behavioral problems, this can inform clinicians about the urgency to intervene or not, she added.

Although the study is limited by the fact that data were based on parent reports rather than objective testing, the findings nonetheless provide epidemiologic evidence to support attention to symptoms as early as the first year of life.

"This study strengthens evidence that snoring, observed apneas at home, and mouth breathing – along with any underlying obstructive sleep apnea that these symptoms suggest – can cause or promote future emergence of hyperactivity and other problematic behavior in childhood. The study adds unique data on the first 1-2 years of life and suggests that sleep apnea symptoms this early in life can predict behavioral problems at ages 4 and 7," Dr. Ronald D. Chervin, a coauthor of the study and director of the Sleep Disorders Center at the University of Michigan, Ann Arbor, said in an interview.

Pediatricians and families should be aware that symptoms of sleep apnea at any age should not be ignored, and merit, in some cases, investigation to diagnose sleep apnea, he added, noting that "treatment in the form of adenotonsillectomy or other measures when necessary could help to reverse, prevent, or reduce behavioral consequences of obstructive sleep apnea, at present and in the future."

The authors said they had no relevant financial disclosures to report. This study was supported by grants from the National Heart, Lung, and Blood Institute and funded by the National Institutes of Health.

Sleep-disordered breathing in infancy and early childhood increases the likelihood of problematic behavior in later childhood, findings from a large, population-based, longitudinal study suggest.

The findings, based on an analysis of data from more than 11,000 participants in the Avon Longitudinal Study of Parents and Children, underscore the importance of addressing sleep-disordered breathing symptoms as early as the first year of life, Karen Bonuck, Ph.D., of the Albert Einstein College of Medicine, N.Y., and her colleagues reported online in the March 5 issue of Pediatrics.

Parental reports on children’s snoring, mouth breathing, and observed apnea identified five early and five late symptom trajectories, or clusters, among the children in the study. The early clusters included those with symptoms arising between 6 and 42 months of age, and the later clusters included those with symptoms between 6 and 69 months of age. The later clusters represented extensions of early clusters.

© Mykola Velychko - Fotolia.com

After researchers controlled for 15 possible confounders, including factors such as fish intake, Family Adversity index, mother and home score, smoking and alcohol use during pregnancy, and race, these clusters predicted approximately 20%-60% increased odds of problematic behaviors at age 4 years, and approximately 40%-100% increased odds of problematic behaviors at age 7 years, as measured using the Strength and Difficulties Questionnaire (SDQ). Behavioral problems assessed included hyperactivity, conduct problems, peer difficulties, and emotional difficulties (Pediatrics 2012 March 5 [doi: 10.1542/peds.2011-1402]).

The strongest and most persistent associations were for a "worst case" cluster of patients in the early symptoms cluster, whose symptoms peaked at 30 months and persisted. The associations between symptoms and SDQ scores in this group were comparable at 4 and 7 years (odds ratios, 1.49 and 1.72, respectively).

However, a "worst case" cluster in the later symptom group, which had peak symptoms at 30 months that abated thereafter, also had increased odds of hyperactivity (OR, 1.85), conduct problems (OR, 1.60), and peer difficulties at age 7 years (OR, 1.37), according to SDQ subscale analyses.

Also, a "late symptom" cluster, with symptoms that increased after 30 months was associated with increased odds of emotional difficulties at 7 years (OR, 1.65) and hyperactivity at age 7 years (OR, 1.88).

"Even very early symptom peaks at 6 and 18 months are associated with [approximately] 40% and 50%, respectively, increased behavioral morbidity at 7 years of age," the investigators said, noting that this may be because of the "increased vulnerability to sleep-disordered breathing effects during this early critical period of brain development, when there is the greatest need for sleep."

Of note, the effects of sleep disordered breathing exceeded those of maternal smoking, maternal education, and paternal employment in multivariate analysis, and only male gender and not being the second or later-born child had greater adverse effects, they said.

Additionally, greater family adversity was associated with poorer behavioral outcomes, and higher home environment scores were associated with improved outcomes.

Sleep-disordered breathing, which can range from mouth breathing to snoring to obstructive sleep apnea, typically peaks between ages 2 and 6 years, but also can occur in younger children. It also is known to be associated with neurobehavioral morbidity, and although understanding how and when symptom patterns in early life affect neurobehavioral outcomes has important clinical implications, existing studies are primarily cross-sectional and generally of insufficient quality, the investigators said.

The findings are important because, depending on how you define sleep-disordered breathing, levels of snoring can range from 5% to 10%-20%, while apnea levels are about 1%-2%, Dr. Bonuck said in an interview.

"What prompted this study was a desire to examine sleep-disordered breathing in a population, rather than selected samples of, let’s say, children who had adenotonsillectomy or who had a sleep study, and to do so over time. Certainly there are a spate of studies examining associations between sleep-disordered breathing, but few followed this many children for as long a period of time," she said.

By pinpointing the sleep-disordered breathing profile of those with the worst emotional/behavioral problems, this can inform clinicians about the urgency to intervene or not, she added.

Although the study is limited by the fact that data were based on parent reports rather than objective testing, the findings nonetheless provide epidemiologic evidence to support attention to symptoms as early as the first year of life.

"This study strengthens evidence that snoring, observed apneas at home, and mouth breathing – along with any underlying obstructive sleep apnea that these symptoms suggest – can cause or promote future emergence of hyperactivity and other problematic behavior in childhood. The study adds unique data on the first 1-2 years of life and suggests that sleep apnea symptoms this early in life can predict behavioral problems at ages 4 and 7," Dr. Ronald D. Chervin, a coauthor of the study and director of the Sleep Disorders Center at the University of Michigan, Ann Arbor, said in an interview.

Pediatricians and families should be aware that symptoms of sleep apnea at any age should not be ignored, and merit, in some cases, investigation to diagnose sleep apnea, he added, noting that "treatment in the form of adenotonsillectomy or other measures when necessary could help to reverse, prevent, or reduce behavioral consequences of obstructive sleep apnea, at present and in the future."

The authors said they had no relevant financial disclosures to report. This study was supported by grants from the National Heart, Lung, and Blood Institute and funded by the National Institutes of Health.

Sleep-disordered breathing in infancy and early childhood increases the likelihood of problematic behavior in later childhood, findings from a large, population-based, longitudinal study suggest.

The findings, based on an analysis of data from more than 11,000 participants in the Avon Longitudinal Study of Parents and Children, underscore the importance of addressing sleep-disordered breathing symptoms as early as the first year of life, Karen Bonuck, Ph.D., of the Albert Einstein College of Medicine, N.Y., and her colleagues reported online in the March 5 issue of Pediatrics.

Parental reports on children’s snoring, mouth breathing, and observed apnea identified five early and five late symptom trajectories, or clusters, among the children in the study. The early clusters included those with symptoms arising between 6 and 42 months of age, and the later clusters included those with symptoms between 6 and 69 months of age. The later clusters represented extensions of early clusters.

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After researchers controlled for 15 possible confounders, including factors such as fish intake, Family Adversity index, mother and home score, smoking and alcohol use during pregnancy, and race, these clusters predicted approximately 20%-60% increased odds of problematic behaviors at age 4 years, and approximately 40%-100% increased odds of problematic behaviors at age 7 years, as measured using the Strength and Difficulties Questionnaire (SDQ). Behavioral problems assessed included hyperactivity, conduct problems, peer difficulties, and emotional difficulties (Pediatrics 2012 March 5 [doi: 10.1542/peds.2011-1402]).

The strongest and most persistent associations were for a "worst case" cluster of patients in the early symptoms cluster, whose symptoms peaked at 30 months and persisted. The associations between symptoms and SDQ scores in this group were comparable at 4 and 7 years (odds ratios, 1.49 and 1.72, respectively).

However, a "worst case" cluster in the later symptom group, which had peak symptoms at 30 months that abated thereafter, also had increased odds of hyperactivity (OR, 1.85), conduct problems (OR, 1.60), and peer difficulties at age 7 years (OR, 1.37), according to SDQ subscale analyses.

Also, a "late symptom" cluster, with symptoms that increased after 30 months was associated with increased odds of emotional difficulties at 7 years (OR, 1.65) and hyperactivity at age 7 years (OR, 1.88).

"Even very early symptom peaks at 6 and 18 months are associated with [approximately] 40% and 50%, respectively, increased behavioral morbidity at 7 years of age," the investigators said, noting that this may be because of the "increased vulnerability to sleep-disordered breathing effects during this early critical period of brain development, when there is the greatest need for sleep."

Of note, the effects of sleep disordered breathing exceeded those of maternal smoking, maternal education, and paternal employment in multivariate analysis, and only male gender and not being the second or later-born child had greater adverse effects, they said.

Additionally, greater family adversity was associated with poorer behavioral outcomes, and higher home environment scores were associated with improved outcomes.

Sleep-disordered breathing, which can range from mouth breathing to snoring to obstructive sleep apnea, typically peaks between ages 2 and 6 years, but also can occur in younger children. It also is known to be associated with neurobehavioral morbidity, and although understanding how and when symptom patterns in early life affect neurobehavioral outcomes has important clinical implications, existing studies are primarily cross-sectional and generally of insufficient quality, the investigators said.

The findings are important because, depending on how you define sleep-disordered breathing, levels of snoring can range from 5% to 10%-20%, while apnea levels are about 1%-2%, Dr. Bonuck said in an interview.

"What prompted this study was a desire to examine sleep-disordered breathing in a population, rather than selected samples of, let’s say, children who had adenotonsillectomy or who had a sleep study, and to do so over time. Certainly there are a spate of studies examining associations between sleep-disordered breathing, but few followed this many children for as long a period of time," she said.

By pinpointing the sleep-disordered breathing profile of those with the worst emotional/behavioral problems, this can inform clinicians about the urgency to intervene or not, she added.

Although the study is limited by the fact that data were based on parent reports rather than objective testing, the findings nonetheless provide epidemiologic evidence to support attention to symptoms as early as the first year of life.

"This study strengthens evidence that snoring, observed apneas at home, and mouth breathing – along with any underlying obstructive sleep apnea that these symptoms suggest – can cause or promote future emergence of hyperactivity and other problematic behavior in childhood. The study adds unique data on the first 1-2 years of life and suggests that sleep apnea symptoms this early in life can predict behavioral problems at ages 4 and 7," Dr. Ronald D. Chervin, a coauthor of the study and director of the Sleep Disorders Center at the University of Michigan, Ann Arbor, said in an interview.

Pediatricians and families should be aware that symptoms of sleep apnea at any age should not be ignored, and merit, in some cases, investigation to diagnose sleep apnea, he added, noting that "treatment in the form of adenotonsillectomy or other measures when necessary could help to reverse, prevent, or reduce behavioral consequences of obstructive sleep apnea, at present and in the future."

The authors said they had no relevant financial disclosures to report. This study was supported by grants from the National Heart, Lung, and Blood Institute and funded by the National Institutes of Health.

DALLAS – Compared with expectant management, labor induction for cases involving a suspected large-for-dates fetus was associated with a threefold reduction in the risk of neonatal trauma and an improved likelihood of spontaneous vaginal birth in a randomized controlled trial involving 817 women.

