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Early Predictors of GDM Identified in Women With PCOS
BOSTON – A prospective cohort study of women with polycystic ovarian syndrome who developed gestational diabetes mellitus during pregnancy has implicated fasting blood glucose, non–high density lipoprotein, and sex hormone–binding globulin as significant predictive factors for the development of GDM.
“Polycystic ovarian syndrome [PCOS] is the most common reproductive disorder in women of reproductive age and is commonly associated with metabolic disorders including diabetes and obesity. In women with GDM, a history of PCOS is associated with higher incidence of complications and postpregnancy glucose intolerance. Risk factors during early pregnancy in women with PCOS for development of GDM have not been well characterized,” said Dr. Wenyu Huang of Northwestern University, Chicago.
To provide some clarity, Dr. Huang and his colleagues conducted a prospective cohort study. Inclusion criteria were age 18-45 years, diagnosis of PCOS prior to conception, singlet pregnancy, and enrollment during the first trimester. Preexisting chronic disease including diabetes, hypertension, and thyroid, kidney, or cardiovascular disease was grounds for exclusion. The findings were presented at the annual meeting of the Endocrine Society.
The 248 women with PCOS enrolled from 2011 to 2013 from a screened population of 25,000 pregnant women were followed from their first prenatal visit (before week 18) to delivery. Blood was collected at the first visit for analysis of metabolic hormones. A 75-g oral glucose tolerance test (OGTT) was carried out at week 24-28 and diagnosis of GDM was according to 2013 American Diabetes Association OGTT criteria.
Of the 248 women, 75 (30.2%) developed GDM, and 173 (69.8%) women had normal OGTT results. Examination over the same time period early in pregnancy revealed a higher incidence of GDM in women with PCOS.
In a univariate analysis, PCOS patients who developed GDM had higher fasting blood glucose (FBG), Homeostasis Model Assessment-Insulin resistance (HOMA-IR) score, total cholesterol, low-density lipoprotein cholesterol, non-HDL cholesterol, systolic and diastolic blood pressures, and free testosterone index. These patients also had lower levels of sex hormone–binding globulin (SHBG) and higher likelihood of family history of diabetes and earlier delivery.
Multiple logistic regression revealed associations between increased incidence of GDM and FBG greater than or equal to 4.86 mmol/L, non-HDL cholesterol greater than or equal to 2.84 mmol/L, and SHBG greater than or equal to 222 nmol/L. The predictive power of the three factors for the development of GDM in PCOS was relatively strong.
Future studies could aim to validate the prediction model and clarify the pathogenic basis of GDM in PCOS women, according to the researchers .
The study was funded by the Beijing Science Committee. Dr. Huang had no disclosures.
BOSTON – A prospective cohort study of women with polycystic ovarian syndrome who developed gestational diabetes mellitus during pregnancy has implicated fasting blood glucose, non–high density lipoprotein, and sex hormone–binding globulin as significant predictive factors for the development of GDM.
“Polycystic ovarian syndrome [PCOS] is the most common reproductive disorder in women of reproductive age and is commonly associated with metabolic disorders including diabetes and obesity. In women with GDM, a history of PCOS is associated with higher incidence of complications and postpregnancy glucose intolerance. Risk factors during early pregnancy in women with PCOS for development of GDM have not been well characterized,” said Dr. Wenyu Huang of Northwestern University, Chicago.
To provide some clarity, Dr. Huang and his colleagues conducted a prospective cohort study. Inclusion criteria were age 18-45 years, diagnosis of PCOS prior to conception, singlet pregnancy, and enrollment during the first trimester. Preexisting chronic disease including diabetes, hypertension, and thyroid, kidney, or cardiovascular disease was grounds for exclusion. The findings were presented at the annual meeting of the Endocrine Society.
The 248 women with PCOS enrolled from 2011 to 2013 from a screened population of 25,000 pregnant women were followed from their first prenatal visit (before week 18) to delivery. Blood was collected at the first visit for analysis of metabolic hormones. A 75-g oral glucose tolerance test (OGTT) was carried out at week 24-28 and diagnosis of GDM was according to 2013 American Diabetes Association OGTT criteria.
Of the 248 women, 75 (30.2%) developed GDM, and 173 (69.8%) women had normal OGTT results. Examination over the same time period early in pregnancy revealed a higher incidence of GDM in women with PCOS.
In a univariate analysis, PCOS patients who developed GDM had higher fasting blood glucose (FBG), Homeostasis Model Assessment-Insulin resistance (HOMA-IR) score, total cholesterol, low-density lipoprotein cholesterol, non-HDL cholesterol, systolic and diastolic blood pressures, and free testosterone index. These patients also had lower levels of sex hormone–binding globulin (SHBG) and higher likelihood of family history of diabetes and earlier delivery.
Multiple logistic regression revealed associations between increased incidence of GDM and FBG greater than or equal to 4.86 mmol/L, non-HDL cholesterol greater than or equal to 2.84 mmol/L, and SHBG greater than or equal to 222 nmol/L. The predictive power of the three factors for the development of GDM in PCOS was relatively strong.
Future studies could aim to validate the prediction model and clarify the pathogenic basis of GDM in PCOS women, according to the researchers .
The study was funded by the Beijing Science Committee. Dr. Huang had no disclosures.
BOSTON – A prospective cohort study of women with polycystic ovarian syndrome who developed gestational diabetes mellitus during pregnancy has implicated fasting blood glucose, non–high density lipoprotein, and sex hormone–binding globulin as significant predictive factors for the development of GDM.
“Polycystic ovarian syndrome [PCOS] is the most common reproductive disorder in women of reproductive age and is commonly associated with metabolic disorders including diabetes and obesity. In women with GDM, a history of PCOS is associated with higher incidence of complications and postpregnancy glucose intolerance. Risk factors during early pregnancy in women with PCOS for development of GDM have not been well characterized,” said Dr. Wenyu Huang of Northwestern University, Chicago.
To provide some clarity, Dr. Huang and his colleagues conducted a prospective cohort study. Inclusion criteria were age 18-45 years, diagnosis of PCOS prior to conception, singlet pregnancy, and enrollment during the first trimester. Preexisting chronic disease including diabetes, hypertension, and thyroid, kidney, or cardiovascular disease was grounds for exclusion. The findings were presented at the annual meeting of the Endocrine Society.
The 248 women with PCOS enrolled from 2011 to 2013 from a screened population of 25,000 pregnant women were followed from their first prenatal visit (before week 18) to delivery. Blood was collected at the first visit for analysis of metabolic hormones. A 75-g oral glucose tolerance test (OGTT) was carried out at week 24-28 and diagnosis of GDM was according to 2013 American Diabetes Association OGTT criteria.
Of the 248 women, 75 (30.2%) developed GDM, and 173 (69.8%) women had normal OGTT results. Examination over the same time period early in pregnancy revealed a higher incidence of GDM in women with PCOS.
In a univariate analysis, PCOS patients who developed GDM had higher fasting blood glucose (FBG), Homeostasis Model Assessment-Insulin resistance (HOMA-IR) score, total cholesterol, low-density lipoprotein cholesterol, non-HDL cholesterol, systolic and diastolic blood pressures, and free testosterone index. These patients also had lower levels of sex hormone–binding globulin (SHBG) and higher likelihood of family history of diabetes and earlier delivery.
Multiple logistic regression revealed associations between increased incidence of GDM and FBG greater than or equal to 4.86 mmol/L, non-HDL cholesterol greater than or equal to 2.84 mmol/L, and SHBG greater than or equal to 222 nmol/L. The predictive power of the three factors for the development of GDM in PCOS was relatively strong.
Future studies could aim to validate the prediction model and clarify the pathogenic basis of GDM in PCOS women, according to the researchers .
The study was funded by the Beijing Science Committee. Dr. Huang had no disclosures.
Early predictors of GDM identified in women with PCOS
BOSTON – A prospective cohort study of women with polycystic ovarian syndrome who developed gestational diabetes mellitus during pregnancy has implicated fasting blood glucose, non–high density lipoprotein, and sex hormone–binding globulin as significant predictive factors for the development of GDM.
“Polycystic ovarian syndrome [PCOS] is the most common reproductive disorder in women of reproductive age and is commonly associated with metabolic disorders including diabetes and obesity. In women with GDM, a history of PCOS is associated with higher incidence of complications and postpregnancy glucose intolerance. Risk factors during early pregnancy in women with PCOS for development of GDM have not been well characterized,” said Dr. Wenyu Huang of Northwestern University, Chicago.
To provide some clarity, Dr. Huang and his colleagues conducted a prospective cohort study. Inclusion criteria were age 18-45 years, diagnosis of PCOS prior to conception, singlet pregnancy, and enrollment during the first trimester. Preexisting chronic disease including diabetes, hypertension, and thyroid, kidney, or cardiovascular disease was grounds for exclusion. The findings were presented at the annual meeting of the Endocrine Society.
The 248 women with PCOS enrolled from 2011 to 2013 from a screened population of 25,000 pregnant women were followed from their first prenatal visit (before week 18) to delivery. Blood was collected at the first visit for analysis of metabolic hormones. A 75-g oral glucose tolerance test (OGTT) was carried out at week 24-28 and diagnosis of GDM was according to 2013 American Diabetes Association OGTT criteria.
Of the 248 women, 75 (30.2%) developed GDM, and 173 (69.8%) women had normal OGTT results. Examination over the same time period early in pregnancy revealed a higher incidence of GDM in women with PCOS.
In a univariate analysis, PCOS patients who developed GDM had higher fasting blood glucose (FBG), Homeostasis Model Assessment-Insulin resistance (HOMA-IR) score, total cholesterol, low-density lipoprotein cholesterol, non-HDL cholesterol, systolic and diastolic blood pressures, and free testosterone index. These patients also had lower levels of sex hormone–binding globulin (SHBG) and higher likelihood of family history of diabetes and earlier delivery.
Multiple logistic regression revealed associations between increased incidence of GDM and FBG greater than or equal to 4.86 mmol/L, non-HDL cholesterol greater than or equal to 2.84 mmol/L, and SHBG greater than or equal to 222 nmol/L. The predictive power of the three factors for the development of GDM in PCOS was relatively strong.
Future studies could aim to validate the prediction model and clarify the pathogenic basis of GDM in PCOS women, according to the researchers .
The study was funded by the Beijing Science Committee. Dr. Huang had no disclosures.
BOSTON – A prospective cohort study of women with polycystic ovarian syndrome who developed gestational diabetes mellitus during pregnancy has implicated fasting blood glucose, non–high density lipoprotein, and sex hormone–binding globulin as significant predictive factors for the development of GDM.
“Polycystic ovarian syndrome [PCOS] is the most common reproductive disorder in women of reproductive age and is commonly associated with metabolic disorders including diabetes and obesity. In women with GDM, a history of PCOS is associated with higher incidence of complications and postpregnancy glucose intolerance. Risk factors during early pregnancy in women with PCOS for development of GDM have not been well characterized,” said Dr. Wenyu Huang of Northwestern University, Chicago.
To provide some clarity, Dr. Huang and his colleagues conducted a prospective cohort study. Inclusion criteria were age 18-45 years, diagnosis of PCOS prior to conception, singlet pregnancy, and enrollment during the first trimester. Preexisting chronic disease including diabetes, hypertension, and thyroid, kidney, or cardiovascular disease was grounds for exclusion. The findings were presented at the annual meeting of the Endocrine Society.
The 248 women with PCOS enrolled from 2011 to 2013 from a screened population of 25,000 pregnant women were followed from their first prenatal visit (before week 18) to delivery. Blood was collected at the first visit for analysis of metabolic hormones. A 75-g oral glucose tolerance test (OGTT) was carried out at week 24-28 and diagnosis of GDM was according to 2013 American Diabetes Association OGTT criteria.
