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STOCKHOLM – Intranasal administration of a glucagon powder successfully increased blood glucose within 20 minutes of simulated hypoglycemia in a study of children and adolescents with type 1 diabetes.

The primary outcome of a 25 mg/dL or more increase in plasma glucose from nadir was reached within 20 minutes of intranasal glucagon administration in 47 of 48 of treatments. Levels of blood glucose achieved and the time to reach the primary outcome were on par with those seen with intramuscular injection of glucagon, Dr. Jennifer Scherr of Yale University in New Haven, Conn., reported at the annual meeting of the European Association for the Study of Diabetes.

Current emergency treatment for hypoglycemia consists of use of an intramuscular glucagon injection kit, which often is not immediately accessible when needed, particularly in the case of children who might experience hypoglycemia at school, where kits are perhaps locked up or kept by school nurses. The children are under the care of many others, Dr. Scherr observed, noting there might not always be someone experienced on hand to give the injections. She added that, while intramuscular injection of glucagon took several steps, giving the nasal powder was a “single-use, single-step” process that did not involve reconstitution before administration, which makes it simpler for others to give.

Data on the efficacy and safety of intranasal glucagon have been obtained in adults, but this is the first study to look at its use in children and adolescents, where the convenience of intranasal administration may be even greater.

Seven centers participating in the T1D Exchange were involved in the study, recruiting participants between the ages of 4 years to <17 years. Participants were divided into three age cohorts: 4 years to <8 years (n = 18), 8 years to <12 years (n = 18), and 12 years to <17 years (n = 12).

Insulin was given to lower their blood glucose levels to less than 80 mg/dL and then, 5 minutes after stopping insulin, glucagon was given either intranasally or injected and blood glucose measurements made.

The older children were randomized to receive either 1 mg of intramuscular glucagon or the adult dose of 3 mg of intranasal glucagon during one session, then crossed over to the other treatment at a second session. The younger children were randomized to receive either 1 mg of intramuscular glucagon or intranasal glucagon at one of two doses (2 mg or 3 mg) at their first visit, then swapped over to the other intranasal dose.

In the youngest cohort of children, the mean nadir glucose levels reached after the administration of insulin were 68 mg/dL with the 2-mg and 67 mg/dL with the 3-mg intranasal doses and 71 mg/dL with the intramuscular dose. Following glucagon dosing, the respective mean peak glucose levels were 189, 208, and 211 mg/dL respectively, with 11%, 12%, and 6% of patients achieving a rise in glucose of 25 mg/dL or more by 20 minutes. The actual time to achieve the 25 mg/dL or greater risk in glucose was 20, 15, and 10 minutes, respectively, Dr. Scherr reported.

Similar results were seen in the older-age cohorts, with mean nadir glucose levels of 71-75 mg/dL in the 8 to <12-year-old group and 69-73 in the 12 to <17-year-old group. Mean peak blood glucose values after glucagon administration were 201-206 mg/dL and 178-198 mg/dL in these age groups, respectively, and the percentage of children with ≥25 mg/dL rise in glucose was 11% with intranasal delivery and 6% for intramuscular delivery in the younger children and 12% with intranasal and 12% with intramuscular in the older children. The time to achieve this was 20 minutes in most cases.

Nausea with or without vomiting occurred in fewer children treated with the intranasal doses than with intramuscular glucagon, at 39%, 43%, and 67%, respectively, for the 2-mg and 3-mg intranasal and 1-mg intramuscular doses of glucagon. There were more episodes of head and facial discomfort following intranasal than intramuscular delivery (17% and 25% vs. 13%), however, but Dr. Scherr emphasized that these were transient effects.

“Given the efficacy and safety of the intranasal doses, for simplicity a single dose of 3 mg of intranasal can be used across the pediatric population,” she concluded.

But what would happen if a child who had just taken intranasal glucagon blew his or her nose? Dr. Scherr noted that, in the one case in which the primary endpoint was not met with intranasal glucagon, the 6-year-old child blew his nose immediately after intranasal administration of a 2-mg dose and did not absorb the medication. She noted, however, that it was probably unlikely that anyone experiencing a severe hypoglycemic episode warranting treatment would actually be able to blow their nose.

Although it was not addressed in this study, there were data in adults to show that the intranasal route still resulted in good absorption of glucagon even with a stuffed-up nose. Indeed, Dr. Scherr noted that the uptake of intranasal glucagon did not require inhalation, which again might be difficult in a child or adult with hypoglycemia with reduced or lost consciousness.

Dr. Scherr acknowledged the limitation that intranasal glucagon was administered by a trained health care professional in the study and thus may not reflect the experience of the intended nonmedical users. That said, however, other data presented in a poster at the meeting by Dr. Jean-Francois Yale of McGill University in Montreal and associates showed that untrained, nonmedical individuals were able to give intranasal glucagon as successfully as trained caregivers.

Indeed, not only could lay people give the preparation more quickly by an intranasal than intramuscular route in a simulated hypoglycemia rescue situation in adults, their data showed it was associated with a much higher success rate and was much easier to give overall. Importantly, Dr. Yale and his team said, the different route of administration to insulin might actually reduce the risk for confusion and accidental delivery of insulin.

Dr. Scherr noted that intranasal glucagon could be stored at room temperature and had a projected shelf life of 2 years.

The study sponsor was T1D Exchange supported by Locemia Solutions ULC and the Leona M. and Harry B. Helmsley Charitable Trust. Dr. Scherr reported having no financial disclosures relevant to the current study and receiving product support from Medtronic Diabetes for investigator-initiated studies.

The study findings have previously been presented during a poster session at the annual meeting of the American Diabetes Association and were highlighted in an oral session at the EASD meeting on the future of diabetes therapy.

STOCKHOLM – Intranasal administration of a glucagon powder successfully increased blood glucose within 20 minutes of simulated hypoglycemia in a study of children and adolescents with type 1 diabetes.

The primary outcome of a 25 mg/dL or more increase in plasma glucose from nadir was reached within 20 minutes of intranasal glucagon administration in 47 of 48 of treatments. Levels of blood glucose achieved and the time to reach the primary outcome were on par with those seen with intramuscular injection of glucagon, Dr. Jennifer Scherr of Yale University in New Haven, Conn., reported at the annual meeting of the European Association for the Study of Diabetes.

Current emergency treatment for hypoglycemia consists of use of an intramuscular glucagon injection kit, which often is not immediately accessible when needed, particularly in the case of children who might experience hypoglycemia at school, where kits are perhaps locked up or kept by school nurses. The children are under the care of many others, Dr. Scherr observed, noting there might not always be someone experienced on hand to give the injections. She added that, while intramuscular injection of glucagon took several steps, giving the nasal powder was a “single-use, single-step” process that did not involve reconstitution before administration, which makes it simpler for others to give.

Data on the efficacy and safety of intranasal glucagon have been obtained in adults, but this is the first study to look at its use in children and adolescents, where the convenience of intranasal administration may be even greater.

Seven centers participating in the T1D Exchange were involved in the study, recruiting participants between the ages of 4 years to <17 years. Participants were divided into three age cohorts: 4 years to <8 years (n = 18), 8 years to <12 years (n = 18), and 12 years to <17 years (n = 12).

Insulin was given to lower their blood glucose levels to less than 80 mg/dL and then, 5 minutes after stopping insulin, glucagon was given either intranasally or injected and blood glucose measurements made.

The older children were randomized to receive either 1 mg of intramuscular glucagon or the adult dose of 3 mg of intranasal glucagon during one session, then crossed over to the other treatment at a second session. The younger children were randomized to receive either 1 mg of intramuscular glucagon or intranasal glucagon at one of two doses (2 mg or 3 mg) at their first visit, then swapped over to the other intranasal dose.

In the youngest cohort of children, the mean nadir glucose levels reached after the administration of insulin were 68 mg/dL with the 2-mg and 67 mg/dL with the 3-mg intranasal doses and 71 mg/dL with the intramuscular dose. Following glucagon dosing, the respective mean peak glucose levels were 189, 208, and 211 mg/dL respectively, with 11%, 12%, and 6% of patients achieving a rise in glucose of 25 mg/dL or more by 20 minutes. The actual time to achieve the 25 mg/dL or greater risk in glucose was 20, 15, and 10 minutes, respectively, Dr. Scherr reported.