Induction did not increase the cesarean section rate, compared with expectant management, but neonates in the induction group did have a higher rate of severe icterus, Dr. Michel Boulvain reported at the annual meeting of the Society for Maternal-Fetal Medicine.

The rates of neonatal trauma were 2.2% in the 407 women who were randomized to be induced, and 6.6% in 410 controls who underwent expectant management (relative risk, 0.34). The likelihood of a spontaneous vaginal delivery also was significantly higher in the induction group (RR, 1.14), said Dr. Boulvain of University Hospitals of Geneva, Switzerland.

The cesarean section rates in the induction and expectant management groups were 28% and 31.7%, respectively.

Women in the induction group delivered a mean of 9 days earlier, and birth weight in that group was 300 g less than in the expectant management group.

The study was conducted in collaboration with 20 teaching hospitals that are members of the Research Group in Obstetrics and Gynecology (GROG) in France, Switzerland, and Belgium. Study participants were women who underwent a clinical screening at 36-38 weeks’ gestation indicating an estimated fetal weight above the 90th percentile, and who then underwent sonography indicating an estimated fetal weight above the 95th percentile. Those randomized to induction were induced within 3 days.

Women with diabetes treated with insulin, and those with a history of cesarean section or shoulder dystocia were excluded.

Baseline characteristics were similar in the induction and expectant management groups, and no differences were seen with respect to very severe outcomes, Dr. Boulvain said.

The findings with respect to the individual outcomes from the composite neonatal trauma outcome – such as shoulder dystocia, brachial plexus injury, and fractures – each were improved in the induction group, compared with the expectant management group, which is encouraging, he noted.

The increase in the rate of icterus, however, is disturbing, and might be explained by fact that the induction group delivered more than a week earlier, or by increased attention to that outcome in the induction group, he said.

It could also be a direct effect of the oxytocin, he suggested.

Nonetheless, the conclusion of the findings is that induction of labor at 37-38 weeks’ gestation when estimated fetal weight is above the 95th percentile decreases risk of outcomes such as shoulder dystocia and fracture without increasing the risk of cesarean section, and increases the likelihood of spontaneous vaginal delivery, he said.

He added that decisions about management should be made with consideration of the characteristic and preference of the patient, keeping in mind that prior cesarean section and other conditions can preclude induction, and also keeping in mind that icterus is a potential concern.

Dr. Boulvain said he had no relevant financial disclosures.

DALLAS – Compared with expectant management, labor induction for cases involving a suspected large-for-dates fetus was associated with a threefold reduction in the risk of neonatal trauma and an improved likelihood of spontaneous vaginal birth in a randomized controlled trial involving 817 women.

Induction did not increase the cesarean section rate, compared with expectant management, but neonates in the induction group did have a higher rate of severe icterus, Dr. Michel Boulvain reported at the annual meeting of the Society for Maternal-Fetal Medicine.

The rates of neonatal trauma were 2.2% in the 407 women who were randomized to be induced, and 6.6% in 410 controls who underwent expectant management (relative risk, 0.34). The likelihood of a spontaneous vaginal delivery also was significantly higher in the induction group (RR, 1.14), said Dr. Boulvain of University Hospitals of Geneva, Switzerland.

The cesarean section rates in the induction and expectant management groups were 28% and 31.7%, respectively.

Women in the induction group delivered a mean of 9 days earlier, and birth weight in that group was 300 g less than in the expectant management group.

The study was conducted in collaboration with 20 teaching hospitals that are members of the Research Group in Obstetrics and Gynecology (GROG) in France, Switzerland, and Belgium. Study participants were women who underwent a clinical screening at 36-38 weeks’ gestation indicating an estimated fetal weight above the 90th percentile, and who then underwent sonography indicating an estimated fetal weight above the 95th percentile. Those randomized to induction were induced within 3 days.

Women with diabetes treated with insulin, and those with a history of cesarean section or shoulder dystocia were excluded.

Baseline characteristics were similar in the induction and expectant management groups, and no differences were seen with respect to very severe outcomes, Dr. Boulvain said.

The findings with respect to the individual outcomes from the composite neonatal trauma outcome – such as shoulder dystocia, brachial plexus injury, and fractures – each were improved in the induction group, compared with the expectant management group, which is encouraging, he noted.

The increase in the rate of icterus, however, is disturbing, and might be explained by fact that the induction group delivered more than a week earlier, or by increased attention to that outcome in the induction group, he said.

It could also be a direct effect of the oxytocin, he suggested.

Nonetheless, the conclusion of the findings is that induction of labor at 37-38 weeks’ gestation when estimated fetal weight is above the 95th percentile decreases risk of outcomes such as shoulder dystocia and fracture without increasing the risk of cesarean section, and increases the likelihood of spontaneous vaginal delivery, he said.

He added that decisions about management should be made with consideration of the characteristic and preference of the patient, keeping in mind that prior cesarean section and other conditions can preclude induction, and also keeping in mind that icterus is a potential concern.

Dr. Boulvain said he had no relevant financial disclosures.

DALLAS – Compared with expectant management, labor induction for cases involving a suspected large-for-dates fetus was associated with a threefold reduction in the risk of neonatal trauma and an improved likelihood of spontaneous vaginal birth in a randomized controlled trial involving 817 women.

Induction did not increase the cesarean section rate, compared with expectant management, but neonates in the induction group did have a higher rate of severe icterus, Dr. Michel Boulvain reported at the annual meeting of the Society for Maternal-Fetal Medicine.

The rates of neonatal trauma were 2.2% in the 407 women who were randomized to be induced, and 6.6% in 410 controls who underwent expectant management (relative risk, 0.34). The likelihood of a spontaneous vaginal delivery also was significantly higher in the induction group (RR, 1.14), said Dr. Boulvain of University Hospitals of Geneva, Switzerland.

The cesarean section rates in the induction and expectant management groups were 28% and 31.7%, respectively.

Women in the induction group delivered a mean of 9 days earlier, and birth weight in that group was 300 g less than in the expectant management group.

The study was conducted in collaboration with 20 teaching hospitals that are members of the Research Group in Obstetrics and Gynecology (GROG) in France, Switzerland, and Belgium. Study participants were women who underwent a clinical screening at 36-38 weeks’ gestation indicating an estimated fetal weight above the 90th percentile, and who then underwent sonography indicating an estimated fetal weight above the 95th percentile. Those randomized to induction were induced within 3 days.

Women with diabetes treated with insulin, and those with a history of cesarean section or shoulder dystocia were excluded.

Baseline characteristics were similar in the induction and expectant management groups, and no differences were seen with respect to very severe outcomes, Dr. Boulvain said.

The findings with respect to the individual outcomes from the composite neonatal trauma outcome – such as shoulder dystocia, brachial plexus injury, and fractures – each were improved in the induction group, compared with the expectant management group, which is encouraging, he noted.

The increase in the rate of icterus, however, is disturbing, and might be explained by fact that the induction group delivered more than a week earlier, or by increased attention to that outcome in the induction group, he said.

It could also be a direct effect of the oxytocin, he suggested.

Nonetheless, the conclusion of the findings is that induction of labor at 37-38 weeks’ gestation when estimated fetal weight is above the 95th percentile decreases risk of outcomes such as shoulder dystocia and fracture without increasing the risk of cesarean section, and increases the likelihood of spontaneous vaginal delivery, he said.

He added that decisions about management should be made with consideration of the characteristic and preference of the patient, keeping in mind that prior cesarean section and other conditions can preclude induction, and also keeping in mind that icterus is a potential concern.

Dr. Boulvain said he had no relevant financial disclosures.

Major Finding: At weeks 4, 8, and 12, all of the 303 patients randomized to receive treatment with TAK-875 at doses ranging from 6.25 to 200 mg once daily, as well as all of the 62 patients randomized to receive 4 mg of glimepiride once daily, achieved significant mean reductions from baseline in HbA_1c, compared with placebo.

Data Source: A phase II, randomized, double-blind, placebo- and active comparator–controlled trial.

Disclosures: The study was sponsored by Takeda Global Research and Development, for which Dr. Burant serves as an unpaid consultant and adviser. All other study authors are employed by the company.

The oral, highly potent, and selective free fatty acid receptor 1 agonist TAK-875 significantly improved glycemic control in patients with type 2 diabetes without increasing treatment-emergent hypoglycemic events in a phase II, randomized controlled trial comparing TAK-875, glimepiride, and placebo.

Activation of free fatty acid receptor 1 (FFAR1), also known as G-protein–coupled receptor 40, has been shown in preclinical studies to stimulate glucose-dependent beta-cell insulin secretion. The current findings show that it is a potential therapeutic target in the treatment of type 2 diabetes, Dr. Charles F. Burant of the University of Michigan, Ann Arbor, and his colleagues reported.

At weeks 4, 8, and 12 of treatment, all of the 303 patients who were randomized to receive treatment with TAK-875 at doses ranging from 6.25 to 200 mg once daily, as well as all of the 62 patients randomized to receive treatment with 4-mg glimepiride (a sulphonylurea that acts as an insulin secretagogue) once daily, achieved significant least-squares mean reductions from baseline in hemoglobin A_1c, compared with the 61 patients randomized to a placebo group. At 12 weeks, mean reductions in the TAK-875 group ranged from 0.65 percentage points with the 6.25-mg dose to roughly 1.0 percentage point with the 50-mg and higher doses; in the glimepiride group, the mean reduction was 1.05 percentage points, compared with 0.13 in the placebo group, the investigators said (Lancet 2012 Feb. 27 [doi:10.1016/S0140-6736(11)61879-5]).

Only the decrease in the 6.25-mg TAK-875 group was significantly smaller than that in the glimepiride group, they noted.

Additionally, the percentage of patients reaching the American Diabetes Association target of HbA_1c less than 7.0% by 12 weeks was generally similar in the 25- to 200-mg TAK-875 and glimepiride groups, and changes, relative to the placebo group, were significant, they said.

About 2% and 3% of the TAK-875 patients and the placebo patients, respectively, experienced treatment-emergent hypoglycemic events during treatment, compared with 19% of the glimepiride patients, and the events were mild to moderate in intensity in all groups. This finding suggests a therapeutic advantage of agents targeting FFAR1, compared with sulphonylureas, which are associated with frequent occurrence of hypoglycemia.

The percentage of patients with treatment-emergent adverse events that were determined by the investigators to be related to the study drug was lowest in the TAK-875 patients (7%, compared with 11% in the placebo group and 23% in the glimepiride group).

Participants in this double-blind study were outpatient adults aged 18-80 with type 2 diabetes who had not responded to either an 8-week diet and exercise plan or to metformin treatment and who were enrolled during November 2009–September 2010 at 95 sites in the United States, Mexico, and Guatemala. Baseline characteristics were similar in all groups.

After a 2-week, single-blind, placebo run-in period, the patients were treated for 12 weeks, followed by a 2-week follow-up period.

The fact that a significant change in HbA_1c, as compared with placebo, was apparent at 4 weeks after treatment initiation with all doses of TAK-875 suggests a rapid onset of action.

View on the News

Durability Questioned

The findings by Dr. Burant and colleagues promise to raise many questions about the potential of TAK-875 in the treatment of type 2 diabetes, according to Dr. Clifford J. Bailey.