Of the 248 women, 75 (30.2%) developed GDM, and 173 (69.8%) women had normal OGTT results. Examination over the same time period early in pregnancy revealed a higher incidence of GDM in women with PCOS.
In a univariate analysis, PCOS patients who developed GDM had higher fasting blood glucose (FBG), Homeostasis Model Assessment-Insulin resistance (HOMA-IR) score, total cholesterol, low-density lipoprotein cholesterol, non-HDL cholesterol, systolic and diastolic blood pressures, and free testosterone index. These patients also had lower levels of sex hormone–binding globulin (SHBG) and higher likelihood of family history of diabetes and earlier delivery.
Multiple logistic regression revealed associations between increased incidence of GDM and FBG greater than or equal to 4.86 mmol/L, non-HDL cholesterol greater than or equal to 2.84 mmol/L, and SHBG greater than or equal to 222 nmol/L. The predictive power of the three factors for the development of GDM in PCOS was relatively strong.
Future studies could aim to validate the prediction model and clarify the pathogenic basis of GDM in PCOS women, according to the researchers .
The study was funded by the Beijing Science Committee. Dr. Huang had no disclosures.
BOSTON – A prospective cohort study of women with polycystic ovarian syndrome who developed gestational diabetes mellitus during pregnancy has implicated fasting blood glucose, non–high density lipoprotein, and sex hormone–binding globulin as significant predictive factors for the development of GDM.
“Polycystic ovarian syndrome [PCOS] is the most common reproductive disorder in women of reproductive age and is commonly associated with metabolic disorders including diabetes and obesity. In women with GDM, a history of PCOS is associated with higher incidence of complications and postpregnancy glucose intolerance. Risk factors during early pregnancy in women with PCOS for development of GDM have not been well characterized,” said Dr. Wenyu Huang of Northwestern University, Chicago.
To provide some clarity, Dr. Huang and his colleagues conducted a prospective cohort study. Inclusion criteria were age 18-45 years, diagnosis of PCOS prior to conception, singlet pregnancy, and enrollment during the first trimester. Preexisting chronic disease including diabetes, hypertension, and thyroid, kidney, or cardiovascular disease was grounds for exclusion. The findings were presented at the annual meeting of the Endocrine Society.
The 248 women with PCOS enrolled from 2011 to 2013 from a screened population of 25,000 pregnant women were followed from their first prenatal visit (before week 18) to delivery. Blood was collected at the first visit for analysis of metabolic hormones. A 75-g oral glucose tolerance test (OGTT) was carried out at week 24-28 and diagnosis of GDM was according to 2013 American Diabetes Association OGTT criteria.
Of the 248 women, 75 (30.2%) developed GDM, and 173 (69.8%) women had normal OGTT results. Examination over the same time period early in pregnancy revealed a higher incidence of GDM in women with PCOS.
In a univariate analysis, PCOS patients who developed GDM had higher fasting blood glucose (FBG), Homeostasis Model Assessment-Insulin resistance (HOMA-IR) score, total cholesterol, low-density lipoprotein cholesterol, non-HDL cholesterol, systolic and diastolic blood pressures, and free testosterone index. These patients also had lower levels of sex hormone–binding globulin (SHBG) and higher likelihood of family history of diabetes and earlier delivery.
Multiple logistic regression revealed associations between increased incidence of GDM and FBG greater than or equal to 4.86 mmol/L, non-HDL cholesterol greater than or equal to 2.84 mmol/L, and SHBG greater than or equal to 222 nmol/L. The predictive power of the three factors for the development of GDM in PCOS was relatively strong.
Future studies could aim to validate the prediction model and clarify the pathogenic basis of GDM in PCOS women, according to the researchers .
The study was funded by the Beijing Science Committee. Dr. Huang had no disclosures.
Key clinical point: Several factors may be predictive of early development of gestational diabetes mellitus in pregnant women with polycystic ovarian syndrome.
Major finding: Multiple logistic regression revealed associations between increased incidence of gestational diabetes mellitus and fasting blood glucose greater than or equal to 4.86 mmol/L, non-HDL cholesterol greater than or equal to 2.84 mmol/L, and sex hormone–binding globulin greater than or equal to 222 nmol/L.
Data source: Prospective cohort study involving 248 women.
Disclosures: The study was funded by the Beijing Science Committee. Dr. Huang had no disclosures.
VIDEO: More routine use of unilateral thyroidectomy advocated for papillary thyroid microcarcinoma
BOSTON – A study of over 60 years of patient data from the Mayo Clinic suggests a reconsideration of the routine use of unilateral thyroid lobectomy (UL) as the initial treatment for papillary thyroid microcarcinoma.
“Papillary thyroid microcarcinoma [PTM] patients have a normal life expectancy and typically are cured by adequate tumor resection. More than 99% of PTM patients are not at risk of either distant spread or mortality from cancer,” said Dr. Ian D. Hay of the Mayo Clinic, Rochester, Minn. Unilateral thyroid lobectomy is one treatment option for papillary thyroid microcarcinoma along with conventional bilateral nodal resection approaches of near-total thyroidectomy (NT) or total thyroidectomy (TT), or selective radioactive iodine remnant ablation (RRA).
Awareness of PTM is not new; examination of thyroid glands at autopsy going back decades has revealed their presence in 6%-36% of samples. A more recent development is the use of high-resolution ultrasound-guided biopsies of papillary thyroid carcinoma (PTC) lesions as small as 3 cm. For example, at the Mayo Clinic the diagnosis of PTM was about one annually from 1935 to 1944, while from 2005 to 2014 the average was close to one per day. “At Mayo, 34% of PTCs seen since 1995 are PTMs,” Dr. Hay said at the annual meeting of the Endocrine Society.
The best initial management of PTMs is disputed, with observation favored by some, TT and RRA favored by others, and ethanol ablation having been found to be effective by institutions including the Mayo Clinic. UL has been deemphasized, despite the 2015 American Thyroid Association Guidelines recommendation of UL as the usual surgical procedure for adults with PTM.
Dr. Hay and his colleagues sought to provide some clarity to the issue by taking advantage of the institute’s database of adult (18+ years) PTM patients who were consecutively treated from 1935 to 2014. The decades of data allowed a long-term look at patient outcomes. They examined data from 1,345 patients, 954 women and 391 men with a median age at surgery of 48 years. The mean follow-up was 15.4 years, representing almost 21,000 patient years. Data on tumor recurrence and cause-specific mortality were derived from a data base of over 4,300 PTC patients representing over 66,000 patient-years of observation.
Median tumor size was 7 mm (range, 0.08-1.0 cm). Extrathyroid invasion was evident in 18 (1.3%) cases and 298 tumors (26%) were multifocal. There were 399 (30%) node-positive tumors at diagnosis and 4 (0.3%) cases featuring initial distant metastases.
The mean MACIS (metastasis, age at presentation, completeness of surgical resection, invasion [extrathyroidal], size) score was 4.25 with little variation in score over time. Almost all (96%) patients had a MACIS score of under 6. Bilateral lobar resection was done in 1,132 (95%) patients, with NT or TT comprising 80% of the cases. UL was done in only 202 (15%) cases. The use of TT skyrocketed from 3% of the cases done in the first 2 decades to 40% in the last 2 decades. Regional nodes were removed at surgery in 743 (55%) cases, either by “node picking” (23%) or compartmental dissection (32%).
Overall survival following surgery in PTM patients was similar to age- and gender-matched controls (397 deaths observed, 431 deaths expected; P = .16). Only four (0.3%) patients died of PTM. The rates of locoregional recurrence were similar for the unilateral and bilateral approaches (P = .90). In 1,148 patients with potentially curable PTM, defined as the absence of metastasis at diagnosis and no gross residual disease, the rates of tumor recurrence 10, 20, and 40 years after surgery were 6%, 7%, and 10%, respectively. In these 1,148 patients, the 30-year locoregional recurrence rates after UL alone were similar to those seen after NT or TT followed by RRA (P = .99).
UL did not result in permanent unilateral vocal cord paresis or permanent hypoparathyroidism. These adversities were more likely to develop following bilateral lobectomy.
“Since [UL] produces comparable recurrence results when compared to bilateral surgery and is not associated with either cord paresis or hypoparathyroidism, then perhaps it is overdue for institutions like Mayo to individualize our treatment policies and more often employ UL when surgery, and not observation or ultrasound-guided percutaneous ethanol ablation, is chosen to treat PTM,” said Dr. Hay.
Dr. Hay was adamant on the overuse of ultrasound in the detection of small-diameter carcinomas in the decision for bilateral surgery. “It’s embarrassing how much we are wasting resources and doing too much ultrasound too often,” he said in an interview.
Dr. Hay had no disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
BOSTON – A study of over 60 years of patient data from the Mayo Clinic suggests a reconsideration of the routine use of unilateral thyroid lobectomy (UL) as the initial treatment for papillary thyroid microcarcinoma.
“Papillary thyroid microcarcinoma [PTM] patients have a normal life expectancy and typically are cured by adequate tumor resection. More than 99% of PTM patients are not at risk of either distant spread or mortality from cancer,” said Dr. Ian D. Hay of the Mayo Clinic, Rochester, Minn. Unilateral thyroid lobectomy is one treatment option for papillary thyroid microcarcinoma along with conventional bilateral nodal resection approaches of near-total thyroidectomy (NT) or total thyroidectomy (TT), or selective radioactive iodine remnant ablation (RRA).
Awareness of PTM is not new; examination of thyroid glands at autopsy going back decades has revealed their presence in 6%-36% of samples. A more recent development is the use of high-resolution ultrasound-guided biopsies of papillary thyroid carcinoma (PTC) lesions as small as 3 cm. For example, at the Mayo Clinic the diagnosis of PTM was about one annually from 1935 to 1944, while from 2005 to 2014 the average was close to one per day. “At Mayo, 34% of PTCs seen since 1995 are PTMs,” Dr. Hay said at the annual meeting of the Endocrine Society.
The best initial management of PTMs is disputed, with observation favored by some, TT and RRA favored by others, and ethanol ablation having been found to be effective by institutions including the Mayo Clinic. UL has been deemphasized, despite the 2015 American Thyroid Association Guidelines recommendation of UL as the usual surgical procedure for adults with PTM.
Dr. Hay and his colleagues sought to provide some clarity to the issue by taking advantage of the institute’s database of adult (18+ years) PTM patients who were consecutively treated from 1935 to 2014. The decades of data allowed a long-term look at patient outcomes. They examined data from 1,345 patients, 954 women and 391 men with a median age at surgery of 48 years. The mean follow-up was 15.4 years, representing almost 21,000 patient years. Data on tumor recurrence and cause-specific mortality were derived from a data base of over 4,300 PTC patients representing over 66,000 patient-years of observation.
Median tumor size was 7 mm (range, 0.08-1.0 cm). Extrathyroid invasion was evident in 18 (1.3%) cases and 298 tumors (26%) were multifocal. There were 399 (30%) node-positive tumors at diagnosis and 4 (0.3%) cases featuring initial distant metastases.
The mean MACIS (metastasis, age at presentation, completeness of surgical resection, invasion [extrathyroidal], size) score was 4.25 with little variation in score over time. Almost all (96%) patients had a MACIS score of under 6. Bilateral lobar resection was done in 1,132 (95%) patients, with NT or TT comprising 80% of the cases. UL was done in only 202 (15%) cases. The use of TT skyrocketed from 3% of the cases done in the first 2 decades to 40% in the last 2 decades. Regional nodes were removed at surgery in 743 (55%) cases, either by “node picking” (23%) or compartmental dissection (32%).