Similar results were seen in the older-age cohorts, with mean nadir glucose levels of 71-75 mg/dL in the 8 to <12-year-old group and 69-73 in the 12 to <17-year-old group. Mean peak blood glucose values after glucagon administration were 201-206 mg/dL and 178-198 mg/dL in these age groups, respectively, and the percentage of children with ≥25 mg/dL rise in glucose was 11% with intranasal delivery and 6% for intramuscular delivery in the younger children and 12% with intranasal and 12% with intramuscular in the older children. The time to achieve this was 20 minutes in most cases.

Nausea with or without vomiting occurred in fewer children treated with the intranasal doses than with intramuscular glucagon, at 39%, 43%, and 67%, respectively, for the 2-mg and 3-mg intranasal and 1-mg intramuscular doses of glucagon. There were more episodes of head and facial discomfort following intranasal than intramuscular delivery (17% and 25% vs. 13%), however, but Dr. Scherr emphasized that these were transient effects.

“Given the efficacy and safety of the intranasal doses, for simplicity a single dose of 3 mg of intranasal can be used across the pediatric population,” she concluded.

But what would happen if a child who had just taken intranasal glucagon blew his or her nose? Dr. Scherr noted that, in the one case in which the primary endpoint was not met with intranasal glucagon, the 6-year-old child blew his nose immediately after intranasal administration of a 2-mg dose and did not absorb the medication. She noted, however, that it was probably unlikely that anyone experiencing a severe hypoglycemic episode warranting treatment would actually be able to blow their nose.

Although it was not addressed in this study, there were data in adults to show that the intranasal route still resulted in good absorption of glucagon even with a stuffed-up nose. Indeed, Dr. Scherr noted that the uptake of intranasal glucagon did not require inhalation, which again might be difficult in a child or adult with hypoglycemia with reduced or lost consciousness.

Dr. Scherr acknowledged the limitation that intranasal glucagon was administered by a trained health care professional in the study and thus may not reflect the experience of the intended nonmedical users. That said, however, other data presented in a poster at the meeting by Dr. Jean-Francois Yale of McGill University in Montreal and associates showed that untrained, nonmedical individuals were able to give intranasal glucagon as successfully as trained caregivers.

Indeed, not only could lay people give the preparation more quickly by an intranasal than intramuscular route in a simulated hypoglycemia rescue situation in adults, their data showed it was associated with a much higher success rate and was much easier to give overall. Importantly, Dr. Yale and his team said, the different route of administration to insulin might actually reduce the risk for confusion and accidental delivery of insulin.

Dr. Scherr noted that intranasal glucagon could be stored at room temperature and had a projected shelf life of 2 years.

The study sponsor was T1D Exchange supported by Locemia Solutions ULC and the Leona M. and Harry B. Helmsley Charitable Trust. Dr. Scherr reported having no financial disclosures relevant to the current study and receiving product support from Medtronic Diabetes for investigator-initiated studies.

The study findings have previously been presented during a poster session at the annual meeting of the American Diabetes Association and were highlighted in an oral session at the EASD meeting on the future of diabetes therapy.

STOCKHOLM – Intranasal administration of a glucagon powder successfully increased blood glucose within 20 minutes of simulated hypoglycemia in a study of children and adolescents with type 1 diabetes.

The primary outcome of a 25 mg/dL or more increase in plasma glucose from nadir was reached within 20 minutes of intranasal glucagon administration in 47 of 48 of treatments. Levels of blood glucose achieved and the time to reach the primary outcome were on par with those seen with intramuscular injection of glucagon, Dr. Jennifer Scherr of Yale University in New Haven, Conn., reported at the annual meeting of the European Association for the Study of Diabetes.

Current emergency treatment for hypoglycemia consists of use of an intramuscular glucagon injection kit, which often is not immediately accessible when needed, particularly in the case of children who might experience hypoglycemia at school, where kits are perhaps locked up or kept by school nurses. The children are under the care of many others, Dr. Scherr observed, noting there might not always be someone experienced on hand to give the injections. She added that, while intramuscular injection of glucagon took several steps, giving the nasal powder was a “single-use, single-step” process that did not involve reconstitution before administration, which makes it simpler for others to give.

Data on the efficacy and safety of intranasal glucagon have been obtained in adults, but this is the first study to look at its use in children and adolescents, where the convenience of intranasal administration may be even greater.

Seven centers participating in the T1D Exchange were involved in the study, recruiting participants between the ages of 4 years to <17 years. Participants were divided into three age cohorts: 4 years to <8 years (n = 18), 8 years to <12 years (n = 18), and 12 years to <17 years (n = 12).

Insulin was given to lower their blood glucose levels to less than 80 mg/dL and then, 5 minutes after stopping insulin, glucagon was given either intranasally or injected and blood glucose measurements made.

The older children were randomized to receive either 1 mg of intramuscular glucagon or the adult dose of 3 mg of intranasal glucagon during one session, then crossed over to the other treatment at a second session. The younger children were randomized to receive either 1 mg of intramuscular glucagon or intranasal glucagon at one of two doses (2 mg or 3 mg) at their first visit, then swapped over to the other intranasal dose.

In the youngest cohort of children, the mean nadir glucose levels reached after the administration of insulin were 68 mg/dL with the 2-mg and 67 mg/dL with the 3-mg intranasal doses and 71 mg/dL with the intramuscular dose. Following glucagon dosing, the respective mean peak glucose levels were 189, 208, and 211 mg/dL respectively, with 11%, 12%, and 6% of patients achieving a rise in glucose of 25 mg/dL or more by 20 minutes. The actual time to achieve the 25 mg/dL or greater risk in glucose was 20, 15, and 10 minutes, respectively, Dr. Scherr reported.

Similar results were seen in the older-age cohorts, with mean nadir glucose levels of 71-75 mg/dL in the 8 to <12-year-old group and 69-73 in the 12 to <17-year-old group. Mean peak blood glucose values after glucagon administration were 201-206 mg/dL and 178-198 mg/dL in these age groups, respectively, and the percentage of children with ≥25 mg/dL rise in glucose was 11% with intranasal delivery and 6% for intramuscular delivery in the younger children and 12% with intranasal and 12% with intramuscular in the older children. The time to achieve this was 20 minutes in most cases.

Nausea with or without vomiting occurred in fewer children treated with the intranasal doses than with intramuscular glucagon, at 39%, 43%, and 67%, respectively, for the 2-mg and 3-mg intranasal and 1-mg intramuscular doses of glucagon. There were more episodes of head and facial discomfort following intranasal than intramuscular delivery (17% and 25% vs. 13%), however, but Dr. Scherr emphasized that these were transient effects.

“Given the efficacy and safety of the intranasal doses, for simplicity a single dose of 3 mg of intranasal can be used across the pediatric population,” she concluded.

But what would happen if a child who had just taken intranasal glucagon blew his or her nose? Dr. Scherr noted that, in the one case in which the primary endpoint was not met with intranasal glucagon, the 6-year-old child blew his nose immediately after intranasal administration of a 2-mg dose and did not absorb the medication. She noted, however, that it was probably unlikely that anyone experiencing a severe hypoglycemic episode warranting treatment would actually be able to blow their nose.

Although it was not addressed in this study, there were data in adults to show that the intranasal route still resulted in good absorption of glucagon even with a stuffed-up nose. Indeed, Dr. Scherr noted that the uptake of intranasal glucagon did not require inhalation, which again might be difficult in a child or adult with hypoglycemia with reduced or lost consciousness.

Dr. Scherr acknowledged the limitation that intranasal glucagon was administered by a trained health care professional in the study and thus may not reflect the experience of the intended nonmedical users. That said, however, other data presented in a poster at the meeting by Dr. Jean-Francois Yale of McGill University in Montreal and associates showed that untrained, nonmedical individuals were able to give intranasal glucagon as successfully as trained caregivers.

