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Severe foot pathology predicts death in diabetes
MUNICH – When it comes to predicting mortality in diabetes patients, the foot may trump the heart.
Over a 5-year period, patients who had the most severe foot pathology were almost four times more likely to die than those who had a constellation of cardiovascular risk factors. The association with foot pathology stayed strong and, in a multivariate analysis, was the only factor that remained significantly associated with death in the cohort, Dragan Tesic, MD, said at the annual meeting of the European Association for the Study of Diabetes.
“On average, our patients with severe foot pathology had a 5-year shortening of their lifespan,” said Dr. Tesic of the University of Novi Sad, Serbia. This finding was even more pronounced in younger patients: Those aged 55 years and younger with severe foot pathology died a median of 14 years earlier than their normal expected lifespan would have ended.
Dr. Tesic and his colleagues conducted a 5-year mortality analysis of 244 patients with diabetes, 12% of whom had type 1 disease. The analysis included cardiovascular risk factors (hypertension, triglycerides, cholesterol levels, fibrinogen, proteinuria, and smoking); diabetes duration; coronary artery and cerebrovascular disease; and peripheral artery disease.
Foot pathology was determined according the recently published clinical guidelines by the International Working Group on the Diabetic Foot (IWGDF) (Diab Met Res Rev. 2016. doi: 10.1002/dmrr.2694).
The document parses the diabetic foot into four severity categories:
• 0: No peripheral neuropathy.
• 1: Peripheral neuropathy.
• 2: Peripheral neuropathy with peripheral artery disease and/or a foot deformity.
• 3: Peripheral neuropathy and a history of a foot ulcer or a lower-extremity amputation.
At baseline, patients were a median of 68 years old, though they ranged in age from 36 to 83 years. The mean duration of diabetes was 17 years, and the mean HbA1c was 8.9%. About half had retinopathy; no one was on hemodialysis.
By 5 years, 53 patients (22%) had died. Their median age was 70 years – 5 years short of the Serbian national life expectancy. However, deaths were evenly distributed among the age groups, Dr. Tesic said: 30% of deceased patients were aged 40-64, 41% aged 65-74, and 28% aged 74 and older.
The causes of death were sudden cardiac death (38%), acute coronary syndrome (32%), stroke (11%), cancer (13%), and sepsis (6%).
There were no significant between-group differences in the type of diabetes; any lipid parameter; diabetic retinopathy; proteinuria; or cardiovascular or cerebrovascular disease. However, patients who died had significantly more severe foot pathology, with 71% scoring either a 2 or 3 on the IWGDF scale compared with 36% of those who were still alive. This level of foot pathology was seen in every age group of the deceased patients: 75% of those in the youngest, 54% of those in the middle group, and 73% of those in the oldest group.
Those who died had developed their foot lesions earlier (66 years vs. 69 years). They had poorer ankle reflexes, and worse results on the Neuropad, a visual indicator test for human diabetic neuropathy. Those who died were older (70 years vs. 66 years), had a longer diabetes duration (20 years vs. 17 years), and more hypertension (79% vs. 61%).
But in a multivariate analysis, only the IWGDF score remained a significant predictor of mortality (odds ratio, 3.78). All of the cardiovascular risk factors, as well as age, diabetes duration, and glucose measures, had no effect on survivalk in that analysis.
The study underscores the importance of preventing and treating diabetic neuropathy and foot complications, Dr. Tesic stressed.
“I like to say that I see an opportunity in every difficulty. The examination of the diabetic foot may be time-consuming, but without that we are not delivering adequate or appropriate care to our patients.”
He had no financial disclosures.
MUNICH – When it comes to predicting mortality in diabetes patients, the foot may trump the heart.
Over a 5-year period, patients who had the most severe foot pathology were almost four times more likely to die than those who had a constellation of cardiovascular risk factors. The association with foot pathology stayed strong and, in a multivariate analysis, was the only factor that remained significantly associated with death in the cohort, Dragan Tesic, MD, said at the annual meeting of the European Association for the Study of Diabetes.
“On average, our patients with severe foot pathology had a 5-year shortening of their lifespan,” said Dr. Tesic of the University of Novi Sad, Serbia. This finding was even more pronounced in younger patients: Those aged 55 years and younger with severe foot pathology died a median of 14 years earlier than their normal expected lifespan would have ended.
Dr. Tesic and his colleagues conducted a 5-year mortality analysis of 244 patients with diabetes, 12% of whom had type 1 disease. The analysis included cardiovascular risk factors (hypertension, triglycerides, cholesterol levels, fibrinogen, proteinuria, and smoking); diabetes duration; coronary artery and cerebrovascular disease; and peripheral artery disease.
Foot pathology was determined according the recently published clinical guidelines by the International Working Group on the Diabetic Foot (IWGDF) (Diab Met Res Rev. 2016. doi: 10.1002/dmrr.2694).
The document parses the diabetic foot into four severity categories:
• 0: No peripheral neuropathy.
• 1: Peripheral neuropathy.
• 2: Peripheral neuropathy with peripheral artery disease and/or a foot deformity.
• 3: Peripheral neuropathy and a history of a foot ulcer or a lower-extremity amputation.
At baseline, patients were a median of 68 years old, though they ranged in age from 36 to 83 years. The mean duration of diabetes was 17 years, and the mean HbA1c was 8.9%. About half had retinopathy; no one was on hemodialysis.
By 5 years, 53 patients (22%) had died. Their median age was 70 years – 5 years short of the Serbian national life expectancy. However, deaths were evenly distributed among the age groups, Dr. Tesic said: 30% of deceased patients were aged 40-64, 41% aged 65-74, and 28% aged 74 and older.
The causes of death were sudden cardiac death (38%), acute coronary syndrome (32%), stroke (11%), cancer (13%), and sepsis (6%).
There were no significant between-group differences in the type of diabetes; any lipid parameter; diabetic retinopathy; proteinuria; or cardiovascular or cerebrovascular disease. However, patients who died had significantly more severe foot pathology, with 71% scoring either a 2 or 3 on the IWGDF scale compared with 36% of those who were still alive. This level of foot pathology was seen in every age group of the deceased patients: 75% of those in the youngest, 54% of those in the middle group, and 73% of those in the oldest group.
Those who died had developed their foot lesions earlier (66 years vs. 69 years). They had poorer ankle reflexes, and worse results on the Neuropad, a visual indicator test for human diabetic neuropathy. Those who died were older (70 years vs. 66 years), had a longer diabetes duration (20 years vs. 17 years), and more hypertension (79% vs. 61%).
But in a multivariate analysis, only the IWGDF score remained a significant predictor of mortality (odds ratio, 3.78). All of the cardiovascular risk factors, as well as age, diabetes duration, and glucose measures, had no effect on survivalk in that analysis.
The study underscores the importance of preventing and treating diabetic neuropathy and foot complications, Dr. Tesic stressed.
“I like to say that I see an opportunity in every difficulty. The examination of the diabetic foot may be time-consuming, but without that we are not delivering adequate or appropriate care to our patients.”
He had no financial disclosures.
MUNICH – When it comes to predicting mortality in diabetes patients, the foot may trump the heart.
Over a 5-year period, patients who had the most severe foot pathology were almost four times more likely to die than those who had a constellation of cardiovascular risk factors. The association with foot pathology stayed strong and, in a multivariate analysis, was the only factor that remained significantly associated with death in the cohort, Dragan Tesic, MD, said at the annual meeting of the European Association for the Study of Diabetes.
“On average, our patients with severe foot pathology had a 5-year shortening of their lifespan,” said Dr. Tesic of the University of Novi Sad, Serbia. This finding was even more pronounced in younger patients: Those aged 55 years and younger with severe foot pathology died a median of 14 years earlier than their normal expected lifespan would have ended.
Dr. Tesic and his colleagues conducted a 5-year mortality analysis of 244 patients with diabetes, 12% of whom had type 1 disease. The analysis included cardiovascular risk factors (hypertension, triglycerides, cholesterol levels, fibrinogen, proteinuria, and smoking); diabetes duration; coronary artery and cerebrovascular disease; and peripheral artery disease.
Foot pathology was determined according the recently published clinical guidelines by the International Working Group on the Diabetic Foot (IWGDF) (Diab Met Res Rev. 2016. doi: 10.1002/dmrr.2694).
The document parses the diabetic foot into four severity categories:
• 0: No peripheral neuropathy.
• 1: Peripheral neuropathy.
• 2: Peripheral neuropathy with peripheral artery disease and/or a foot deformity.
• 3: Peripheral neuropathy and a history of a foot ulcer or a lower-extremity amputation.
At baseline, patients were a median of 68 years old, though they ranged in age from 36 to 83 years. The mean duration of diabetes was 17 years, and the mean HbA1c was 8.9%. About half had retinopathy; no one was on hemodialysis.
By 5 years, 53 patients (22%) had died. Their median age was 70 years – 5 years short of the Serbian national life expectancy. However, deaths were evenly distributed among the age groups, Dr. Tesic said: 30% of deceased patients were aged 40-64, 41% aged 65-74, and 28% aged 74 and older.
The causes of death were sudden cardiac death (38%), acute coronary syndrome (32%), stroke (11%), cancer (13%), and sepsis (6%).
There were no significant between-group differences in the type of diabetes; any lipid parameter; diabetic retinopathy; proteinuria; or cardiovascular or cerebrovascular disease. However, patients who died had significantly more severe foot pathology, with 71% scoring either a 2 or 3 on the IWGDF scale compared with 36% of those who were still alive. This level of foot pathology was seen in every age group of the deceased patients: 75% of those in the youngest, 54% of those in the middle group, and 73% of those in the oldest group.
Those who died had developed their foot lesions earlier (66 years vs. 69 years). They had poorer ankle reflexes, and worse results on the Neuropad, a visual indicator test for human diabetic neuropathy. Those who died were older (70 years vs. 66 years), had a longer diabetes duration (20 years vs. 17 years), and more hypertension (79% vs. 61%).
But in a multivariate analysis, only the IWGDF score remained a significant predictor of mortality (odds ratio, 3.78). All of the cardiovascular risk factors, as well as age, diabetes duration, and glucose measures, had no effect on survivalk in that analysis.
The study underscores the importance of preventing and treating diabetic neuropathy and foot complications, Dr. Tesic stressed.
“I like to say that I see an opportunity in every difficulty. The examination of the diabetic foot may be time-consuming, but without that we are not delivering adequate or appropriate care to our patients.”
He had no financial disclosures.
AT EASD 2016
Key clinical point: Severe foot pathology was a better predictor of mortality than cardiovascular risk factors.
Major finding: Patients with severe foot pathology were almost four times more likely to die over 5 years.
Data source: The study comprised 244 patients with types 1 and 2 diabetes.
Disclosures: Dr. Tesic had no financial disclosures.
When 1 + 1 = 3: Rational drug combinations in type 2 diabetes
MUNICH – Enough studies exist now to support the notion of dual therapy in type 2 diabetes. But, with 13 classes of antihyperglycemic drugs approved in the United States – 7 of which are considered major – how does anyone make sense of the myriad of possible combinations?
It’s not a bad problem to have, Ele Ferrannini, MD, said shortly before the DURATION-8 data were presented at the annual meeting of the European Association for the Study of Diabetes.
“We have seen an explosion of pharmacological treatment options for type 2 diabetes in the last 20 years, which is really unprecedented, especially if we compare that to what has happened in hypertension or cardiology,” said Dr. Ferrannini of the University of Pisa (Italy). “This has given us the blessing of multiple options for treatment. But we are also now at a slight disadvantage. We all agree that we should advocate for combination treatment as early and aggressively as possible for our type 2 diabetes patients, but the question is, What combination?”
The question cannot be answered fully, he said. “If we had to test each possible combination in dual therapy, and counted all 13 classes, that would be 78 combinations. And if we started talking about triple therapy – which may eventually arrive – we could be talking about 286 possible combinations. So it’s just not possible to formally test the efficacy and the risk/benefit profile of every one. That means we have to start thinking about rational combinations based on mechanism of action.”
The combination of dapagliflozin and exenatide, tested in DURATION-8 is a good example, he said. “It’s rational,” because exenatide and dapagliflozin work completely independently of each other, each adding a unique method of action without overtargeting the same system and increasing the risk of adverse events.
Dapagliflozin is an inhibitor of the renal sodium-glucose cotransporter–2 (SGLT-2). This class of drugs works in the proximal renal tubule, where these glucose transporters absorb “huge amounts” of glucose, he said. “Whatever escapes there is then mopped up by the SGLT-1 cotransporters further along the nephron,” Dr. Ferrannini said. “SGLT inhibitors cause an upward and leftward shift of the relationship between plasma glucose and glycosuria for the same glomerular filtration rate.”
In the presence of an SGLT-2 inhibitor, glycosuria is increased, no matter what the plasma glucose level is. “This even takes place well within the euglycemic range, which is why these drugs cause glycosuria even in nondiabetic individuals,” Dr. Ferrannini said.
Numerous studies have shown that this class of drugs works well independently, and also pairs well with metformin, sulfonylureas, dipeptidyl peptidase–4 inhibitors, and insulin. Several studies of dapagliflozin have found that adding 10 mg to monotherapy reduced HbA1c on the order of almost 1%, regardless of the concomitant medication.
Dapagliflozin works especially well in patients with very high HbA1c levels, Dr. Ferrannini said, as shown in a 2010 dose-ranging study he led. “If the initial HbA1c was above 10%, the drop associated with adding dapagliflozin was surprisingly large, on the order of 3%-4%,” he said Diabetes Care 2010 Oct;33(10):2217-24.
The primary response on HbA1c is also quite durable, unlike the response seen in sulfonylureas, for example, which eventually wanes. “Every time you give this pill, you get glycosuria. It just doesn’t change,” he said.
Dapagliflozin also exerts a sustained benefit on systolic blood pressure, and causes a very consistent 2- to 3-kg decrease in body weight, no matter whether it’s given alone or with metformin, insulin, or a sulphonylurea.
But when it comes to shedding calories through urine, the body can’t be tricked forever, it seems. “You could assume very easily that body weight would continue to decline with an SGLT-2 inhibitor, but in fact it levels off after 2-3 kg. There can only be one explanation for this, and that is an increase in calorie intake. The body feels this loss of calories, particularly this massive loss of carbohydrate calories through the urine, and responds by implementing adaptive behaviors that increase calorie intake,” Dr. Ferrannini said.
In other words, hunger strikes. And strikes hard. That’s where the incretins come into play, he said.
“If we could interfere with this response that limits weight loss, we could probably continue to lose weight, and also see general improvements in HbA1c. And a very important element of incretin action is that they restore insulin release in patients with diabetes” and moderate appetite, he said.
Incretins like exenatide, a glucagonlike peptide–1 receptor agonist, impose their weight loss effect through an entirely different system. “By delaying gastric emptying and also – more importantly – through neural signaling, they potentiate satiety, thus limiting calorie intake, reducing energy balance, and leading to a reduction in body weight,” Dr. Ferrannini said.