FFAR1 agonists are “different and interesting” in that they may be capable of restricted initiation of insulin secretion, and “will mainly potentiate nutrient-induced insulin secretion, which will favor enhanced prandial insulin secretion and reduce the risk of interprandial hypoglycemia,” Dr. Bailey wrote in an editorial accompanying the report.

However, among the varied matters that must be addressed are durability of stimulatory effects, impact on insulin resistance, and safety, he noted (Lancet 2012 Feb. 27 [doi: 10.106/S0140-6736(12)60165-2]).

“The question of durability looms large over insulin-releasing pharmacotherapies. The stimulatory effect of sulphonylureas seems to wear off and restrict long-term efficacy in many patients,” he said.

Vitals

Major Finding: At weeks 4, 8, and 12, all of the 303 patients randomized to receive treatment with TAK-875 at doses ranging from 6.25 to 200 mg once daily, as well as all of the 62 patients randomized to receive 4 mg of glimepiride once daily, achieved significant mean reductions from baseline in HbA_1c, compared with placebo.

Data Source: A phase II, randomized, double-blind, placebo- and active comparator–controlled trial.

Disclosures: The study was sponsored by Takeda Global Research and Development, for which Dr. Burant serves as an unpaid consultant and adviser. All other study authors are employed by the company.

The oral, highly potent, and selective free fatty acid receptor 1 agonist TAK-875 significantly improved glycemic control in patients with type 2 diabetes without increasing treatment-emergent hypoglycemic events in a phase II, randomized controlled trial comparing TAK-875, glimepiride, and placebo.

Activation of free fatty acid receptor 1 (FFAR1), also known as G-protein–coupled receptor 40, has been shown in preclinical studies to stimulate glucose-dependent beta-cell insulin secretion. The current findings show that it is a potential therapeutic target in the treatment of type 2 diabetes, Dr. Charles F. Burant of the University of Michigan, Ann Arbor, and his colleagues reported.

At weeks 4, 8, and 12 of treatment, all of the 303 patients who were randomized to receive treatment with TAK-875 at doses ranging from 6.25 to 200 mg once daily, as well as all of the 62 patients randomized to receive treatment with 4-mg glimepiride (a sulphonylurea that acts as an insulin secretagogue) once daily, achieved significant least-squares mean reductions from baseline in hemoglobin A_1c, compared with the 61 patients randomized to a placebo group. At 12 weeks, mean reductions in the TAK-875 group ranged from 0.65 percentage points with the 6.25-mg dose to roughly 1.0 percentage point with the 50-mg and higher doses; in the glimepiride group, the mean reduction was 1.05 percentage points, compared with 0.13 in the placebo group, the investigators said (Lancet 2012 Feb. 27 [doi:10.1016/S0140-6736(11)61879-5]).

Only the decrease in the 6.25-mg TAK-875 group was significantly smaller than that in the glimepiride group, they noted.

Additionally, the percentage of patients reaching the American Diabetes Association target of HbA_1c less than 7.0% by 12 weeks was generally similar in the 25- to 200-mg TAK-875 and glimepiride groups, and changes, relative to the placebo group, were significant, they said.

About 2% and 3% of the TAK-875 patients and the placebo patients, respectively, experienced treatment-emergent hypoglycemic events during treatment, compared with 19% of the glimepiride patients, and the events were mild to moderate in intensity in all groups. This finding suggests a therapeutic advantage of agents targeting FFAR1, compared with sulphonylureas, which are associated with frequent occurrence of hypoglycemia.

The percentage of patients with treatment-emergent adverse events that were determined by the investigators to be related to the study drug was lowest in the TAK-875 patients (7%, compared with 11% in the placebo group and 23% in the glimepiride group).

Participants in this double-blind study were outpatient adults aged 18-80 with type 2 diabetes who had not responded to either an 8-week diet and exercise plan or to metformin treatment and who were enrolled during November 2009–September 2010 at 95 sites in the United States, Mexico, and Guatemala. Baseline characteristics were similar in all groups.

After a 2-week, single-blind, placebo run-in period, the patients were treated for 12 weeks, followed by a 2-week follow-up period.

The fact that a significant change in HbA_1c, as compared with placebo, was apparent at 4 weeks after treatment initiation with all doses of TAK-875 suggests a rapid onset of action.

View on the News

Durability Questioned

The findings by Dr. Burant and colleagues promise to raise many questions about the potential of TAK-875 in the treatment of type 2 diabetes, according to Dr. Clifford J. Bailey.

FFAR1 agonists are “different and interesting” in that they may be capable of restricted initiation of insulin secretion, and “will mainly potentiate nutrient-induced insulin secretion, which will favor enhanced prandial insulin secretion and reduce the risk of interprandial hypoglycemia,” Dr. Bailey wrote in an editorial accompanying the report.

However, among the varied matters that must be addressed are durability of stimulatory effects, impact on insulin resistance, and safety, he noted (Lancet 2012 Feb. 27 [doi: 10.106/S0140-6736(12)60165-2]).

“The question of durability looms large over insulin-releasing pharmacotherapies. The stimulatory effect of sulphonylureas seems to wear off and restrict long-term efficacy in many patients,” he said.

Vitals

Major Finding: At weeks 4, 8, and 12, all of the 303 patients randomized to receive treatment with TAK-875 at doses ranging from 6.25 to 200 mg once daily, as well as all of the 62 patients randomized to receive 4 mg of glimepiride once daily, achieved significant mean reductions from baseline in HbA_1c, compared with placebo.

Data Source: A phase II, randomized, double-blind, placebo- and active comparator–controlled trial.

Disclosures: The study was sponsored by Takeda Global Research and Development, for which Dr. Burant serves as an unpaid consultant and adviser. All other study authors are employed by the company.

The oral, highly potent, and selective free fatty acid receptor 1 agonist TAK-875 significantly improved glycemic control in patients with type 2 diabetes without increasing treatment-emergent hypoglycemic events in a phase II, randomized controlled trial comparing TAK-875, glimepiride, and placebo.

Activation of free fatty acid receptor 1 (FFAR1), also known as G-protein–coupled receptor 40, has been shown in preclinical studies to stimulate glucose-dependent beta-cell insulin secretion. The current findings show that it is a potential therapeutic target in the treatment of type 2 diabetes, Dr. Charles F. Burant of the University of Michigan, Ann Arbor, and his colleagues reported.

At weeks 4, 8, and 12 of treatment, all of the 303 patients who were randomized to receive treatment with TAK-875 at doses ranging from 6.25 to 200 mg once daily, as well as all of the 62 patients randomized to receive treatment with 4-mg glimepiride (a sulphonylurea that acts as an insulin secretagogue) once daily, achieved significant least-squares mean reductions from baseline in hemoglobin A_1c, compared with the 61 patients randomized to a placebo group. At 12 weeks, mean reductions in the TAK-875 group ranged from 0.65 percentage points with the 6.25-mg dose to roughly 1.0 percentage point with the 50-mg and higher doses; in the glimepiride group, the mean reduction was 1.05 percentage points, compared with 0.13 in the placebo group, the investigators said (Lancet 2012 Feb. 27 [doi:10.1016/S0140-6736(11)61879-5]).

Only the decrease in the 6.25-mg TAK-875 group was significantly smaller than that in the glimepiride group, they noted.

Additionally, the percentage of patients reaching the American Diabetes Association target of HbA_1c less than 7.0% by 12 weeks was generally similar in the 25- to 200-mg TAK-875 and glimepiride groups, and changes, relative to the placebo group, were significant, they said.

About 2% and 3% of the TAK-875 patients and the placebo patients, respectively, experienced treatment-emergent hypoglycemic events during treatment, compared with 19% of the glimepiride patients, and the events were mild to moderate in intensity in all groups. This finding suggests a therapeutic advantage of agents targeting FFAR1, compared with sulphonylureas, which are associated with frequent occurrence of hypoglycemia.

The percentage of patients with treatment-emergent adverse events that were determined by the investigators to be related to the study drug was lowest in the TAK-875 patients (7%, compared with 11% in the placebo group and 23% in the glimepiride group).

Participants in this double-blind study were outpatient adults aged 18-80 with type 2 diabetes who had not responded to either an 8-week diet and exercise plan or to metformin treatment and who were enrolled during November 2009–September 2010 at 95 sites in the United States, Mexico, and Guatemala. Baseline characteristics were similar in all groups.

After a 2-week, single-blind, placebo run-in period, the patients were treated for 12 weeks, followed by a 2-week follow-up period.

The fact that a significant change in HbA_1c, as compared with placebo, was apparent at 4 weeks after treatment initiation with all doses of TAK-875 suggests a rapid onset of action.

View on the News

Durability Questioned

The findings by Dr. Burant and colleagues promise to raise many questions about the potential of TAK-875 in the treatment of type 2 diabetes, according to Dr. Clifford J. Bailey.

FFAR1 agonists are “different and interesting” in that they may be capable of restricted initiation of insulin secretion, and “will mainly potentiate nutrient-induced insulin secretion, which will favor enhanced prandial insulin secretion and reduce the risk of interprandial hypoglycemia,” Dr. Bailey wrote in an editorial accompanying the report.

However, among the varied matters that must be addressed are durability of stimulatory effects, impact on insulin resistance, and safety, he noted (Lancet 2012 Feb. 27 [doi: 10.106/S0140-6736(12)60165-2]).

“The question of durability looms large over insulin-releasing pharmacotherapies. The stimulatory effect of sulphonylureas seems to wear off and restrict long-term efficacy in many patients,” he said.

Vitals

Hypnotic drugs are associated with a more than threefold increase in the risk of death, even when prescribed in limited quantities, according to findings from a large matched cohort study.

The risk was increased more than fivefold among those receiving the highest quantities, Dr. Daniel F. Kripke of the Scripps Clinic Viterbi Family Sleep Center in La Jolla, Calif., and his colleagues reported in BMJ Open.

Photo (c) Nastasic/iStockphoto

In addition, the use of hypnotic drugs was associated with an increased incidence of cancer among those receiving higher quantities.

The hazard ratios for death in 10,529 patients from a large health system who received hypnotic prescriptions for poor sleep, compared with 23,676 matched controls with no hypnotic prescription, were 3.60 for those prescribed 0.4-18 doses per year, 4.43 for those prescribed 18-132 doses per year, and 5.32 for those prescribed more than 132 doses per year, the investigators reported (BMJ Open 2012 [doi:10.1136/bmjopen-2012-000850]).

The “modestly increased statistically significant” elevations of incident cancer were seen in those in the middle and highest tertiles of prescribed doses (hazard ratios, 1.20 and 1.35, respectively), and the hazard ratio for lymphomas and for lung, colon, and prostate cancers were even greater than those for current smoking, they added.
The associations held in separate analyses of several different hypnotics, including new short-acting hypnotics and older hypnotics, and after poor health was controlled for. Analyses were performed for zolpidem, temazepam, eszopiclone, zaleplon, other benzodiazepines, barbiturates, and sedative antihistamines. The highest mortality risk was with eszopiclone.

The data also were adjusted for age, sex, smoking, body mass index, ethnicity, marital status, alcohol use, and prior cancer.