Indeed, not only could lay people give the preparation more quickly by an intranasal than intramuscular route in a simulated hypoglycemia rescue situation in adults, their data showed it was associated with a much higher success rate and was much easier to give overall. Importantly, Dr. Yale and his team said, the different route of administration to insulin might actually reduce the risk for confusion and accidental delivery of insulin.

Dr. Scherr noted that intranasal glucagon could be stored at room temperature and had a projected shelf life of 2 years.

The study sponsor was T1D Exchange supported by Locemia Solutions ULC and the Leona M. and Harry B. Helmsley Charitable Trust. Dr. Scherr reported having no financial disclosures relevant to the current study and receiving product support from Medtronic Diabetes for investigator-initiated studies.

The study findings have previously been presented during a poster session at the annual meeting of the American Diabetes Association and were highlighted in an oral session at the EASD meeting on the future of diabetes therapy.

STOCKHOLM – Data from the Swedish National Diabetes Registry add to evidence that high blood glucose levels increase the risk for dementia in individuals with type 2 diabetes and imply that better glycemic control might potentially help prevent such cognitive decline.

In the large observational study, hemoglobin A_1c levels in excess of 10% increased the rate of dementia by 23%-77% depending on the time-fixed or time-updated statistical analysis performed, with hazard ratios (HRs) of 1.23 and 1.77, respectively, compared with a reference HbA_1c of less than 6%.

Sara Freeman/Frontline Medical News

“An HbA_1c between 6% and 7% was associated with a lower [HR, 0.82; 95% confidence interval, 0.86-0.91; P <.001] risk of any dementia compared to the reference, but as HbA_1c increased and was above 10% [HR, 1.23; 95% CI, 1.11-1.35; P <.001] the risk was higher for individuals,” Dr. Aidin Rawshani reported at the annual meeting of the European Association for the Study of Diabetes.

For the study, Dr. Rawshani and his colleagues at the Institute of Medicine at the University of Gothenburg (Sweden) identified all individuals with type 2 diabetes (2DM) who were registered in the Swedish National Diabetes Registry between 2003 and 2012 and who did not have dementia at enrollment. Data on individuals’ socioeconomic status, hospital admissions, outpatient visits, and deaths were then obtained from four Swedish databases and ICD-10 codes to identify those who later developed Alzheimer’s or vascular, unspecified, or any dementia.

Over a mean follow-up of 4.8 years, accounting for 1.7 million person-years, there were 353,214 individuals with 2DM without dementia at enrollment into the registry. Of these, 13,159 were reported to have any dementia, with 3,499 and 3,377 having Alzheimer’s disease or vascular dementia.

Cox regression analysis was used to assess the association between dementia and glycemic control, as well as other pertinent patient characteristics, risk factors, complications and comorbidities, and medication use. All covariates were modeled as both time-dependent and time-variable predictors.

The study population was divided into six groups according to baseline HbA_1c: <6% (n = 118,433); 6% to <7% (n = 117,397); 7% to <8% (n = 49,049); 8% to <9% (n = 23,143); 9% to <10% (n = 9,096); ≥10% (n = 8,354). Over half (55%-60%) of subjects were men, the mean age was approximately 68 years, and the duration of diabetes ranged from 4 to 10 years.

Dr. Rawshani reported that the crude event rate for any dementia was 7.25 cases per 1,000 person-years for the lowest (<6%) and 8.47 for the highest (≥10%) levels of HbA_1c. The crude event rates for the other HbA_1c categories were 7.91, 8.75, 9.13, and 8.71 per 1,000 person-years, respectively.

Modeling HbA_1c as a continuous variable showed that there was no dementia risk at an HbA_1c of 6.7% but that it increased substantially thereafter. Dementia risk also was found to increase with increasing age, diastolic blood pressure, high-density-lipoprotein cholesterol, and low-density-lipoprotein cholesterol, he said.

Looking at time-updated covariates, individuals who developed microalbuminuria (HR, 1.22; 95% CI, 1.15-1.29; P <.001) or macroalbuminuria (HR, 1.39; 95% CI, 1.29-1.50; P <.001) had a higher risk for dementia than those without albuminuria.

A higher risk for dementia also was seen in patients who did not perform any daily physical activity versus those who did, with a HR of 2.21 (95% CI, 2.05-2.38; P <.001).

Comorbid stroke increased the risk for dementia by 43% (HR, 1.43; 95% CI, 1.34-1.53; P <.001), with little risk increase for comorbid atrial fibrillation (HR, 1.11; 95% CI, 1.04-1.18; P <.003) or coronary heart disease (HR, 1.02; 95% CI, 1.02-1.16; P <.009).

Conversely, the use of statins (HR, 0.87; 95% CI, 0.82-0.92; P <.001) and antihypertensive medication (HR, 0.69; 95% CI, 0.64-0.73; P <.001) was associated with lower dementia risk.

The respective Cox analysis–predicted survival rates at 10 years for the patients who did and did not develop dementia during follow-up were 40% and 70%.

“Our conclusion is that higher HbA_1c levels are associated with an increased risk of dementia among persons with type 2 diabetes,” Dr. Rawshani said.

“The conclusion is interesting,” Dr. Naveed Sattar, professor of metabolic medicine at the Institute of Cardiovascular and Medical Sciences, University of Glasgow (Scotland), said in an interview. Dr. Sattar, who was not involved in the study, said that, while interesting, there was no mention that the very lowest blood glucose levels also were linked to an increased risk. There was a J-shaped curve, he observed.

“In people who have very low blood glucose levels, below guideline levels, I suspect that there are other reasons that they are sick and they’re hemoglobin A_1c is low because of this and that then leads to dementia.” Dr. Sattar observed. He added that perhaps it was not necessarily the hyperglycemia causing dementia, it was more likely a case of reverse causality.

“The study showed clearly that high BMI, high LDL, and high blood pressure were also associated with more dementia,” Dr. Sattar said. “And, it also showed that being on antihypertensives and cholesterol-lowering tablets gives you a low risk of dementia,” he added. “So the things we are doing in diabetes to keep blood pressure down, smoking down, cholesterol down, are working and, together with keeping hemoglobin in the normal range, should help to lower the risk of dementia. That’s epidemiology, and we now need the trials to prove it, but it’s going to be very, very tough.”

Dr. Rawshani did not report having any disclosures. Dr. Sattar said that he had no disclosures relevant to his comments.

STOCKHOLM – Data from the Swedish National Diabetes Registry add to evidence that high blood glucose levels increase the risk for dementia in individuals with type 2 diabetes and imply that better glycemic control might potentially help prevent such cognitive decline.

In the large observational study, hemoglobin A_1c levels in excess of 10% increased the rate of dementia by 23%-77% depending on the time-fixed or time-updated statistical analysis performed, with hazard ratios (HRs) of 1.23 and 1.77, respectively, compared with a reference HbA_1c of less than 6%.

Sara Freeman/Frontline Medical News

“An HbA_1c between 6% and 7% was associated with a lower [HR, 0.82; 95% confidence interval, 0.86-0.91; P <.001] risk of any dementia compared to the reference, but as HbA_1c increased and was above 10% [HR, 1.23; 95% CI, 1.11-1.35; P <.001] the risk was higher for individuals,” Dr. Aidin Rawshani reported at the annual meeting of the European Association for the Study of Diabetes.

For the study, Dr. Rawshani and his colleagues at the Institute of Medicine at the University of Gothenburg (Sweden) identified all individuals with type 2 diabetes (2DM) who were registered in the Swedish National Diabetes Registry between 2003 and 2012 and who did not have dementia at enrollment. Data on individuals’ socioeconomic status, hospital admissions, outpatient visits, and deaths were then obtained from four Swedish databases and ICD-10 codes to identify those who later developed Alzheimer’s or vascular, unspecified, or any dementia.

Over a mean follow-up of 4.8 years, accounting for 1.7 million person-years, there were 353,214 individuals with 2DM without dementia at enrollment into the registry. Of these, 13,159 were reported to have any dementia, with 3,499 and 3,377 having Alzheimer’s disease or vascular dementia.