Therefore, using a combination like dapagliflozin and exenatide makes complete physiologic sense, he said. Both drugs improve HbA1c, and decrease body weight and systolic blood pressure. Dapagliflozin accomplishes these tasks by increasing urinary glucose excretion, which leads to decreased vascular stiffness and better blood pressure. Exenatide works in a completely different pathway - insulin signaling - and has the additional benefit of decreasing inflammation.
The positive results of DURATION-8 support this clinical assumption, he concluded. “I would submit that combination therapy with exenatide and dapagliflozin is a rational approach, and takes advantage of the unique properties of both of these drugs,” he said.
Dr. Ferrannini has received research finding from AstraZeneca, which manufactures dapagliflozin and exenatide, as well as other companies that market diabetes drugs.
On Twitter @Alz_Gal
MUNICH – Enough studies exist now to support the notion of dual therapy in type 2 diabetes. But, with 13 classes of antihyperglycemic drugs approved in the United States – 7 of which are considered major – how does anyone make sense of the myriad of possible combinations?
It’s not a bad problem to have, Ele Ferrannini, MD, said shortly before the DURATION-8 data were presented at the annual meeting of the European Association for the Study of Diabetes.
“We have seen an explosion of pharmacological treatment options for type 2 diabetes in the last 20 years, which is really unprecedented, especially if we compare that to what has happened in hypertension or cardiology,” said Dr. Ferrannini of the University of Pisa (Italy). “This has given us the blessing of multiple options for treatment. But we are also now at a slight disadvantage. We all agree that we should advocate for combination treatment as early and aggressively as possible for our type 2 diabetes patients, but the question is, What combination?”
The question cannot be answered fully, he said. “If we had to test each possible combination in dual therapy, and counted all 13 classes, that would be 78 combinations. And if we started talking about triple therapy – which may eventually arrive – we could be talking about 286 possible combinations. So it’s just not possible to formally test the efficacy and the risk/benefit profile of every one. That means we have to start thinking about rational combinations based on mechanism of action.”
The combination of dapagliflozin and exenatide, tested in DURATION-8 is a good example, he said. “It’s rational,” because exenatide and dapagliflozin work completely independently of each other, each adding a unique method of action without overtargeting the same system and increasing the risk of adverse events.
Dapagliflozin is an inhibitor of the renal sodium-glucose cotransporter–2 (SGLT-2). This class of drugs works in the proximal renal tubule, where these glucose transporters absorb “huge amounts” of glucose, he said. “Whatever escapes there is then mopped up by the SGLT-1 cotransporters further along the nephron,” Dr. Ferrannini said. “SGLT inhibitors cause an upward and leftward shift of the relationship between plasma glucose and glycosuria for the same glomerular filtration rate.”
In the presence of an SGLT-2 inhibitor, glycosuria is increased, no matter what the plasma glucose level is. “This even takes place well within the euglycemic range, which is why these drugs cause glycosuria even in nondiabetic individuals,” Dr. Ferrannini said.
Numerous studies have shown that this class of drugs works well independently, and also pairs well with metformin, sulfonylureas, dipeptidyl peptidase–4 inhibitors, and insulin. Several studies of dapagliflozin have found that adding 10 mg to monotherapy reduced HbA1c on the order of almost 1%, regardless of the concomitant medication.
Dapagliflozin works especially well in patients with very high HbA1c levels, Dr. Ferrannini said, as shown in a 2010 dose-ranging study he led. “If the initial HbA1c was above 10%, the drop associated with adding dapagliflozin was surprisingly large, on the order of 3%-4%,” he said Diabetes Care 2010 Oct;33(10):2217-24.
The primary response on HbA1c is also quite durable, unlike the response seen in sulfonylureas, for example, which eventually wanes. “Every time you give this pill, you get glycosuria. It just doesn’t change,” he said.
Dapagliflozin also exerts a sustained benefit on systolic blood pressure, and causes a very consistent 2- to 3-kg decrease in body weight, no matter whether it’s given alone or with metformin, insulin, or a sulphonylurea.
But when it comes to shedding calories through urine, the body can’t be tricked forever, it seems. “You could assume very easily that body weight would continue to decline with an SGLT-2 inhibitor, but in fact it levels off after 2-3 kg. There can only be one explanation for this, and that is an increase in calorie intake. The body feels this loss of calories, particularly this massive loss of carbohydrate calories through the urine, and responds by implementing adaptive behaviors that increase calorie intake,” Dr. Ferrannini said.
In other words, hunger strikes. And strikes hard. That’s where the incretins come into play, he said.
“If we could interfere with this response that limits weight loss, we could probably continue to lose weight, and also see general improvements in HbA1c. And a very important element of incretin action is that they restore insulin release in patients with diabetes” and moderate appetite, he said.
Incretins like exenatide, a glucagonlike peptide–1 receptor agonist, impose their weight loss effect through an entirely different system. “By delaying gastric emptying and also – more importantly – through neural signaling, they potentiate satiety, thus limiting calorie intake, reducing energy balance, and leading to a reduction in body weight,” Dr. Ferrannini said.
Therefore, using a combination like dapagliflozin and exenatide makes complete physiologic sense, he said. Both drugs improve HbA1c, and decrease body weight and systolic blood pressure. Dapagliflozin accomplishes these tasks by increasing urinary glucose excretion, which leads to decreased vascular stiffness and better blood pressure. Exenatide works in a completely different pathway - insulin signaling - and has the additional benefit of decreasing inflammation.
The positive results of DURATION-8 support this clinical assumption, he concluded. “I would submit that combination therapy with exenatide and dapagliflozin is a rational approach, and takes advantage of the unique properties of both of these drugs,” he said.
Dr. Ferrannini has received research finding from AstraZeneca, which manufactures dapagliflozin and exenatide, as well as other companies that market diabetes drugs.
On Twitter @Alz_Gal
MUNICH – Enough studies exist now to support the notion of dual therapy in type 2 diabetes. But, with 13 classes of antihyperglycemic drugs approved in the United States – 7 of which are considered major – how does anyone make sense of the myriad of possible combinations?
It’s not a bad problem to have, Ele Ferrannini, MD, said shortly before the DURATION-8 data were presented at the annual meeting of the European Association for the Study of Diabetes.
“We have seen an explosion of pharmacological treatment options for type 2 diabetes in the last 20 years, which is really unprecedented, especially if we compare that to what has happened in hypertension or cardiology,” said Dr. Ferrannini of the University of Pisa (Italy). “This has given us the blessing of multiple options for treatment. But we are also now at a slight disadvantage. We all agree that we should advocate for combination treatment as early and aggressively as possible for our type 2 diabetes patients, but the question is, What combination?”
The question cannot be answered fully, he said. “If we had to test each possible combination in dual therapy, and counted all 13 classes, that would be 78 combinations. And if we started talking about triple therapy – which may eventually arrive – we could be talking about 286 possible combinations. So it’s just not possible to formally test the efficacy and the risk/benefit profile of every one. That means we have to start thinking about rational combinations based on mechanism of action.”
The combination of dapagliflozin and exenatide, tested in DURATION-8 is a good example, he said. “It’s rational,” because exenatide and dapagliflozin work completely independently of each other, each adding a unique method of action without overtargeting the same system and increasing the risk of adverse events.
Dapagliflozin is an inhibitor of the renal sodium-glucose cotransporter–2 (SGLT-2). This class of drugs works in the proximal renal tubule, where these glucose transporters absorb “huge amounts” of glucose, he said. “Whatever escapes there is then mopped up by the SGLT-1 cotransporters further along the nephron,” Dr. Ferrannini said. “SGLT inhibitors cause an upward and leftward shift of the relationship between plasma glucose and glycosuria for the same glomerular filtration rate.”
In the presence of an SGLT-2 inhibitor, glycosuria is increased, no matter what the plasma glucose level is. “This even takes place well within the euglycemic range, which is why these drugs cause glycosuria even in nondiabetic individuals,” Dr. Ferrannini said.
Numerous studies have shown that this class of drugs works well independently, and also pairs well with metformin, sulfonylureas, dipeptidyl peptidase–4 inhibitors, and insulin. Several studies of dapagliflozin have found that adding 10 mg to monotherapy reduced HbA1c on the order of almost 1%, regardless of the concomitant medication.
Dapagliflozin works especially well in patients with very high HbA1c levels, Dr. Ferrannini said, as shown in a 2010 dose-ranging study he led. “If the initial HbA1c was above 10%, the drop associated with adding dapagliflozin was surprisingly large, on the order of 3%-4%,” he said Diabetes Care 2010 Oct;33(10):2217-24.
The primary response on HbA1c is also quite durable, unlike the response seen in sulfonylureas, for example, which eventually wanes. “Every time you give this pill, you get glycosuria. It just doesn’t change,” he said.
Dapagliflozin also exerts a sustained benefit on systolic blood pressure, and causes a very consistent 2- to 3-kg decrease in body weight, no matter whether it’s given alone or with metformin, insulin, or a sulphonylurea.
But when it comes to shedding calories through urine, the body can’t be tricked forever, it seems. “You could assume very easily that body weight would continue to decline with an SGLT-2 inhibitor, but in fact it levels off after 2-3 kg. There can only be one explanation for this, and that is an increase in calorie intake. The body feels this loss of calories, particularly this massive loss of carbohydrate calories through the urine, and responds by implementing adaptive behaviors that increase calorie intake,” Dr. Ferrannini said.
In other words, hunger strikes. And strikes hard. That’s where the incretins come into play, he said.
“If we could interfere with this response that limits weight loss, we could probably continue to lose weight, and also see general improvements in HbA1c. And a very important element of incretin action is that they restore insulin release in patients with diabetes” and moderate appetite, he said.
Incretins like exenatide, a glucagonlike peptide–1 receptor agonist, impose their weight loss effect through an entirely different system. “By delaying gastric emptying and also – more importantly – through neural signaling, they potentiate satiety, thus limiting calorie intake, reducing energy balance, and leading to a reduction in body weight,” Dr. Ferrannini said.
Therefore, using a combination like dapagliflozin and exenatide makes complete physiologic sense, he said. Both drugs improve HbA1c, and decrease body weight and systolic blood pressure. Dapagliflozin accomplishes these tasks by increasing urinary glucose excretion, which leads to decreased vascular stiffness and better blood pressure. Exenatide works in a completely different pathway - insulin signaling - and has the additional benefit of decreasing inflammation.
The positive results of DURATION-8 support this clinical assumption, he concluded. “I would submit that combination therapy with exenatide and dapagliflozin is a rational approach, and takes advantage of the unique properties of both of these drugs,” he said.
Dr. Ferrannini has received research finding from AstraZeneca, which manufactures dapagliflozin and exenatide, as well as other companies that market diabetes drugs.
On Twitter @Alz_Gal
EXPERT ANALYSIS FROM EASD 2016
Liraglutide cut risk of microvascular renal complications by 22% in type 2 diabetes; no eye benefit
MUNICH – Liraglutide posted positive secondary endpoints in a large randomized trial, reducing the risk of microvascular events by 16% and protecting renal function in people with type 2 diabetes.
A 22% decreased risk of renal complications was the major driver of microvascular protection in the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome) trial, Johannes Mann, MD, said at the annual meeting of the European Association for the Study of Diabetes. Somewhat disappointingly, the glucagonlike peptide–1 (GLP-1) receptor inhibitor didn’t decrease the chance of an eye-related microvascular event, said Dr. Mann of Friedrich Alexander University in Erlangen, Germany.
LEADER randomized 9,340 patients with type 2 diabetes to 1.8 mg or the maximum tolerated dose of subcutaneous liraglutide once daily or to placebo, in addition to standard care (N Engl J Med. 2016 June 13. doi: 10.1056/NEJMoa1603827)
The primary endpoint, reported in June, was a 13% reduction in the risk of a composite cardiovascular outcome (cardiovascular death, nonfatal heart attack, or nonfatal stroke) over 3.8 years of follow-up. This was driven by a 22% reduction in the risk of cardiovascular death; the drug did not significantly impact the other endpoints.
Microvascular and safety endpoints were key secondary outcomes. The study population was already at high risk for renal complications, Dr. Mann said: 20% had a moderate renal impairment at baseline, 20% had microalbuminuria, and 5% had macroalbuminuria.
The renal microvascular endpoint was a composite of several measures: new-onset persistent macroalbuminuria, persistent doubling of serum creatinine, end-stage renal disease, or death from renal failure. It occurred in 7.6% of the liraglutide group and 8.9% of the placebo group. The difference represented a 22% reduction in the time to a first renal event (hazard ratio, 0.78). This was entirely driven by a significant 23% decrease in the chance of new-onset macroalbuminuria (hazard ratio, 0.74), which occurred in 3.4% of the liraglutide group and 4.6% of the placebo group.
There were no significant between-group differences in any of the other renal endpoints, Dr. Mann said.
The eye microvascular endpoint was a composite of vitreous hemorrhage or treatment with photocoagulation or an intravitreal agent. The composite endpoint occurred in 2.3% of the liraglutide group and 2% of the placebo group, which was not a significant difference (HR, 1.15).
The drug was not associated with an increased risk of pancreatitis, with 18 suspected events in the treated group vs. 33 in the placebo group, not a significant difference. None of the cases was time bound; they occurred randomly throughout the trial in both treatment arms, said Michael A. Nauck, MD, of St. Josef Hospital, Bochum, Germany,
But any cases were a cause of concern, Dr. Nauck said, especially since liraglutide, like any GLP-1 agonist, causes increases in the pancreatic enzymes lipase and amylase. Therefore, each suspected case of acute pancreatitis that occurred in either group was fully adjudicated according to three diagnostic criteria: characteristic upper abdominal pain, increased pancreatic enzymes, and imaging findings.
Most of the cases (79% on liraglutide and 58% on placebo) had two of these criteria; the rest fulfilled all three. Any one was enough to prompt a pancreatitis work-up. Pain was the presenting symptom in 40% of liraglutide patients and 74% of placebo patients. Elevated enzymes prompted the work-up in another 40% of liraglutide patients and in 26% of placebo patients. The combination of pain and elevated enzymes was present in 6% of liraglutide patients, and in none of the placebo patients.
But pancreatic imaging was negative in 77% of liraglutide patients and 61% of placebo patients, suggesting that most of the reports did not represent a true acute inflammatory pancreatitis, Dr. Nauck said.
There was no significant liraglutide-associated increase in the risk of any neoplasm, whether malignant (HR, 1.06) or benign (HR, 1.16).
Pancreatic cancer occurred in 13 patients taking liraglutide and 9 taking placebo – not a significant difference. There were numerically fewer cases of prostate cancer and leukemia among those taking the drug, but again, the difference was not statistically significant, and the analysis didn’t control for any confounding factors.
“We are not going to say that liraglutide is in any way protective against these cancers,” Dr. Nauck said.
LEADER was sponsored by Novo Nordisk and the National Institutes of Health. Dr. Nauck is on Novo Nordisk’s advisory panel and speakers board, and receives research funding from the company. Dr Mann is an investigator and consultant for the company.
MUNICH – Liraglutide posted positive secondary endpoints in a large randomized trial, reducing the risk of microvascular events by 16% and protecting renal function in people with type 2 diabetes.