Overall survival following surgery in PTM patients was similar to age- and gender-matched controls (397 deaths observed, 431 deaths expected; P = .16). Only four (0.3%) patients died of PTM. The rates of locoregional recurrence were similar for the unilateral and bilateral approaches (P = .90). In 1,148 patients with potentially curable PTM, defined as the absence of metastasis at diagnosis and no gross residual disease, the rates of tumor recurrence 10, 20, and 40 years after surgery were 6%, 7%, and 10%, respectively. In these 1,148 patients, the 30-year locoregional recurrence rates after UL alone were similar to those seen after NT or TT followed by RRA (P = .99).
UL did not result in permanent unilateral vocal cord paresis or permanent hypoparathyroidism. These adversities were more likely to develop following bilateral lobectomy.
“Since [UL] produces comparable recurrence results when compared to bilateral surgery and is not associated with either cord paresis or hypoparathyroidism, then perhaps it is overdue for institutions like Mayo to individualize our treatment policies and more often employ UL when surgery, and not observation or ultrasound-guided percutaneous ethanol ablation, is chosen to treat PTM,” said Dr. Hay.
Dr. Hay was adamant on the overuse of ultrasound in the detection of small-diameter carcinomas in the decision for bilateral surgery. “It’s embarrassing how much we are wasting resources and doing too much ultrasound too often,” he said in an interview.
Dr. Hay had no disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
BOSTON – A study of over 60 years of patient data from the Mayo Clinic suggests a reconsideration of the routine use of unilateral thyroid lobectomy (UL) as the initial treatment for papillary thyroid microcarcinoma.
“Papillary thyroid microcarcinoma [PTM] patients have a normal life expectancy and typically are cured by adequate tumor resection. More than 99% of PTM patients are not at risk of either distant spread or mortality from cancer,” said Dr. Ian D. Hay of the Mayo Clinic, Rochester, Minn. Unilateral thyroid lobectomy is one treatment option for papillary thyroid microcarcinoma along with conventional bilateral nodal resection approaches of near-total thyroidectomy (NT) or total thyroidectomy (TT), or selective radioactive iodine remnant ablation (RRA).
Awareness of PTM is not new; examination of thyroid glands at autopsy going back decades has revealed their presence in 6%-36% of samples. A more recent development is the use of high-resolution ultrasound-guided biopsies of papillary thyroid carcinoma (PTC) lesions as small as 3 cm. For example, at the Mayo Clinic the diagnosis of PTM was about one annually from 1935 to 1944, while from 2005 to 2014 the average was close to one per day. “At Mayo, 34% of PTCs seen since 1995 are PTMs,” Dr. Hay said at the annual meeting of the Endocrine Society.
The best initial management of PTMs is disputed, with observation favored by some, TT and RRA favored by others, and ethanol ablation having been found to be effective by institutions including the Mayo Clinic. UL has been deemphasized, despite the 2015 American Thyroid Association Guidelines recommendation of UL as the usual surgical procedure for adults with PTM.
Dr. Hay and his colleagues sought to provide some clarity to the issue by taking advantage of the institute’s database of adult (18+ years) PTM patients who were consecutively treated from 1935 to 2014. The decades of data allowed a long-term look at patient outcomes. They examined data from 1,345 patients, 954 women and 391 men with a median age at surgery of 48 years. The mean follow-up was 15.4 years, representing almost 21,000 patient years. Data on tumor recurrence and cause-specific mortality were derived from a data base of over 4,300 PTC patients representing over 66,000 patient-years of observation.
Median tumor size was 7 mm (range, 0.08-1.0 cm). Extrathyroid invasion was evident in 18 (1.3%) cases and 298 tumors (26%) were multifocal. There were 399 (30%) node-positive tumors at diagnosis and 4 (0.3%) cases featuring initial distant metastases.
The mean MACIS (metastasis, age at presentation, completeness of surgical resection, invasion [extrathyroidal], size) score was 4.25 with little variation in score over time. Almost all (96%) patients had a MACIS score of under 6. Bilateral lobar resection was done in 1,132 (95%) patients, with NT or TT comprising 80% of the cases. UL was done in only 202 (15%) cases. The use of TT skyrocketed from 3% of the cases done in the first 2 decades to 40% in the last 2 decades. Regional nodes were removed at surgery in 743 (55%) cases, either by “node picking” (23%) or compartmental dissection (32%).
Overall survival following surgery in PTM patients was similar to age- and gender-matched controls (397 deaths observed, 431 deaths expected; P = .16). Only four (0.3%) patients died of PTM. The rates of locoregional recurrence were similar for the unilateral and bilateral approaches (P = .90). In 1,148 patients with potentially curable PTM, defined as the absence of metastasis at diagnosis and no gross residual disease, the rates of tumor recurrence 10, 20, and 40 years after surgery were 6%, 7%, and 10%, respectively. In these 1,148 patients, the 30-year locoregional recurrence rates after UL alone were similar to those seen after NT or TT followed by RRA (P = .99).
UL did not result in permanent unilateral vocal cord paresis or permanent hypoparathyroidism. These adversities were more likely to develop following bilateral lobectomy.
“Since [UL] produces comparable recurrence results when compared to bilateral surgery and is not associated with either cord paresis or hypoparathyroidism, then perhaps it is overdue for institutions like Mayo to individualize our treatment policies and more often employ UL when surgery, and not observation or ultrasound-guided percutaneous ethanol ablation, is chosen to treat PTM,” said Dr. Hay.
Dr. Hay was adamant on the overuse of ultrasound in the detection of small-diameter carcinomas in the decision for bilateral surgery. “It’s embarrassing how much we are wasting resources and doing too much ultrasound too often,” he said in an interview.
Dr. Hay had no disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ENDO 2016
Key clinical point: Unilateral thryoidectomy should be reconsidered as a routine strategy in treatment of papillary thyroid microcarcinoma.
Major finding: Data compiled from over 80 years at a single institution indicates the value of unilateral thyroidectomy in terms of recurrence and morbidity.
Data source: Retrospective analysis of data from 1,153 adult patients.
Disclosures: Dr. Hay had no disclosures.
Low Thyroid Function Increases Odds of Type 2 Diabetes
BOSTON – Results of a population-based study involving more than 8,000 adults from the Netherlands who were diabetes free at baseline has implicated low thyroid function with a 13% increased likelihood of developing type 2 diabetes, and up to 40% higher in individuals with prediabetes.
The heightened risk exists even for individuals with subclinical hypothyroidism, in whom thyroid-stimulating hormone (TSH) in the blood is still in the normal concentration range.
“These findings suggest we should consider screening people with prediabetes for low thyroid function,” Dr. Layal Chaker of Erasmus Medical Center, Rotterdam, the Netherlands, said at the annual meeting of the Endocrine Society.
Thyroid screening is recommended for patients with type 1 diabetes, since they are at increased risk of thyroid disease. An association between thyroid dysfunction in the form of hypothyroidism and type 2 diabetes has been surmised, since type 2 diabetes and hypothyroidism tend to be more prevalent in older adults, and since hypothyroidism has been linked with weight gain and reduced sensitivity to insulin.
To further study the link between thyroid function and diabetes, Dr. Chaker and her colleagues studied data from 8,452 participants aged 45 years and above (mean age 62 years, 58% female) from the Rotterdam Study, a prospective, longitudinal cohort study in the Ommoord district of Rotterdam that was undertaken to investigate the risk factors of cardiovascular, neurological, ophthalmologic, and endocrine diseases in the elderly. The cohort was considered representative of the general population in the Netherlands. All participants had blood tests to measure blood glucose, TSH, and free thyroxine (FT4). Normal blood glucose was considered to be under 5.9 mmol/L, prediabetes as over 5.9 to less than 7.0 mmol/L glucose, and diabetes as above 7.0 mmol/L.
Prediabetes and type 2 diabetes developed in 1,100 and 798 subjects, respectively, during a mean follow-up of 7.9 years. Higher TSH levels increased the risk of development of type 2 diabetes risk (hazard ratio [HR] 1.13, 95% confidence interval [CI], 1.08-1.18, per logTSH). This risk held even for subjects whose TSH levels were at the lower end of the reference range of thyroid function (HR 1.24, CI, 1.06-1.45). The risk of diabetes was reduced in subjects with FT4 levels that were elevated (HR 0.96, CI, 0.93-0.99, per pmol/L) and for those whose FT4 levels were in the reference range (HR 0.96, CI, 0.92-0.99). Low thyroid function, even within the normal range, was associated with a 1.4 times risk of progression from prediabetes to type 2 diabetes (P = .002).
“Low and, surprisingly, low-normal thyroid function are risk factors for incident diabetes, especially in individuals with prediabetes,” said Dr. Chaker.
The data point to the need to clarify whether screening for and treatment of subclinical hypothyroidism can help curb the development of diabetes, she added.
Dr. Chaker had no disclosures.
BOSTON – Results of a population-based study involving more than 8,000 adults from the Netherlands who were diabetes free at baseline has implicated low thyroid function with a 13% increased likelihood of developing type 2 diabetes, and up to 40% higher in individuals with prediabetes.
The heightened risk exists even for individuals with subclinical hypothyroidism, in whom thyroid-stimulating hormone (TSH) in the blood is still in the normal concentration range.
“These findings suggest we should consider screening people with prediabetes for low thyroid function,” Dr. Layal Chaker of Erasmus Medical Center, Rotterdam, the Netherlands, said at the annual meeting of the Endocrine Society.
Thyroid screening is recommended for patients with type 1 diabetes, since they are at increased risk of thyroid disease. An association between thyroid dysfunction in the form of hypothyroidism and type 2 diabetes has been surmised, since type 2 diabetes and hypothyroidism tend to be more prevalent in older adults, and since hypothyroidism has been linked with weight gain and reduced sensitivity to insulin.
To further study the link between thyroid function and diabetes, Dr. Chaker and her colleagues studied data from 8,452 participants aged 45 years and above (mean age 62 years, 58% female) from the Rotterdam Study, a prospective, longitudinal cohort study in the Ommoord district of Rotterdam that was undertaken to investigate the risk factors of cardiovascular, neurological, ophthalmologic, and endocrine diseases in the elderly. The cohort was considered representative of the general population in the Netherlands. All participants had blood tests to measure blood glucose, TSH, and free thyroxine (FT4). Normal blood glucose was considered to be under 5.9 mmol/L, prediabetes as over 5.9 to less than 7.0 mmol/L glucose, and diabetes as above 7.0 mmol/L.
Prediabetes and type 2 diabetes developed in 1,100 and 798 subjects, respectively, during a mean follow-up of 7.9 years. Higher TSH levels increased the risk of development of type 2 diabetes risk (hazard ratio [HR] 1.13, 95% confidence interval [CI], 1.08-1.18, per logTSH). This risk held even for subjects whose TSH levels were at the lower end of the reference range of thyroid function (HR 1.24, CI, 1.06-1.45). The risk of diabetes was reduced in subjects with FT4 levels that were elevated (HR 0.96, CI, 0.93-0.99, per pmol/L) and for those whose FT4 levels were in the reference range (HR 0.96, CI, 0.92-0.99). Low thyroid function, even within the normal range, was associated with a 1.4 times risk of progression from prediabetes to type 2 diabetes (P = .002).
“Low and, surprisingly, low-normal thyroid function are risk factors for incident diabetes, especially in individuals with prediabetes,” said Dr. Chaker.
The data point to the need to clarify whether screening for and treatment of subclinical hypothyroidism can help curb the development of diabetes, she added.
Dr. Chaker had no disclosures.
BOSTON – Results of a population-based study involving more than 8,000 adults from the Netherlands who were diabetes free at baseline has implicated low thyroid function with a 13% increased likelihood of developing type 2 diabetes, and up to 40% higher in individuals with prediabetes.
The heightened risk exists even for individuals with subclinical hypothyroidism, in whom thyroid-stimulating hormone (TSH) in the blood is still in the normal concentration range.
“These findings suggest we should consider screening people with prediabetes for low thyroid function,” Dr. Layal Chaker of Erasmus Medical Center, Rotterdam, the Netherlands, said at the annual meeting of the Endocrine Society.