Cox regression analysis was used to assess the association between dementia and glycemic control, as well as other pertinent patient characteristics, risk factors, complications and comorbidities, and medication use. All covariates were modeled as both time-dependent and time-variable predictors.

The study population was divided into six groups according to baseline HbA_1c: <6% (n = 118,433); 6% to <7% (n = 117,397); 7% to <8% (n = 49,049); 8% to <9% (n = 23,143); 9% to <10% (n = 9,096); ≥10% (n = 8,354). Over half (55%-60%) of subjects were men, the mean age was approximately 68 years, and the duration of diabetes ranged from 4 to 10 years.

Dr. Rawshani reported that the crude event rate for any dementia was 7.25 cases per 1,000 person-years for the lowest (<6%) and 8.47 for the highest (≥10%) levels of HbA_1c. The crude event rates for the other HbA_1c categories were 7.91, 8.75, 9.13, and 8.71 per 1,000 person-years, respectively.

Modeling HbA_1c as a continuous variable showed that there was no dementia risk at an HbA_1c of 6.7% but that it increased substantially thereafter. Dementia risk also was found to increase with increasing age, diastolic blood pressure, high-density-lipoprotein cholesterol, and low-density-lipoprotein cholesterol, he said.

Looking at time-updated covariates, individuals who developed microalbuminuria (HR, 1.22; 95% CI, 1.15-1.29; P <.001) or macroalbuminuria (HR, 1.39; 95% CI, 1.29-1.50; P <.001) had a higher risk for dementia than those without albuminuria.

A higher risk for dementia also was seen in patients who did not perform any daily physical activity versus those who did, with a HR of 2.21 (95% CI, 2.05-2.38; P <.001).

Comorbid stroke increased the risk for dementia by 43% (HR, 1.43; 95% CI, 1.34-1.53; P <.001), with little risk increase for comorbid atrial fibrillation (HR, 1.11; 95% CI, 1.04-1.18; P <.003) or coronary heart disease (HR, 1.02; 95% CI, 1.02-1.16; P <.009).

Conversely, the use of statins (HR, 0.87; 95% CI, 0.82-0.92; P <.001) and antihypertensive medication (HR, 0.69; 95% CI, 0.64-0.73; P <.001) was associated with lower dementia risk.

The respective Cox analysis–predicted survival rates at 10 years for the patients who did and did not develop dementia during follow-up were 40% and 70%.

“Our conclusion is that higher HbA_1c levels are associated with an increased risk of dementia among persons with type 2 diabetes,” Dr. Rawshani said.

“The conclusion is interesting,” Dr. Naveed Sattar, professor of metabolic medicine at the Institute of Cardiovascular and Medical Sciences, University of Glasgow (Scotland), said in an interview. Dr. Sattar, who was not involved in the study, said that, while interesting, there was no mention that the very lowest blood glucose levels also were linked to an increased risk. There was a J-shaped curve, he observed.

“In people who have very low blood glucose levels, below guideline levels, I suspect that there are other reasons that they are sick and they’re hemoglobin A_1c is low because of this and that then leads to dementia.” Dr. Sattar observed. He added that perhaps it was not necessarily the hyperglycemia causing dementia, it was more likely a case of reverse causality.

“The study showed clearly that high BMI, high LDL, and high blood pressure were also associated with more dementia,” Dr. Sattar said. “And, it also showed that being on antihypertensives and cholesterol-lowering tablets gives you a low risk of dementia,” he added. “So the things we are doing in diabetes to keep blood pressure down, smoking down, cholesterol down, are working and, together with keeping hemoglobin in the normal range, should help to lower the risk of dementia. That’s epidemiology, and we now need the trials to prove it, but it’s going to be very, very tough.”

Dr. Rawshani did not report having any disclosures. Dr. Sattar said that he had no disclosures relevant to his comments.

STOCKHOLM – Data from the Swedish National Diabetes Registry add to evidence that high blood glucose levels increase the risk for dementia in individuals with type 2 diabetes and imply that better glycemic control might potentially help prevent such cognitive decline.

In the large observational study, hemoglobin A_1c levels in excess of 10% increased the rate of dementia by 23%-77% depending on the time-fixed or time-updated statistical analysis performed, with hazard ratios (HRs) of 1.23 and 1.77, respectively, compared with a reference HbA_1c of less than 6%.

Sara Freeman/Frontline Medical News

“An HbA_1c between 6% and 7% was associated with a lower [HR, 0.82; 95% confidence interval, 0.86-0.91; P <.001] risk of any dementia compared to the reference, but as HbA_1c increased and was above 10% [HR, 1.23; 95% CI, 1.11-1.35; P <.001] the risk was higher for individuals,” Dr. Aidin Rawshani reported at the annual meeting of the European Association for the Study of Diabetes.

For the study, Dr. Rawshani and his colleagues at the Institute of Medicine at the University of Gothenburg (Sweden) identified all individuals with type 2 diabetes (2DM) who were registered in the Swedish National Diabetes Registry between 2003 and 2012 and who did not have dementia at enrollment. Data on individuals’ socioeconomic status, hospital admissions, outpatient visits, and deaths were then obtained from four Swedish databases and ICD-10 codes to identify those who later developed Alzheimer’s or vascular, unspecified, or any dementia.

Over a mean follow-up of 4.8 years, accounting for 1.7 million person-years, there were 353,214 individuals with 2DM without dementia at enrollment into the registry. Of these, 13,159 were reported to have any dementia, with 3,499 and 3,377 having Alzheimer’s disease or vascular dementia.

Cox regression analysis was used to assess the association between dementia and glycemic control, as well as other pertinent patient characteristics, risk factors, complications and comorbidities, and medication use. All covariates were modeled as both time-dependent and time-variable predictors.

The study population was divided into six groups according to baseline HbA_1c: <6% (n = 118,433); 6% to <7% (n = 117,397); 7% to <8% (n = 49,049); 8% to <9% (n = 23,143); 9% to <10% (n = 9,096); ≥10% (n = 8,354). Over half (55%-60%) of subjects were men, the mean age was approximately 68 years, and the duration of diabetes ranged from 4 to 10 years.

Dr. Rawshani reported that the crude event rate for any dementia was 7.25 cases per 1,000 person-years for the lowest (<6%) and 8.47 for the highest (≥10%) levels of HbA_1c. The crude event rates for the other HbA_1c categories were 7.91, 8.75, 9.13, and 8.71 per 1,000 person-years, respectively.

Modeling HbA_1c as a continuous variable showed that there was no dementia risk at an HbA_1c of 6.7% but that it increased substantially thereafter. Dementia risk also was found to increase with increasing age, diastolic blood pressure, high-density-lipoprotein cholesterol, and low-density-lipoprotein cholesterol, he said.

Looking at time-updated covariates, individuals who developed microalbuminuria (HR, 1.22; 95% CI, 1.15-1.29; P <.001) or macroalbuminuria (HR, 1.39; 95% CI, 1.29-1.50; P <.001) had a higher risk for dementia than those without albuminuria.

A higher risk for dementia also was seen in patients who did not perform any daily physical activity versus those who did, with a HR of 2.21 (95% CI, 2.05-2.38; P <.001).

Comorbid stroke increased the risk for dementia by 43% (HR, 1.43; 95% CI, 1.34-1.53; P <.001), with little risk increase for comorbid atrial fibrillation (HR, 1.11; 95% CI, 1.04-1.18; P <.003) or coronary heart disease (HR, 1.02; 95% CI, 1.02-1.16; P <.009).

Conversely, the use of statins (HR, 0.87; 95% CI, 0.82-0.92; P <.001) and antihypertensive medication (HR, 0.69; 95% CI, 0.64-0.73; P <.001) was associated with lower dementia risk.

The respective Cox analysis–predicted survival rates at 10 years for the patients who did and did not develop dementia during follow-up were 40% and 70%.

“Our conclusion is that higher HbA_1c levels are associated with an increased risk of dementia among persons with type 2 diabetes,” Dr. Rawshani said.