Even after different classes of comorbidities and each patient’s overall burden of comorbidities were considered, the results remained robust in each comorbidity group.

“Whereas the raw death rate of the user cohort was 4.86 times that of non-user controls, adjustment for all covariates … with stratification by comorbidities only reduced the overall HR to 4.56,” the investigators wrote.

Subjects in this study were members of a large U.S. health system, and had a mean age of 54 years. All were followed for an average of 2.5 years between 2002 and 2007. Patient data were derived from longitudinal electronic medical records, and hypnotic users and nonusers were well matched with respect to age, sex, period of observation, and BMI. They did not differ in ethnicity, marital status, or smoking status, the investigators said.

The findings, which support those of numerous prior studies that also suggested a link between hypnotics and increased mortality and between hypnotics and cancer, are important given that hypnotic drugs are among the most widely used treatments in medicine; an estimated 6%-10% of adults in the United States used hypnotics in 2010, the investigators reported.

Of note, the top third of hypnotic users in this study were prescribed nearly 93% of all the prescription doses of hypnotics.

“Perhaps the most striking finding was that an increased hazard for death was present even in the lowest tertile of hypnotic use, such that hypnotic drugs were associated with a 3.6-fold increased risk of dying for patients using less than 18 hypnotic pills per year,” they wrote. The minimal impact of the major confounders that were controlled for in this study suggest it is unlikely that confounding of other inadequately assessed confounders could explain the high mortality rate seen with hypnotics.

As for why the association exists, multiple causal pathways have been demonstrated, the researchers noted.

These include, but are not limited to, mixed-drug overdoses and increased incidences of depression, impaired motor and cognitive skills, sleep apnea, gastroesophageal conditions, and infections. All of these, the authors pointed out, could contribute to mortality, such as by automobile accidents with impaired motor and cognitive skills or by cancer with gastroesophageal conditions and infections.
The findings are limited by the fact that the electronic health records used in this study provide information on medication orders only, and not on dispensing or ingestion of the medications. The investigators also were unable to control for depression, anxiety, and other emotional factors. Still, they asserted that the findings raise concerns about the use of hypnotics.

Rough order-of-magnitude estimates suggest that in 2010, hypnotics may have been associated with 320,000-507,000 excess deaths in the United States alone, the investigators reported.

Although this study cannot define what portion of the mortality associated with hypnotics was directly attributable to the drugs, the consistency of the estimates suggests that the effect of hypnotics was substantial.

“Even 10,000 yearly excess deaths caused by hypnotics would be too many,” they said, concluding that it is prudent to weigh the evidence of mortality risks, as shown in this and 24 prior studies, against the meager benefits of hypnotics, in order to reconsider whether even short-term use is sufficiently safe.

Dr. Kripke reported a family interest in an investment corporation, which has a small percentage of its assets in stock of Sanofi-Aventis and Johnson & Johnson. The other authors reported having no relevant financial disclosures.

Hypnotic drugs are associated with a more than threefold increase in the risk of death, even when prescribed in limited quantities, according to findings from a large matched cohort study.

The risk was increased more than fivefold among those receiving the highest quantities, Dr. Daniel F. Kripke of the Scripps Clinic Viterbi Family Sleep Center in La Jolla, Calif., and his colleagues reported in BMJ Open.

Photo (c) Nastasic/iStockphoto

In addition, the use of hypnotic drugs was associated with an increased incidence of cancer among those receiving higher quantities.

The hazard ratios for death in 10,529 patients from a large health system who received hypnotic prescriptions for poor sleep, compared with 23,676 matched controls with no hypnotic prescription, were 3.60 for those prescribed 0.4-18 doses per year, 4.43 for those prescribed 18-132 doses per year, and 5.32 for those prescribed more than 132 doses per year, the investigators reported (BMJ Open 2012 [doi:10.1136/bmjopen-2012-000850]).

The “modestly increased statistically significant” elevations of incident cancer were seen in those in the middle and highest tertiles of prescribed doses (hazard ratios, 1.20 and 1.35, respectively), and the hazard ratio for lymphomas and for lung, colon, and prostate cancers were even greater than those for current smoking, they added.
The associations held in separate analyses of several different hypnotics, including new short-acting hypnotics and older hypnotics, and after poor health was controlled for. Analyses were performed for zolpidem, temazepam, eszopiclone, zaleplon, other benzodiazepines, barbiturates, and sedative antihistamines. The highest mortality risk was with eszopiclone.

The data also were adjusted for age, sex, smoking, body mass index, ethnicity, marital status, alcohol use, and prior cancer.

Even after different classes of comorbidities and each patient’s overall burden of comorbidities were considered, the results remained robust in each comorbidity group.

“Whereas the raw death rate of the user cohort was 4.86 times that of non-user controls, adjustment for all covariates … with stratification by comorbidities only reduced the overall HR to 4.56,” the investigators wrote.

Subjects in this study were members of a large U.S. health system, and had a mean age of 54 years. All were followed for an average of 2.5 years between 2002 and 2007. Patient data were derived from longitudinal electronic medical records, and hypnotic users and nonusers were well matched with respect to age, sex, period of observation, and BMI. They did not differ in ethnicity, marital status, or smoking status, the investigators said.

The findings, which support those of numerous prior studies that also suggested a link between hypnotics and increased mortality and between hypnotics and cancer, are important given that hypnotic drugs are among the most widely used treatments in medicine; an estimated 6%-10% of adults in the United States used hypnotics in 2010, the investigators reported.

Of note, the top third of hypnotic users in this study were prescribed nearly 93% of all the prescription doses of hypnotics.

“Perhaps the most striking finding was that an increased hazard for death was present even in the lowest tertile of hypnotic use, such that hypnotic drugs were associated with a 3.6-fold increased risk of dying for patients using less than 18 hypnotic pills per year,” they wrote. The minimal impact of the major confounders that were controlled for in this study suggest it is unlikely that confounding of other inadequately assessed confounders could explain the high mortality rate seen with hypnotics.

As for why the association exists, multiple causal pathways have been demonstrated, the researchers noted.

These include, but are not limited to, mixed-drug overdoses and increased incidences of depression, impaired motor and cognitive skills, sleep apnea, gastroesophageal conditions, and infections. All of these, the authors pointed out, could contribute to mortality, such as by automobile accidents with impaired motor and cognitive skills or by cancer with gastroesophageal conditions and infections.
The findings are limited by the fact that the electronic health records used in this study provide information on medication orders only, and not on dispensing or ingestion of the medications. The investigators also were unable to control for depression, anxiety, and other emotional factors. Still, they asserted that the findings raise concerns about the use of hypnotics.

Rough order-of-magnitude estimates suggest that in 2010, hypnotics may have been associated with 320,000-507,000 excess deaths in the United States alone, the investigators reported.

Although this study cannot define what portion of the mortality associated with hypnotics was directly attributable to the drugs, the consistency of the estimates suggests that the effect of hypnotics was substantial.

“Even 10,000 yearly excess deaths caused by hypnotics would be too many,” they said, concluding that it is prudent to weigh the evidence of mortality risks, as shown in this and 24 prior studies, against the meager benefits of hypnotics, in order to reconsider whether even short-term use is sufficiently safe.

Dr. Kripke reported a family interest in an investment corporation, which has a small percentage of its assets in stock of Sanofi-Aventis and Johnson & Johnson. The other authors reported having no relevant financial disclosures.

Hypnotic drugs are associated with a more than threefold increase in the risk of death, even when prescribed in limited quantities, according to findings from a large matched cohort study.

The risk was increased more than fivefold among those receiving the highest quantities, Dr. Daniel F. Kripke of the Scripps Clinic Viterbi Family Sleep Center in La Jolla, Calif., and his colleagues reported in BMJ Open.

Photo (c) Nastasic/iStockphoto

In addition, the use of hypnotic drugs was associated with an increased incidence of cancer among those receiving higher quantities.

The hazard ratios for death in 10,529 patients from a large health system who received hypnotic prescriptions for poor sleep, compared with 23,676 matched controls with no hypnotic prescription, were 3.60 for those prescribed 0.4-18 doses per year, 4.43 for those prescribed 18-132 doses per year, and 5.32 for those prescribed more than 132 doses per year, the investigators reported (BMJ Open 2012 [doi:10.1136/bmjopen-2012-000850]).

The “modestly increased statistically significant” elevations of incident cancer were seen in those in the middle and highest tertiles of prescribed doses (hazard ratios, 1.20 and 1.35, respectively), and the hazard ratio for lymphomas and for lung, colon, and prostate cancers were even greater than those for current smoking, they added.
The associations held in separate analyses of several different hypnotics, including new short-acting hypnotics and older hypnotics, and after poor health was controlled for. Analyses were performed for zolpidem, temazepam, eszopiclone, zaleplon, other benzodiazepines, barbiturates, and sedative antihistamines. The highest mortality risk was with eszopiclone.

The data also were adjusted for age, sex, smoking, body mass index, ethnicity, marital status, alcohol use, and prior cancer.

Even after different classes of comorbidities and each patient’s overall burden of comorbidities were considered, the results remained robust in each comorbidity group.

“Whereas the raw death rate of the user cohort was 4.86 times that of non-user controls, adjustment for all covariates … with stratification by comorbidities only reduced the overall HR to 4.56,” the investigators wrote.

Subjects in this study were members of a large U.S. health system, and had a mean age of 54 years. All were followed for an average of 2.5 years between 2002 and 2007. Patient data were derived from longitudinal electronic medical records, and hypnotic users and nonusers were well matched with respect to age, sex, period of observation, and BMI. They did not differ in ethnicity, marital status, or smoking status, the investigators said.

The findings, which support those of numerous prior studies that also suggested a link between hypnotics and increased mortality and between hypnotics and cancer, are important given that hypnotic drugs are among the most widely used treatments in medicine; an estimated 6%-10% of adults in the United States used hypnotics in 2010, the investigators reported.

Of note, the top third of hypnotic users in this study were prescribed nearly 93% of all the prescription doses of hypnotics.

“Perhaps the most striking finding was that an increased hazard for death was present even in the lowest tertile of hypnotic use, such that hypnotic drugs were associated with a 3.6-fold increased risk of dying for patients using less than 18 hypnotic pills per year,” they wrote. The minimal impact of the major confounders that were controlled for in this study suggest it is unlikely that confounding of other inadequately assessed confounders could explain the high mortality rate seen with hypnotics.

As for why the association exists, multiple causal pathways have been demonstrated, the researchers noted.

These include, but are not limited to, mixed-drug overdoses and increased incidences of depression, impaired motor and cognitive skills, sleep apnea, gastroesophageal conditions, and infections. All of these, the authors pointed out, could contribute to mortality, such as by automobile accidents with impaired motor and cognitive skills or by cancer with gastroesophageal conditions and infections.
The findings are limited by the fact that the electronic health records used in this study provide information on medication orders only, and not on dispensing or ingestion of the medications. The investigators also were unable to control for depression, anxiety, and other emotional factors. Still, they asserted that the findings raise concerns about the use of hypnotics.

Rough order-of-magnitude estimates suggest that in 2010, hypnotics may have been associated with 320,000-507,000 excess deaths in the United States alone, the investigators reported.