Thyroid screening is recommended for patients with type 1 diabetes, since they are at increased risk of thyroid disease. An association between thyroid dysfunction in the form of hypothyroidism and type 2 diabetes has been surmised, since type 2 diabetes and hypothyroidism tend to be more prevalent in older adults, and since hypothyroidism has been linked with weight gain and reduced sensitivity to insulin.
To further study the link between thyroid function and diabetes, Dr. Chaker and her colleagues studied data from 8,452 participants aged 45 years and above (mean age 62 years, 58% female) from the Rotterdam Study, a prospective, longitudinal cohort study in the Ommoord district of Rotterdam that was undertaken to investigate the risk factors of cardiovascular, neurological, ophthalmologic, and endocrine diseases in the elderly. The cohort was considered representative of the general population in the Netherlands. All participants had blood tests to measure blood glucose, TSH, and free thyroxine (FT4). Normal blood glucose was considered to be under 5.9 mmol/L, prediabetes as over 5.9 to less than 7.0 mmol/L glucose, and diabetes as above 7.0 mmol/L.
Prediabetes and type 2 diabetes developed in 1,100 and 798 subjects, respectively, during a mean follow-up of 7.9 years. Higher TSH levels increased the risk of development of type 2 diabetes risk (hazard ratio [HR] 1.13, 95% confidence interval [CI], 1.08-1.18, per logTSH). This risk held even for subjects whose TSH levels were at the lower end of the reference range of thyroid function (HR 1.24, CI, 1.06-1.45). The risk of diabetes was reduced in subjects with FT4 levels that were elevated (HR 0.96, CI, 0.93-0.99, per pmol/L) and for those whose FT4 levels were in the reference range (HR 0.96, CI, 0.92-0.99). Low thyroid function, even within the normal range, was associated with a 1.4 times risk of progression from prediabetes to type 2 diabetes (P = .002).
“Low and, surprisingly, low-normal thyroid function are risk factors for incident diabetes, especially in individuals with prediabetes,” said Dr. Chaker.
The data point to the need to clarify whether screening for and treatment of subclinical hypothyroidism can help curb the development of diabetes, she added.
Dr. Chaker had no disclosures.
AT ENDO 2016
VIDEO: Low thyroid function increases odds of type 2 diabetes
BOSTON – Results of a population-based study involving more than 8,000 adults from the Netherlands who were diabetes free at baseline has implicated low thyroid function with a 13% increased likelihood of developing type 2 diabetes, and up to 40% higher in individuals with prediabetes.
The heightened risk exists even for individuals with subclinical hypothyroidism, in whom thyroid-stimulating hormone (TSH) in the blood is still in the normal concentration range.
“These findings suggest we should consider screening people with prediabetes for low thyroid function,” Dr. Layal Chaker of Erasmus Medical Center, Rotterdam, the Netherlands, said at the annual meeting of the Endocrine Society.
Thyroid screening is recommended for patients with type 1 diabetes, since they are at increased risk of thyroid disease. An association between thyroid dysfunction in the form of hypothyroidism and type 2 diabetes has been surmised, since type 2 diabetes and hypothyroidism tend to be more prevalent in older adults, and since hypothyroidism has been linked with weight gain and reduced sensitivity to insulin.
To further study the link between thyroid function and diabetes, Dr. Chaker and her colleagues studied data from 8,452 participants aged 45 years and above (mean age 62 years, 58% female) from the Rotterdam Study, a prospective, longitudinal cohort study in the Ommoord district of Rotterdam that was undertaken to investigate the risk factors of cardiovascular, neurological, ophthalmologic, and endocrine diseases in the elderly. The cohort was considered representative of the general population in the Netherlands. All participants had blood tests to measure blood glucose, TSH, and free thyroxine (FT4). Normal blood glucose was considered to be under 5.9 mmol/L, prediabetes as over 5.9 to less than 7.0 mmol/L glucose, and diabetes as above 7.0 mmol/L.
Prediabetes and type 2 diabetes developed in 1,100 and 798 subjects, respectively, during a mean follow-up of 7.9 years. Higher TSH levels increased the risk of development of type 2 diabetes risk (hazard ratio [HR] 1.13, 95% confidence interval [CI], 1.08-1.18, per logTSH). This risk held even for subjects whose TSH levels were at the lower end of the reference range of thyroid function (HR 1.24, CI, 1.06-1.45). The risk of diabetes was reduced in subjects with FT4 levels that were elevated (HR 0.96, CI, 0.93-0.99, per pmol/L) and for those whose FT4 levels were in the reference range (HR 0.96, CI, 0.92-0.99). Low thyroid function, even within the normal range, was associated with a 1.4 times risk of progression from prediabetes to type 2 diabetes (P = .002).
“Low and, surprisingly, low-normal thyroid function are risk factors for incident diabetes, especially in individuals with prediabetes,” said Dr. Chaker.
The data point to the need to clarify whether screening for and treatment of subclinical hypothyroidism can help curb the development of diabetes, she added.
Dr. Chaker had no disclosures.
BOSTON – Results of a population-based study involving more than 8,000 adults from the Netherlands who were diabetes free at baseline has implicated low thyroid function with a 13% increased likelihood of developing type 2 diabetes, and up to 40% higher in individuals with prediabetes.
The heightened risk exists even for individuals with subclinical hypothyroidism, in whom thyroid-stimulating hormone (TSH) in the blood is still in the normal concentration range.
“These findings suggest we should consider screening people with prediabetes for low thyroid function,” Dr. Layal Chaker of Erasmus Medical Center, Rotterdam, the Netherlands, said at the annual meeting of the Endocrine Society.
Thyroid screening is recommended for patients with type 1 diabetes, since they are at increased risk of thyroid disease. An association between thyroid dysfunction in the form of hypothyroidism and type 2 diabetes has been surmised, since type 2 diabetes and hypothyroidism tend to be more prevalent in older adults, and since hypothyroidism has been linked with weight gain and reduced sensitivity to insulin.
To further study the link between thyroid function and diabetes, Dr. Chaker and her colleagues studied data from 8,452 participants aged 45 years and above (mean age 62 years, 58% female) from the Rotterdam Study, a prospective, longitudinal cohort study in the Ommoord district of Rotterdam that was undertaken to investigate the risk factors of cardiovascular, neurological, ophthalmologic, and endocrine diseases in the elderly. The cohort was considered representative of the general population in the Netherlands. All participants had blood tests to measure blood glucose, TSH, and free thyroxine (FT4). Normal blood glucose was considered to be under 5.9 mmol/L, prediabetes as over 5.9 to less than 7.0 mmol/L glucose, and diabetes as above 7.0 mmol/L.
Prediabetes and type 2 diabetes developed in 1,100 and 798 subjects, respectively, during a mean follow-up of 7.9 years. Higher TSH levels increased the risk of development of type 2 diabetes risk (hazard ratio [HR] 1.13, 95% confidence interval [CI], 1.08-1.18, per logTSH). This risk held even for subjects whose TSH levels were at the lower end of the reference range of thyroid function (HR 1.24, CI, 1.06-1.45). The risk of diabetes was reduced in subjects with FT4 levels that were elevated (HR 0.96, CI, 0.93-0.99, per pmol/L) and for those whose FT4 levels were in the reference range (HR 0.96, CI, 0.92-0.99). Low thyroid function, even within the normal range, was associated with a 1.4 times risk of progression from prediabetes to type 2 diabetes (P = .002).
“Low and, surprisingly, low-normal thyroid function are risk factors for incident diabetes, especially in individuals with prediabetes,” said Dr. Chaker.
The data point to the need to clarify whether screening for and treatment of subclinical hypothyroidism can help curb the development of diabetes, she added.
Dr. Chaker had no disclosures.
BOSTON – Results of a population-based study involving more than 8,000 adults from the Netherlands who were diabetes free at baseline has implicated low thyroid function with a 13% increased likelihood of developing type 2 diabetes, and up to 40% higher in individuals with prediabetes.
The heightened risk exists even for individuals with subclinical hypothyroidism, in whom thyroid-stimulating hormone (TSH) in the blood is still in the normal concentration range.
“These findings suggest we should consider screening people with prediabetes for low thyroid function,” Dr. Layal Chaker of Erasmus Medical Center, Rotterdam, the Netherlands, said at the annual meeting of the Endocrine Society.
Thyroid screening is recommended for patients with type 1 diabetes, since they are at increased risk of thyroid disease. An association between thyroid dysfunction in the form of hypothyroidism and type 2 diabetes has been surmised, since type 2 diabetes and hypothyroidism tend to be more prevalent in older adults, and since hypothyroidism has been linked with weight gain and reduced sensitivity to insulin.
To further study the link between thyroid function and diabetes, Dr. Chaker and her colleagues studied data from 8,452 participants aged 45 years and above (mean age 62 years, 58% female) from the Rotterdam Study, a prospective, longitudinal cohort study in the Ommoord district of Rotterdam that was undertaken to investigate the risk factors of cardiovascular, neurological, ophthalmologic, and endocrine diseases in the elderly. The cohort was considered representative of the general population in the Netherlands. All participants had blood tests to measure blood glucose, TSH, and free thyroxine (FT4). Normal blood glucose was considered to be under 5.9 mmol/L, prediabetes as over 5.9 to less than 7.0 mmol/L glucose, and diabetes as above 7.0 mmol/L.
Prediabetes and type 2 diabetes developed in 1,100 and 798 subjects, respectively, during a mean follow-up of 7.9 years. Higher TSH levels increased the risk of development of type 2 diabetes risk (hazard ratio [HR] 1.13, 95% confidence interval [CI], 1.08-1.18, per logTSH). This risk held even for subjects whose TSH levels were at the lower end of the reference range of thyroid function (HR 1.24, CI, 1.06-1.45). The risk of diabetes was reduced in subjects with FT4 levels that were elevated (HR 0.96, CI, 0.93-0.99, per pmol/L) and for those whose FT4 levels were in the reference range (HR 0.96, CI, 0.92-0.99). Low thyroid function, even within the normal range, was associated with a 1.4 times risk of progression from prediabetes to type 2 diabetes (P = .002).
“Low and, surprisingly, low-normal thyroid function are risk factors for incident diabetes, especially in individuals with prediabetes,” said Dr. Chaker.
The data point to the need to clarify whether screening for and treatment of subclinical hypothyroidism can help curb the development of diabetes, she added.
Dr. Chaker had no disclosures.
AT ENDO 2016
Key clinical point: Hypothyroidism increases the risk of developing type 2 diabetes.
Major finding: Higher TSH levels increased the risk of development of type 2 diabetes risk (hazard ratio 1.13, 95% confidence interval, 1.08-1.18, per logTSH).
Data source: Population-based study of 8,452 adult from the Netherlands
Disclosures: Dr. Chaker had no disclosures.
VIDEO: Liraglutide acts on GLP-1 receptors to lessen desire for high-fat foods
BOSTON – Two related studies of brain structure and the mechanism of the analog of glucagon-like peptide (GLP) hormone liraglutide indicate that the drug works to decrease reward-related activation of brain sites linked to desire for unhealthy foods in patients with type 2 diabetes.
“Our finding suggests that liraglutide may make people more attentive to what they are eating, particularly high-calories or high-fat foods,” said study co-investigator Olivia Farr, PhD, of Beth Israel Deaconess Hospital and Harvard Medical School, Boston.
Liraglutide, which has been approved for weight management for obese patients and those with type 2 diabetes, is known to promote weight loss, but the mechanism by which this occurs has not been fully understood. The investigators undertook two studies, one to examine human brains to identify GLP-1 receptors and the other to examine the impact liraglutide administration may have on neural responses to food cues in patients with type 2 diabetes.