A 22% decreased risk of renal complications was the major driver of microvascular protection in the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome) trial, Johannes Mann, MD, said at the annual meeting of the European Association for the Study of Diabetes. Somewhat disappointingly, the glucagonlike peptide–1 (GLP-1) receptor inhibitor didn’t decrease the chance of an eye-related microvascular event, said Dr. Mann of Friedrich Alexander University in Erlangen, Germany.
LEADER randomized 9,340 patients with type 2 diabetes to 1.8 mg or the maximum tolerated dose of subcutaneous liraglutide once daily or to placebo, in addition to standard care (N Engl J Med. 2016 June 13. doi: 10.1056/NEJMoa1603827)
The primary endpoint, reported in June, was a 13% reduction in the risk of a composite cardiovascular outcome (cardiovascular death, nonfatal heart attack, or nonfatal stroke) over 3.8 years of follow-up. This was driven by a 22% reduction in the risk of cardiovascular death; the drug did not significantly impact the other endpoints.
Microvascular and safety endpoints were key secondary outcomes. The study population was already at high risk for renal complications, Dr. Mann said: 20% had a moderate renal impairment at baseline, 20% had microalbuminuria, and 5% had macroalbuminuria.
The renal microvascular endpoint was a composite of several measures: new-onset persistent macroalbuminuria, persistent doubling of serum creatinine, end-stage renal disease, or death from renal failure. It occurred in 7.6% of the liraglutide group and 8.9% of the placebo group. The difference represented a 22% reduction in the time to a first renal event (hazard ratio, 0.78). This was entirely driven by a significant 23% decrease in the chance of new-onset macroalbuminuria (hazard ratio, 0.74), which occurred in 3.4% of the liraglutide group and 4.6% of the placebo group.
There were no significant between-group differences in any of the other renal endpoints, Dr. Mann said.
The eye microvascular endpoint was a composite of vitreous hemorrhage or treatment with photocoagulation or an intravitreal agent. The composite endpoint occurred in 2.3% of the liraglutide group and 2% of the placebo group, which was not a significant difference (HR, 1.15).
The drug was not associated with an increased risk of pancreatitis, with 18 suspected events in the treated group vs. 33 in the placebo group, not a significant difference. None of the cases was time bound; they occurred randomly throughout the trial in both treatment arms, said Michael A. Nauck, MD, of St. Josef Hospital, Bochum, Germany,
But any cases were a cause of concern, Dr. Nauck said, especially since liraglutide, like any GLP-1 agonist, causes increases in the pancreatic enzymes lipase and amylase. Therefore, each suspected case of acute pancreatitis that occurred in either group was fully adjudicated according to three diagnostic criteria: characteristic upper abdominal pain, increased pancreatic enzymes, and imaging findings.
Most of the cases (79% on liraglutide and 58% on placebo) had two of these criteria; the rest fulfilled all three. Any one was enough to prompt a pancreatitis work-up. Pain was the presenting symptom in 40% of liraglutide patients and 74% of placebo patients. Elevated enzymes prompted the work-up in another 40% of liraglutide patients and in 26% of placebo patients. The combination of pain and elevated enzymes was present in 6% of liraglutide patients, and in none of the placebo patients.
But pancreatic imaging was negative in 77% of liraglutide patients and 61% of placebo patients, suggesting that most of the reports did not represent a true acute inflammatory pancreatitis, Dr. Nauck said.
There was no significant liraglutide-associated increase in the risk of any neoplasm, whether malignant (HR, 1.06) or benign (HR, 1.16).
Pancreatic cancer occurred in 13 patients taking liraglutide and 9 taking placebo – not a significant difference. There were numerically fewer cases of prostate cancer and leukemia among those taking the drug, but again, the difference was not statistically significant, and the analysis didn’t control for any confounding factors.
“We are not going to say that liraglutide is in any way protective against these cancers,” Dr. Nauck said.
LEADER was sponsored by Novo Nordisk and the National Institutes of Health. Dr. Nauck is on Novo Nordisk’s advisory panel and speakers board, and receives research funding from the company. Dr Mann is an investigator and consultant for the company.
MUNICH – Liraglutide posted positive secondary endpoints in a large randomized trial, reducing the risk of microvascular events by 16% and protecting renal function in people with type 2 diabetes.
A 22% decreased risk of renal complications was the major driver of microvascular protection in the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome) trial, Johannes Mann, MD, said at the annual meeting of the European Association for the Study of Diabetes. Somewhat disappointingly, the glucagonlike peptide–1 (GLP-1) receptor inhibitor didn’t decrease the chance of an eye-related microvascular event, said Dr. Mann of Friedrich Alexander University in Erlangen, Germany.
LEADER randomized 9,340 patients with type 2 diabetes to 1.8 mg or the maximum tolerated dose of subcutaneous liraglutide once daily or to placebo, in addition to standard care (N Engl J Med. 2016 June 13. doi: 10.1056/NEJMoa1603827)
The primary endpoint, reported in June, was a 13% reduction in the risk of a composite cardiovascular outcome (cardiovascular death, nonfatal heart attack, or nonfatal stroke) over 3.8 years of follow-up. This was driven by a 22% reduction in the risk of cardiovascular death; the drug did not significantly impact the other endpoints.
Microvascular and safety endpoints were key secondary outcomes. The study population was already at high risk for renal complications, Dr. Mann said: 20% had a moderate renal impairment at baseline, 20% had microalbuminuria, and 5% had macroalbuminuria.
The renal microvascular endpoint was a composite of several measures: new-onset persistent macroalbuminuria, persistent doubling of serum creatinine, end-stage renal disease, or death from renal failure. It occurred in 7.6% of the liraglutide group and 8.9% of the placebo group. The difference represented a 22% reduction in the time to a first renal event (hazard ratio, 0.78). This was entirely driven by a significant 23% decrease in the chance of new-onset macroalbuminuria (hazard ratio, 0.74), which occurred in 3.4% of the liraglutide group and 4.6% of the placebo group.
There were no significant between-group differences in any of the other renal endpoints, Dr. Mann said.
The eye microvascular endpoint was a composite of vitreous hemorrhage or treatment with photocoagulation or an intravitreal agent. The composite endpoint occurred in 2.3% of the liraglutide group and 2% of the placebo group, which was not a significant difference (HR, 1.15).
The drug was not associated with an increased risk of pancreatitis, with 18 suspected events in the treated group vs. 33 in the placebo group, not a significant difference. None of the cases was time bound; they occurred randomly throughout the trial in both treatment arms, said Michael A. Nauck, MD, of St. Josef Hospital, Bochum, Germany,
But any cases were a cause of concern, Dr. Nauck said, especially since liraglutide, like any GLP-1 agonist, causes increases in the pancreatic enzymes lipase and amylase. Therefore, each suspected case of acute pancreatitis that occurred in either group was fully adjudicated according to three diagnostic criteria: characteristic upper abdominal pain, increased pancreatic enzymes, and imaging findings.
Most of the cases (79% on liraglutide and 58% on placebo) had two of these criteria; the rest fulfilled all three. Any one was enough to prompt a pancreatitis work-up. Pain was the presenting symptom in 40% of liraglutide patients and 74% of placebo patients. Elevated enzymes prompted the work-up in another 40% of liraglutide patients and in 26% of placebo patients. The combination of pain and elevated enzymes was present in 6% of liraglutide patients, and in none of the placebo patients.
But pancreatic imaging was negative in 77% of liraglutide patients and 61% of placebo patients, suggesting that most of the reports did not represent a true acute inflammatory pancreatitis, Dr. Nauck said.
There was no significant liraglutide-associated increase in the risk of any neoplasm, whether malignant (HR, 1.06) or benign (HR, 1.16).
Pancreatic cancer occurred in 13 patients taking liraglutide and 9 taking placebo – not a significant difference. There were numerically fewer cases of prostate cancer and leukemia among those taking the drug, but again, the difference was not statistically significant, and the analysis didn’t control for any confounding factors.
“We are not going to say that liraglutide is in any way protective against these cancers,” Dr. Nauck said.
LEADER was sponsored by Novo Nordisk and the National Institutes of Health. Dr. Nauck is on Novo Nordisk’s advisory panel and speakers board, and receives research funding from the company. Dr Mann is an investigator and consultant for the company.
AT EASD 2016
Key clinical point: Liraglutide protected kidney function but conferred no benefit on microvascular eye complications in patients with type 2 diabetes.
Major finding: The benefit was driven by a 24% decreased risk of macroalbuminuria.
Data source: The LEADER trial randomized 9,340 patients with type 2 diabetes to daily 1.8 mg liraglutide or placebo, in addition to standard care.
Disclosures: LEADER was sponsored by Novo Nordisk and the National Institutes of Health. Dr. Nauck is on Novo Nordisk’s advisory panel and speakers board, and receives research funding from the company. Dr Mann is an investigator and consultant for the company.
Dulaglutide plus insulin glargine drops HbA1c in poorly controlled type 2
MUNICH – Once-weekly dulaglutide paired with insulin glargine plus metformin allowed 69% of patients with poorly controlled type 2 diabetes to achieve a hemoglobin A1c of 7% or lower.
Over the 28-week study, 51% of the group reached an HbA1c of 6.5% or lower – significantly better than the 17% who achieved this goal on insulin glargine with or without metformin, Paolo Pozzilli, MD, reported at the annual meeting of the European Association for the Study of Diabetes.
The combination was safe, with just one incident of severe hypoglycemia, and well tolerated, said Dr. Pozzilli of the University Campus Bio-Medico, Rome. Nausea – the most troublesome side effect of any glucagonlike peptide receptor agonist occurred in 12% of those taking the drug. Diarrhea occurred in 11% and vomiting in 6%. All of the gastrointestinal side effects were significantly more common than they were in the placebo group.
“I would say that the combination treatment of dulaglutide and insulin glargine – with or without metformin – is a reasonable, well-tolerated, and effective option for patients with type 2 diabetes who are not hitting their treatment goals,” he said.
Dr. Pozzilli reported results of Lily’s AWARD-9 trial. The placebo-controlled trial comprised 300 patients with poorly controlled type 2 diabetes (HbA1c, 7%-10.5%), despite being on insulin glargine and metformin. They were randomized to weekly subcutaneous placebo or 1.5 mg dulaglutide injections, in addition to their usual medications. There was no up titration on the study drug – patients started out with the full dose immediately. The study’s completion rate was high, with 92% of the investigational group and 87% of the control group finishing the 28-week treatment.
The group was typical for poorly controlled type 2 patients. Their mean age was 60 years; about 60% were men; and almost all were white. The mean body mass index was 32 kg/m2. The mean disease duration was 13 years, and the mean HbA1c was 8.4%. Their mean fasting plasma glucose was 8.7 mmol/L.
The effect of dual therapy was quickly evident, with HbA1c levels beginning to drop within 2 weeks. By 12 weeks, the separation between groups was statistically significant (dulaglutide HbA1c about 7%, placebo about 8%). By 28 weeks, the combination group had reached a mean HbA1c of 6.92%, compared with 7.69% in the placebo group. The response curve of the combination group appeared to be on a continuing decline when the study ended. The final measure represented an HbA1c decrease of 1.44% for the combination group and 0.67% for the placebo group.
By 28 weeks, 69% of the dulaglutide group and 35% of the placebo group had achieved an HbA1c of 7% or lower – a significant difference. Half of the dulaglutide group (51%) achieved a measure of 6.5% or lower, compared with 17% of the placebo group – also a significant difference.
The addition of dulaglutide moderated the need to increase the insulin that occurred over the study period. By 28 weeks, those taking dulaglutide had increased their insulin by a mean of 0.14 U/kg, compared with an increase of 0.27 U/kg in the placebo group. This difference was also statistically significant.
Patients in the combination group lost significantly more weight as well (mean 1.91 kg vs. a gain of 0.5 kg in the placebo group). Weight loss was quickly evident; by 4 weeks, patients had lost more than 1 kg. This “encouraging sign might help boost patient compliance,” Dr. Pozzilli said.
The side-effect profile was acceptable, compared with placebo. Hypoglycemia occurred in about 55% of those taking dulaglutide and 51% of those taking the placebo; it was symptomatic in 35% and 30%, respectively. Nocturnal hypoglycemia occurred in 28% and 29%, respectively. There was one case of severe hypoglycemia, which occurred in the dulaglutide group.
In addition to the GI side effects, there was one injection site reaction in the dulaglutide group. There were no cases of pancreatitis or pancreatic cancer.
The study was sponsored by Eli Lilly. Dr. Pozzilli is on the company’s speakers’ bureau and receives research grant money from it.
MUNICH – Once-weekly dulaglutide paired with insulin glargine plus metformin allowed 69% of patients with poorly controlled type 2 diabetes to achieve a hemoglobin A1c of 7% or lower.
Over the 28-week study, 51% of the group reached an HbA1c of 6.5% or lower – significantly better than the 17% who achieved this goal on insulin glargine with or without metformin, Paolo Pozzilli, MD, reported at the annual meeting of the European Association for the Study of Diabetes.
The combination was safe, with just one incident of severe hypoglycemia, and well tolerated, said Dr. Pozzilli of the University Campus Bio-Medico, Rome. Nausea – the most troublesome side effect of any glucagonlike peptide receptor agonist occurred in 12% of those taking the drug. Diarrhea occurred in 11% and vomiting in 6%. All of the gastrointestinal side effects were significantly more common than they were in the placebo group.
“I would say that the combination treatment of dulaglutide and insulin glargine – with or without metformin – is a reasonable, well-tolerated, and effective option for patients with type 2 diabetes who are not hitting their treatment goals,” he said.
Dr. Pozzilli reported results of Lily’s AWARD-9 trial. The placebo-controlled trial comprised 300 patients with poorly controlled type 2 diabetes (HbA1c, 7%-10.5%), despite being on insulin glargine and metformin. They were randomized to weekly subcutaneous placebo or 1.5 mg dulaglutide injections, in addition to their usual medications. There was no up titration on the study drug – patients started out with the full dose immediately. The study’s completion rate was high, with 92% of the investigational group and 87% of the control group finishing the 28-week treatment.
The group was typical for poorly controlled type 2 patients. Their mean age was 60 years; about 60% were men; and almost all were white. The mean body mass index was 32 kg/m2. The mean disease duration was 13 years, and the mean HbA1c was 8.4%. Their mean fasting plasma glucose was 8.7 mmol/L.
The effect of dual therapy was quickly evident, with HbA1c levels beginning to drop within 2 weeks. By 12 weeks, the separation between groups was statistically significant (dulaglutide HbA1c about 7%, placebo about 8%). By 28 weeks, the combination group had reached a mean HbA1c of 6.92%, compared with 7.69% in the placebo group. The response curve of the combination group appeared to be on a continuing decline when the study ended. The final measure represented an HbA1c decrease of 1.44% for the combination group and 0.67% for the placebo group.
By 28 weeks, 69% of the dulaglutide group and 35% of the placebo group had achieved an HbA1c of 7% or lower – a significant difference. Half of the dulaglutide group (51%) achieved a measure of 6.5% or lower, compared with 17% of the placebo group – also a significant difference.
The addition of dulaglutide moderated the need to increase the insulin that occurred over the study period. By 28 weeks, those taking dulaglutide had increased their insulin by a mean of 0.14 U/kg, compared with an increase of 0.27 U/kg in the placebo group. This difference was also statistically significant.