Although this study cannot define what portion of the mortality associated with hypnotics was directly attributable to the drugs, the consistency of the estimates suggests that the effect of hypnotics was substantial.

“Even 10,000 yearly excess deaths caused by hypnotics would be too many,” they said, concluding that it is prudent to weigh the evidence of mortality risks, as shown in this and 24 prior studies, against the meager benefits of hypnotics, in order to reconsider whether even short-term use is sufficiently safe.

Dr. Kripke reported a family interest in an investment corporation, which has a small percentage of its assets in stock of Sanofi-Aventis and Johnson & Johnson. The other authors reported having no relevant financial disclosures.

The oral, highly potent, and selective free fatty acid receptor 1 agonist TAK-875 significantly improved glycemic control in patients with type 2 diabetes without increasing treatment-emergent hypoglycemic events in a phase II, randomized, controlled trial comparing TAK-875, glimepiride, and placebo.

Activation of free fatty acid receptor 1 (FFAR1), which is also known as G-protein–coupled receptor 40, has been shown in preclinical studies to stimulate glucose-dependent beta-cell insulin secretion. The current findings show that it is a potential therapeutic target in the treatment of type 2 diabetes, Dr. Charles F. Burant of the University of Michigan, Ann Arbor and his colleagues reported online in the Feb. 27 issue of the Lancet.

At weeks 4, 8, and 12 of treatment, all of the 303 patients who were randomized to receive treatment with TAK-875 at doses ranging from 6.25 to 200 mg once daily, as well as all of the 62 patients randomized to receive treatment with 4-mg glimepiride (a sulphonylurea that acts as an insulin secretagogue) once daily, achieved significant least-squares mean reductions from baseline in hemoglobin A_1c, compared with the 61 patients randomized to a placebo group. At 12 weeks, mean reductions in the TAK-875 group ranged from 0.65 percentage points with the 6.25-mg dose to roughly 1.0 percentage points with the 50-mg and higher doses; in the glimepiride group, the mean reduction was 1.05 percentage points, compared with 0.13 in the placebo group, the investigators said (Lancet 2012 Feb. 27 [doi:10.1016/S0140-6736(11)61879-5]).

Only the decrease in the 6.25-mg TAK-875 group was significantly smaller than that in the glimepiride group, they noted.

Additionally, the percentage of patients reaching the American Diabetes Association target of HbA_1c less than 7.0% by 12 weeks was generally similar in the 25- to 200-mg TAK-875 and glimepiride groups, and changes, relative to the placebo group, were significant, they said.

About 2% and 3% of the TAK-875 patients and the placebo patients, respectively, experienced treatment-emergent hypoglycemic events during treatment, compared with 19% of the glimepiride patients, and the events were mild to moderate in intensity in all groups. This finding suggests a therapeutic advantage of agents targeting FFAR1, compared with sulphonylureas, which are associated with frequent occurrence of hypoglycemia.

The incidence of other treatment-related adverse events was also similar in the TAK-875 and placebo patients (occurring in 49% and 48%, respectively), compared with 61% in the glimepiride patients, and these also were typically mild or moderate in nature, with no noted dose relationship.

The percentage of patients with treatment-emergent adverse events that were determined by the investigators to be related to the study drug was lowest in the TAK-875 patients (7%, compared with 11% in the placebo group and 23% in the glimepiride group).

Participants in this double-blind study were outpatient adults, aged 18-80 years, with type 2 diabetes who had not responded to either an 8-week diet and exercise plan or to metformin treatment, and who were enrolled during November 2009–September 2010 in 95 sites in the United States, Mexico, and Guatemala. Baseline characteristics were similar in all groups.

After a 2-week, single-blind, placebo run-in period, the patients were treated for 12 weeks, followed by a 2-week follow-up period.

The fact that a significant change in HbA_1c, as compared with placebo, was apparent at 4 weeks after treatment initiation with all doses of TAK-875 suggests a rapid onset of action.

"By comparison with placebo, the improvement in HbA_1c on TAK-875 is associated with both a reduction in fasting and post-challenge glucose and a decrease in AUC [area under the curve] for glucose during [oral glucose tolerance testing]. The improvement in glucose homeostasis is probably driven by glucose-dependent insulin secretion as the insulinogenic index, a measure of beta-cell function, was increased," the investigators wrote, adding that the mechanism of increased insulin secretion is "probably a direct effect of TAK-875 on beta-cell FFAR1, increasing the levels of intracellular secondary messengers that augment insulin secretion."

The promising results in this study are limited by a fairly short study period and small sample size, the investigators noted.

Additional studies of longer duration are needed to assess true efficacy, durability of clinical efficacy, and safety of TAK-875, and to "establish the appropriate placement of FFAR1 agonists in the treatment framework for type 2 diabetes," they said.

Additional therapeutic agents for type 2 diabetes are needed, particularly given the expected increase in the number of cases in the next few decades, and the insufficient effects and/or unacceptable side effects of currently available treatments. It appears, based on this and other studies, that activation FFAR1 receptors can be beneficial in the treatment of type 2 diabetes, the researchers concluded.

This study was sponsored by Takeda Global Research and Development, for which Dr. Burant serves as an unpaid consultant and advisor. All other study authors are employed by the company.

The oral, highly potent, and selective free fatty acid receptor 1 agonist TAK-875 significantly improved glycemic control in patients with type 2 diabetes without increasing treatment-emergent hypoglycemic events in a phase II, randomized, controlled trial comparing TAK-875, glimepiride, and placebo.

Activation of free fatty acid receptor 1 (FFAR1), which is also known as G-protein–coupled receptor 40, has been shown in preclinical studies to stimulate glucose-dependent beta-cell insulin secretion. The current findings show that it is a potential therapeutic target in the treatment of type 2 diabetes, Dr. Charles F. Burant of the University of Michigan, Ann Arbor and his colleagues reported online in the Feb. 27 issue of the Lancet.

At weeks 4, 8, and 12 of treatment, all of the 303 patients who were randomized to receive treatment with TAK-875 at doses ranging from 6.25 to 200 mg once daily, as well as all of the 62 patients randomized to receive treatment with 4-mg glimepiride (a sulphonylurea that acts as an insulin secretagogue) once daily, achieved significant least-squares mean reductions from baseline in hemoglobin A_1c, compared with the 61 patients randomized to a placebo group. At 12 weeks, mean reductions in the TAK-875 group ranged from 0.65 percentage points with the 6.25-mg dose to roughly 1.0 percentage points with the 50-mg and higher doses; in the glimepiride group, the mean reduction was 1.05 percentage points, compared with 0.13 in the placebo group, the investigators said (Lancet 2012 Feb. 27 [doi:10.1016/S0140-6736(11)61879-5]).

Only the decrease in the 6.25-mg TAK-875 group was significantly smaller than that in the glimepiride group, they noted.

Additionally, the percentage of patients reaching the American Diabetes Association target of HbA_1c less than 7.0% by 12 weeks was generally similar in the 25- to 200-mg TAK-875 and glimepiride groups, and changes, relative to the placebo group, were significant, they said.

About 2% and 3% of the TAK-875 patients and the placebo patients, respectively, experienced treatment-emergent hypoglycemic events during treatment, compared with 19% of the glimepiride patients, and the events were mild to moderate in intensity in all groups. This finding suggests a therapeutic advantage of agents targeting FFAR1, compared with sulphonylureas, which are associated with frequent occurrence of hypoglycemia.

The incidence of other treatment-related adverse events was also similar in the TAK-875 and placebo patients (occurring in 49% and 48%, respectively), compared with 61% in the glimepiride patients, and these also were typically mild or moderate in nature, with no noted dose relationship.

The percentage of patients with treatment-emergent adverse events that were determined by the investigators to be related to the study drug was lowest in the TAK-875 patients (7%, compared with 11% in the placebo group and 23% in the glimepiride group).

Participants in this double-blind study were outpatient adults, aged 18-80 years, with type 2 diabetes who had not responded to either an 8-week diet and exercise plan or to metformin treatment, and who were enrolled during November 2009–September 2010 in 95 sites in the United States, Mexico, and Guatemala. Baseline characteristics were similar in all groups.

After a 2-week, single-blind, placebo run-in period, the patients were treated for 12 weeks, followed by a 2-week follow-up period.

The fact that a significant change in HbA_1c, as compared with placebo, was apparent at 4 weeks after treatment initiation with all doses of TAK-875 suggests a rapid onset of action.

"By comparison with placebo, the improvement in HbA_1c on TAK-875 is associated with both a reduction in fasting and post-challenge glucose and a decrease in AUC [area under the curve] for glucose during [oral glucose tolerance testing]. The improvement in glucose homeostasis is probably driven by glucose-dependent insulin secretion as the insulinogenic index, a measure of beta-cell function, was increased," the investigators wrote, adding that the mechanism of increased insulin secretion is "probably a direct effect of TAK-875 on beta-cell FFAR1, increasing the levels of intracellular secondary messengers that augment insulin secretion."

The promising results in this study are limited by a fairly short study period and small sample size, the investigators noted.

Additional studies of longer duration are needed to assess true efficacy, durability of clinical efficacy, and safety of TAK-875, and to "establish the appropriate placement of FFAR1 agonists in the treatment framework for type 2 diabetes," they said.

Additional therapeutic agents for type 2 diabetes are needed, particularly given the expected increase in the number of cases in the next few decades, and the insufficient effects and/or unacceptable side effects of currently available treatments. It appears, based on this and other studies, that activation FFAR1 receptors can be beneficial in the treatment of type 2 diabetes, the researchers concluded.

This study was sponsored by Takeda Global Research and Development, for which Dr. Burant serves as an unpaid consultant and advisor. All other study authors are employed by the company.

The oral, highly potent, and selective free fatty acid receptor 1 agonist TAK-875 significantly improved glycemic control in patients with type 2 diabetes without increasing treatment-emergent hypoglycemic events in a phase II, randomized, controlled trial comparing TAK-875, glimepiride, and placebo.

Activation of free fatty acid receptor 1 (FFAR1), which is also known as G-protein–coupled receptor 40, has been shown in preclinical studies to stimulate glucose-dependent beta-cell insulin secretion. The current findings show that it is a potential therapeutic target in the treatment of type 2 diabetes, Dr. Charles F. Burant of the University of Michigan, Ann Arbor and his colleagues reported online in the Feb. 27 issue of the Lancet.

At weeks 4, 8, and 12 of treatment, all of the 303 patients who were randomized to receive treatment with TAK-875 at doses ranging from 6.25 to 200 mg once daily, as well as all of the 62 patients randomized to receive treatment with 4-mg glimepiride (a sulphonylurea that acts as an insulin secretagogue) once daily, achieved significant least-squares mean reductions from baseline in hemoglobin A_1c, compared with the 61 patients randomized to a placebo group. At 12 weeks, mean reductions in the TAK-875 group ranged from 0.65 percentage points with the 6.25-mg dose to roughly 1.0 percentage points with the 50-mg and higher doses; in the glimepiride group, the mean reduction was 1.05 percentage points, compared with 0.13 in the placebo group, the investigators said (Lancet 2012 Feb. 27 [doi:10.1016/S0140-6736(11)61879-5]).