Immunohistochemical examination of 22 human brain samples identified GLP-1 receptors in the hypothalamus, medulla oblongata, and parietal cortex. GLP-1 receptors have previously only been identified in animals. The findings support the role of the receptors in weight loss in patients on liraglutide.
The researchers then performed a second randomized, placebo-controlled, double-blind, cross-over study involving 18 adult patients with type 2 diabetes. The subjects received, in random order, injections of placebo or liraglutide. Liraglutide was titrated to 0.6 mg at visit 1, 1.2 mg at visit 2, and 1.8 mg at visit 3, which were a week apart, with the highest dose maintained in the 3 days between visits 3 and 4. The total period was 17 days. Visit 4 was an overnight stay followed by functional magnetic resonance imaging (fMRI). Then, after a 3-week washout period, the participants received the other treatment on the same schedule, with another fMRI scan.
During the fMRI, participants viewed images of different foods that had been determined in pre-trial testing to be generally perceived as desirable (typically cakes, pastries, fried food, and fast food) and undesirable (typically leafy greens, fruits, vegetables, and other low-calorie food). In addition, non-food images were shown to verify that the brain activation was driven by the food images. The regions of the brain that became active during inspection of the images were determined.
Liraglutide decreased activation of the parietal cortex in response to the highly desirable food images. Additionally, activation in the insula and putamen was reduced; these regions are involved in the brain’s reward system. Increased perception of hunger and appetite by the participants when they viewed images of desirable foods correlated with increased activation of GLP-1 receptors in the parietal and visual cortices during liraglutide treatment. In participants experiencing nausea, decreased brain activation in the cingulate cortex was apparent. Hypothalamus-related activity was not evident.
“This decreased activation means that individuals on liraglutide find highly desirable foods less attention-grabbing and less rewarding than they typically would without liraglutide,” said Dr. Farr.
The researchers suggested that liraglutide could be suited for weight loss in those who opt for high-fat food as a means of pleasure. Further, the data point to a central mechanism contributing to or underlying effects of liraglutide on metabolism/weight loss.
The Harvard researchers are seeking to confirm the findings in a larger study using the 3-mg dose of liraglutide that has been approved for obesity. In addition, they will explore whether the brain response to liraglutide is a general phenomenon or whether individuals differ.
Dr. Farr had no disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
BOSTON – Two related studies of brain structure and the mechanism of the analog of glucagon-like peptide (GLP) hormone liraglutide indicate that the drug works to decrease reward-related activation of brain sites linked to desire for unhealthy foods in patients with type 2 diabetes.
“Our finding suggests that liraglutide may make people more attentive to what they are eating, particularly high-calories or high-fat foods,” said study co-investigator Olivia Farr, PhD, of Beth Israel Deaconess Hospital and Harvard Medical School, Boston.
Liraglutide, which has been approved for weight management for obese patients and those with type 2 diabetes, is known to promote weight loss, but the mechanism by which this occurs has not been fully understood. The investigators undertook two studies, one to examine human brains to identify GLP-1 receptors and the other to examine the impact liraglutide administration may have on neural responses to food cues in patients with type 2 diabetes.
Immunohistochemical examination of 22 human brain samples identified GLP-1 receptors in the hypothalamus, medulla oblongata, and parietal cortex. GLP-1 receptors have previously only been identified in animals. The findings support the role of the receptors in weight loss in patients on liraglutide.
The researchers then performed a second randomized, placebo-controlled, double-blind, cross-over study involving 18 adult patients with type 2 diabetes. The subjects received, in random order, injections of placebo or liraglutide. Liraglutide was titrated to 0.6 mg at visit 1, 1.2 mg at visit 2, and 1.8 mg at visit 3, which were a week apart, with the highest dose maintained in the 3 days between visits 3 and 4. The total period was 17 days. Visit 4 was an overnight stay followed by functional magnetic resonance imaging (fMRI). Then, after a 3-week washout period, the participants received the other treatment on the same schedule, with another fMRI scan.
During the fMRI, participants viewed images of different foods that had been determined in pre-trial testing to be generally perceived as desirable (typically cakes, pastries, fried food, and fast food) and undesirable (typically leafy greens, fruits, vegetables, and other low-calorie food). In addition, non-food images were shown to verify that the brain activation was driven by the food images. The regions of the brain that became active during inspection of the images were determined.
Liraglutide decreased activation of the parietal cortex in response to the highly desirable food images. Additionally, activation in the insula and putamen was reduced; these regions are involved in the brain’s reward system. Increased perception of hunger and appetite by the participants when they viewed images of desirable foods correlated with increased activation of GLP-1 receptors in the parietal and visual cortices during liraglutide treatment. In participants experiencing nausea, decreased brain activation in the cingulate cortex was apparent. Hypothalamus-related activity was not evident.
“This decreased activation means that individuals on liraglutide find highly desirable foods less attention-grabbing and less rewarding than they typically would without liraglutide,” said Dr. Farr.
The researchers suggested that liraglutide could be suited for weight loss in those who opt for high-fat food as a means of pleasure. Further, the data point to a central mechanism contributing to or underlying effects of liraglutide on metabolism/weight loss.
The Harvard researchers are seeking to confirm the findings in a larger study using the 3-mg dose of liraglutide that has been approved for obesity. In addition, they will explore whether the brain response to liraglutide is a general phenomenon or whether individuals differ.
Dr. Farr had no disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
BOSTON – Two related studies of brain structure and the mechanism of the analog of glucagon-like peptide (GLP) hormone liraglutide indicate that the drug works to decrease reward-related activation of brain sites linked to desire for unhealthy foods in patients with type 2 diabetes.
“Our finding suggests that liraglutide may make people more attentive to what they are eating, particularly high-calories or high-fat foods,” said study co-investigator Olivia Farr, PhD, of Beth Israel Deaconess Hospital and Harvard Medical School, Boston.
Liraglutide, which has been approved for weight management for obese patients and those with type 2 diabetes, is known to promote weight loss, but the mechanism by which this occurs has not been fully understood. The investigators undertook two studies, one to examine human brains to identify GLP-1 receptors and the other to examine the impact liraglutide administration may have on neural responses to food cues in patients with type 2 diabetes.
Immunohistochemical examination of 22 human brain samples identified GLP-1 receptors in the hypothalamus, medulla oblongata, and parietal cortex. GLP-1 receptors have previously only been identified in animals. The findings support the role of the receptors in weight loss in patients on liraglutide.
The researchers then performed a second randomized, placebo-controlled, double-blind, cross-over study involving 18 adult patients with type 2 diabetes. The subjects received, in random order, injections of placebo or liraglutide. Liraglutide was titrated to 0.6 mg at visit 1, 1.2 mg at visit 2, and 1.8 mg at visit 3, which were a week apart, with the highest dose maintained in the 3 days between visits 3 and 4. The total period was 17 days. Visit 4 was an overnight stay followed by functional magnetic resonance imaging (fMRI). Then, after a 3-week washout period, the participants received the other treatment on the same schedule, with another fMRI scan.
During the fMRI, participants viewed images of different foods that had been determined in pre-trial testing to be generally perceived as desirable (typically cakes, pastries, fried food, and fast food) and undesirable (typically leafy greens, fruits, vegetables, and other low-calorie food). In addition, non-food images were shown to verify that the brain activation was driven by the food images. The regions of the brain that became active during inspection of the images were determined.
Liraglutide decreased activation of the parietal cortex in response to the highly desirable food images. Additionally, activation in the insula and putamen was reduced; these regions are involved in the brain’s reward system. Increased perception of hunger and appetite by the participants when they viewed images of desirable foods correlated with increased activation of GLP-1 receptors in the parietal and visual cortices during liraglutide treatment. In participants experiencing nausea, decreased brain activation in the cingulate cortex was apparent. Hypothalamus-related activity was not evident.
“This decreased activation means that individuals on liraglutide find highly desirable foods less attention-grabbing and less rewarding than they typically would without liraglutide,” said Dr. Farr.
The researchers suggested that liraglutide could be suited for weight loss in those who opt for high-fat food as a means of pleasure. Further, the data point to a central mechanism contributing to or underlying effects of liraglutide on metabolism/weight loss.
The Harvard researchers are seeking to confirm the findings in a larger study using the 3-mg dose of liraglutide that has been approved for obesity. In addition, they will explore whether the brain response to liraglutide is a general phenomenon or whether individuals differ.
Dr. Farr had no disclosures.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Bionic glucagon delivery improved hypoglycemia control in T1D patients
BOSTON – A wearable, closed-loop bionic pancreas system that automatically delivers glucagon has been found to improve hypoglycemia control in patients with type 1 diabetes.
A double-blind, randomized, placebo-controlled, cross-over study (NCT02181127) has demonstrated the value of automated injection of glucagon in establishing glycemic regulation in adult patients with type 1 diabetes. “Automated glucagon delivery reduces hypoglycemia and increases time in range without an increase in mean glucose, with no difference in insulin dose,” said Dr. Laya Ekhlaspour of Massachusetts General Hospital, Boston.
Glycemic regulation can be problematic in young adults with type 1 diabetes, whose blood glucose levels can fall below 70 mg/dL for over 2 hours daily, even with glycemic control using conventional insulin pump therapy. The typical response to hypoglycemia – supplying glucose in a quickly digested form – is a short-term solution and is not effective during sleep.
Dr. Ekhlaspour and her colleagues surmised that a closed-loop system comprising a wearable bionic pancreas system that automatically delivers glucagon could reduce the incidence and severity of hypoglycemia when used along with the conventional insulin therapies of multiple daily injection (MDI) or continuous subcutaneous insulin infusion (CSII).
Of 31 subjects screened, 27 were eligible in terms of the frequency of hypoglycemia, but 5 were excluded because of scheduling problems, leaving 22 patients. The participants, adults with type 1 diabetes, had blood glucose levels below 60 mg/dL on average at least twice a week, and some periods with blood glucose below 50 mg/dL.
In addition to self-administered insulin (CSII or MDI), the subjects also received glucagon or placebo for 24 hours at a time using the automated wearable bionic pancreas system. In the 2-week study, the subjects (mean age 42 years; mean duration of diabetes 25 years) were randomized to receive glucagon or placebo for a total of 7 days each. The subjects were not told which preparation they were receiving.
The primary outcome of area over the curve (AOC) under 60 mg/dL was reduced by 75% on days when glucagon was supplied (851 mg/dL/min), compared with days when placebo was supplied (3,414 mg/dL/min), a significant difference. The difference in AOC was even more pronounced at night (117 vs. 1,309 mg/dL/min).
The percentage of subjects with blood glucose of 70 -180 mg/dL was significantly greater on days when glucagon was administered than when placebo was given (69% versus 62%). Subjects spent 74% less time with blood glucose under 60 mg/dL on days when glucagon was supplied, compared with placebo (1.2% versus 4.7%).
Symptomatic hypoglycemia episodes were significantly fewer for glucagon, compared with placebo (0.6 versus 1.2). The need for oral carbohydrates was reduced when glucagon was provided (1.3 versus 1.9 interventions per day). Nausea severity rankings for glucagon and placebo on the visual analog scale were similar.
Dr. Ekhlaspour had no disclosures.
BOSTON – A wearable, closed-loop bionic pancreas system that automatically delivers glucagon has been found to improve hypoglycemia control in patients with type 1 diabetes.
A double-blind, randomized, placebo-controlled, cross-over study (NCT02181127) has demonstrated the value of automated injection of glucagon in establishing glycemic regulation in adult patients with type 1 diabetes. “Automated glucagon delivery reduces hypoglycemia and increases time in range without an increase in mean glucose, with no difference in insulin dose,” said Dr. Laya Ekhlaspour of Massachusetts General Hospital, Boston.
Glycemic regulation can be problematic in young adults with type 1 diabetes, whose blood glucose levels can fall below 70 mg/dL for over 2 hours daily, even with glycemic control using conventional insulin pump therapy. The typical response to hypoglycemia – supplying glucose in a quickly digested form – is a short-term solution and is not effective during sleep.