Patients in the combination group lost significantly more weight as well (mean 1.91 kg vs. a gain of 0.5 kg in the placebo group). Weight loss was quickly evident; by 4 weeks, patients had lost more than 1 kg. This “encouraging sign might help boost patient compliance,” Dr. Pozzilli said.
The side-effect profile was acceptable, compared with placebo. Hypoglycemia occurred in about 55% of those taking dulaglutide and 51% of those taking the placebo; it was symptomatic in 35% and 30%, respectively. Nocturnal hypoglycemia occurred in 28% and 29%, respectively. There was one case of severe hypoglycemia, which occurred in the dulaglutide group.
In addition to the GI side effects, there was one injection site reaction in the dulaglutide group. There were no cases of pancreatitis or pancreatic cancer.
The study was sponsored by Eli Lilly. Dr. Pozzilli is on the company’s speakers’ bureau and receives research grant money from it.
MUNICH – Once-weekly dulaglutide paired with insulin glargine plus metformin allowed 69% of patients with poorly controlled type 2 diabetes to achieve a hemoglobin A1c of 7% or lower.
Over the 28-week study, 51% of the group reached an HbA1c of 6.5% or lower – significantly better than the 17% who achieved this goal on insulin glargine with or without metformin, Paolo Pozzilli, MD, reported at the annual meeting of the European Association for the Study of Diabetes.
The combination was safe, with just one incident of severe hypoglycemia, and well tolerated, said Dr. Pozzilli of the University Campus Bio-Medico, Rome. Nausea – the most troublesome side effect of any glucagonlike peptide receptor agonist occurred in 12% of those taking the drug. Diarrhea occurred in 11% and vomiting in 6%. All of the gastrointestinal side effects were significantly more common than they were in the placebo group.
“I would say that the combination treatment of dulaglutide and insulin glargine – with or without metformin – is a reasonable, well-tolerated, and effective option for patients with type 2 diabetes who are not hitting their treatment goals,” he said.
Dr. Pozzilli reported results of Lily’s AWARD-9 trial. The placebo-controlled trial comprised 300 patients with poorly controlled type 2 diabetes (HbA1c, 7%-10.5%), despite being on insulin glargine and metformin. They were randomized to weekly subcutaneous placebo or 1.5 mg dulaglutide injections, in addition to their usual medications. There was no up titration on the study drug – patients started out with the full dose immediately. The study’s completion rate was high, with 92% of the investigational group and 87% of the control group finishing the 28-week treatment.
The group was typical for poorly controlled type 2 patients. Their mean age was 60 years; about 60% were men; and almost all were white. The mean body mass index was 32 kg/m2. The mean disease duration was 13 years, and the mean HbA1c was 8.4%. Their mean fasting plasma glucose was 8.7 mmol/L.
The effect of dual therapy was quickly evident, with HbA1c levels beginning to drop within 2 weeks. By 12 weeks, the separation between groups was statistically significant (dulaglutide HbA1c about 7%, placebo about 8%). By 28 weeks, the combination group had reached a mean HbA1c of 6.92%, compared with 7.69% in the placebo group. The response curve of the combination group appeared to be on a continuing decline when the study ended. The final measure represented an HbA1c decrease of 1.44% for the combination group and 0.67% for the placebo group.
By 28 weeks, 69% of the dulaglutide group and 35% of the placebo group had achieved an HbA1c of 7% or lower – a significant difference. Half of the dulaglutide group (51%) achieved a measure of 6.5% or lower, compared with 17% of the placebo group – also a significant difference.
The addition of dulaglutide moderated the need to increase the insulin that occurred over the study period. By 28 weeks, those taking dulaglutide had increased their insulin by a mean of 0.14 U/kg, compared with an increase of 0.27 U/kg in the placebo group. This difference was also statistically significant.
Patients in the combination group lost significantly more weight as well (mean 1.91 kg vs. a gain of 0.5 kg in the placebo group). Weight loss was quickly evident; by 4 weeks, patients had lost more than 1 kg. This “encouraging sign might help boost patient compliance,” Dr. Pozzilli said.
The side-effect profile was acceptable, compared with placebo. Hypoglycemia occurred in about 55% of those taking dulaglutide and 51% of those taking the placebo; it was symptomatic in 35% and 30%, respectively. Nocturnal hypoglycemia occurred in 28% and 29%, respectively. There was one case of severe hypoglycemia, which occurred in the dulaglutide group.
In addition to the GI side effects, there was one injection site reaction in the dulaglutide group. There were no cases of pancreatitis or pancreatic cancer.
The study was sponsored by Eli Lilly. Dr. Pozzilli is on the company’s speakers’ bureau and receives research grant money from it.
AT EASD 2016
Key clinical point: Adding dulaglutide to insulin glargine and metformin significantly improved long-term blood glucose levels.
Major finding: The combination of dulaglutide plus insulin glargine and metformin took 69% of patients to an HbA1c of 7% or lower.
Data source: The randomized, placebo-controlled AWARD-9 study comprised 300 patients with poorly controlled type 2 diabetes.
Disclosures: Eli Lilly sponsored the trials. Dr. Pozzilli is on the company’s speaker’s bureau and receives research funding from it.
Insulin-dependent pilots can fly safely with glucose monitoring protocol
MUNICH – British commercial pilots with insulin-dependent diabetes are flying safely, thanks to a rigorous protocol of hourly blood glucose monitoring during every flight.
Almost every one of the 8,897 readings reported so far has been in the safe “green zone” of 5-15 mmol/L, Julia Hine, MD, said at the annual meeting of the European Association for the Study of Diabetes.
Only 3.8% fell in the cautionary “amber” range of 4-5 mmol/L or 15-19 mmol/L. Just 0.2% (22) were in the “red” range of below 4 mmol/L or above 20 mmol/L – an occurrence that demands immediate release of airplane control to the copilot.
Reassuringly, only five of those readings occurred during flight, said Dr. Hine of the Royal Surrey County Hospital, England. The rest were taken during the preflight preparation period.
She said the 4-year data confirm that the protocol works, allowing highly skilled professionals to return to their work without compromising personal safety or the safety of those entrusted to their care.
“The testing protocol can be performed safely in the cockpit, with no safety concerns,” Dr. Hine said. “It represents an advance in patient care, showing that insulin-dependent patients can perform complex occupational duties.”
The protocol was instituted in 2012, after a consortium of commercial pilots met with diabetes specialists to create a way for certified pilots to regain their class 1 licenses after a diabetes diagnosis. It’s overseen by the U.K. Civil Aviation Authority and Irish Aviation Authority. Dr. Hine said the U.K. has the largest cadre of certified pilots who have insulin-dependent diabetes in the world. Canada is the only other country with such a program, although, she said, “There are a number of European states that have expressed interest in the program.”
In the United States, a diagnosis of insulin-dependent diabetes currently excludes pilots from flying commercial aircraft. The American Diabetes Association has been lobbying for easing of this strict FAA ban since at least 2014, stating that “the FAA’s blanket ban is not medically justified.” Specifically, the ADA favors a position in which “individual assessment of people with diabetes is the appropriate approach to determining whether a person is qualified to perform certain activities,” according to a statement.
The British protocol requires stringent pre- and in-flight blood sugar monitoring. Levels must be obtained at least 1 hour before reporting for duty and at least 2 hours before commencing a flight.
Blood sugar must be regularly measured during flight at well. For pilots using insulin, levels should be drawn every 2 hours, and for those on oral medications, every 2-4 hours. A final level must be drawn 30 minutes before landing.
Additional testing is required if the pilot experiences any symptoms related to fluctuating blood sugar. All results are read out loud, reported to the copilot and into the plane’s voice data recorder, and recorded in the pilot’s flight data record.
Levels in the amber range require the pilot to take corrective action. For low blood glucose levels, the pilot must consume 10-15 grams of carbohydrate, retest after 30 minutes, and adjust insulin. For high blood glucose levels, the pilot should review insulin dosing and modify carbohydrate intake, then retest in 45 minutes.
Readings in the red range demand immediate action, which includes handing over control of the flight, repeat testing, modifying insulin and carbohydrate intake, and retesting. The pilot may only resume duty when blood glucose returns to a green level.
There is a special protocol for pilots on insulin pumps, which are not guaranteed to function if there is a sudden loss of cabin pressure.
Dr. Hine and her colleague David Russell-Jones, MD, who is the program’s medical director, presented 4 years’ worth of data on 16 of the 26 pilots who have participated in the program. All of these pilots are otherwise healthy men with well-controlled diabetes who were deemed at low risk for glycemic events. They are an average of 40 years old with an average disease duration of 8 years. Their average HbA1c was 53 mmol/l before licensure and 54.8 mmol/l afterwards. All of the pilots have normal renal function, no retinopathy, no changes in blood pressure, and good awareness of hypoglycemia.
Among them, they have accumulated 4,900 flight hours and 8,897 blood glucose readings. Most of the flights (88%) were medium- or short-haul flights of less than 6 hours.
Even though 96% of readings fell into the 5-20 mmol/l green range, the bulk of those readings were in the range of 5-9 mmol/l. There was very little hourly variation in blood glucose levels during flights up to 6 hours, showing that the protocol is effective at establishing stable glycemia.
Right now, the program is in place only for current pilots who have a new diagnosis of diabetes. But, said Dr. Russell-Jones, it may be expanded at some point to encompass people with diabetes who wish to train to become a commercial pilot.
Neither Dr. Hines nor Dr. Russell-Jones reported any financial conflicts.
On Twitter @Alz_Gal
MUNICH – British commercial pilots with insulin-dependent diabetes are flying safely, thanks to a rigorous protocol of hourly blood glucose monitoring during every flight.
Almost every one of the 8,897 readings reported so far has been in the safe “green zone” of 5-15 mmol/L, Julia Hine, MD, said at the annual meeting of the European Association for the Study of Diabetes.
Only 3.8% fell in the cautionary “amber” range of 4-5 mmol/L or 15-19 mmol/L. Just 0.2% (22) were in the “red” range of below 4 mmol/L or above 20 mmol/L – an occurrence that demands immediate release of airplane control to the copilot.
Reassuringly, only five of those readings occurred during flight, said Dr. Hine of the Royal Surrey County Hospital, England. The rest were taken during the preflight preparation period.
She said the 4-year data confirm that the protocol works, allowing highly skilled professionals to return to their work without compromising personal safety or the safety of those entrusted to their care.
“The testing protocol can be performed safely in the cockpit, with no safety concerns,” Dr. Hine said. “It represents an advance in patient care, showing that insulin-dependent patients can perform complex occupational duties.”
The protocol was instituted in 2012, after a consortium of commercial pilots met with diabetes specialists to create a way for certified pilots to regain their class 1 licenses after a diabetes diagnosis. It’s overseen by the U.K. Civil Aviation Authority and Irish Aviation Authority. Dr. Hine said the U.K. has the largest cadre of certified pilots who have insulin-dependent diabetes in the world. Canada is the only other country with such a program, although, she said, “There are a number of European states that have expressed interest in the program.”
In the United States, a diagnosis of insulin-dependent diabetes currently excludes pilots from flying commercial aircraft. The American Diabetes Association has been lobbying for easing of this strict FAA ban since at least 2014, stating that “the FAA’s blanket ban is not medically justified.” Specifically, the ADA favors a position in which “individual assessment of people with diabetes is the appropriate approach to determining whether a person is qualified to perform certain activities,” according to a statement.
The British protocol requires stringent pre- and in-flight blood sugar monitoring. Levels must be obtained at least 1 hour before reporting for duty and at least 2 hours before commencing a flight.
Blood sugar must be regularly measured during flight at well. For pilots using insulin, levels should be drawn every 2 hours, and for those on oral medications, every 2-4 hours. A final level must be drawn 30 minutes before landing.
Additional testing is required if the pilot experiences any symptoms related to fluctuating blood sugar. All results are read out loud, reported to the copilot and into the plane’s voice data recorder, and recorded in the pilot’s flight data record.
Levels in the amber range require the pilot to take corrective action. For low blood glucose levels, the pilot must consume 10-15 grams of carbohydrate, retest after 30 minutes, and adjust insulin. For high blood glucose levels, the pilot should review insulin dosing and modify carbohydrate intake, then retest in 45 minutes.
Readings in the red range demand immediate action, which includes handing over control of the flight, repeat testing, modifying insulin and carbohydrate intake, and retesting. The pilot may only resume duty when blood glucose returns to a green level.
There is a special protocol for pilots on insulin pumps, which are not guaranteed to function if there is a sudden loss of cabin pressure.
Dr. Hine and her colleague David Russell-Jones, MD, who is the program’s medical director, presented 4 years’ worth of data on 16 of the 26 pilots who have participated in the program. All of these pilots are otherwise healthy men with well-controlled diabetes who were deemed at low risk for glycemic events. They are an average of 40 years old with an average disease duration of 8 years. Their average HbA1c was 53 mmol/l before licensure and 54.8 mmol/l afterwards. All of the pilots have normal renal function, no retinopathy, no changes in blood pressure, and good awareness of hypoglycemia.
Among them, they have accumulated 4,900 flight hours and 8,897 blood glucose readings. Most of the flights (88%) were medium- or short-haul flights of less than 6 hours.
Even though 96% of readings fell into the 5-20 mmol/l green range, the bulk of those readings were in the range of 5-9 mmol/l. There was very little hourly variation in blood glucose levels during flights up to 6 hours, showing that the protocol is effective at establishing stable glycemia.
Right now, the program is in place only for current pilots who have a new diagnosis of diabetes. But, said Dr. Russell-Jones, it may be expanded at some point to encompass people with diabetes who wish to train to become a commercial pilot.
Neither Dr. Hines nor Dr. Russell-Jones reported any financial conflicts.
On Twitter @Alz_Gal
MUNICH – British commercial pilots with insulin-dependent diabetes are flying safely, thanks to a rigorous protocol of hourly blood glucose monitoring during every flight.
Almost every one of the 8,897 readings reported so far has been in the safe “green zone” of 5-15 mmol/L, Julia Hine, MD, said at the annual meeting of the European Association for the Study of Diabetes.
Only 3.8% fell in the cautionary “amber” range of 4-5 mmol/L or 15-19 mmol/L. Just 0.2% (22) were in the “red” range of below 4 mmol/L or above 20 mmol/L – an occurrence that demands immediate release of airplane control to the copilot.
Reassuringly, only five of those readings occurred during flight, said Dr. Hine of the Royal Surrey County Hospital, England. The rest were taken during the preflight preparation period.
She said the 4-year data confirm that the protocol works, allowing highly skilled professionals to return to their work without compromising personal safety or the safety of those entrusted to their care.
“The testing protocol can be performed safely in the cockpit, with no safety concerns,” Dr. Hine said. “It represents an advance in patient care, showing that insulin-dependent patients can perform complex occupational duties.”
The protocol was instituted in 2012, after a consortium of commercial pilots met with diabetes specialists to create a way for certified pilots to regain their class 1 licenses after a diabetes diagnosis. It’s overseen by the U.K. Civil Aviation Authority and Irish Aviation Authority. Dr. Hine said the U.K. has the largest cadre of certified pilots who have insulin-dependent diabetes in the world. Canada is the only other country with such a program, although, she said, “There are a number of European states that have expressed interest in the program.”