Only the decrease in the 6.25-mg TAK-875 group was significantly smaller than that in the glimepiride group, they noted.

Additionally, the percentage of patients reaching the American Diabetes Association target of HbA_1c less than 7.0% by 12 weeks was generally similar in the 25- to 200-mg TAK-875 and glimepiride groups, and changes, relative to the placebo group, were significant, they said.

About 2% and 3% of the TAK-875 patients and the placebo patients, respectively, experienced treatment-emergent hypoglycemic events during treatment, compared with 19% of the glimepiride patients, and the events were mild to moderate in intensity in all groups. This finding suggests a therapeutic advantage of agents targeting FFAR1, compared with sulphonylureas, which are associated with frequent occurrence of hypoglycemia.

The incidence of other treatment-related adverse events was also similar in the TAK-875 and placebo patients (occurring in 49% and 48%, respectively), compared with 61% in the glimepiride patients, and these also were typically mild or moderate in nature, with no noted dose relationship.

The percentage of patients with treatment-emergent adverse events that were determined by the investigators to be related to the study drug was lowest in the TAK-875 patients (7%, compared with 11% in the placebo group and 23% in the glimepiride group).

Participants in this double-blind study were outpatient adults, aged 18-80 years, with type 2 diabetes who had not responded to either an 8-week diet and exercise plan or to metformin treatment, and who were enrolled during November 2009–September 2010 in 95 sites in the United States, Mexico, and Guatemala. Baseline characteristics were similar in all groups.

After a 2-week, single-blind, placebo run-in period, the patients were treated for 12 weeks, followed by a 2-week follow-up period.

The fact that a significant change in HbA_1c, as compared with placebo, was apparent at 4 weeks after treatment initiation with all doses of TAK-875 suggests a rapid onset of action.

"By comparison with placebo, the improvement in HbA_1c on TAK-875 is associated with both a reduction in fasting and post-challenge glucose and a decrease in AUC [area under the curve] for glucose during [oral glucose tolerance testing]. The improvement in glucose homeostasis is probably driven by glucose-dependent insulin secretion as the insulinogenic index, a measure of beta-cell function, was increased," the investigators wrote, adding that the mechanism of increased insulin secretion is "probably a direct effect of TAK-875 on beta-cell FFAR1, increasing the levels of intracellular secondary messengers that augment insulin secretion."

The promising results in this study are limited by a fairly short study period and small sample size, the investigators noted.

Additional studies of longer duration are needed to assess true efficacy, durability of clinical efficacy, and safety of TAK-875, and to "establish the appropriate placement of FFAR1 agonists in the treatment framework for type 2 diabetes," they said.

Additional therapeutic agents for type 2 diabetes are needed, particularly given the expected increase in the number of cases in the next few decades, and the insufficient effects and/or unacceptable side effects of currently available treatments. It appears, based on this and other studies, that activation FFAR1 receptors can be beneficial in the treatment of type 2 diabetes, the researchers concluded.

This study was sponsored by Takeda Global Research and Development, for which Dr. Burant serves as an unpaid consultant and advisor. All other study authors are employed by the company.

DALLAS – Biweekly injections of 17-alpha-hydroxyprogesterone caproate, or 17P, did not significantly prolong pregnancy in a randomized open-label French study involving 188 women with an episode of successfully arrested preterm labor and a short cervix.

The median time from randomization to delivery was 64 days in 94 women who received 17P, and 67 days in 94 control subjects, Dr. Patrick Rozenberg reported at the annual meeting of the Society for Maternal-Fetal Medicine.

The rates of delivery prior to 37, 34, and 32 weeks’ gestation also did not differ significantly between the groups, with 39% and 38%, 16% and 20%, and 9% and 14% in the treatment and control groups, respectively, delivering at those time points, said Dr. Rozenberg of Poissy (France) Saint-Germain Hospital.

The findings contrast with those from several smaller trials that suggested 17P might reduce the risk of preterm delivery in women with preterm labor arrested by tocolysis.

Women in the current study had singleton pregnancies at 24-32 weeks’ gestation and a cervical length less than 25 mm, and were admitted at one of 13 French university hospitals with preterm labor. All were successfully treated with 12 mg of intramuscular betamethasone, which was repeated after 24 hours. The women were then randomized to receive or not receive 17P.

The 17P treatment group received 500 mg of intramuscular 17P beginning after tocolysis ended, and then twice weekly until 36 weeks’ gestation or until delivery. The control group received no progesterone, but all other management in both groups was left to the discretion of the attending physician, Dr. Rozenberg said, noting that clinical characteristics, including gestational age and cervical length, were similar in both the treatment and control groups, as were additional management, need for readmission for preterm labor, and tocolysis.

Neonatal outcomes, including birth weight and complications, also were similar between the groups, and there were no adverse effects associated with treatment.

Although several studies suggest that progesterone can reduce the rate of prematurity, many questions remain about optimal timing, mode of administration, dosing, and indications, Dr. Rozenberg noted. The findings of this study, however, do not support its use in women with a short cervix and an episode of preterm labor successfully treated with tocolysis.

"We could say that treatment with progesterone in patients with preterm labor and a short cervix below 25 mm did not prolong pregnancy, did not reduce the rate of prematurity and related complications, and was not associated with adverse effects. In conclusion, once the pathologic process of preterm labor begins, progesterone is no longer effective," he said.

Dr. Rozenberg said he had no relevant financial disclosures.

DALLAS – Biweekly injections of 17-alpha-hydroxyprogesterone caproate, or 17P, did not significantly prolong pregnancy in a randomized open-label French study involving 188 women with an episode of successfully arrested preterm labor and a short cervix.

The median time from randomization to delivery was 64 days in 94 women who received 17P, and 67 days in 94 control subjects, Dr. Patrick Rozenberg reported at the annual meeting of the Society for Maternal-Fetal Medicine.

The rates of delivery prior to 37, 34, and 32 weeks’ gestation also did not differ significantly between the groups, with 39% and 38%, 16% and 20%, and 9% and 14% in the treatment and control groups, respectively, delivering at those time points, said Dr. Rozenberg of Poissy (France) Saint-Germain Hospital.

The findings contrast with those from several smaller trials that suggested 17P might reduce the risk of preterm delivery in women with preterm labor arrested by tocolysis.

Women in the current study had singleton pregnancies at 24-32 weeks’ gestation and a cervical length less than 25 mm, and were admitted at one of 13 French university hospitals with preterm labor. All were successfully treated with 12 mg of intramuscular betamethasone, which was repeated after 24 hours. The women were then randomized to receive or not receive 17P.

The 17P treatment group received 500 mg of intramuscular 17P beginning after tocolysis ended, and then twice weekly until 36 weeks’ gestation or until delivery. The control group received no progesterone, but all other management in both groups was left to the discretion of the attending physician, Dr. Rozenberg said, noting that clinical characteristics, including gestational age and cervical length, were similar in both the treatment and control groups, as were additional management, need for readmission for preterm labor, and tocolysis.

Neonatal outcomes, including birth weight and complications, also were similar between the groups, and there were no adverse effects associated with treatment.

Although several studies suggest that progesterone can reduce the rate of prematurity, many questions remain about optimal timing, mode of administration, dosing, and indications, Dr. Rozenberg noted. The findings of this study, however, do not support its use in women with a short cervix and an episode of preterm labor successfully treated with tocolysis.

"We could say that treatment with progesterone in patients with preterm labor and a short cervix below 25 mm did not prolong pregnancy, did not reduce the rate of prematurity and related complications, and was not associated with adverse effects. In conclusion, once the pathologic process of preterm labor begins, progesterone is no longer effective," he said.

Dr. Rozenberg said he had no relevant financial disclosures.

DALLAS – Biweekly injections of 17-alpha-hydroxyprogesterone caproate, or 17P, did not significantly prolong pregnancy in a randomized open-label French study involving 188 women with an episode of successfully arrested preterm labor and a short cervix.

The median time from randomization to delivery was 64 days in 94 women who received 17P, and 67 days in 94 control subjects, Dr. Patrick Rozenberg reported at the annual meeting of the Society for Maternal-Fetal Medicine.

The rates of delivery prior to 37, 34, and 32 weeks’ gestation also did not differ significantly between the groups, with 39% and 38%, 16% and 20%, and 9% and 14% in the treatment and control groups, respectively, delivering at those time points, said Dr. Rozenberg of Poissy (France) Saint-Germain Hospital.

The findings contrast with those from several smaller trials that suggested 17P might reduce the risk of preterm delivery in women with preterm labor arrested by tocolysis.

Women in the current study had singleton pregnancies at 24-32 weeks’ gestation and a cervical length less than 25 mm, and were admitted at one of 13 French university hospitals with preterm labor. All were successfully treated with 12 mg of intramuscular betamethasone, which was repeated after 24 hours. The women were then randomized to receive or not receive 17P.

The 17P treatment group received 500 mg of intramuscular 17P beginning after tocolysis ended, and then twice weekly until 36 weeks’ gestation or until delivery. The control group received no progesterone, but all other management in both groups was left to the discretion of the attending physician, Dr. Rozenberg said, noting that clinical characteristics, including gestational age and cervical length, were similar in both the treatment and control groups, as were additional management, need for readmission for preterm labor, and tocolysis.

Neonatal outcomes, including birth weight and complications, also were similar between the groups, and there were no adverse effects associated with treatment.

Although several studies suggest that progesterone can reduce the rate of prematurity, many questions remain about optimal timing, mode of administration, dosing, and indications, Dr. Rozenberg noted. The findings of this study, however, do not support its use in women with a short cervix and an episode of preterm labor successfully treated with tocolysis.

"We could say that treatment with progesterone in patients with preterm labor and a short cervix below 25 mm did not prolong pregnancy, did not reduce the rate of prematurity and related complications, and was not associated with adverse effects. In conclusion, once the pathologic process of preterm labor begins, progesterone is no longer effective," he said.

Dr. Rozenberg said he had no relevant financial disclosures.

DALLAS – MicroRNA 210 is strongly associated with the presence of preeclampsia, and predicts the condition months prior to its onset, according to findings in a subset of women from a case-control study and women from a separate prospective cohort.

If validated as a reliable biomarker in larger studies, microRNA 210 (MIR210) could be used to risk-stratify women for development of hypertensive disorders of pregnancy, including preeclampsia, Dr. Michal A. Elovitz reported at the annual meeting of the Society for Maternal-Fetal Medicine.

The levels of MIR210, as well as levels of MIR517a and MIR517c, were first analyzed in 28 maternal serum samples from women with preeclampsia who were enrolled in the Preeclampsia: Mechanisms and Consequences study. The microRNA levels were compared with those from samples collected from 14 control patients without preeclampsia at the time of delivery. Samples in the cases were collected either at the time of diagnosis or at the time of delivery, said Dr. Elovitz of the department of obstetrics and gynecology at the University of Pennsylvania, Philadelphia.

The MIR517a and MIR517c levels did not differ between the groups, but MIR210 levels differed significantly in the cases and controls. In fact, each 1-unit increase in MIR210 was associated with a 9.5-fold increase in the odds of being a case vs. a control, Dr. Elovitz said, noting that controlling for race did not change the effect size, and that MIR210 had a "very high" predictive ability for being a case.