Dr. Ekhlaspour and her colleagues surmised that a closed-loop system comprising a wearable bionic pancreas system that automatically delivers glucagon could reduce the incidence and severity of hypoglycemia when used along with the conventional insulin therapies of multiple daily injection (MDI) or continuous subcutaneous insulin infusion (CSII).
Of 31 subjects screened, 27 were eligible in terms of the frequency of hypoglycemia, but 5 were excluded because of scheduling problems, leaving 22 patients. The participants, adults with type 1 diabetes, had blood glucose levels below 60 mg/dL on average at least twice a week, and some periods with blood glucose below 50 mg/dL.
In addition to self-administered insulin (CSII or MDI), the subjects also received glucagon or placebo for 24 hours at a time using the automated wearable bionic pancreas system. In the 2-week study, the subjects (mean age 42 years; mean duration of diabetes 25 years) were randomized to receive glucagon or placebo for a total of 7 days each. The subjects were not told which preparation they were receiving.
The primary outcome of area over the curve (AOC) under 60 mg/dL was reduced by 75% on days when glucagon was supplied (851 mg/dL/min), compared with days when placebo was supplied (3,414 mg/dL/min), a significant difference. The difference in AOC was even more pronounced at night (117 vs. 1,309 mg/dL/min).
The percentage of subjects with blood glucose of 70 -180 mg/dL was significantly greater on days when glucagon was administered than when placebo was given (69% versus 62%). Subjects spent 74% less time with blood glucose under 60 mg/dL on days when glucagon was supplied, compared with placebo (1.2% versus 4.7%).
Symptomatic hypoglycemia episodes were significantly fewer for glucagon, compared with placebo (0.6 versus 1.2). The need for oral carbohydrates was reduced when glucagon was provided (1.3 versus 1.9 interventions per day). Nausea severity rankings for glucagon and placebo on the visual analog scale were similar.
Dr. Ekhlaspour had no disclosures.
BOSTON – A wearable, closed-loop bionic pancreas system that automatically delivers glucagon has been found to improve hypoglycemia control in patients with type 1 diabetes.
A double-blind, randomized, placebo-controlled, cross-over study (NCT02181127) has demonstrated the value of automated injection of glucagon in establishing glycemic regulation in adult patients with type 1 diabetes. “Automated glucagon delivery reduces hypoglycemia and increases time in range without an increase in mean glucose, with no difference in insulin dose,” said Dr. Laya Ekhlaspour of Massachusetts General Hospital, Boston.
Glycemic regulation can be problematic in young adults with type 1 diabetes, whose blood glucose levels can fall below 70 mg/dL for over 2 hours daily, even with glycemic control using conventional insulin pump therapy. The typical response to hypoglycemia – supplying glucose in a quickly digested form – is a short-term solution and is not effective during sleep.
Dr. Ekhlaspour and her colleagues surmised that a closed-loop system comprising a wearable bionic pancreas system that automatically delivers glucagon could reduce the incidence and severity of hypoglycemia when used along with the conventional insulin therapies of multiple daily injection (MDI) or continuous subcutaneous insulin infusion (CSII).
Of 31 subjects screened, 27 were eligible in terms of the frequency of hypoglycemia, but 5 were excluded because of scheduling problems, leaving 22 patients. The participants, adults with type 1 diabetes, had blood glucose levels below 60 mg/dL on average at least twice a week, and some periods with blood glucose below 50 mg/dL.
In addition to self-administered insulin (CSII or MDI), the subjects also received glucagon or placebo for 24 hours at a time using the automated wearable bionic pancreas system. In the 2-week study, the subjects (mean age 42 years; mean duration of diabetes 25 years) were randomized to receive glucagon or placebo for a total of 7 days each. The subjects were not told which preparation they were receiving.
The primary outcome of area over the curve (AOC) under 60 mg/dL was reduced by 75% on days when glucagon was supplied (851 mg/dL/min), compared with days when placebo was supplied (3,414 mg/dL/min), a significant difference. The difference in AOC was even more pronounced at night (117 vs. 1,309 mg/dL/min).
The percentage of subjects with blood glucose of 70 -180 mg/dL was significantly greater on days when glucagon was administered than when placebo was given (69% versus 62%). Subjects spent 74% less time with blood glucose under 60 mg/dL on days when glucagon was supplied, compared with placebo (1.2% versus 4.7%).
Symptomatic hypoglycemia episodes were significantly fewer for glucagon, compared with placebo (0.6 versus 1.2). The need for oral carbohydrates was reduced when glucagon was provided (1.3 versus 1.9 interventions per day). Nausea severity rankings for glucagon and placebo on the visual analog scale were similar.
Dr. Ekhlaspour had no disclosures.
Faster aspart speeds onset of activity in Type 1 diabetes
BOSTON – A new formulation of faster-acting insulin aspart (faster aspart) provided more rapid and extensive glucose-lowering activity than did standard insulin aspart, based on results of a randomized, double-blind, crossover study presented at the annual meeting of the Endocrine Society.
Subcutaneous injections of faster aspart of 0.1 (low dose), 0.2 (moderate dose), and 0.4 (high dose) U/kg were associated with an onset of activity that was twice as fast as that of standard insulin aspart and with insulin exposure that was two-fold higher in the first 30 minutes, said Dr. Tim Heise, CEO of finance and administration for Profil Institute for Metabolic Research, Neuss, Germany.
“Faster aspart was well tolerated, and no safety issues were identified. No injection site infections were observed, and no serious adverse events were reported,” said Dr. Heise.
Faster aspart consists of insulin aspart along with niacinamide as an absorption modifier and L-arginine as a stabilizer. The aim of a faster-acting mealtime insulin is to mimic more closely the physiologic mealtime insulin response of the healthy pancreas.
What has not been clear is whether the benefits of faster aspart are concentration-dependent and whether the effective concentrations are clinically relevant.
The pharmacokinetic and pharmacodynamic properties of faster aspart were tested at three clinically relevant doses in 46 adults, aged 18 to 64 years, with type 1 diabetes. Study participants had been treated for a year or more with multiple daily injections of insulin or continuous subcutaneous insulin injection; their total insulin dose was less than 1.2 U/kg/day with less than 0.7 U/kg/day as a bolus dose. Body mass index ranged from about 19 to 28 kg/m2. Of the subjects, 76% were men, all were white, and they had diabetes for about 21 years.
At all three doses, onset of activity was about twice as rapid with faster aspart as with standard insulin aspart; 50% of the maximum exposure to the dose was achieved in 8 to 12 minutes with faster aspart. This rapid appearance of activity was especially evident within 30 minutes of injection, with the kinetics becoming more similar to those of standard insulin aspart from 30 to 60 minutes.
Blood glucose was lowered by 0.3 mmol/L from baseline at a rate up to 26% faster with faster aspart. Similar to the exposure data, glucose reduction was especially evident in the first 30 minutes following injection of faster aspart, with the decline in glucose levels being about twice as great compared to insulin aspart.
Further information from a phase 3 study evaluating faster aspart will be reported at the American Diabetes Association meeting to be held this summer, according to Dr. Heise.
BOSTON – A new formulation of faster-acting insulin aspart (faster aspart) provided more rapid and extensive glucose-lowering activity than did standard insulin aspart, based on results of a randomized, double-blind, crossover study presented at the annual meeting of the Endocrine Society.
Subcutaneous injections of faster aspart of 0.1 (low dose), 0.2 (moderate dose), and 0.4 (high dose) U/kg were associated with an onset of activity that was twice as fast as that of standard insulin aspart and with insulin exposure that was two-fold higher in the first 30 minutes, said Dr. Tim Heise, CEO of finance and administration for Profil Institute for Metabolic Research, Neuss, Germany.
“Faster aspart was well tolerated, and no safety issues were identified. No injection site infections were observed, and no serious adverse events were reported,” said Dr. Heise.
Faster aspart consists of insulin aspart along with niacinamide as an absorption modifier and L-arginine as a stabilizer. The aim of a faster-acting mealtime insulin is to mimic more closely the physiologic mealtime insulin response of the healthy pancreas.
What has not been clear is whether the benefits of faster aspart are concentration-dependent and whether the effective concentrations are clinically relevant.
The pharmacokinetic and pharmacodynamic properties of faster aspart were tested at three clinically relevant doses in 46 adults, aged 18 to 64 years, with type 1 diabetes. Study participants had been treated for a year or more with multiple daily injections of insulin or continuous subcutaneous insulin injection; their total insulin dose was less than 1.2 U/kg/day with less than 0.7 U/kg/day as a bolus dose. Body mass index ranged from about 19 to 28 kg/m2. Of the subjects, 76% were men, all were white, and they had diabetes for about 21 years.
At all three doses, onset of activity was about twice as rapid with faster aspart as with standard insulin aspart; 50% of the maximum exposure to the dose was achieved in 8 to 12 minutes with faster aspart. This rapid appearance of activity was especially evident within 30 minutes of injection, with the kinetics becoming more similar to those of standard insulin aspart from 30 to 60 minutes.
Blood glucose was lowered by 0.3 mmol/L from baseline at a rate up to 26% faster with faster aspart. Similar to the exposure data, glucose reduction was especially evident in the first 30 minutes following injection of faster aspart, with the decline in glucose levels being about twice as great compared to insulin aspart.
Further information from a phase 3 study evaluating faster aspart will be reported at the American Diabetes Association meeting to be held this summer, according to Dr. Heise.
BOSTON – A new formulation of faster-acting insulin aspart (faster aspart) provided more rapid and extensive glucose-lowering activity than did standard insulin aspart, based on results of a randomized, double-blind, crossover study presented at the annual meeting of the Endocrine Society.
Subcutaneous injections of faster aspart of 0.1 (low dose), 0.2 (moderate dose), and 0.4 (high dose) U/kg were associated with an onset of activity that was twice as fast as that of standard insulin aspart and with insulin exposure that was two-fold higher in the first 30 minutes, said Dr. Tim Heise, CEO of finance and administration for Profil Institute for Metabolic Research, Neuss, Germany.
“Faster aspart was well tolerated, and no safety issues were identified. No injection site infections were observed, and no serious adverse events were reported,” said Dr. Heise.
Faster aspart consists of insulin aspart along with niacinamide as an absorption modifier and L-arginine as a stabilizer. The aim of a faster-acting mealtime insulin is to mimic more closely the physiologic mealtime insulin response of the healthy pancreas.
What has not been clear is whether the benefits of faster aspart are concentration-dependent and whether the effective concentrations are clinically relevant.
The pharmacokinetic and pharmacodynamic properties of faster aspart were tested at three clinically relevant doses in 46 adults, aged 18 to 64 years, with type 1 diabetes. Study participants had been treated for a year or more with multiple daily injections of insulin or continuous subcutaneous insulin injection; their total insulin dose was less than 1.2 U/kg/day with less than 0.7 U/kg/day as a bolus dose. Body mass index ranged from about 19 to 28 kg/m2. Of the subjects, 76% were men, all were white, and they had diabetes for about 21 years.
At all three doses, onset of activity was about twice as rapid with faster aspart as with standard insulin aspart; 50% of the maximum exposure to the dose was achieved in 8 to 12 minutes with faster aspart. This rapid appearance of activity was especially evident within 30 minutes of injection, with the kinetics becoming more similar to those of standard insulin aspart from 30 to 60 minutes.
Blood glucose was lowered by 0.3 mmol/L from baseline at a rate up to 26% faster with faster aspart. Similar to the exposure data, glucose reduction was especially evident in the first 30 minutes following injection of faster aspart, with the decline in glucose levels being about twice as great compared to insulin aspart.
Further information from a phase 3 study evaluating faster aspart will be reported at the American Diabetes Association meeting to be held this summer, according to Dr. Heise.