In the United States, a diagnosis of insulin-dependent diabetes currently excludes pilots from flying commercial aircraft. The American Diabetes Association has been lobbying for easing of this strict FAA ban since at least 2014, stating that “the FAA’s blanket ban is not medically justified.” Specifically, the ADA favors a position in which “individual assessment of people with diabetes is the appropriate approach to determining whether a person is qualified to perform certain activities,” according to a statement.
The British protocol requires stringent pre- and in-flight blood sugar monitoring. Levels must be obtained at least 1 hour before reporting for duty and at least 2 hours before commencing a flight.
Blood sugar must be regularly measured during flight at well. For pilots using insulin, levels should be drawn every 2 hours, and for those on oral medications, every 2-4 hours. A final level must be drawn 30 minutes before landing.
Additional testing is required if the pilot experiences any symptoms related to fluctuating blood sugar. All results are read out loud, reported to the copilot and into the plane’s voice data recorder, and recorded in the pilot’s flight data record.
Levels in the amber range require the pilot to take corrective action. For low blood glucose levels, the pilot must consume 10-15 grams of carbohydrate, retest after 30 minutes, and adjust insulin. For high blood glucose levels, the pilot should review insulin dosing and modify carbohydrate intake, then retest in 45 minutes.
Readings in the red range demand immediate action, which includes handing over control of the flight, repeat testing, modifying insulin and carbohydrate intake, and retesting. The pilot may only resume duty when blood glucose returns to a green level.
There is a special protocol for pilots on insulin pumps, which are not guaranteed to function if there is a sudden loss of cabin pressure.
Dr. Hine and her colleague David Russell-Jones, MD, who is the program’s medical director, presented 4 years’ worth of data on 16 of the 26 pilots who have participated in the program. All of these pilots are otherwise healthy men with well-controlled diabetes who were deemed at low risk for glycemic events. They are an average of 40 years old with an average disease duration of 8 years. Their average HbA1c was 53 mmol/l before licensure and 54.8 mmol/l afterwards. All of the pilots have normal renal function, no retinopathy, no changes in blood pressure, and good awareness of hypoglycemia.
Among them, they have accumulated 4,900 flight hours and 8,897 blood glucose readings. Most of the flights (88%) were medium- or short-haul flights of less than 6 hours.
Even though 96% of readings fell into the 5-20 mmol/l green range, the bulk of those readings were in the range of 5-9 mmol/l. There was very little hourly variation in blood glucose levels during flights up to 6 hours, showing that the protocol is effective at establishing stable glycemia.
Right now, the program is in place only for current pilots who have a new diagnosis of diabetes. But, said Dr. Russell-Jones, it may be expanded at some point to encompass people with diabetes who wish to train to become a commercial pilot.
Neither Dr. Hines nor Dr. Russell-Jones reported any financial conflicts.
On Twitter @Alz_Gal
AT EASD 2016
Key clinical point: A protocol of regular blood glucose monitoring during flight is keeping British commercial pilots in the air.
Major finding: Of 8,897 blood glucose readings, only 22 were in the dangerous “red” range that demands handing over control of the plane to the copilot.
Data source: The 16 pilots in the program have amassed 4,900 flight hours.
Disclosures: Neither Dr. Hine nor Dr. Russell-Jones had any financial disclosures.
Brain atrophy is already evident in patients with prediabetes
MUNICH – Brain changes suggestive of cerebral microvascular dysfunction are already apparent in patients with prediabetes.
The changes – increased white matter hyperintensities and decreased white matter volume – are even more pronounced in subjects with type 2 diabetes, Marnix van Agtmaal, MD, said at the annual meeting of the European Association for the Study of Diabetes. Patients with frank diabetes also showed an increase in intracranial cerebrospinal fluid – a correlate of the decrease in brain volume, said Dr. van Agtmaal of Maastricht (the Netherlands) University Medical Center.
The changes are probably caused by diabetes-related endothelial dysfunction, he said.
“The brain is highly dependent on properly functioning microcirculation. This is critical, since the brain has high energy demand and no energy reserve. In prediabetes and type 2 diabetes, microvascular endothelial dysfunction occurs. This leads to cerebral hypoperfusion, which in turns causes chronic ischemia. This contributes to small vessel disease leading to brain atrophy and, eventually, cognitive decline and dementia.”
The 2,251 subjects in the analysis were drawn from the Maastricht study, an ongoing observational study of people with type 2 diabetes.
Among the group, 350 had prediabetes, defined as impaired fasting glucose, impaired glucose tolerance, or a combination of the two. Type 2 diabetes was present in 528. The rest had healthy glucose metabolism.
As the cohort progressed from healthy glucose metabolism to prediabetes and then diabetes, they became older (aged 58 years in the healthy group vs. 62 years in the diabetes group), heavier, and displayed worsening cardiovascular risk factors, with increasing systolic blood pressure and progressively poorer lipid profiles. Kidney function was preserved in all patients, however.
The groups were not balanced in terms of sex: 56% of those with healthy glucose metabolism were women, compared with 47% of those with prediabetes and 31% of those with type 2 diabetes.
Dr. van Agtmaal and his colleagues examined white matter hyperintensities, white matter volume, gray matter volume, and intracranial CSF. They conducted three linear regression models: a crude unadjusted model, a partially adjusted model that controlled for age, sex, and intracranial volume; and a fully adjusted model that controlled for those factors, plus systolic blood pressure, lipids, smoking, kidney function, and education.
There was a clear linear association between white matter hyperintensity (WMH) volume and healthy glucose metabolism, prediabetes, and type 2 diabetes. In the crude analysis, the healthy subjects carried about 0.75 mL of WMH. Prediabetic subjects carried about 1.25 mL, and those with diabetes, about 2 mL.
In both the partially and fully adjusted models, this relationship was somewhat attenuated, but it remained significant for both prediabetes and diabetes.
The crude model also found that both diabetes groups had significantly lower white matter volume than did the healthy subjects. In healthy subjects, the mean volume was about 480 mL. This was about 467 mL in those with prediabetes and 466 mL in those with type 2 diabetes. Again, the partially and fully adjusted models slightly attenuated the relationship, but it remained significant in both disease states.
The crude model showed that gray matter was decreased in both prediabetes and type 2 diabetes. In healthy subjects, total gray matter was about 667 mL. In those with prediabetes, it was about 655 mL, and in those with type 2 diabetes, about 645 mL. However, the significant associations disappeared for both diabetes and prediabetes in both adjusted models.
Intracranial CSF was also different among the three groups in the crude model. In the healthy subjects, the total intracranial CSF volume was about 248 mL. In those with prediabetes, it was about 255 mL, and in those with type 2 diabetes, about 270 mL.
The association with prediabetes disappeared in the fully adjusted model – but for type 2 diabetes, it remained strongly significant.
Dr. van Agtmaal has not correlated the imaging findings with any cognitive testing on these subjects but said that study is coming.
“Further analysis will also look at cognitive decline and the development of dementia in the group,” he said. “We also intend to look at associations with other outcomes of cerebral dysfunction, including depression.”
Dr. van Agtmaal had no financial disclosures.
MUNICH – Brain changes suggestive of cerebral microvascular dysfunction are already apparent in patients with prediabetes.
The changes – increased white matter hyperintensities and decreased white matter volume – are even more pronounced in subjects with type 2 diabetes, Marnix van Agtmaal, MD, said at the annual meeting of the European Association for the Study of Diabetes. Patients with frank diabetes also showed an increase in intracranial cerebrospinal fluid – a correlate of the decrease in brain volume, said Dr. van Agtmaal of Maastricht (the Netherlands) University Medical Center.
The changes are probably caused by diabetes-related endothelial dysfunction, he said.
“The brain is highly dependent on properly functioning microcirculation. This is critical, since the brain has high energy demand and no energy reserve. In prediabetes and type 2 diabetes, microvascular endothelial dysfunction occurs. This leads to cerebral hypoperfusion, which in turns causes chronic ischemia. This contributes to small vessel disease leading to brain atrophy and, eventually, cognitive decline and dementia.”
The 2,251 subjects in the analysis were drawn from the Maastricht study, an ongoing observational study of people with type 2 diabetes.
Among the group, 350 had prediabetes, defined as impaired fasting glucose, impaired glucose tolerance, or a combination of the two. Type 2 diabetes was present in 528. The rest had healthy glucose metabolism.
As the cohort progressed from healthy glucose metabolism to prediabetes and then diabetes, they became older (aged 58 years in the healthy group vs. 62 years in the diabetes group), heavier, and displayed worsening cardiovascular risk factors, with increasing systolic blood pressure and progressively poorer lipid profiles. Kidney function was preserved in all patients, however.
The groups were not balanced in terms of sex: 56% of those with healthy glucose metabolism were women, compared with 47% of those with prediabetes and 31% of those with type 2 diabetes.
Dr. van Agtmaal and his colleagues examined white matter hyperintensities, white matter volume, gray matter volume, and intracranial CSF. They conducted three linear regression models: a crude unadjusted model, a partially adjusted model that controlled for age, sex, and intracranial volume; and a fully adjusted model that controlled for those factors, plus systolic blood pressure, lipids, smoking, kidney function, and education.
There was a clear linear association between white matter hyperintensity (WMH) volume and healthy glucose metabolism, prediabetes, and type 2 diabetes. In the crude analysis, the healthy subjects carried about 0.75 mL of WMH. Prediabetic subjects carried about 1.25 mL, and those with diabetes, about 2 mL.
In both the partially and fully adjusted models, this relationship was somewhat attenuated, but it remained significant for both prediabetes and diabetes.
The crude model also found that both diabetes groups had significantly lower white matter volume than did the healthy subjects. In healthy subjects, the mean volume was about 480 mL. This was about 467 mL in those with prediabetes and 466 mL in those with type 2 diabetes. Again, the partially and fully adjusted models slightly attenuated the relationship, but it remained significant in both disease states.
The crude model showed that gray matter was decreased in both prediabetes and type 2 diabetes. In healthy subjects, total gray matter was about 667 mL. In those with prediabetes, it was about 655 mL, and in those with type 2 diabetes, about 645 mL. However, the significant associations disappeared for both diabetes and prediabetes in both adjusted models.
Intracranial CSF was also different among the three groups in the crude model. In the healthy subjects, the total intracranial CSF volume was about 248 mL. In those with prediabetes, it was about 255 mL, and in those with type 2 diabetes, about 270 mL.
The association with prediabetes disappeared in the fully adjusted model – but for type 2 diabetes, it remained strongly significant.
Dr. van Agtmaal has not correlated the imaging findings with any cognitive testing on these subjects but said that study is coming.
“Further analysis will also look at cognitive decline and the development of dementia in the group,” he said. “We also intend to look at associations with other outcomes of cerebral dysfunction, including depression.”
Dr. van Agtmaal had no financial disclosures.
MUNICH – Brain changes suggestive of cerebral microvascular dysfunction are already apparent in patients with prediabetes.
The changes – increased white matter hyperintensities and decreased white matter volume – are even more pronounced in subjects with type 2 diabetes, Marnix van Agtmaal, MD, said at the annual meeting of the European Association for the Study of Diabetes. Patients with frank diabetes also showed an increase in intracranial cerebrospinal fluid – a correlate of the decrease in brain volume, said Dr. van Agtmaal of Maastricht (the Netherlands) University Medical Center.
The changes are probably caused by diabetes-related endothelial dysfunction, he said.
“The brain is highly dependent on properly functioning microcirculation. This is critical, since the brain has high energy demand and no energy reserve. In prediabetes and type 2 diabetes, microvascular endothelial dysfunction occurs. This leads to cerebral hypoperfusion, which in turns causes chronic ischemia. This contributes to small vessel disease leading to brain atrophy and, eventually, cognitive decline and dementia.”
The 2,251 subjects in the analysis were drawn from the Maastricht study, an ongoing observational study of people with type 2 diabetes.
Among the group, 350 had prediabetes, defined as impaired fasting glucose, impaired glucose tolerance, or a combination of the two. Type 2 diabetes was present in 528. The rest had healthy glucose metabolism.
As the cohort progressed from healthy glucose metabolism to prediabetes and then diabetes, they became older (aged 58 years in the healthy group vs. 62 years in the diabetes group), heavier, and displayed worsening cardiovascular risk factors, with increasing systolic blood pressure and progressively poorer lipid profiles. Kidney function was preserved in all patients, however.
The groups were not balanced in terms of sex: 56% of those with healthy glucose metabolism were women, compared with 47% of those with prediabetes and 31% of those with type 2 diabetes.
Dr. van Agtmaal and his colleagues examined white matter hyperintensities, white matter volume, gray matter volume, and intracranial CSF. They conducted three linear regression models: a crude unadjusted model, a partially adjusted model that controlled for age, sex, and intracranial volume; and a fully adjusted model that controlled for those factors, plus systolic blood pressure, lipids, smoking, kidney function, and education.
There was a clear linear association between white matter hyperintensity (WMH) volume and healthy glucose metabolism, prediabetes, and type 2 diabetes. In the crude analysis, the healthy subjects carried about 0.75 mL of WMH. Prediabetic subjects carried about 1.25 mL, and those with diabetes, about 2 mL.
In both the partially and fully adjusted models, this relationship was somewhat attenuated, but it remained significant for both prediabetes and diabetes.
The crude model also found that both diabetes groups had significantly lower white matter volume than did the healthy subjects. In healthy subjects, the mean volume was about 480 mL. This was about 467 mL in those with prediabetes and 466 mL in those with type 2 diabetes. Again, the partially and fully adjusted models slightly attenuated the relationship, but it remained significant in both disease states.
The crude model showed that gray matter was decreased in both prediabetes and type 2 diabetes. In healthy subjects, total gray matter was about 667 mL. In those with prediabetes, it was about 655 mL, and in those with type 2 diabetes, about 645 mL. However, the significant associations disappeared for both diabetes and prediabetes in both adjusted models.
Intracranial CSF was also different among the three groups in the crude model. In the healthy subjects, the total intracranial CSF volume was about 248 mL. In those with prediabetes, it was about 255 mL, and in those with type 2 diabetes, about 270 mL.
The association with prediabetes disappeared in the fully adjusted model – but for type 2 diabetes, it remained strongly significant.
Dr. van Agtmaal has not correlated the imaging findings with any cognitive testing on these subjects but said that study is coming.
“Further analysis will also look at cognitive decline and the development of dementia in the group,” he said. “We also intend to look at associations with other outcomes of cerebral dysfunction, including depression.”
Dr. van Agtmaal had no financial disclosures.
AT EASD 2016
Key clinical point: People with prediabetes and type 2 diabetes have more white matter hyperintensities and lower white matter volume than do those with healthy glucose metabolism.
Major finding: Healthy subjects carried about 0.75 mL of white matter hyperintensities, while prediabetic subjects carried about 1.25 mL, and those with diabetes, about 2.0 mL.
Data source: The subset of the Maastricht Study comprised 2,251 subjects.
Disclosures: Dr. van Agtmaal had no financial disclosures.
Both prepregnancy and gestational diabetes bode ill for babies
MUNICH – Pregestational maternal diabetes is even riskier for newborns than gestational diabetes, increasing the chance of neonatal hypoglycemia by 36 times over a normal pregnancy.