As expected, the gestational age at delivery was lower in the cases than the controls, but there were no significant differences in the rates of chronic hypertension, the number of African American women, and the number of fetuses with intrauterine growth restriction between the groups.

MIR210 levels also differed significantly in 38 cases and 57 controls from a separate prospective cohort of women undergoing integrated or sequential screening. Serum samples in that cohort were collected during the second trimester, at 15-17 weeks’ gestation.

Each 1-unit increase in MIR210 was associated in this cohort with a 2.9-fold increase in the likelihood of developing a hypertensive disease of pregnancy, Dr. Elovitz said, adding that the MIR210 in this population had "fair" predictive ability. When analysis was limited just to those who eventually developed preeclampsia, however, each 1-unit increase in MIR210 was associated with a 3.8-fold increase in the odds of developing preeclampsia.

Because there was such a wide range of MIR210 levels, she and her colleagues also looked at a 10-unit increase, and found that each of these units was associated with a 6.7-fold increase in the risk of preeclampsia. MIR210 in this scenario had a "fairly good" predictive value, she said.

In this portion of the study, no differences were seen between cases and controls with respect to gestational age at time of blood draw, number of African American women, rate of intrauterine fetal death, or rate of preterm birth at less than 37 weeks’ gestation.

MicroRNAs have emerged as critical players in many biological systems and in certain disease states, Dr. Elovitz explained.

MIR515a and MIR515c were included in the current analyses because they have previously been shown to be uniquely expressed in placental tissues, and increased in placental tissues from women with preeclampsia, compared with controls. MIR210 has been found to be very highly expressed in placental tissues, and is known to be highly involved in hypoxic conditions and to be a promising biomarker in other disease states, she said.

The current findings are important because preeclampsia is a leading cause of morbidity and mortality in pregnancy, and remains the leading cause of medically indicated preterm birth.

"Several randomized, controlled trials have failed to identify successful preventative strategies to decrease development of preeclampsia. Indeed, the pathogenesis of preeclampsia has not been revealed," she said, adding that consequently, the ability to identify those at risk is poor, and the ability to offer interventions based on the true pathogenesis of the disease has not been achieved.

The findings – although limited by the case-cohort design, small study populations, and the lack of a panel of microRNAs – suggest that MIR210 is a reliable biomarker for hypertensive disorders of pregnancy, including preeclampsia. The findings are strengthened by the focus on specific microRNAs and by the use of two cohorts.

"Further work is obviously necessary. We need to validate MIR210 as a reliable biomarker, and we need to unravel the role of MIR210 and other microRNAs in the pathogenesis of preeclampsia," Dr. Elovitz concluded.

Dr. Elovitz said she had no conflicts to disclose.

DALLAS – MicroRNA 210 is strongly associated with the presence of preeclampsia, and predicts the condition months prior to its onset, according to findings in a subset of women from a case-control study and women from a separate prospective cohort.

If validated as a reliable biomarker in larger studies, microRNA 210 (MIR210) could be used to risk-stratify women for development of hypertensive disorders of pregnancy, including preeclampsia, Dr. Michal A. Elovitz reported at the annual meeting of the Society for Maternal-Fetal Medicine.

The levels of MIR210, as well as levels of MIR517a and MIR517c, were first analyzed in 28 maternal serum samples from women with preeclampsia who were enrolled in the Preeclampsia: Mechanisms and Consequences study. The microRNA levels were compared with those from samples collected from 14 control patients without preeclampsia at the time of delivery. Samples in the cases were collected either at the time of diagnosis or at the time of delivery, said Dr. Elovitz of the department of obstetrics and gynecology at the University of Pennsylvania, Philadelphia.

The MIR517a and MIR517c levels did not differ between the groups, but MIR210 levels differed significantly in the cases and controls. In fact, each 1-unit increase in MIR210 was associated with a 9.5-fold increase in the odds of being a case vs. a control, Dr. Elovitz said, noting that controlling for race did not change the effect size, and that MIR210 had a "very high" predictive ability for being a case.

As expected, the gestational age at delivery was lower in the cases than the controls, but there were no significant differences in the rates of chronic hypertension, the number of African American women, and the number of fetuses with intrauterine growth restriction between the groups.

MIR210 levels also differed significantly in 38 cases and 57 controls from a separate prospective cohort of women undergoing integrated or sequential screening. Serum samples in that cohort were collected during the second trimester, at 15-17 weeks’ gestation.

Each 1-unit increase in MIR210 was associated in this cohort with a 2.9-fold increase in the likelihood of developing a hypertensive disease of pregnancy, Dr. Elovitz said, adding that the MIR210 in this population had "fair" predictive ability. When analysis was limited just to those who eventually developed preeclampsia, however, each 1-unit increase in MIR210 was associated with a 3.8-fold increase in the odds of developing preeclampsia.

Because there was such a wide range of MIR210 levels, she and her colleagues also looked at a 10-unit increase, and found that each of these units was associated with a 6.7-fold increase in the risk of preeclampsia. MIR210 in this scenario had a "fairly good" predictive value, she said.

In this portion of the study, no differences were seen between cases and controls with respect to gestational age at time of blood draw, number of African American women, rate of intrauterine fetal death, or rate of preterm birth at less than 37 weeks’ gestation.

MicroRNAs have emerged as critical players in many biological systems and in certain disease states, Dr. Elovitz explained.

MIR515a and MIR515c were included in the current analyses because they have previously been shown to be uniquely expressed in placental tissues, and increased in placental tissues from women with preeclampsia, compared with controls. MIR210 has been found to be very highly expressed in placental tissues, and is known to be highly involved in hypoxic conditions and to be a promising biomarker in other disease states, she said.

The current findings are important because preeclampsia is a leading cause of morbidity and mortality in pregnancy, and remains the leading cause of medically indicated preterm birth.

"Several randomized, controlled trials have failed to identify successful preventative strategies to decrease development of preeclampsia. Indeed, the pathogenesis of preeclampsia has not been revealed," she said, adding that consequently, the ability to identify those at risk is poor, and the ability to offer interventions based on the true pathogenesis of the disease has not been achieved.

The findings – although limited by the case-cohort design, small study populations, and the lack of a panel of microRNAs – suggest that MIR210 is a reliable biomarker for hypertensive disorders of pregnancy, including preeclampsia. The findings are strengthened by the focus on specific microRNAs and by the use of two cohorts.

"Further work is obviously necessary. We need to validate MIR210 as a reliable biomarker, and we need to unravel the role of MIR210 and other microRNAs in the pathogenesis of preeclampsia," Dr. Elovitz concluded.

Dr. Elovitz said she had no conflicts to disclose.

DALLAS – MicroRNA 210 is strongly associated with the presence of preeclampsia, and predicts the condition months prior to its onset, according to findings in a subset of women from a case-control study and women from a separate prospective cohort.

If validated as a reliable biomarker in larger studies, microRNA 210 (MIR210) could be used to risk-stratify women for development of hypertensive disorders of pregnancy, including preeclampsia, Dr. Michal A. Elovitz reported at the annual meeting of the Society for Maternal-Fetal Medicine.

The levels of MIR210, as well as levels of MIR517a and MIR517c, were first analyzed in 28 maternal serum samples from women with preeclampsia who were enrolled in the Preeclampsia: Mechanisms and Consequences study. The microRNA levels were compared with those from samples collected from 14 control patients without preeclampsia at the time of delivery. Samples in the cases were collected either at the time of diagnosis or at the time of delivery, said Dr. Elovitz of the department of obstetrics and gynecology at the University of Pennsylvania, Philadelphia.

The MIR517a and MIR517c levels did not differ between the groups, but MIR210 levels differed significantly in the cases and controls. In fact, each 1-unit increase in MIR210 was associated with a 9.5-fold increase in the odds of being a case vs. a control, Dr. Elovitz said, noting that controlling for race did not change the effect size, and that MIR210 had a "very high" predictive ability for being a case.

As expected, the gestational age at delivery was lower in the cases than the controls, but there were no significant differences in the rates of chronic hypertension, the number of African American women, and the number of fetuses with intrauterine growth restriction between the groups.

MIR210 levels also differed significantly in 38 cases and 57 controls from a separate prospective cohort of women undergoing integrated or sequential screening. Serum samples in that cohort were collected during the second trimester, at 15-17 weeks’ gestation.

Each 1-unit increase in MIR210 was associated in this cohort with a 2.9-fold increase in the likelihood of developing a hypertensive disease of pregnancy, Dr. Elovitz said, adding that the MIR210 in this population had "fair" predictive ability. When analysis was limited just to those who eventually developed preeclampsia, however, each 1-unit increase in MIR210 was associated with a 3.8-fold increase in the odds of developing preeclampsia.

Because there was such a wide range of MIR210 levels, she and her colleagues also looked at a 10-unit increase, and found that each of these units was associated with a 6.7-fold increase in the risk of preeclampsia. MIR210 in this scenario had a "fairly good" predictive value, she said.

In this portion of the study, no differences were seen between cases and controls with respect to gestational age at time of blood draw, number of African American women, rate of intrauterine fetal death, or rate of preterm birth at less than 37 weeks’ gestation.

MicroRNAs have emerged as critical players in many biological systems and in certain disease states, Dr. Elovitz explained.

MIR515a and MIR515c were included in the current analyses because they have previously been shown to be uniquely expressed in placental tissues, and increased in placental tissues from women with preeclampsia, compared with controls. MIR210 has been found to be very highly expressed in placental tissues, and is known to be highly involved in hypoxic conditions and to be a promising biomarker in other disease states, she said.

The current findings are important because preeclampsia is a leading cause of morbidity and mortality in pregnancy, and remains the leading cause of medically indicated preterm birth.

"Several randomized, controlled trials have failed to identify successful preventative strategies to decrease development of preeclampsia. Indeed, the pathogenesis of preeclampsia has not been revealed," she said, adding that consequently, the ability to identify those at risk is poor, and the ability to offer interventions based on the true pathogenesis of the disease has not been achieved.

The findings – although limited by the case-cohort design, small study populations, and the lack of a panel of microRNAs – suggest that MIR210 is a reliable biomarker for hypertensive disorders of pregnancy, including preeclampsia. The findings are strengthened by the focus on specific microRNAs and by the use of two cohorts.

"Further work is obviously necessary. We need to validate MIR210 as a reliable biomarker, and we need to unravel the role of MIR210 and other microRNAs in the pathogenesis of preeclampsia," Dr. Elovitz concluded.

Dr. Elovitz said she had no conflicts to disclose.

DALLAS – Numerous prescription drugs inhibit the metabolism of 17-alpha hydroxyprogesterone caproate, or 17P, and could impact its efficacy for the prevention of preterm delivery, according to findings from a study evaluating the effects of 25 specific medications.

Of the 25 medications tested, 16 were found to inhibit the metabolism of 17P, Dr. Courtney Cuppett reported at the annual meeting of the Society for Maternal-Fetal Medicine.

Those with the strongest inhibitory effects were the asthma drug montelukast (Singulair), and the protease inhibitors nelfinavir (Viracept) and ritonavir (Norvir), which were associated with 90%-100% inhibition of 17P.