Key clinical point: As a faster-acting mealtime insulin, faster aspart may mimic more closely the physiologic mealtime insulin response of the healthy pancreas.
Major finding: At all three doses, onset of activity was about twice as rapid with faster aspart as with standard insulin aspart; 50% of the maximum exposure to the dose was achieved in 8 to 12 minutes with faster aspart.
Data source: Double-blind, randomized, cross-over study of responses to subcutaneous injections of faster aspart of 0.1 (low dose), 0.2 (moderate dose), and 0.4 (high dose) U/kg in 46 study participants with type 1 diabetes.
Disclosures: The study was funded by Novo Nordisk, the developer of faster-acting insulin aspart. Dr. Heine disclosed a variety of research support from drug companies, including funding from Novo Nordisk.
Stem cell therapy for MS: Steady progress but not ready for general use
NEW ORLEANS – Stem cell-mediated functional regeneration continues to attract interest in the treatment of multiple sclerosis (MS). The reality, however, is daunting.
“Several types of cell-based therapeutic strategies are under investigation, with different risks, benefits, and goals. Some of these strategies show promise but significant methodological questions need to be answered,” Dr. Andrew D. Goodman said at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
The present reality is that stem cell transplantation is not yet ready for general use to treat MS. Yet, the possible benefits of the approach demand further exploration, including clinical trials, according to Dr. Goodman, professor of neurology, chief of the neuroimmunology unit, and director of the multiple sclerosis center at the University of Rochester (N.Y.).
MS stem cell therapy hinges on the pluripotent nature of stem cells, particularly mesenchymal stem cells (MSCs) and hematopoietic stem cells. MS therapy would involve regeneration of nerve cell myelin in the brain and/or spinal cord and possibly suppression of inflammation.
Autologous HSC transplantation
Immunoablation followed by the autologous HSC transplantation (HSCT) has been explored in the ASTIMS phase II randomized trials (Neurology. Mar 10;84[10]:981-8 and HALT-MS, JAMA Neurol. 2015 Feb;72[2]:159-69), and in a Northwestern University case series (JAMA. 2015 Jan 20;313[3]:275-84).
ASTIMS compared high-dose chemotherapy followed by autologous HSCT with mitoxantrone (which is no longer used). Only 22% percent of patients had relapsing-remitting MS (RRMS; the one where HSCT generally works) and 78% had primary progressive MS (where HSCT generally does not work well or is not optimal). Yet, HSCT worked, with new T2 lesions reduced by 79%. No difference in disability progression was evident. Interim (3-year) results of HALT-MS were encouraging, with sustained remission of active RRMS and improved neurologic function. The Northwestern case series also documented improvements in neurologic disability and other clinical outcomes.
“The available data suggest that immunoablation and HSCT is highly effective in active RRMS. Patients most likely to benefit are young and still ambulatory with a relatively recent disease onset featuring highly active MS with MRI lesion activity and continued activity despite first- and second-line agents,” Dr. Goodman said.
While encouraging, the small patient numbers of the two trials and uncontrolled nature of the case series prevent conclusions concerning the therapeutic use of autologous HSCT in RRMS. Furthermore, risks of the approach include MS relapse, treatment-related adverse effects, adverse effects due to myelosuppression and immunoablation, and secondary autoimmune disorders that may arise at a later time.
Mesenchymal stem cell transplantation
MSCs offer the advantages of a variety of sources in adult tissue, established methods of culture, and either local or peripheral administration. Their finite capacity for proliferation is a drawback. Studies to date of MSC transplantation in MS have involved about 100 patients, so it is much too early to consider MSC use. Even if therapy is contemplated, whether it should be directed at quelling inflammation or to promote repair is undecided. As well, cell production and delivery issues need to be addressed, Dr. Goodman said.
Human oligodendrocyte progenitor cell transplantation
The implantation of CD 140a+ cell populations containing human oligodendrocyte progenitor cells (hOPCs) into the cerebral hemispheres of patients with non-relapsing secondary progressive MS as a means of stabilizing or improving neurological function is being planned. The NYSTEM project, with Dr. Goodman as a lead investigator, will first seek to identify the maximum tolerated dose of hOPCs.
The study is planned with the knowledge of safety issues that include cancer tumorigenesis. Yet exploration of the possible benefits will be evident only by testing in humans. “I don’t know of any way to find out except by trying,” Dr. Goodman said.
Dr. Goodman disclosed receiving research support and/or serving as a consultant to Avanir, Teva, Genzyme/Sanofi, Sun Pharma, Ono, Roche, AbbVie, Biogen, Novartis, Acorda, Purdue, and EMD Serono.
NEW ORLEANS – Stem cell-mediated functional regeneration continues to attract interest in the treatment of multiple sclerosis (MS). The reality, however, is daunting.
“Several types of cell-based therapeutic strategies are under investigation, with different risks, benefits, and goals. Some of these strategies show promise but significant methodological questions need to be answered,” Dr. Andrew D. Goodman said at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
The present reality is that stem cell transplantation is not yet ready for general use to treat MS. Yet, the possible benefits of the approach demand further exploration, including clinical trials, according to Dr. Goodman, professor of neurology, chief of the neuroimmunology unit, and director of the multiple sclerosis center at the University of Rochester (N.Y.).
MS stem cell therapy hinges on the pluripotent nature of stem cells, particularly mesenchymal stem cells (MSCs) and hematopoietic stem cells. MS therapy would involve regeneration of nerve cell myelin in the brain and/or spinal cord and possibly suppression of inflammation.
Autologous HSC transplantation
Immunoablation followed by the autologous HSC transplantation (HSCT) has been explored in the ASTIMS phase II randomized trials (Neurology. Mar 10;84[10]:981-8 and HALT-MS, JAMA Neurol. 2015 Feb;72[2]:159-69), and in a Northwestern University case series (JAMA. 2015 Jan 20;313[3]:275-84).
ASTIMS compared high-dose chemotherapy followed by autologous HSCT with mitoxantrone (which is no longer used). Only 22% percent of patients had relapsing-remitting MS (RRMS; the one where HSCT generally works) and 78% had primary progressive MS (where HSCT generally does not work well or is not optimal). Yet, HSCT worked, with new T2 lesions reduced by 79%. No difference in disability progression was evident. Interim (3-year) results of HALT-MS were encouraging, with sustained remission of active RRMS and improved neurologic function. The Northwestern case series also documented improvements in neurologic disability and other clinical outcomes.
“The available data suggest that immunoablation and HSCT is highly effective in active RRMS. Patients most likely to benefit are young and still ambulatory with a relatively recent disease onset featuring highly active MS with MRI lesion activity and continued activity despite first- and second-line agents,” Dr. Goodman said.
While encouraging, the small patient numbers of the two trials and uncontrolled nature of the case series prevent conclusions concerning the therapeutic use of autologous HSCT in RRMS. Furthermore, risks of the approach include MS relapse, treatment-related adverse effects, adverse effects due to myelosuppression and immunoablation, and secondary autoimmune disorders that may arise at a later time.
Mesenchymal stem cell transplantation
MSCs offer the advantages of a variety of sources in adult tissue, established methods of culture, and either local or peripheral administration. Their finite capacity for proliferation is a drawback. Studies to date of MSC transplantation in MS have involved about 100 patients, so it is much too early to consider MSC use. Even if therapy is contemplated, whether it should be directed at quelling inflammation or to promote repair is undecided. As well, cell production and delivery issues need to be addressed, Dr. Goodman said.
Human oligodendrocyte progenitor cell transplantation
The implantation of CD 140a+ cell populations containing human oligodendrocyte progenitor cells (hOPCs) into the cerebral hemispheres of patients with non-relapsing secondary progressive MS as a means of stabilizing or improving neurological function is being planned. The NYSTEM project, with Dr. Goodman as a lead investigator, will first seek to identify the maximum tolerated dose of hOPCs.
The study is planned with the knowledge of safety issues that include cancer tumorigenesis. Yet exploration of the possible benefits will be evident only by testing in humans. “I don’t know of any way to find out except by trying,” Dr. Goodman said.
Dr. Goodman disclosed receiving research support and/or serving as a consultant to Avanir, Teva, Genzyme/Sanofi, Sun Pharma, Ono, Roche, AbbVie, Biogen, Novartis, Acorda, Purdue, and EMD Serono.
NEW ORLEANS – Stem cell-mediated functional regeneration continues to attract interest in the treatment of multiple sclerosis (MS). The reality, however, is daunting.
“Several types of cell-based therapeutic strategies are under investigation, with different risks, benefits, and goals. Some of these strategies show promise but significant methodological questions need to be answered,” Dr. Andrew D. Goodman said at a meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
The present reality is that stem cell transplantation is not yet ready for general use to treat MS. Yet, the possible benefits of the approach demand further exploration, including clinical trials, according to Dr. Goodman, professor of neurology, chief of the neuroimmunology unit, and director of the multiple sclerosis center at the University of Rochester (N.Y.).
MS stem cell therapy hinges on the pluripotent nature of stem cells, particularly mesenchymal stem cells (MSCs) and hematopoietic stem cells. MS therapy would involve regeneration of nerve cell myelin in the brain and/or spinal cord and possibly suppression of inflammation.
Autologous HSC transplantation
Immunoablation followed by the autologous HSC transplantation (HSCT) has been explored in the ASTIMS phase II randomized trials (Neurology. Mar 10;84[10]:981-8 and HALT-MS, JAMA Neurol. 2015 Feb;72[2]:159-69), and in a Northwestern University case series (JAMA. 2015 Jan 20;313[3]:275-84).
ASTIMS compared high-dose chemotherapy followed by autologous HSCT with mitoxantrone (which is no longer used). Only 22% percent of patients had relapsing-remitting MS (RRMS; the one where HSCT generally works) and 78% had primary progressive MS (where HSCT generally does not work well or is not optimal). Yet, HSCT worked, with new T2 lesions reduced by 79%. No difference in disability progression was evident. Interim (3-year) results of HALT-MS were encouraging, with sustained remission of active RRMS and improved neurologic function. The Northwestern case series also documented improvements in neurologic disability and other clinical outcomes.
“The available data suggest that immunoablation and HSCT is highly effective in active RRMS. Patients most likely to benefit are young and still ambulatory with a relatively recent disease onset featuring highly active MS with MRI lesion activity and continued activity despite first- and second-line agents,” Dr. Goodman said.
While encouraging, the small patient numbers of the two trials and uncontrolled nature of the case series prevent conclusions concerning the therapeutic use of autologous HSCT in RRMS. Furthermore, risks of the approach include MS relapse, treatment-related adverse effects, adverse effects due to myelosuppression and immunoablation, and secondary autoimmune disorders that may arise at a later time.
Mesenchymal stem cell transplantation
MSCs offer the advantages of a variety of sources in adult tissue, established methods of culture, and either local or peripheral administration. Their finite capacity for proliferation is a drawback. Studies to date of MSC transplantation in MS have involved about 100 patients, so it is much too early to consider MSC use. Even if therapy is contemplated, whether it should be directed at quelling inflammation or to promote repair is undecided. As well, cell production and delivery issues need to be addressed, Dr. Goodman said.
Human oligodendrocyte progenitor cell transplantation
The implantation of CD 140a+ cell populations containing human oligodendrocyte progenitor cells (hOPCs) into the cerebral hemispheres of patients with non-relapsing secondary progressive MS as a means of stabilizing or improving neurological function is being planned. The NYSTEM project, with Dr. Goodman as a lead investigator, will first seek to identify the maximum tolerated dose of hOPCs.
The study is planned with the knowledge of safety issues that include cancer tumorigenesis. Yet exploration of the possible benefits will be evident only by testing in humans. “I don’t know of any way to find out except by trying,” Dr. Goodman said.