Baby’s blood sugar isn’t the only thing in danger, though, Basilio Pintaudi, MD, said at the European Association for the Study of Diabetes conference. Women with prepregnancy diabetes are significantly more likely to have babies that are either small or large for gestational age; become jaundiced; have congenital malformations; and experience respiratory distress, hypocalcemia, and hypomagnesemia, said Dr. Pintaudi of Niguarda Ca’ Granda Hospital, Milan.
“Everyone involved in the care of pregnant women should realize there are very real risks for severe neonatal outcomes, for all forms of diabetes – whether it exists before pregnancy or develops during pregnancy,” Dr. Pintaudi said in an interview. “It’s very important to detect both prepregnancy and gestational diabetes early and optimize maternal glucose levels as quickly as possible.”
He and his colleagues studied outcomes in 135,000 pregnancies included in an administrative database in the Italian Puglia region from 2002 to 2012. They found 1,357 singleton pregnancies complicated by gestational diabetes, and 234 by pregestational diabetes. They computed the risks of a number of neonatal outcomes in a multivariate analysis that controlled for hypertensive and thyroid disorders and for several drugs, including antithrombotics, antiplatelets, and ticlopidine. These drugs were chosen as indicators of high-risk pregnancy.
Both gestational and pregestational diabetes were associated with significantly higher risks of neonatal hypoglycemia (odds ratios, 10 and 36, respectively). They were also associated with significantly increased risks of a small for gestational age infant (ORs, 1.7 and 5.8), and large for gestational age infant (ORs, 1.7 and 7.9).
The risk of jaundice was also increased for both gestational and pregestational diabetes (ORs, 1.7 and 2.6).
Fetal malformations were more common in both disorders (ORs, 2.2 and 3.5). The database didn’t include specifics on what type of malformations occurred, but Dr. Pintaudi said prior studies show increases in cardiac and neural tube defects. This problem in particular illustrates the need for early screening and management of pregestational diabetes, he said in an interview.
“The pathophysiology of these malformations is such that they occur in the very early stages of pregnancy, before some women even know they might be pregnant,” he said.
Hypocalcemia and hypomagnesemia of the newborn were more likely in both gestational and pregestational diabetes (ORs, 1.8 and 9.2), as was Cesarean delivery (ORs, 1.9 and 8.5).
Pregestational diabetes alone was also associated with an increased risk of respiratory distress (OR, 2.7) and polyhydramnios (OR, 46.5).
Dr. Pintaudi said that Italy does not recommend universal diabetes screening for women who are or wish to become pregnant. The first evaluation occurs at 16-18 weeks’ gestation, with a repeat evaluation at 24-28 weeks.
He had no financial disclosures.
On Twitter @Alz_Gal
MUNICH – Pregestational maternal diabetes is even riskier for newborns than gestational diabetes, increasing the chance of neonatal hypoglycemia by 36 times over a normal pregnancy.
Baby’s blood sugar isn’t the only thing in danger, though, Basilio Pintaudi, MD, said at the European Association for the Study of Diabetes conference. Women with prepregnancy diabetes are significantly more likely to have babies that are either small or large for gestational age; become jaundiced; have congenital malformations; and experience respiratory distress, hypocalcemia, and hypomagnesemia, said Dr. Pintaudi of Niguarda Ca’ Granda Hospital, Milan.
“Everyone involved in the care of pregnant women should realize there are very real risks for severe neonatal outcomes, for all forms of diabetes – whether it exists before pregnancy or develops during pregnancy,” Dr. Pintaudi said in an interview. “It’s very important to detect both prepregnancy and gestational diabetes early and optimize maternal glucose levels as quickly as possible.”
He and his colleagues studied outcomes in 135,000 pregnancies included in an administrative database in the Italian Puglia region from 2002 to 2012. They found 1,357 singleton pregnancies complicated by gestational diabetes, and 234 by pregestational diabetes. They computed the risks of a number of neonatal outcomes in a multivariate analysis that controlled for hypertensive and thyroid disorders and for several drugs, including antithrombotics, antiplatelets, and ticlopidine. These drugs were chosen as indicators of high-risk pregnancy.
Both gestational and pregestational diabetes were associated with significantly higher risks of neonatal hypoglycemia (odds ratios, 10 and 36, respectively). They were also associated with significantly increased risks of a small for gestational age infant (ORs, 1.7 and 5.8), and large for gestational age infant (ORs, 1.7 and 7.9).
The risk of jaundice was also increased for both gestational and pregestational diabetes (ORs, 1.7 and 2.6).
Fetal malformations were more common in both disorders (ORs, 2.2 and 3.5). The database didn’t include specifics on what type of malformations occurred, but Dr. Pintaudi said prior studies show increases in cardiac and neural tube defects. This problem in particular illustrates the need for early screening and management of pregestational diabetes, he said in an interview.
“The pathophysiology of these malformations is such that they occur in the very early stages of pregnancy, before some women even know they might be pregnant,” he said.
Hypocalcemia and hypomagnesemia of the newborn were more likely in both gestational and pregestational diabetes (ORs, 1.8 and 9.2), as was Cesarean delivery (ORs, 1.9 and 8.5).
Pregestational diabetes alone was also associated with an increased risk of respiratory distress (OR, 2.7) and polyhydramnios (OR, 46.5).
Dr. Pintaudi said that Italy does not recommend universal diabetes screening for women who are or wish to become pregnant. The first evaluation occurs at 16-18 weeks’ gestation, with a repeat evaluation at 24-28 weeks.
He had no financial disclosures.
On Twitter @Alz_Gal
MUNICH – Pregestational maternal diabetes is even riskier for newborns than gestational diabetes, increasing the chance of neonatal hypoglycemia by 36 times over a normal pregnancy.
Baby’s blood sugar isn’t the only thing in danger, though, Basilio Pintaudi, MD, said at the European Association for the Study of Diabetes conference. Women with prepregnancy diabetes are significantly more likely to have babies that are either small or large for gestational age; become jaundiced; have congenital malformations; and experience respiratory distress, hypocalcemia, and hypomagnesemia, said Dr. Pintaudi of Niguarda Ca’ Granda Hospital, Milan.
“Everyone involved in the care of pregnant women should realize there are very real risks for severe neonatal outcomes, for all forms of diabetes – whether it exists before pregnancy or develops during pregnancy,” Dr. Pintaudi said in an interview. “It’s very important to detect both prepregnancy and gestational diabetes early and optimize maternal glucose levels as quickly as possible.”
He and his colleagues studied outcomes in 135,000 pregnancies included in an administrative database in the Italian Puglia region from 2002 to 2012. They found 1,357 singleton pregnancies complicated by gestational diabetes, and 234 by pregestational diabetes. They computed the risks of a number of neonatal outcomes in a multivariate analysis that controlled for hypertensive and thyroid disorders and for several drugs, including antithrombotics, antiplatelets, and ticlopidine. These drugs were chosen as indicators of high-risk pregnancy.
Both gestational and pregestational diabetes were associated with significantly higher risks of neonatal hypoglycemia (odds ratios, 10 and 36, respectively). They were also associated with significantly increased risks of a small for gestational age infant (ORs, 1.7 and 5.8), and large for gestational age infant (ORs, 1.7 and 7.9).
The risk of jaundice was also increased for both gestational and pregestational diabetes (ORs, 1.7 and 2.6).
Fetal malformations were more common in both disorders (ORs, 2.2 and 3.5). The database didn’t include specifics on what type of malformations occurred, but Dr. Pintaudi said prior studies show increases in cardiac and neural tube defects. This problem in particular illustrates the need for early screening and management of pregestational diabetes, he said in an interview.
“The pathophysiology of these malformations is such that they occur in the very early stages of pregnancy, before some women even know they might be pregnant,” he said.
Hypocalcemia and hypomagnesemia of the newborn were more likely in both gestational and pregestational diabetes (ORs, 1.8 and 9.2), as was Cesarean delivery (ORs, 1.9 and 8.5).
Pregestational diabetes alone was also associated with an increased risk of respiratory distress (OR, 2.7) and polyhydramnios (OR, 46.5).
Dr. Pintaudi said that Italy does not recommend universal diabetes screening for women who are or wish to become pregnant. The first evaluation occurs at 16-18 weeks’ gestation, with a repeat evaluation at 24-28 weeks.
He had no financial disclosures.
On Twitter @Alz_Gal
AT EASD 2016
Key clinical point: Pregestational and gestational diabetes increase the risk of a several poor neonatal outcomes.
Major finding: Pregestational diabetes increased the risk of neonatal hypoglycemia by 36 times; gestational diabetes by 10 times.
Data source: The database review comprised 135,000 singleton pregnancies.
Disclosures: Dr. Pintaudi had no financial disclosures.
Four-step screen IDs silent heart attack in type 2 diabetes
MUNICH – A four-component imaging/biomarker screen was highly accurate for identifying silent myocardial infarction among asymptomatic patients with type 2 diabetes.
The screen is far more accurate than the current standards of invasive imaging or only looking for pathologic Q waves, Peter Swoboda, MD, said at the annual meeting of the European Association for the Study of Diabetes.
“By combining these four factors we came up with a tool that has a diagnostic area under the curve [AUC] of 0.85,” said Dr. Swoboda of Leeds (England) University. “This is far better than the 0.58 AUC that we have with Q waves only – a sensitivity of just 25%.”
The study was published online in June in the Journal of Clinical Endocrinology and Metabolism (JCEM 2016. doi: 10.1210/jc.2016-1318).
The screen employs noninvasive imaging and biomarkers to tap multiple clinical hallmarks of silent MI. The components are:
• electrocardiogram.
• echocardiography.
• biomarker assessment.
• cardiac magnetic resonance imaging, focusing on left ventricular ejection fraction and late gadolinium enhancement.
The study cohort comprised 100 patients with type 2 diabetes without known heart disease and with no new cardiac symptoms. They underwent cardiac MRI, a 12-lead electrocardiogram, echocardiography, and serum biomarker assessment. Late gadolinium enhancement identified evidence of silent MI in 17 patients (17%).
There were few differences in the clinical characteristics of those who had experienced MI and those who had not, Dr. Swoboda noted. There were no differences at all in diabetes-related measures, including disease duration or hemoglobin A1c levels. Blood pressures were similar. Patients with MI were significantly older (65 vs. 60 years).
In cardiac-specific measures, left ventricular ejection fraction was similar, as was left ventricular mass, end diastolic volume, and left atrial volume. There were however, other very important differences, Dr. Swoboda noted.
Imaging included a measure called “feature tracking analysis,” which measured the peak global longitudinal strain, systolic strain rate, and early and late diastolic strain rates during contraction. This analysis noted a significant difference in global longitudinal strain between the MI and non-MI groups.
Ventricular filling velocities as measured by the E/A ratio on ECG were also significantly different between the MI and non-MI groups (0.75 vs. 0.89, respectively). ECG also found pathologic Q waves in significantly more MI patients (24% vs. 7%).
Finally, the serum biomarker panel showed a very strong increase in B-type natriuretic peptide (NT-proBNP) among MI patients, compared with non-MI patients (105 vs. 52 ng/L). There were no significant differences in the other biomarkers, including C-reactive protein and high-sensitive cardiac troponin.
Dr. Swoboda and his team then compiled these findings into a composite measure, assigning them optimum cutoff measures:
• Age older than 62 years.
• E/A ratio 0.72 or lower.
• Global longitudinal strain of at least 18.4%.
• NT-proBNP more than 29 ng/L.
The system resulted in a diagnostic accuracy AUC of 0.85 – significantly better than any of the AUCs generated by the individual components. All patients who scored 0 or 1 were free of MI. Among the 28 with a score of 2, only three had experienced a silent MI. Among the 21 with a score of 3, seven had experienced a silent MI and 14 had not. Among the 16 with a score of 4, seven had experienced a silent MI and nine had not.
While Dr. Swoboda called the screening method “simple” during discussion, a colleague in the audience disagreed with that.
“A simple test is something like a blood test only, not an MRI. Not imaging. That is expensive and takes time,” said Naveed Sattar, MD, of the University of Glasgow, Scotland. “However, I do think your data add more to the evidence that BNP can be a really valuable marker of cardiovascular risk in patients with diabetes.”
Dr. Sattar recently examined the value of cardiac serum biomarkers in predicting cardiovascular disease and mortality in nearly 100,000 people without a history of heart disease. In these subjects, he wrote, “NT-proBNP assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention.”
The paper appeared online in Lancet Diabetes in September (Lancet Diab. 2016. doi: 10.1016/S2213-8587[16]30196-6).
Dr. Swoboda agreed that data continue to support the increased use of NT-proBNP as a marker of heart disease.
“I think that in the future, diabetes medicine is moving toward individualized patient care, based on individualized risk factors. The future of assessing asymptomatic cardiac patients might be a combination of BNP and MRI.”
Dr. Swoboda had no financial disclosures. Some of Dr. Sattar’s coauthors reported relationships with pharmaceutical companies.
MUNICH – A four-component imaging/biomarker screen was highly accurate for identifying silent myocardial infarction among asymptomatic patients with type 2 diabetes.
The screen is far more accurate than the current standards of invasive imaging or only looking for pathologic Q waves, Peter Swoboda, MD, said at the annual meeting of the European Association for the Study of Diabetes.
“By combining these four factors we came up with a tool that has a diagnostic area under the curve [AUC] of 0.85,” said Dr. Swoboda of Leeds (England) University. “This is far better than the 0.58 AUC that we have with Q waves only – a sensitivity of just 25%.”
The study was published online in June in the Journal of Clinical Endocrinology and Metabolism (JCEM 2016. doi: 10.1210/jc.2016-1318).
The screen employs noninvasive imaging and biomarkers to tap multiple clinical hallmarks of silent MI. The components are:
• electrocardiogram.
• echocardiography.
• biomarker assessment.
• cardiac magnetic resonance imaging, focusing on left ventricular ejection fraction and late gadolinium enhancement.
The study cohort comprised 100 patients with type 2 diabetes without known heart disease and with no new cardiac symptoms. They underwent cardiac MRI, a 12-lead electrocardiogram, echocardiography, and serum biomarker assessment. Late gadolinium enhancement identified evidence of silent MI in 17 patients (17%).
There were few differences in the clinical characteristics of those who had experienced MI and those who had not, Dr. Swoboda noted. There were no differences at all in diabetes-related measures, including disease duration or hemoglobin A1c levels. Blood pressures were similar. Patients with MI were significantly older (65 vs. 60 years).
In cardiac-specific measures, left ventricular ejection fraction was similar, as was left ventricular mass, end diastolic volume, and left atrial volume. There were however, other very important differences, Dr. Swoboda noted.
Imaging included a measure called “feature tracking analysis,” which measured the peak global longitudinal strain, systolic strain rate, and early and late diastolic strain rates during contraction. This analysis noted a significant difference in global longitudinal strain between the MI and non-MI groups.
Ventricular filling velocities as measured by the E/A ratio on ECG were also significantly different between the MI and non-MI groups (0.75 vs. 0.89, respectively). ECG also found pathologic Q waves in significantly more MI patients (24% vs. 7%).