“The conclusion is interesting,” Dr. Naveed Sattar, professor of metabolic medicine at the Institute of Cardiovascular and Medical Sciences, University of Glasgow (Scotland), said in an interview. Dr. Sattar, who was not involved in the study, said that, while interesting, there was no mention that the very lowest blood glucose levels also were linked to an increased risk. There was a J-shaped curve, he observed.

“In people who have very low blood glucose levels, below guideline levels, I suspect that there are other reasons that they are sick and they’re hemoglobin A_1c is low because of this and that then leads to dementia.” Dr. Sattar observed. He added that perhaps it was not necessarily the hyperglycemia causing dementia, it was more likely a case of reverse causality.

“The study showed clearly that high BMI, high LDL, and high blood pressure were also associated with more dementia,” Dr. Sattar said. “And, it also showed that being on antihypertensives and cholesterol-lowering tablets gives you a low risk of dementia,” he added. “So the things we are doing in diabetes to keep blood pressure down, smoking down, cholesterol down, are working and, together with keeping hemoglobin in the normal range, should help to lower the risk of dementia. That’s epidemiology, and we now need the trials to prove it, but it’s going to be very, very tough.”

Dr. Rawshani did not report having any disclosures. Dr. Sattar said that he had no disclosures relevant to his comments.

ESTES PARK, COLO. – Primary aldosteronism, traditionally seen as a rare, stump-the-experts-type disorder, is now accepted as the cause of 5%-10% of all cases of what has been considered essential hypertension.

Primary aldosteronism is a readily treatable disorder, either surgically or medically, depending upon the subtype. So it’s essential to know which hypertensive patients to screen and how to confirm the diagnosis and then to move forward to identify the subtype in play, Dr. Michael T. McDermott said at a conference on internal medicine sponsored by the University of Colorado.

Primary aldosteronism occurs when the adrenal gland produces excessive aldosterone without being stimulated by renin. Aldosterone causes sodium retention in the kidney in exchange for potassium and hydrogen ions. The result is the triple harms of hypertension, hypokalemia, and metabolic acidosis, explained Dr. McDermott, professor of medicine and clinical pharmacology and director of endocrinology and diabetes practice at University of Colorado Hospital in Aurora.

The two main subtypes of primary aldosteronism are idiopathic hyperaldosteronism (IHA), also known as bilateral adrenal hyperplasia, which accounts for two-thirds of all cases, and unilateral aldosterone-producing adenoma, which accounts for the remaining third.

Which hypertensive patients should be screened for primary aldosteronism? Anyone with resistant hypertension as defined by inadequate blood pressure control while on three or more antihypertensive drugs; those with severe hypertension, meaning readings greater than 160/100 mm Hg; patients with onset of hypertension before age 20; and any hypertensive patient with hypokalemia, which can either be provoked by diuretic therapy or in some cases occurs spontaneously, the endocrinologist continued.

Screening for primary aldosteronism entails getting a morning blood sample to measure plasma aldosterone and plasma renin activity after having the patient sit for 10 minutes. A positive screen requires both a plasma aldosterone level greater than 15 ng/dL and a plasma aldosterone/plasma renin activity ratio greater than 20.

“You can do this screening test in a patient on any medication except spironolactone. They have to stop that drug for at least 2 weeks first,” according to Dr. McDermott.

Confirmation of a positive screening test requires demonstration that the elevated aldosterone can’t be suppressed via volume expansion. This volume expansion can be accomplished in two ways: putting the patient on a high-salt diet for 3 days, which can generally be accomplished simply by eating some potato chips daily on top of a typically high-salt American diet, or by intravenous infusion of 2 L of normal saline over the course of 4 hours.

If a 24-hour urine collection on day 3 of a high-salt diet shows an aldosterone level in excess of 12 mcg, the diagnosis of primary aldosteronism is confirmed.

“If anyone in this room who doesn’t have primary aldosteronism had a high-salt diet for 3 days and we did a 24-hour urine on the third day, your aldosterone would be zero. So a level over 12 mcg is clearly abnormal,” Dr. McDermott emphasized.

Likewise, a plasma aldosterone greater than 10 ng/dL following the IV saline infusion is also confirmatory.

A good clinical clue that primary aldosteronism is due to an aldosterone-producing tumor is severe hypertension and/or severe hypokalemia in a patient under 40 years of age. A plasma aldosterone greater than 25 ng/dL or a urine aldosterone in excess of 30 mcg/24 hours is another useful clue because a tumor produces a lot more aldosterone than does bilateral adrenal hyperplasia.

If, and only if, a patient is willing to undergo surgery in the event further work-up establishes the presence of an aldosterone-producing tumor, the next step is an abdominal CT scan. If it reveals a unilateral hypodense nodule greater than 1 cm in size and the patient is less than 35 years old, referral for unilateral laparoscopic or open adrenalectomy is warranted. Preoperatively the patient should be placed on either spironolactone or eplerenone; these aldosterone antagonists block the effects of aldosterone on the kidney, with resultant normalization of hypertension and hypokalemia.

Bilateral adrenal hyperplasia is much more common than an aldosterone-producing tumor in patients older than age 35, so even when a unilateral nodule is found in such a patient it’s worthwhile to consider adrenal vein sampling. If the sampling lateralizes to one side then adrenalectomy can be offered. If there is no lateralization, however, the patient has IHA and medical management is appropriate. An aldosterone antagonist will normalize the hypokalemia but may not be sufficient to control the elevated blood pressure, in which case a calcium channel blocker, ACE inhibitor, and/or angiotensin receptor blocker can be added.

Dr. McDermott reported having no financial conflicts with regard to his presentation.

[email protected]

ESTES PARK, COLO. – Primary aldosteronism, traditionally seen as a rare, stump-the-experts-type disorder, is now accepted as the cause of 5%-10% of all cases of what has been considered essential hypertension.

Primary aldosteronism is a readily treatable disorder, either surgically or medically, depending upon the subtype. So it’s essential to know which hypertensive patients to screen and how to confirm the diagnosis and then to move forward to identify the subtype in play, Dr. Michael T. McDermott said at a conference on internal medicine sponsored by the University of Colorado.

Primary aldosteronism occurs when the adrenal gland produces excessive aldosterone without being stimulated by renin. Aldosterone causes sodium retention in the kidney in exchange for potassium and hydrogen ions. The result is the triple harms of hypertension, hypokalemia, and metabolic acidosis, explained Dr. McDermott, professor of medicine and clinical pharmacology and director of endocrinology and diabetes practice at University of Colorado Hospital in Aurora.

The two main subtypes of primary aldosteronism are idiopathic hyperaldosteronism (IHA), also known as bilateral adrenal hyperplasia, which accounts for two-thirds of all cases, and unilateral aldosterone-producing adenoma, which accounts for the remaining third.

Which hypertensive patients should be screened for primary aldosteronism? Anyone with resistant hypertension as defined by inadequate blood pressure control while on three or more antihypertensive drugs; those with severe hypertension, meaning readings greater than 160/100 mm Hg; patients with onset of hypertension before age 20; and any hypertensive patient with hypokalemia, which can either be provoked by diuretic therapy or in some cases occurs spontaneously, the endocrinologist continued.

Screening for primary aldosteronism entails getting a morning blood sample to measure plasma aldosterone and plasma renin activity after having the patient sit for 10 minutes. A positive screen requires both a plasma aldosterone level greater than 15 ng/dL and a plasma aldosterone/plasma renin activity ratio greater than 20.

“You can do this screening test in a patient on any medication except spironolactone. They have to stop that drug for at least 2 weeks first,” according to Dr. McDermott.

Confirmation of a positive screening test requires demonstration that the elevated aldosterone can’t be suppressed via volume expansion. This volume expansion can be accomplished in two ways: putting the patient on a high-salt diet for 3 days, which can generally be accomplished simply by eating some potato chips daily on top of a typically high-salt American diet, or by intravenous infusion of 2 L of normal saline over the course of 4 hours.

If a 24-hour urine collection on day 3 of a high-salt diet shows an aldosterone level in excess of 12 mcg, the diagnosis of primary aldosteronism is confirmed.