Dr. Goodman disclosed receiving research support and/or serving as a consultant to Avanir, Teva, Genzyme/Sanofi, Sun Pharma, Ono, Roche, AbbVie, Biogen, Novartis, Acorda, Purdue, and EMD Serono.
EXPERT ANALYSIS FROM ACTRIMS FORUM 2016
Brain atrophy may be a clinically relevant measure in PPMS: Data from INFORMS
NEW ORLEANS – The recently published results of the INFORMS multicenter, double-blind, placebo-controlled parallel-group study (NCT00731692) that compared the efficacy of fingolimod in slowing disease progression in primary progressive multiple sclerosis (PPMS) with placebo proved disappointing. However, further scrutiny of the data has provided valuable insights, such as supportive evidence for brain atrophy as a clinically relevant measure in PPMS patients.
“The degree of clinical worsening was directly associated with patient’s extent of brain volume loss. Patients in the extreme category of disability progression had more brain volume loss than patients with only one progression or those who remained clinically stable,” wrote Dr. Jerry Wolinsky of the University of Texas Health Science Center at Houston and his colleagues in a poster presented Feb. 19 at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
In INFORMS, 970 patients with PPMS were randomly allocated (1:1) to receive oral fingolimod 0.5 mg or placebo for at least 36 months and for up to 5 years. The anti-inflammatory effects of fingolimod did not slow disease progression in PPMS.
While INFORMS did not pan out in terms of the primary endpoint, the long duration of the study, use of various progression measures, and rigorous patient selection offered the unique opportunity to assess the associations of magnetic resonance imaging of the brain over at least 3 years of the clinical progression occurring in patients with PPMS.
All patients had being clinically diagnosed with PPMS, with disease duration of 2-10 years and objective evidence of progression in disability in the prior 2 years. The composite endpoint of INFORMS based on the change in Expanded Disability Status Scale (EDSS), 25-Foot Timed Walk Test, or 9-Hole Peg Test was used to gauge 3-month confirmed disease progression (3CDP). The patients were classified according to EDSS-determined disease progression as extreme (more than one occurrence of 3CDP; n = 162), moderate (one occurrence of 3CDP; n = 309), and stable (no 3CDP; n = 499).
Mean age, % male, and baseline EDSS scores were similar across the three categories (whole population: 48.4 ± 8.4 years; 51.6%; and 4.7 ± 1.0, respectively). Mean number of gadolinium-positive lesions in the extreme and stable category was 0.39 ± 1.1 and 0.25 ± 1.0, respectively. Baseline T2 lesion volume was 10,160.8 ± 12,743.3 mm3 in extreme patients and 9,585.8 ± 12,421.6 mm3 in stable patients.
Patients in the extreme category displayed greater changes in the three endpoint measures than did the moderate and stable categories. At month 36, the mean change in brain volume, compared with baseline, was –1.76 ± 1.4 in the extreme group and –1.26 ± 0.9 in stable group. Corresponding values for mean number of gadolinium-positive lesions were 0.40 ± 1.4 and 0.10 ± 0.5. Corresponding numbers of new/newly enlarging T2 lesions from baseline to month 36 were 1.7 ± 4.6 and 0.9 ± 2.9.
Patients in the extreme category exceeded the recently proposed cut-off for pathologically increased brain volume loss by about 60%, compared with only about 14% for patients in the stable category.
The higher change in brain volume from baseline in patients who progressed to extreme disability “supports brain atrophy as a clinically relevant measure of neuroprotection in PPMS trials,” wrote Dr. Wolinsky and his colleagues.
The study was funded by Novartis Pharma AG. Dr. Wolinsky disclosed consulting fees from Genzyme/Sanofi, Hoffmann-La Roche/Genentech, Forward Pharma, Alkermes, AbbVie, Novartis Pharmaceuticals, Teva, and XenoPort and advisory board participation for Hoffman-La Roche/Genentech, Forward Pharma, EMD Serono, Actelion, Novartis Pharmaceuticals, Teva, and Xenoport. He performed contract research for Genzyme/Sanofi.
NEW ORLEANS – The recently published results of the INFORMS multicenter, double-blind, placebo-controlled parallel-group study (NCT00731692) that compared the efficacy of fingolimod in slowing disease progression in primary progressive multiple sclerosis (PPMS) with placebo proved disappointing. However, further scrutiny of the data has provided valuable insights, such as supportive evidence for brain atrophy as a clinically relevant measure in PPMS patients.
“The degree of clinical worsening was directly associated with patient’s extent of brain volume loss. Patients in the extreme category of disability progression had more brain volume loss than patients with only one progression or those who remained clinically stable,” wrote Dr. Jerry Wolinsky of the University of Texas Health Science Center at Houston and his colleagues in a poster presented Feb. 19 at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
In INFORMS, 970 patients with PPMS were randomly allocated (1:1) to receive oral fingolimod 0.5 mg or placebo for at least 36 months and for up to 5 years. The anti-inflammatory effects of fingolimod did not slow disease progression in PPMS.
While INFORMS did not pan out in terms of the primary endpoint, the long duration of the study, use of various progression measures, and rigorous patient selection offered the unique opportunity to assess the associations of magnetic resonance imaging of the brain over at least 3 years of the clinical progression occurring in patients with PPMS.
All patients had being clinically diagnosed with PPMS, with disease duration of 2-10 years and objective evidence of progression in disability in the prior 2 years. The composite endpoint of INFORMS based on the change in Expanded Disability Status Scale (EDSS), 25-Foot Timed Walk Test, or 9-Hole Peg Test was used to gauge 3-month confirmed disease progression (3CDP). The patients were classified according to EDSS-determined disease progression as extreme (more than one occurrence of 3CDP; n = 162), moderate (one occurrence of 3CDP; n = 309), and stable (no 3CDP; n = 499).
Mean age, % male, and baseline EDSS scores were similar across the three categories (whole population: 48.4 ± 8.4 years; 51.6%; and 4.7 ± 1.0, respectively). Mean number of gadolinium-positive lesions in the extreme and stable category was 0.39 ± 1.1 and 0.25 ± 1.0, respectively. Baseline T2 lesion volume was 10,160.8 ± 12,743.3 mm3 in extreme patients and 9,585.8 ± 12,421.6 mm3 in stable patients.
Patients in the extreme category displayed greater changes in the three endpoint measures than did the moderate and stable categories. At month 36, the mean change in brain volume, compared with baseline, was –1.76 ± 1.4 in the extreme group and –1.26 ± 0.9 in stable group. Corresponding values for mean number of gadolinium-positive lesions were 0.40 ± 1.4 and 0.10 ± 0.5. Corresponding numbers of new/newly enlarging T2 lesions from baseline to month 36 were 1.7 ± 4.6 and 0.9 ± 2.9.
Patients in the extreme category exceeded the recently proposed cut-off for pathologically increased brain volume loss by about 60%, compared with only about 14% for patients in the stable category.
The higher change in brain volume from baseline in patients who progressed to extreme disability “supports brain atrophy as a clinically relevant measure of neuroprotection in PPMS trials,” wrote Dr. Wolinsky and his colleagues.
The study was funded by Novartis Pharma AG. Dr. Wolinsky disclosed consulting fees from Genzyme/Sanofi, Hoffmann-La Roche/Genentech, Forward Pharma, Alkermes, AbbVie, Novartis Pharmaceuticals, Teva, and XenoPort and advisory board participation for Hoffman-La Roche/Genentech, Forward Pharma, EMD Serono, Actelion, Novartis Pharmaceuticals, Teva, and Xenoport. He performed contract research for Genzyme/Sanofi.
NEW ORLEANS – The recently published results of the INFORMS multicenter, double-blind, placebo-controlled parallel-group study (NCT00731692) that compared the efficacy of fingolimod in slowing disease progression in primary progressive multiple sclerosis (PPMS) with placebo proved disappointing. However, further scrutiny of the data has provided valuable insights, such as supportive evidence for brain atrophy as a clinically relevant measure in PPMS patients.
“The degree of clinical worsening was directly associated with patient’s extent of brain volume loss. Patients in the extreme category of disability progression had more brain volume loss than patients with only one progression or those who remained clinically stable,” wrote Dr. Jerry Wolinsky of the University of Texas Health Science Center at Houston and his colleagues in a poster presented Feb. 19 at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
In INFORMS, 970 patients with PPMS were randomly allocated (1:1) to receive oral fingolimod 0.5 mg or placebo for at least 36 months and for up to 5 years. The anti-inflammatory effects of fingolimod did not slow disease progression in PPMS.
While INFORMS did not pan out in terms of the primary endpoint, the long duration of the study, use of various progression measures, and rigorous patient selection offered the unique opportunity to assess the associations of magnetic resonance imaging of the brain over at least 3 years of the clinical progression occurring in patients with PPMS.
All patients had being clinically diagnosed with PPMS, with disease duration of 2-10 years and objective evidence of progression in disability in the prior 2 years. The composite endpoint of INFORMS based on the change in Expanded Disability Status Scale (EDSS), 25-Foot Timed Walk Test, or 9-Hole Peg Test was used to gauge 3-month confirmed disease progression (3CDP). The patients were classified according to EDSS-determined disease progression as extreme (more than one occurrence of 3CDP; n = 162), moderate (one occurrence of 3CDP; n = 309), and stable (no 3CDP; n = 499).
Mean age, % male, and baseline EDSS scores were similar across the three categories (whole population: 48.4 ± 8.4 years; 51.6%; and 4.7 ± 1.0, respectively). Mean number of gadolinium-positive lesions in the extreme and stable category was 0.39 ± 1.1 and 0.25 ± 1.0, respectively. Baseline T2 lesion volume was 10,160.8 ± 12,743.3 mm3 in extreme patients and 9,585.8 ± 12,421.6 mm3 in stable patients.
Patients in the extreme category displayed greater changes in the three endpoint measures than did the moderate and stable categories. At month 36, the mean change in brain volume, compared with baseline, was –1.76 ± 1.4 in the extreme group and –1.26 ± 0.9 in stable group. Corresponding values for mean number of gadolinium-positive lesions were 0.40 ± 1.4 and 0.10 ± 0.5. Corresponding numbers of new/newly enlarging T2 lesions from baseline to month 36 were 1.7 ± 4.6 and 0.9 ± 2.9.
Patients in the extreme category exceeded the recently proposed cut-off for pathologically increased brain volume loss by about 60%, compared with only about 14% for patients in the stable category.
The higher change in brain volume from baseline in patients who progressed to extreme disability “supports brain atrophy as a clinically relevant measure of neuroprotection in PPMS trials,” wrote Dr. Wolinsky and his colleagues.
The study was funded by Novartis Pharma AG. Dr. Wolinsky disclosed consulting fees from Genzyme/Sanofi, Hoffmann-La Roche/Genentech, Forward Pharma, Alkermes, AbbVie, Novartis Pharmaceuticals, Teva, and XenoPort and advisory board participation for Hoffman-La Roche/Genentech, Forward Pharma, EMD Serono, Actelion, Novartis Pharmaceuticals, Teva, and Xenoport. He performed contract research for Genzyme/Sanofi.
Key clinical point: Brain atrophy could be a clinically useful and relevant measure in primary progressing multiple sclerosis.
Major finding: Progression to extreme disability was associated with greater brain volume loss.
Data source: Data from the multinational, double-blind, placebo-controlled, parallel-group INFORMS trial.
Disclosures: The study was funded by Novartis Pharma AG. Dr. Wolinsky disclosed consulting fees from Genzyme/Sanofi, Hoffmann-La Roche/Genentech, Forward Pharma, Alkermes, AbbVie, Novartis Pharmaceuticals, Teva, and XenoPort, and advisory board participation for Hoffman-La Roche/Genentech, Forward Pharma, EMD Serono, Actelion, Novartis Pharmaceuticals, Teva, and Xenoport. He performed contract research for Genzyme/Sanofi.