Finally, the serum biomarker panel showed a very strong increase in B-type natriuretic peptide (NT-proBNP) among MI patients, compared with non-MI patients (105 vs. 52 ng/L). There were no significant differences in the other biomarkers, including C-reactive protein and high-sensitive cardiac troponin.
Dr. Swoboda and his team then compiled these findings into a composite measure, assigning them optimum cutoff measures:
• Age older than 62 years.
• E/A ratio 0.72 or lower.
• Global longitudinal strain of at least 18.4%.
• NT-proBNP more than 29 ng/L.
The system resulted in a diagnostic accuracy AUC of 0.85 – significantly better than any of the AUCs generated by the individual components. All patients who scored 0 or 1 were free of MI. Among the 28 with a score of 2, only three had experienced a silent MI. Among the 21 with a score of 3, seven had experienced a silent MI and 14 had not. Among the 16 with a score of 4, seven had experienced a silent MI and nine had not.
While Dr. Swoboda called the screening method “simple” during discussion, a colleague in the audience disagreed with that.
“A simple test is something like a blood test only, not an MRI. Not imaging. That is expensive and takes time,” said Naveed Sattar, MD, of the University of Glasgow, Scotland. “However, I do think your data add more to the evidence that BNP can be a really valuable marker of cardiovascular risk in patients with diabetes.”
Dr. Sattar recently examined the value of cardiac serum biomarkers in predicting cardiovascular disease and mortality in nearly 100,000 people without a history of heart disease. In these subjects, he wrote, “NT-proBNP assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention.”
The paper appeared online in Lancet Diabetes in September (Lancet Diab. 2016. doi: 10.1016/S2213-8587[16]30196-6).
Dr. Swoboda agreed that data continue to support the increased use of NT-proBNP as a marker of heart disease.
“I think that in the future, diabetes medicine is moving toward individualized patient care, based on individualized risk factors. The future of assessing asymptomatic cardiac patients might be a combination of BNP and MRI.”
Dr. Swoboda had no financial disclosures. Some of Dr. Sattar’s coauthors reported relationships with pharmaceutical companies.
MUNICH – A four-component imaging/biomarker screen was highly accurate for identifying silent myocardial infarction among asymptomatic patients with type 2 diabetes.
The screen is far more accurate than the current standards of invasive imaging or only looking for pathologic Q waves, Peter Swoboda, MD, said at the annual meeting of the European Association for the Study of Diabetes.
“By combining these four factors we came up with a tool that has a diagnostic area under the curve [AUC] of 0.85,” said Dr. Swoboda of Leeds (England) University. “This is far better than the 0.58 AUC that we have with Q waves only – a sensitivity of just 25%.”
The study was published online in June in the Journal of Clinical Endocrinology and Metabolism (JCEM 2016. doi: 10.1210/jc.2016-1318).
The screen employs noninvasive imaging and biomarkers to tap multiple clinical hallmarks of silent MI. The components are:
• electrocardiogram.
• echocardiography.
• biomarker assessment.
• cardiac magnetic resonance imaging, focusing on left ventricular ejection fraction and late gadolinium enhancement.
The study cohort comprised 100 patients with type 2 diabetes without known heart disease and with no new cardiac symptoms. They underwent cardiac MRI, a 12-lead electrocardiogram, echocardiography, and serum biomarker assessment. Late gadolinium enhancement identified evidence of silent MI in 17 patients (17%).
There were few differences in the clinical characteristics of those who had experienced MI and those who had not, Dr. Swoboda noted. There were no differences at all in diabetes-related measures, including disease duration or hemoglobin A1c levels. Blood pressures were similar. Patients with MI were significantly older (65 vs. 60 years).
In cardiac-specific measures, left ventricular ejection fraction was similar, as was left ventricular mass, end diastolic volume, and left atrial volume. There were however, other very important differences, Dr. Swoboda noted.
Imaging included a measure called “feature tracking analysis,” which measured the peak global longitudinal strain, systolic strain rate, and early and late diastolic strain rates during contraction. This analysis noted a significant difference in global longitudinal strain between the MI and non-MI groups.
Ventricular filling velocities as measured by the E/A ratio on ECG were also significantly different between the MI and non-MI groups (0.75 vs. 0.89, respectively). ECG also found pathologic Q waves in significantly more MI patients (24% vs. 7%).
Finally, the serum biomarker panel showed a very strong increase in B-type natriuretic peptide (NT-proBNP) among MI patients, compared with non-MI patients (105 vs. 52 ng/L). There were no significant differences in the other biomarkers, including C-reactive protein and high-sensitive cardiac troponin.
Dr. Swoboda and his team then compiled these findings into a composite measure, assigning them optimum cutoff measures:
• Age older than 62 years.
• E/A ratio 0.72 or lower.
• Global longitudinal strain of at least 18.4%.
• NT-proBNP more than 29 ng/L.
The system resulted in a diagnostic accuracy AUC of 0.85 – significantly better than any of the AUCs generated by the individual components. All patients who scored 0 or 1 were free of MI. Among the 28 with a score of 2, only three had experienced a silent MI. Among the 21 with a score of 3, seven had experienced a silent MI and 14 had not. Among the 16 with a score of 4, seven had experienced a silent MI and nine had not.
While Dr. Swoboda called the screening method “simple” during discussion, a colleague in the audience disagreed with that.
“A simple test is something like a blood test only, not an MRI. Not imaging. That is expensive and takes time,” said Naveed Sattar, MD, of the University of Glasgow, Scotland. “However, I do think your data add more to the evidence that BNP can be a really valuable marker of cardiovascular risk in patients with diabetes.”
Dr. Sattar recently examined the value of cardiac serum biomarkers in predicting cardiovascular disease and mortality in nearly 100,000 people without a history of heart disease. In these subjects, he wrote, “NT-proBNP assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention.”
The paper appeared online in Lancet Diabetes in September (Lancet Diab. 2016. doi: 10.1016/S2213-8587[16]30196-6).
Dr. Swoboda agreed that data continue to support the increased use of NT-proBNP as a marker of heart disease.
“I think that in the future, diabetes medicine is moving toward individualized patient care, based on individualized risk factors. The future of assessing asymptomatic cardiac patients might be a combination of BNP and MRI.”
Dr. Swoboda had no financial disclosures. Some of Dr. Sattar’s coauthors reported relationships with pharmaceutical companies.
AT EASD 2016
Key clinical point: A four-component screen accurately identified silent myocardial infarction in asymptomatic patients with type 2 diabetes
Major finding: The tool had an 82% sensitivity and 72% specificity for silent MI.
Data source: It was created in a cohort of 100 patients with type 2 diabetes and no history of heart disease.
Disclosures: Dr. Swoboda had no financial disclosures.
Data are mixed on cancerous transformation of cardiac mucosa in Barrett’s esophagus
CHICAGO – If scouring data is what makes a gastroenterologist feel good about risk assessment, there may be a lot of unhappy gastroenterologists out there, at least when it comes to the risk of cancer arising from cardiac mucosa in Barrett’s esophagus, according to Nicholas J. Shaheen, MD.
The risk arising from this nonintestinal metaplasia growth is probably quite low in real life, but the extant literature gives doctors a lot of contradictions, he said at the meeting sponsored by the American Gastroenterological Association.
“The risk of cancer with cardiac mucosa is unclear,” said Dr. Shaheen of the University of North Carolina at Chapel Hill. “Some data do suggest that, at least when present in the tubular esophagus in patients with gastroesophageal reflux symptoms, there may be a risk of adenocarcinoma close to what’s seen in patients with intestinal metaplasia. Other data suggest the risk is quite low, perhaps even approximating that of the general population.”
The reasons for what Dr. Shaheen called “remarkable variability” in these data probably arise more from sampling error than real life. The studies are retrospective, and many lack long-term follow-up data, are plagued with insufficient numbers, and – perhaps most importantly – are not grounded in any standard clinical methodology.
“People who do endoscopy for a living understand that the stuff you read about systematic biopsy protocols is hardly ever honored in the breach. None of these studies ever reports the biopsy protocol from which the samples were taken.”
This lack of protocol means that studies on the cancer risk of columnar lined esophagus (CLE), which is negative for intestinal metaplasia are probably flawed from the beginning.
“The truth is that most gastroenterologists do a lousy job of biopsying Barrett’s, so there is probably a lot of sampling error in these studies, and they are contaminated with a high rate of intestinal metaplasia [IM],” said Dr. Shaheen.
And these studies do not report on the length of the CLE segment from which the biopsy was taken. “The likelihood of finding goblet cells [a characteristic of cardiac mucosa] increases with the length of Barrett’s. None of the studies is normalized for Barrett’s length. When we see studies saying the cancer risk is higher in the presence of goblet cells, length could be a partially confounding association.”
A 2009 study with a small sample size of 68 CLE patients found that abnormal DNA was just as likely in IM-negative samples as IM-positive ones. All of the samples were significantly different from the control samples, suggesting that any metaplasia in the CLE may already be on the path to cancer, Dr. Shaheen said (Am J Gastro. 2009;104:816-24)
In fact, a 2007 Scandinavian study supported the idea that IM isn’t even necessary for neoplastic progression of CLE (Scand J Gastroenterol 2007;42:1271-4). The investigators followed 712 patients for 12 years, and found that the adenocarcinoma rate was about 0.4 per patient per year whether the sample was IM positive or not.
“This study was enough to put a little shudder in the endoscopy community. If IM doesn’t matter, you’re talking about increasing the work in the endoscopy lab by 100%, because there are twice as many non-IM patients as those with IM.”
A 2008 study seemingly found something similar – but with a caveat, Dr. Shaheen said. The CLE patients in this study were followed for 3.5 years, and the cancer rate was virtually identical. But as the follow-up progressed, more and more biopsies turned up IM positive. “A first negative biopsy looked like it was associated with disease-free survival, but almost all IM-negative samples eventually became IM positive, so this didn’t really answer our question.”
Other studies have found that non-IM CLE has a very low neoplastic risk, and that IM is almost always a prerequisite for cancer to develop. The largest of these was conducted in the Northern Ireland Barrett’s Esophagus Registry in 2011. It followed more than 8,000 patients for 7 years. Patients with IM were 3.5 times more likely to develop a related adenocarcinoma than were those without IM (J Natl Cancer Inst. 2011;103:1049-57).
The contradictory evidence leads Dr. Shaheen to suggest a specific biopsy protocol for patients with Barrett’s esophagus.
“In my opinion, if you see a long segment of Barrett’s – more than 2 cm – and the biopsy is negative for IM, there is a good chance that you have a sampling error there, and a second endoscopy and biopsy are not unreasonable. If you see a short segment of Barrett’s and the biopsy is negative for IM, the cancer risk is unclear, but in general it’s probably pretty low, whether there are goblet cells there or not. I would say retaining these patients under endoscopic surveillance is of dubious value. [With] the likely low absolute risk of cancer in this patient population, no blanket recommendation for surveillance is advisable.”
Dr. Shaheen had no relevant financial disclosures.
On Twitter @Alz_Gal
CHICAGO – If scouring data is what makes a gastroenterologist feel good about risk assessment, there may be a lot of unhappy gastroenterologists out there, at least when it comes to the risk of cancer arising from cardiac mucosa in Barrett’s esophagus, according to Nicholas J. Shaheen, MD.
The risk arising from this nonintestinal metaplasia growth is probably quite low in real life, but the extant literature gives doctors a lot of contradictions, he said at the meeting sponsored by the American Gastroenterological Association.
“The risk of cancer with cardiac mucosa is unclear,” said Dr. Shaheen of the University of North Carolina at Chapel Hill. “Some data do suggest that, at least when present in the tubular esophagus in patients with gastroesophageal reflux symptoms, there may be a risk of adenocarcinoma close to what’s seen in patients with intestinal metaplasia. Other data suggest the risk is quite low, perhaps even approximating that of the general population.”
The reasons for what Dr. Shaheen called “remarkable variability” in these data probably arise more from sampling error than real life. The studies are retrospective, and many lack long-term follow-up data, are plagued with insufficient numbers, and – perhaps most importantly – are not grounded in any standard clinical methodology.
“People who do endoscopy for a living understand that the stuff you read about systematic biopsy protocols is hardly ever honored in the breach. None of these studies ever reports the biopsy protocol from which the samples were taken.”
This lack of protocol means that studies on the cancer risk of columnar lined esophagus (CLE), which is negative for intestinal metaplasia are probably flawed from the beginning.
“The truth is that most gastroenterologists do a lousy job of biopsying Barrett’s, so there is probably a lot of sampling error in these studies, and they are contaminated with a high rate of intestinal metaplasia [IM],” said Dr. Shaheen.
And these studies do not report on the length of the CLE segment from which the biopsy was taken. “The likelihood of finding goblet cells [a characteristic of cardiac mucosa] increases with the length of Barrett’s. None of the studies is normalized for Barrett’s length. When we see studies saying the cancer risk is higher in the presence of goblet cells, length could be a partially confounding association.”
A 2009 study with a small sample size of 68 CLE patients found that abnormal DNA was just as likely in IM-negative samples as IM-positive ones. All of the samples were significantly different from the control samples, suggesting that any metaplasia in the CLE may already be on the path to cancer, Dr. Shaheen said (Am J Gastro. 2009;104:816-24)
In fact, a 2007 Scandinavian study supported the idea that IM isn’t even necessary for neoplastic progression of CLE (Scand J Gastroenterol 2007;42:1271-4). The investigators followed 712 patients for 12 years, and found that the adenocarcinoma rate was about 0.4 per patient per year whether the sample was IM positive or not.
“This study was enough to put a little shudder in the endoscopy community. If IM doesn’t matter, you’re talking about increasing the work in the endoscopy lab by 100%, because there are twice as many non-IM patients as those with IM.”
A 2008 study seemingly found something similar – but with a caveat, Dr. Shaheen said. The CLE patients in this study were followed for 3.5 years, and the cancer rate was virtually identical. But as the follow-up progressed, more and more biopsies turned up IM positive. “A first negative biopsy looked like it was associated with disease-free survival, but almost all IM-negative samples eventually became IM positive, so this didn’t really answer our question.”
Other studies have found that non-IM CLE has a very low neoplastic risk, and that IM is almost always a prerequisite for cancer to develop. The largest of these was conducted in the Northern Ireland Barrett’s Esophagus Registry in 2011. It followed more than 8,000 patients for 7 years. Patients with IM were 3.5 times more likely to develop a related adenocarcinoma than were those without IM (J Natl Cancer Inst. 2011;103:1049-57).
The contradictory evidence leads Dr. Shaheen to suggest a specific biopsy protocol for patients with Barrett’s esophagus.
“In my opinion, if you see a long segment of Barrett’s – more than 2 cm – and the biopsy is negative for IM, there is a good chance that you have a sampling error there, and a second endoscopy and biopsy are not unreasonable. If you see a short segment of Barrett’s and the biopsy is negative for IM, the cancer risk is unclear, but in general it’s probably pretty low, whether there are goblet cells there or not. I would say retaining these patients under endoscopic surveillance is of dubious value. [With] the likely low absolute risk of cancer in this patient population, no blanket recommendation for surveillance is advisable.”