“If anyone in this room who doesn’t have primary aldosteronism had a high-salt diet for 3 days and we did a 24-hour urine on the third day, your aldosterone would be zero. So a level over 12 mcg is clearly abnormal,” Dr. McDermott emphasized.

Likewise, a plasma aldosterone greater than 10 ng/dL following the IV saline infusion is also confirmatory.

A good clinical clue that primary aldosteronism is due to an aldosterone-producing tumor is severe hypertension and/or severe hypokalemia in a patient under 40 years of age. A plasma aldosterone greater than 25 ng/dL or a urine aldosterone in excess of 30 mcg/24 hours is another useful clue because a tumor produces a lot more aldosterone than does bilateral adrenal hyperplasia.

If, and only if, a patient is willing to undergo surgery in the event further work-up establishes the presence of an aldosterone-producing tumor, the next step is an abdominal CT scan. If it reveals a unilateral hypodense nodule greater than 1 cm in size and the patient is less than 35 years old, referral for unilateral laparoscopic or open adrenalectomy is warranted. Preoperatively the patient should be placed on either spironolactone or eplerenone; these aldosterone antagonists block the effects of aldosterone on the kidney, with resultant normalization of hypertension and hypokalemia.

Bilateral adrenal hyperplasia is much more common than an aldosterone-producing tumor in patients older than age 35, so even when a unilateral nodule is found in such a patient it’s worthwhile to consider adrenal vein sampling. If the sampling lateralizes to one side then adrenalectomy can be offered. If there is no lateralization, however, the patient has IHA and medical management is appropriate. An aldosterone antagonist will normalize the hypokalemia but may not be sufficient to control the elevated blood pressure, in which case a calcium channel blocker, ACE inhibitor, and/or angiotensin receptor blocker can be added.

Dr. McDermott reported having no financial conflicts with regard to his presentation.

[email protected]

ESTES PARK, COLO. – Primary aldosteronism, traditionally seen as a rare, stump-the-experts-type disorder, is now accepted as the cause of 5%-10% of all cases of what has been considered essential hypertension.

Primary aldosteronism is a readily treatable disorder, either surgically or medically, depending upon the subtype. So it’s essential to know which hypertensive patients to screen and how to confirm the diagnosis and then to move forward to identify the subtype in play, Dr. Michael T. McDermott said at a conference on internal medicine sponsored by the University of Colorado.

Primary aldosteronism occurs when the adrenal gland produces excessive aldosterone without being stimulated by renin. Aldosterone causes sodium retention in the kidney in exchange for potassium and hydrogen ions. The result is the triple harms of hypertension, hypokalemia, and metabolic acidosis, explained Dr. McDermott, professor of medicine and clinical pharmacology and director of endocrinology and diabetes practice at University of Colorado Hospital in Aurora.

The two main subtypes of primary aldosteronism are idiopathic hyperaldosteronism (IHA), also known as bilateral adrenal hyperplasia, which accounts for two-thirds of all cases, and unilateral aldosterone-producing adenoma, which accounts for the remaining third.

Which hypertensive patients should be screened for primary aldosteronism? Anyone with resistant hypertension as defined by inadequate blood pressure control while on three or more antihypertensive drugs; those with severe hypertension, meaning readings greater than 160/100 mm Hg; patients with onset of hypertension before age 20; and any hypertensive patient with hypokalemia, which can either be provoked by diuretic therapy or in some cases occurs spontaneously, the endocrinologist continued.

Screening for primary aldosteronism entails getting a morning blood sample to measure plasma aldosterone and plasma renin activity after having the patient sit for 10 minutes. A positive screen requires both a plasma aldosterone level greater than 15 ng/dL and a plasma aldosterone/plasma renin activity ratio greater than 20.

“You can do this screening test in a patient on any medication except spironolactone. They have to stop that drug for at least 2 weeks first,” according to Dr. McDermott.

Confirmation of a positive screening test requires demonstration that the elevated aldosterone can’t be suppressed via volume expansion. This volume expansion can be accomplished in two ways: putting the patient on a high-salt diet for 3 days, which can generally be accomplished simply by eating some potato chips daily on top of a typically high-salt American diet, or by intravenous infusion of 2 L of normal saline over the course of 4 hours.

If a 24-hour urine collection on day 3 of a high-salt diet shows an aldosterone level in excess of 12 mcg, the diagnosis of primary aldosteronism is confirmed.

“If anyone in this room who doesn’t have primary aldosteronism had a high-salt diet for 3 days and we did a 24-hour urine on the third day, your aldosterone would be zero. So a level over 12 mcg is clearly abnormal,” Dr. McDermott emphasized.

Likewise, a plasma aldosterone greater than 10 ng/dL following the IV saline infusion is also confirmatory.

A good clinical clue that primary aldosteronism is due to an aldosterone-producing tumor is severe hypertension and/or severe hypokalemia in a patient under 40 years of age. A plasma aldosterone greater than 25 ng/dL or a urine aldosterone in excess of 30 mcg/24 hours is another useful clue because a tumor produces a lot more aldosterone than does bilateral adrenal hyperplasia.

If, and only if, a patient is willing to undergo surgery in the event further work-up establishes the presence of an aldosterone-producing tumor, the next step is an abdominal CT scan. If it reveals a unilateral hypodense nodule greater than 1 cm in size and the patient is less than 35 years old, referral for unilateral laparoscopic or open adrenalectomy is warranted. Preoperatively the patient should be placed on either spironolactone or eplerenone; these aldosterone antagonists block the effects of aldosterone on the kidney, with resultant normalization of hypertension and hypokalemia.

Bilateral adrenal hyperplasia is much more common than an aldosterone-producing tumor in patients older than age 35, so even when a unilateral nodule is found in such a patient it’s worthwhile to consider adrenal vein sampling. If the sampling lateralizes to one side then adrenalectomy can be offered. If there is no lateralization, however, the patient has IHA and medical management is appropriate. An aldosterone antagonist will normalize the hypokalemia but may not be sufficient to control the elevated blood pressure, in which case a calcium channel blocker, ACE inhibitor, and/or angiotensin receptor blocker can be added.

Dr. McDermott reported having no financial conflicts with regard to his presentation.

[email protected]

LONDON – Further data from two large-scale diabetes trials continue to indicate that there is no increased risk for heart failure with either lixisenatide or sitagliptin compared to placebo.

The findings from ELIXA (the evaluation of lixisenatide in acute coronary syndromes) and TECOS (the Trial Evaluating Cardiovascular Outcomes With Sitagliptin), presented at the annual congress of the European Society of Cardiology, provide reassuring evidence of the cardiovascular safety of both drugs, and add to the trials’ results previously presented at the 2015 annual scientific sessions of the American Diabetes Association, according to the key investigators for the separately-run trials.

Sara Freeman/Frontline Medical News

“ELIXA demonstrates the cardiovascular safety of lixisenatide,” Dr. Eldrin Lewis, associate professor of medicine at Harvard Medical School and of Brigham and Women’s Hospital in Boston. “Additional analyses indicate safety with respect to heart failure events as well as all-cause mortality, and the hazard ratio after heart failure hospitalizations demonstrate that this endpoint is very meaningful in diabetes as it is in other populations” he added. Furthermore, the neutral effects of lixisenatide were seen across a wide spectrum of heart failure risk.

TECOS investigator Dr. Paul Armstrong of the University of Alberta in Canada noted similar safety findings with sitagliptin. “We found no increase in the risk of heart failure or related adverse outcomes after sitagliptin therapy,” he said at a press briefing. “We can safely conclude that sitagliptin can be used in patients with type 2 diabetes without concern for worsening heart failure.”

ELIXA and TECOS were two phase 3, randomized, double blind placebo-controlled trials specifically designed to look at cardiovascular outcomes after treatment with the glucagon-like peptide 1 (GLP-1) receptor agonist lixisenatide (intended trade name Lyxumia) or the dipeptyl peptidase 4 (DPP-4) inhibitor sitagliptin (Januvia). The trials enrolled 6,068 and 14,671 patients, respectively, and were performed in the wake of prior trials that had suggested an increased risk for hospitalization for heart failure in patients treated with other DPP-4 inhibitors including saxagliptin (Onglyza) in the SAVOR-TIMI 53 trial and alogliptin (Nesina) in the EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial.