Drugs associated with moderate (50%-80%) inhibition of 17P were fluconazole (Diflucan), itraconazole (Sporanox), diltiazem, esomeprazole (Nexium), tacrolimus, and bergamottin. Those with weak (30%-50%) inhibitory effects included fluticasone, voriconazole (Vfend), nifedipine, erythromycin, sertraline (Zoloft), haloperidol (Haldol), and trazodone, and those with negligible (less than 20%) inhibitory effects included midazolam (Versed), quetiapine (Seroquel), venlafaxine (Effexor), citalopram (Celexa), clarithromycin (Biaxin), metronidazole (Flagyl), cyclosporine, sirolimus (Rapamune), and ondansetron (Zofran), said Dr. Cuppett, a fellow in the department of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh’s Magee-Women’s Hospital.

The hormonal agent 17P has been shown to reduce the incidence of recurrent preterm birth by 33% in a high risk population of women. In 2011, it became the first medication to receive Food and Drug Administration approval for prevention of preterm birth. Its use has become widespread, and it is currently indicated in patients with a history of spontaneous preterm birth. It is administered at a weekly dosage of 250 mg given intramuscularly at 16-36 weeks’ gestation, Dr. Cuppett noted.

"Although this drug is routinely prescribed, there is so much we don’t understand," including the optimal dose and dosing interval and the definition of therapeutic concentration; in addition, "importantly, both the site and mechanism of action are still largely unknown," she said.

One thing that is known, however, is that there is very large interindividual variability in plasma concentrations (range, 5-40 ng/mL) in those receiving a standard dose, she said, noting that such variability can potentially affect efficacy, and may be one reason why only a third of the target population benefited from treatment in trials.

She and her colleagues also found that 17P is metabolized by the drug-metabolizing enzyme CYP3A4, which is primarily found in the liver, but is also found in other tissues, including the placenta, uterus, and cervix. CYP3A4 also is responsible for the metabolism of more than half of all prescription medications.

"Thus, we hypothesized that prescription medications may alter the metabolism of 17P," she said.

Using ideal drug concentrations and incubation conditions identified as part of the study, they incubated pooled human CYP3A4 microsomes with 17P alone and with each of the 25 medications known to be substrates and or inhibitors of CYP3A4.

The finding that the metabolism of 17P is significantly inhibited by several of the prescription medications suggests that these drug-drug interactions may contribute to the large interindividual variability in 17P plasma concentrations observed in patients treated with the standard 17P dose, Dr. Cuppett said.

The clinical implications of the findings are unclear, as the therapeutic window for 17P has not been defined.

"However, if in the future we are able to define the therapeutic window for 17P, the dose and/or dosing interval may be adjusted in women who also take medications that are substrates, inhibitors, and/or inducers of CYP3A4," she said.

Importantly, it should also be considered that if prescription medications inhibit 17P, the converse also could be true.

In the future, it will be important to look for the converse drug-drug interactions and potential for 17P to inhibit prescription medications – particularly those with narrow therapeutic windows – because inhibition of metabolism of such drugs could lead to toxicity.

An example is the protease inhibitors that were shown in this study to inhibit 17P by 90%-100%. If the converse interaction proved true, patients using these drugs would need to be monitored more closely for signs of toxicity, and doses may potentially require adjustment, Dr. Cuppett said.

This study was supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Cuppett said she had no relevant financial disclosures.

DALLAS – Numerous prescription drugs inhibit the metabolism of 17-alpha hydroxyprogesterone caproate, or 17P, and could impact its efficacy for the prevention of preterm delivery, according to findings from a study evaluating the effects of 25 specific medications.

Of the 25 medications tested, 16 were found to inhibit the metabolism of 17P, Dr. Courtney Cuppett reported at the annual meeting of the Society for Maternal-Fetal Medicine.

Those with the strongest inhibitory effects were the asthma drug montelukast (Singulair), and the protease inhibitors nelfinavir (Viracept) and ritonavir (Norvir), which were associated with 90%-100% inhibition of 17P.

Drugs associated with moderate (50%-80%) inhibition of 17P were fluconazole (Diflucan), itraconazole (Sporanox), diltiazem, esomeprazole (Nexium), tacrolimus, and bergamottin. Those with weak (30%-50%) inhibitory effects included fluticasone, voriconazole (Vfend), nifedipine, erythromycin, sertraline (Zoloft), haloperidol (Haldol), and trazodone, and those with negligible (less than 20%) inhibitory effects included midazolam (Versed), quetiapine (Seroquel), venlafaxine (Effexor), citalopram (Celexa), clarithromycin (Biaxin), metronidazole (Flagyl), cyclosporine, sirolimus (Rapamune), and ondansetron (Zofran), said Dr. Cuppett, a fellow in the department of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh’s Magee-Women’s Hospital.

The hormonal agent 17P has been shown to reduce the incidence of recurrent preterm birth by 33% in a high risk population of women. In 2011, it became the first medication to receive Food and Drug Administration approval for prevention of preterm birth. Its use has become widespread, and it is currently indicated in patients with a history of spontaneous preterm birth. It is administered at a weekly dosage of 250 mg given intramuscularly at 16-36 weeks’ gestation, Dr. Cuppett noted.

"Although this drug is routinely prescribed, there is so much we don’t understand," including the optimal dose and dosing interval and the definition of therapeutic concentration; in addition, "importantly, both the site and mechanism of action are still largely unknown," she said.

One thing that is known, however, is that there is very large interindividual variability in plasma concentrations (range, 5-40 ng/mL) in those receiving a standard dose, she said, noting that such variability can potentially affect efficacy, and may be one reason why only a third of the target population benefited from treatment in trials.

She and her colleagues also found that 17P is metabolized by the drug-metabolizing enzyme CYP3A4, which is primarily found in the liver, but is also found in other tissues, including the placenta, uterus, and cervix. CYP3A4 also is responsible for the metabolism of more than half of all prescription medications.

"Thus, we hypothesized that prescription medications may alter the metabolism of 17P," she said.

Using ideal drug concentrations and incubation conditions identified as part of the study, they incubated pooled human CYP3A4 microsomes with 17P alone and with each of the 25 medications known to be substrates and or inhibitors of CYP3A4.

The finding that the metabolism of 17P is significantly inhibited by several of the prescription medications suggests that these drug-drug interactions may contribute to the large interindividual variability in 17P plasma concentrations observed in patients treated with the standard 17P dose, Dr. Cuppett said.

The clinical implications of the findings are unclear, as the therapeutic window for 17P has not been defined.

"However, if in the future we are able to define the therapeutic window for 17P, the dose and/or dosing interval may be adjusted in women who also take medications that are substrates, inhibitors, and/or inducers of CYP3A4," she said.

Importantly, it should also be considered that if prescription medications inhibit 17P, the converse also could be true.

In the future, it will be important to look for the converse drug-drug interactions and potential for 17P to inhibit prescription medications – particularly those with narrow therapeutic windows – because inhibition of metabolism of such drugs could lead to toxicity.

An example is the protease inhibitors that were shown in this study to inhibit 17P by 90%-100%. If the converse interaction proved true, patients using these drugs would need to be monitored more closely for signs of toxicity, and doses may potentially require adjustment, Dr. Cuppett said.

This study was supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Cuppett said she had no relevant financial disclosures.

DALLAS – Numerous prescription drugs inhibit the metabolism of 17-alpha hydroxyprogesterone caproate, or 17P, and could impact its efficacy for the prevention of preterm delivery, according to findings from a study evaluating the effects of 25 specific medications.

Of the 25 medications tested, 16 were found to inhibit the metabolism of 17P, Dr. Courtney Cuppett reported at the annual meeting of the Society for Maternal-Fetal Medicine.

Those with the strongest inhibitory effects were the asthma drug montelukast (Singulair), and the protease inhibitors nelfinavir (Viracept) and ritonavir (Norvir), which were associated with 90%-100% inhibition of 17P.

Drugs associated with moderate (50%-80%) inhibition of 17P were fluconazole (Diflucan), itraconazole (Sporanox), diltiazem, esomeprazole (Nexium), tacrolimus, and bergamottin. Those with weak (30%-50%) inhibitory effects included fluticasone, voriconazole (Vfend), nifedipine, erythromycin, sertraline (Zoloft), haloperidol (Haldol), and trazodone, and those with negligible (less than 20%) inhibitory effects included midazolam (Versed), quetiapine (Seroquel), venlafaxine (Effexor), citalopram (Celexa), clarithromycin (Biaxin), metronidazole (Flagyl), cyclosporine, sirolimus (Rapamune), and ondansetron (Zofran), said Dr. Cuppett, a fellow in the department of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh’s Magee-Women’s Hospital.

The hormonal agent 17P has been shown to reduce the incidence of recurrent preterm birth by 33% in a high risk population of women. In 2011, it became the first medication to receive Food and Drug Administration approval for prevention of preterm birth. Its use has become widespread, and it is currently indicated in patients with a history of spontaneous preterm birth. It is administered at a weekly dosage of 250 mg given intramuscularly at 16-36 weeks’ gestation, Dr. Cuppett noted.

"Although this drug is routinely prescribed, there is so much we don’t understand," including the optimal dose and dosing interval and the definition of therapeutic concentration; in addition, "importantly, both the site and mechanism of action are still largely unknown," she said.

One thing that is known, however, is that there is very large interindividual variability in plasma concentrations (range, 5-40 ng/mL) in those receiving a standard dose, she said, noting that such variability can potentially affect efficacy, and may be one reason why only a third of the target population benefited from treatment in trials.

She and her colleagues also found that 17P is metabolized by the drug-metabolizing enzyme CYP3A4, which is primarily found in the liver, but is also found in other tissues, including the placenta, uterus, and cervix. CYP3A4 also is responsible for the metabolism of more than half of all prescription medications.

"Thus, we hypothesized that prescription medications may alter the metabolism of 17P," she said.

Using ideal drug concentrations and incubation conditions identified as part of the study, they incubated pooled human CYP3A4 microsomes with 17P alone and with each of the 25 medications known to be substrates and or inhibitors of CYP3A4.

The finding that the metabolism of 17P is significantly inhibited by several of the prescription medications suggests that these drug-drug interactions may contribute to the large interindividual variability in 17P plasma concentrations observed in patients treated with the standard 17P dose, Dr. Cuppett said.

The clinical implications of the findings are unclear, as the therapeutic window for 17P has not been defined.

"However, if in the future we are able to define the therapeutic window for 17P, the dose and/or dosing interval may be adjusted in women who also take medications that are substrates, inhibitors, and/or inducers of CYP3A4," she said.

Importantly, it should also be considered that if prescription medications inhibit 17P, the converse also could be true.

In the future, it will be important to look for the converse drug-drug interactions and potential for 17P to inhibit prescription medications – particularly those with narrow therapeutic windows – because inhibition of metabolism of such drugs could lead to toxicity.

An example is the protease inhibitors that were shown in this study to inhibit 17P by 90%-100%. If the converse interaction proved true, patients using these drugs would need to be monitored more closely for signs of toxicity, and doses may potentially require adjustment, Dr. Cuppett said.

This study was supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Cuppett said she had no relevant financial disclosures.