Dr. Shaheen had no relevant financial disclosures.
On Twitter @Alz_Gal
CHICAGO – If scouring data is what makes a gastroenterologist feel good about risk assessment, there may be a lot of unhappy gastroenterologists out there, at least when it comes to the risk of cancer arising from cardiac mucosa in Barrett’s esophagus, according to Nicholas J. Shaheen, MD.
The risk arising from this nonintestinal metaplasia growth is probably quite low in real life, but the extant literature gives doctors a lot of contradictions, he said at the meeting sponsored by the American Gastroenterological Association.
“The risk of cancer with cardiac mucosa is unclear,” said Dr. Shaheen of the University of North Carolina at Chapel Hill. “Some data do suggest that, at least when present in the tubular esophagus in patients with gastroesophageal reflux symptoms, there may be a risk of adenocarcinoma close to what’s seen in patients with intestinal metaplasia. Other data suggest the risk is quite low, perhaps even approximating that of the general population.”
The reasons for what Dr. Shaheen called “remarkable variability” in these data probably arise more from sampling error than real life. The studies are retrospective, and many lack long-term follow-up data, are plagued with insufficient numbers, and – perhaps most importantly – are not grounded in any standard clinical methodology.
“People who do endoscopy for a living understand that the stuff you read about systematic biopsy protocols is hardly ever honored in the breach. None of these studies ever reports the biopsy protocol from which the samples were taken.”
This lack of protocol means that studies on the cancer risk of columnar lined esophagus (CLE), which is negative for intestinal metaplasia are probably flawed from the beginning.
“The truth is that most gastroenterologists do a lousy job of biopsying Barrett’s, so there is probably a lot of sampling error in these studies, and they are contaminated with a high rate of intestinal metaplasia [IM],” said Dr. Shaheen.
And these studies do not report on the length of the CLE segment from which the biopsy was taken. “The likelihood of finding goblet cells [a characteristic of cardiac mucosa] increases with the length of Barrett’s. None of the studies is normalized for Barrett’s length. When we see studies saying the cancer risk is higher in the presence of goblet cells, length could be a partially confounding association.”
A 2009 study with a small sample size of 68 CLE patients found that abnormal DNA was just as likely in IM-negative samples as IM-positive ones. All of the samples were significantly different from the control samples, suggesting that any metaplasia in the CLE may already be on the path to cancer, Dr. Shaheen said (Am J Gastro. 2009;104:816-24)
In fact, a 2007 Scandinavian study supported the idea that IM isn’t even necessary for neoplastic progression of CLE (Scand J Gastroenterol 2007;42:1271-4). The investigators followed 712 patients for 12 years, and found that the adenocarcinoma rate was about 0.4 per patient per year whether the sample was IM positive or not.
“This study was enough to put a little shudder in the endoscopy community. If IM doesn’t matter, you’re talking about increasing the work in the endoscopy lab by 100%, because there are twice as many non-IM patients as those with IM.”
A 2008 study seemingly found something similar – but with a caveat, Dr. Shaheen said. The CLE patients in this study were followed for 3.5 years, and the cancer rate was virtually identical. But as the follow-up progressed, more and more biopsies turned up IM positive. “A first negative biopsy looked like it was associated with disease-free survival, but almost all IM-negative samples eventually became IM positive, so this didn’t really answer our question.”
Other studies have found that non-IM CLE has a very low neoplastic risk, and that IM is almost always a prerequisite for cancer to develop. The largest of these was conducted in the Northern Ireland Barrett’s Esophagus Registry in 2011. It followed more than 8,000 patients for 7 years. Patients with IM were 3.5 times more likely to develop a related adenocarcinoma than were those without IM (J Natl Cancer Inst. 2011;103:1049-57).
The contradictory evidence leads Dr. Shaheen to suggest a specific biopsy protocol for patients with Barrett’s esophagus.
“In my opinion, if you see a long segment of Barrett’s – more than 2 cm – and the biopsy is negative for IM, there is a good chance that you have a sampling error there, and a second endoscopy and biopsy are not unreasonable. If you see a short segment of Barrett’s and the biopsy is negative for IM, the cancer risk is unclear, but in general it’s probably pretty low, whether there are goblet cells there or not. I would say retaining these patients under endoscopic surveillance is of dubious value. [With] the likely low absolute risk of cancer in this patient population, no blanket recommendation for surveillance is advisable.”
Dr. Shaheen had no relevant financial disclosures.
On Twitter @Alz_Gal
EXPERT ANALYSIS FROM THE 2016 JAMES W. FRESTON CONFERENCE
Amyloid pathology associated with neuropsychiatric symptoms in MCI
TORONTO – Patients with mild cognitive impairment have a greater likelihood of having neuropsychiatric symptoms if they test positive for amyloid pathology on PET imaging, according to a study of patients in the Alzheimer’s Disease Neuroimaging Initiative.
Amyloid-positive patients were significantly more likely to develop agitation, anxiety, apathy, and other symptoms over 4 years than were amyloid-negative patients, Naira Goukasian said at the Alzheimer’s Association International Conference 2016.
“In MCI [mild cognitive impairment], we found that amyloid pathology was a significant risk factor for developing these symptoms,” said Ms. Goukasian, a researcher at the University of California, Los Angeles.
She investigated the presence and development of neuropsychiatric symptoms in 1,077 subjects drawn from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. The cohort comprised 275 cognitively normal subjects, 100 with subjective memory complaint, 559 with MCI, and 143 with Alzheimer’s disease. As part of ADNI, all patients had baseline neurocognitive and neuropsychiatric testing, and florbetapir F 18 (Amyvid) scans to determine brain amyloid status. Neuropsychiatric symptoms were measured with the Neuropsychiatric Inventory (NPI) and the Neuropsychiatric Inventory Questionnaire (NPI-Q) at baseline and during every annual visit. Patients were followed for up to 4 years.
At baseline, amyloid pathology was associated with some neuropsychiatric symptomatology in every group except those with subjective memory complaints.
Amyloid-positive control subjects were significantly more likely to present with depression than were amyloid-negative controls. Amyloid-positive MCI patients were significantly more likely to present with anxiety when they had amyloid pathology than when they did not. Amyloid-positive dementia patients were significantly more likely to present with apathy than were amyloid-negative dementia patients.
There were no amyloid-dependent differences in neuropsychiatric symptoms among those with subjective memory complaints.
Over the 4-year follow-up period, no new neuropsychiatric symptoms developed in the control, subjective memory complaint, or dementia groups, whether they were amyloid positive or negative.
Amyloid-positive MCI patients, however, were significantly more likely to develop new symptoms than were amyloid-negative MCI patients, including delusions (13% vs. 2%), hallucinations (8% vs. 2%), anxiety (36% vs. 25%), apathy (38% vs. 22%), agitation (36% vs. 27%), disinhibition (24% vs. 15%), irritability (46% vs. 33%), and motor disturbances (18% vs. 9%).
Ms. Goukasian did not elaborate on the pathophysiologic relationship between amyloid and these symptoms. However, a 2015 study using a similar ADNI cohort localized some of them to specific amyloid-burdened brain regions (J Alzheimers Dis. 2016;49[2]:387-98).
The study by David Bensamoun, MD, and colleagues comprised 657 ADNI participants (230 controls, 308 MCI patients, and 119 Alzheimer’s patients).
In the entire group, Dr. Bensamoun, of the Regional Memory Center, Nice, France, found positive significant correlations between anxiety and global cerebral florbetapir F 18 uptake, as well as uptake in the frontal and cingulate regions. Irritability was associated with global florbetapir F 18 uptake and increased signal in the frontal, cingulate, and parietal regions.
In the MCI subgroup, there was an association between anxiety and frontal and global cerebral uptake. In the Alzheimer’s subgroup, there was an association between irritability and parietal uptake.
“Anxiety and irritability appear to be associated with greater amyloid deposition in the neurodegenerative process leading to Alzheimer’s,” the investigators said.
Ms. Goukasian had no financial disclosures.
On Twitter @alz_gal
TORONTO – Patients with mild cognitive impairment have a greater likelihood of having neuropsychiatric symptoms if they test positive for amyloid pathology on PET imaging, according to a study of patients in the Alzheimer’s Disease Neuroimaging Initiative.
Amyloid-positive patients were significantly more likely to develop agitation, anxiety, apathy, and other symptoms over 4 years than were amyloid-negative patients, Naira Goukasian said at the Alzheimer’s Association International Conference 2016.
“In MCI [mild cognitive impairment], we found that amyloid pathology was a significant risk factor for developing these symptoms,” said Ms. Goukasian, a researcher at the University of California, Los Angeles.
She investigated the presence and development of neuropsychiatric symptoms in 1,077 subjects drawn from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. The cohort comprised 275 cognitively normal subjects, 100 with subjective memory complaint, 559 with MCI, and 143 with Alzheimer’s disease. As part of ADNI, all patients had baseline neurocognitive and neuropsychiatric testing, and florbetapir F 18 (Amyvid) scans to determine brain amyloid status. Neuropsychiatric symptoms were measured with the Neuropsychiatric Inventory (NPI) and the Neuropsychiatric Inventory Questionnaire (NPI-Q) at baseline and during every annual visit. Patients were followed for up to 4 years.
At baseline, amyloid pathology was associated with some neuropsychiatric symptomatology in every group except those with subjective memory complaints.
Amyloid-positive control subjects were significantly more likely to present with depression than were amyloid-negative controls. Amyloid-positive MCI patients were significantly more likely to present with anxiety when they had amyloid pathology than when they did not. Amyloid-positive dementia patients were significantly more likely to present with apathy than were amyloid-negative dementia patients.
There were no amyloid-dependent differences in neuropsychiatric symptoms among those with subjective memory complaints.
Over the 4-year follow-up period, no new neuropsychiatric symptoms developed in the control, subjective memory complaint, or dementia groups, whether they were amyloid positive or negative.
Amyloid-positive MCI patients, however, were significantly more likely to develop new symptoms than were amyloid-negative MCI patients, including delusions (13% vs. 2%), hallucinations (8% vs. 2%), anxiety (36% vs. 25%), apathy (38% vs. 22%), agitation (36% vs. 27%), disinhibition (24% vs. 15%), irritability (46% vs. 33%), and motor disturbances (18% vs. 9%).
Ms. Goukasian did not elaborate on the pathophysiologic relationship between amyloid and these symptoms. However, a 2015 study using a similar ADNI cohort localized some of them to specific amyloid-burdened brain regions (J Alzheimers Dis. 2016;49[2]:387-98).
The study by David Bensamoun, MD, and colleagues comprised 657 ADNI participants (230 controls, 308 MCI patients, and 119 Alzheimer’s patients).
In the entire group, Dr. Bensamoun, of the Regional Memory Center, Nice, France, found positive significant correlations between anxiety and global cerebral florbetapir F 18 uptake, as well as uptake in the frontal and cingulate regions. Irritability was associated with global florbetapir F 18 uptake and increased signal in the frontal, cingulate, and parietal regions.
In the MCI subgroup, there was an association between anxiety and frontal and global cerebral uptake. In the Alzheimer’s subgroup, there was an association between irritability and parietal uptake.
“Anxiety and irritability appear to be associated with greater amyloid deposition in the neurodegenerative process leading to Alzheimer’s,” the investigators said.
Ms. Goukasian had no financial disclosures.
On Twitter @alz_gal
TORONTO – Patients with mild cognitive impairment have a greater likelihood of having neuropsychiatric symptoms if they test positive for amyloid pathology on PET imaging, according to a study of patients in the Alzheimer’s Disease Neuroimaging Initiative.
Amyloid-positive patients were significantly more likely to develop agitation, anxiety, apathy, and other symptoms over 4 years than were amyloid-negative patients, Naira Goukasian said at the Alzheimer’s Association International Conference 2016.
“In MCI [mild cognitive impairment], we found that amyloid pathology was a significant risk factor for developing these symptoms,” said Ms. Goukasian, a researcher at the University of California, Los Angeles.
She investigated the presence and development of neuropsychiatric symptoms in 1,077 subjects drawn from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. The cohort comprised 275 cognitively normal subjects, 100 with subjective memory complaint, 559 with MCI, and 143 with Alzheimer’s disease. As part of ADNI, all patients had baseline neurocognitive and neuropsychiatric testing, and florbetapir F 18 (Amyvid) scans to determine brain amyloid status. Neuropsychiatric symptoms were measured with the Neuropsychiatric Inventory (NPI) and the Neuropsychiatric Inventory Questionnaire (NPI-Q) at baseline and during every annual visit. Patients were followed for up to 4 years.
At baseline, amyloid pathology was associated with some neuropsychiatric symptomatology in every group except those with subjective memory complaints.
Amyloid-positive control subjects were significantly more likely to present with depression than were amyloid-negative controls. Amyloid-positive MCI patients were significantly more likely to present with anxiety when they had amyloid pathology than when they did not. Amyloid-positive dementia patients were significantly more likely to present with apathy than were amyloid-negative dementia patients.
There were no amyloid-dependent differences in neuropsychiatric symptoms among those with subjective memory complaints.
Over the 4-year follow-up period, no new neuropsychiatric symptoms developed in the control, subjective memory complaint, or dementia groups, whether they were amyloid positive or negative.
Amyloid-positive MCI patients, however, were significantly more likely to develop new symptoms than were amyloid-negative MCI patients, including delusions (13% vs. 2%), hallucinations (8% vs. 2%), anxiety (36% vs. 25%), apathy (38% vs. 22%), agitation (36% vs. 27%), disinhibition (24% vs. 15%), irritability (46% vs. 33%), and motor disturbances (18% vs. 9%).
Ms. Goukasian did not elaborate on the pathophysiologic relationship between amyloid and these symptoms. However, a 2015 study using a similar ADNI cohort localized some of them to specific amyloid-burdened brain regions (J Alzheimers Dis. 2016;49[2]:387-98).
The study by David Bensamoun, MD, and colleagues comprised 657 ADNI participants (230 controls, 308 MCI patients, and 119 Alzheimer’s patients).
In the entire group, Dr. Bensamoun, of the Regional Memory Center, Nice, France, found positive significant correlations between anxiety and global cerebral florbetapir F 18 uptake, as well as uptake in the frontal and cingulate regions. Irritability was associated with global florbetapir F 18 uptake and increased signal in the frontal, cingulate, and parietal regions.
In the MCI subgroup, there was an association between anxiety and frontal and global cerebral uptake. In the Alzheimer’s subgroup, there was an association between irritability and parietal uptake.
“Anxiety and irritability appear to be associated with greater amyloid deposition in the neurodegenerative process leading to Alzheimer’s,” the investigators said.
Ms. Goukasian had no financial disclosures.
On Twitter @alz_gal
AT AAIC 2016
Key clinical point: Amyloid pathology is a risk factor for neuropsychiatric symptoms in mild cognitive impairment.
Major finding: Amyloid-positive patients with MCI were more likely than were amyloid-negative patients to develop anxiety (36% vs. 25%), apathy (38% vs. 22%), agitation (36% vs. 27%), and other symptoms.
Data source: The study comprised 1,077 patients drawn from the Alzheimer’s Disease Neuroimaging Initiative.
Disclosures: Ms. Goukasian had no financial disclosures.