Although powered to show superiority of lixisenatide versus placebo in terms of cardiovascular safety, ELIXA was only able to establish noninferiority (HR, 1.02), but results were below limits for noninferiority set by the United States Food and Drug Administration, Dr. Lewis observed. In the updated analysis of ELIXA there was no difference between treatment with the lixisenatide and placebo for the primary composite cardiovascular endpoint plus heart failure hospitalization (hazard ratio, 0.97, 95% confidence interval 0.85-1.10) after 3 years of follow-up. There were also no differences in the rates of heart failure hospitalization (HR, 0.96, 95% CI 0.75-1.23), the primary endpoint plus heart failure hospitalization and coronary revascularization (HR=1.00, 95% CI 0.90-1.11), or death from any cause (HR, 0.94, 95% CI 0.78-1.13).Although the risk for heart failure hospitalization was found to be nine times higher in patients who had a prior history of heart failure in ELIXA than in those who did not there was there was no difference between treatment with the GLP-1 agonist or placebo in patients with (9.7% vs. 10.2%, HR, 0.93, 95% CI 0.66-1.30) or without (2.4% vs. 2.5%, HR, 0.97, 95% CI 0.67-1.40) a history of the disease.

The primary findings of TECOS have been published (doi:10.1056/NEJMoa1501352) and showed sitagliptin to be noninferior to placebo for the primary composite cardiovascular endpoint (HR,0.98; 95% CI, 0.88-1.09; P less than .001). Heart failure hospitalization rates were similar (HR, 1.00; 95% CI, 0.83-1.20; P = .98).

In the updated analysis of TECOS, the prespecified secondary endpoint of time to first hospitalization for heart failure did not differ between the placebo and sitagliptin arms (HR, 1.0; 95% CI, 0.84-1.20, P = .95), nor were there any differences between the treatments in terms of other prespecified secondary endpoints of hospitalization for heart failure or cardiovascular death (HR, 1.02, 95% CI 0.90-1.14, P =.74), or hospitalization for heart failure or all-cause death (HR, 1.00, 95% CI 0.90-1.11, P = .93).

Dr. Armstrong acknowledged that the findings of TECOS were in contrast to the SAVOR-TIMI 53 and EXAMINE trials but that this could be due to several factors: differences in the patients enrolled, the background care provided, and variation in the acquisition or definition of heart failure events between the trials. It could also be due to intrinsic differences among the DPP-4 inhibitors themselves or “chance.”

Dr. Gabriel Steg of Hôpital Bichat in Paris, France who provided independent comment after the presentation of the ELIXA data questioned the value of continuing to perform large-scale noninferiority studies assessing the cardiovascular safety of novel diabetes medicines. More than 150,000 patients have been studied in such trials to date which have shown noninferiority for cardiovascular outcomes.

“Non-inferiority trials are often mistakenly being interpreted as ‘lack of efficacy’ trials and can among nonspecialists generate skepticism regarding treatment of diabetes or the need to control glycemia,” he said. “My conclusion would be to suggest that it is time to stop wasting resources on noninferiority trials and to work on truly improving diabetes care.”

ELXIA was sponsored by Sanofi. Dr. Lewis disclosed receiving research funding from Sanofi, and other drug companies. TECOS was sponsored by Merck. Dr. Armstrong disclosed receiving research funding, educational grants and consulting fees from Merck as well as other companies. Dr. Steg had received research grants from and has acted as a consultant for Sanofi, Merck, and other companies.

LONDON – Further data from two large-scale diabetes trials continue to indicate that there is no increased risk for heart failure with either lixisenatide or sitagliptin compared to placebo.

The findings from ELIXA (the evaluation of lixisenatide in acute coronary syndromes) and TECOS (the Trial Evaluating Cardiovascular Outcomes With Sitagliptin), presented at the annual congress of the European Society of Cardiology, provide reassuring evidence of the cardiovascular safety of both drugs, and add to the trials’ results previously presented at the 2015 annual scientific sessions of the American Diabetes Association, according to the key investigators for the separately-run trials.

Sara Freeman/Frontline Medical News

“ELIXA demonstrates the cardiovascular safety of lixisenatide,” Dr. Eldrin Lewis, associate professor of medicine at Harvard Medical School and of Brigham and Women’s Hospital in Boston. “Additional analyses indicate safety with respect to heart failure events as well as all-cause mortality, and the hazard ratio after heart failure hospitalizations demonstrate that this endpoint is very meaningful in diabetes as it is in other populations” he added. Furthermore, the neutral effects of lixisenatide were seen across a wide spectrum of heart failure risk.

TECOS investigator Dr. Paul Armstrong of the University of Alberta in Canada noted similar safety findings with sitagliptin. “We found no increase in the risk of heart failure or related adverse outcomes after sitagliptin therapy,” he said at a press briefing. “We can safely conclude that sitagliptin can be used in patients with type 2 diabetes without concern for worsening heart failure.”

ELIXA and TECOS were two phase 3, randomized, double blind placebo-controlled trials specifically designed to look at cardiovascular outcomes after treatment with the glucagon-like peptide 1 (GLP-1) receptor agonist lixisenatide (intended trade name Lyxumia) or the dipeptyl peptidase 4 (DPP-4) inhibitor sitagliptin (Januvia). The trials enrolled 6,068 and 14,671 patients, respectively, and were performed in the wake of prior trials that had suggested an increased risk for hospitalization for heart failure in patients treated with other DPP-4 inhibitors including saxagliptin (Onglyza) in the SAVOR-TIMI 53 trial and alogliptin (Nesina) in the EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial.

Although powered to show superiority of lixisenatide versus placebo in terms of cardiovascular safety, ELIXA was only able to establish noninferiority (HR, 1.02), but results were below limits for noninferiority set by the United States Food and Drug Administration, Dr. Lewis observed. In the updated analysis of ELIXA there was no difference between treatment with the lixisenatide and placebo for the primary composite cardiovascular endpoint plus heart failure hospitalization (hazard ratio, 0.97, 95% confidence interval 0.85-1.10) after 3 years of follow-up. There were also no differences in the rates of heart failure hospitalization (HR, 0.96, 95% CI 0.75-1.23), the primary endpoint plus heart failure hospitalization and coronary revascularization (HR=1.00, 95% CI 0.90-1.11), or death from any cause (HR, 0.94, 95% CI 0.78-1.13).Although the risk for heart failure hospitalization was found to be nine times higher in patients who had a prior history of heart failure in ELIXA than in those who did not there was there was no difference between treatment with the GLP-1 agonist or placebo in patients with (9.7% vs. 10.2%, HR, 0.93, 95% CI 0.66-1.30) or without (2.4% vs. 2.5%, HR, 0.97, 95% CI 0.67-1.40) a history of the disease.

The primary findings of TECOS have been published (doi:10.1056/NEJMoa1501352) and showed sitagliptin to be noninferior to placebo for the primary composite cardiovascular endpoint (HR,0.98; 95% CI, 0.88-1.09; P less than .001). Heart failure hospitalization rates were similar (HR, 1.00; 95% CI, 0.83-1.20; P = .98).

In the updated analysis of TECOS, the prespecified secondary endpoint of time to first hospitalization for heart failure did not differ between the placebo and sitagliptin arms (HR, 1.0; 95% CI, 0.84-1.20, P = .95), nor were there any differences between the treatments in terms of other prespecified secondary endpoints of hospitalization for heart failure or cardiovascular death (HR, 1.02, 95% CI 0.90-1.14, P =.74), or hospitalization for heart failure or all-cause death (HR, 1.00, 95% CI 0.90-1.11, P = .93).

Dr. Armstrong acknowledged that the findings of TECOS were in contrast to the SAVOR-TIMI 53 and EXAMINE trials but that this could be due to several factors: differences in the patients enrolled, the background care provided, and variation in the acquisition or definition of heart failure events between the trials. It could also be due to intrinsic differences among the DPP-4 inhibitors themselves or “chance.”

Dr. Gabriel Steg of Hôpital Bichat in Paris, France who provided independent comment after the presentation of the ELIXA data questioned the value of continuing to perform large-scale noninferiority studies assessing the cardiovascular safety of novel diabetes medicines. More than 150,000 patients have been studied in such trials to date which have shown noninferiority for cardiovascular outcomes.

“Non-inferiority trials are often mistakenly being interpreted as ‘lack of efficacy’ trials and can among nonspecialists generate skepticism regarding treatment of diabetes or the need to control glycemia,” he said. “My conclusion would be to suggest that it is time to stop wasting resources on noninferiority trials and to work on truly improving diabetes care.”

ELXIA was sponsored by Sanofi. Dr. Lewis disclosed receiving research funding from Sanofi, and other drug companies. TECOS was sponsored by Merck. Dr. Armstrong disclosed receiving research funding, educational grants and consulting fees from Merck as well as other companies. Dr. Steg had received research grants from and has acted as a consultant for Sanofi, Merck, and other companies.

LONDON – Further data from two large-scale diabetes trials continue to indicate that there is no increased risk for heart failure with either lixisenatide or sitagliptin compared to placebo.

The findings from ELIXA (the evaluation of lixisenatide in acute coronary syndromes) and TECOS (the Trial Evaluating Cardiovascular Outcomes With Sitagliptin), presented at the annual congress of the European Society of Cardiology, provide reassuring evidence of the cardiovascular safety of both drugs, and add to the trials’ results previously presented at the 2015 annual scientific sessions of the American Diabetes Association, according to the key investigators for the separately-run trials.

Sara Freeman/Frontline Medical News

“ELIXA demonstrates the cardiovascular safety of lixisenatide,” Dr. Eldrin Lewis, associate professor of medicine at Harvard Medical School and of Brigham and Women’s Hospital in Boston. “Additional analyses indicate safety with respect to heart failure events as well as all-cause mortality, and the hazard ratio after heart failure hospitalizations demonstrate that this endpoint is very meaningful in diabetes as it is in other populations” he added. Furthermore, the neutral effects of lixisenatide were seen across a wide spectrum of heart failure risk.

TECOS investigator Dr. Paul Armstrong of the University of Alberta in Canada noted similar safety findings with sitagliptin. “We found no increase in the risk of heart failure or related adverse outcomes after sitagliptin therapy,” he said at a press briefing. “We can safely conclude that sitagliptin can be used in patients with type 2 diabetes without concern for worsening heart failure.”

ELIXA and TECOS were two phase 3, randomized, double blind placebo-controlled trials specifically designed to look at cardiovascular outcomes after treatment with the glucagon-like peptide 1 (GLP-1) receptor agonist lixisenatide (intended trade name Lyxumia) or the dipeptyl peptidase 4 (DPP-4) inhibitor sitagliptin (Januvia). The trials enrolled 6,068 and 14,671 patients, respectively, and were performed in the wake of prior trials that had suggested an increased risk for hospitalization for heart failure in patients treated with other DPP-4 inhibitors including saxagliptin (Onglyza) in the SAVOR-TIMI 53 trial and alogliptin (Nesina) in the EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial.

Although powered to show superiority of lixisenatide versus placebo in terms of cardiovascular safety, ELIXA was only able to establish noninferiority (HR, 1.02), but results were below limits for noninferiority set by the United States Food and Drug Administration, Dr. Lewis observed. In the updated analysis of ELIXA there was no difference between treatment with the lixisenatide and placebo for the primary composite cardiovascular endpoint plus heart failure hospitalization (hazard ratio, 0.97, 95% confidence interval 0.85-1.10) after 3 years of follow-up. There were also no differences in the rates of heart failure hospitalization (HR, 0.96, 95% CI 0.75-1.23), the primary endpoint plus heart failure hospitalization and coronary revascularization (HR=1.00, 95% CI 0.90-1.11), or death from any cause (HR, 0.94, 95% CI 0.78-1.13).Although the risk for heart failure hospitalization was found to be nine times higher in patients who had a prior history of heart failure in ELIXA than in those who did not there was there was no difference between treatment with the GLP-1 agonist or placebo in patients with (9.7% vs. 10.2%, HR, 0.93, 95% CI 0.66-1.30) or without (2.4% vs. 2.5%, HR, 0.97, 95% CI 0.67-1.40) a history of the disease.

The primary findings of TECOS have been published (doi:10.1056/NEJMoa1501352) and showed sitagliptin to be noninferior to placebo for the primary composite cardiovascular endpoint (HR,0.98; 95% CI, 0.88-1.09; P less than .001). Heart failure hospitalization rates were similar (HR, 1.00; 95% CI, 0.83-1.20; P = .98).

In the updated analysis of TECOS, the prespecified secondary endpoint of time to first hospitalization for heart failure did not differ between the placebo and sitagliptin arms (HR, 1.0; 95% CI, 0.84-1.20, P = .95), nor were there any differences between the treatments in terms of other prespecified secondary endpoints of hospitalization for heart failure or cardiovascular death (HR, 1.02, 95% CI 0.90-1.14, P =.74), or hospitalization for heart failure or all-cause death (HR, 1.00, 95% CI 0.90-1.11, P = .93).

Dr. Armstrong acknowledged that the findings of TECOS were in contrast to the SAVOR-TIMI 53 and EXAMINE trials but that this could be due to several factors: differences in the patients enrolled, the background care provided, and variation in the acquisition or definition of heart failure events between the trials. It could also be due to intrinsic differences among the DPP-4 inhibitors themselves or “chance.”

Dr. Gabriel Steg of Hôpital Bichat in Paris, France who provided independent comment after the presentation of the ELIXA data questioned the value of continuing to perform large-scale noninferiority studies assessing the cardiovascular safety of novel diabetes medicines. More than 150,000 patients have been studied in such trials to date which have shown noninferiority for cardiovascular outcomes.

“Non-inferiority trials are often mistakenly being interpreted as ‘lack of efficacy’ trials and can among nonspecialists generate skepticism regarding treatment of diabetes or the need to control glycemia,” he said. “My conclusion would be to suggest that it is time to stop wasting resources on noninferiority trials and to work on truly improving diabetes care.”

ELXIA was sponsored by Sanofi. Dr. Lewis disclosed receiving research funding from Sanofi, and other drug companies. TECOS was sponsored by Merck. Dr. Armstrong disclosed receiving research funding, educational grants and consulting fees from Merck as well as other companies. Dr. Steg had received research grants from and has acted as a consultant for Sanofi, Merck, and other companies.

A very-high-calorie version of the typical United States diet caused rapid weight gain, along with other adverse side effects, according to Dr. Guenther Boden and his associates.

The study group of six overweight but otherwise healthy men was fed a roughly 6,000-calorie diet representing the average U.S. diet, composed of 50% carbohydrates, 35% protein, and 15% fat. After consuming this high-calorie diet for 1 week, participants gained an average of 3.5 kg. It took only 2-3 days before subjects developed systemic and adipose insulin resistance and oxidative stress. No inflammatory or endoplasmic reticulum stress was found.

Digital Vision./Thinkstock

Oxidative stress was linked to extensive oxidation and carbonylation of various proteins within adipose tissue, including carbonylation and loss of glucose transporter type 4 (GLUT4) activity. “The observation of carbonylation in proximity to the GLUT4 glucose transport channel strongly suggested that GLUT4 had become dysfunctional, resulting in insulin resistance and providing a likely causal link between overnutrition and insulin resistance,” the investigators noted.

Find the full study in Science Translational Medicine (doi:10.1126/scitranslmed.aac4765).

[email protected]

A very-high-calorie version of the typical United States diet caused rapid weight gain, along with other adverse side effects, according to Dr. Guenther Boden and his associates.

The study group of six overweight but otherwise healthy men was fed a roughly 6,000-calorie diet representing the average U.S. diet, composed of 50% carbohydrates, 35% protein, and 15% fat. After consuming this high-calorie diet for 1 week, participants gained an average of 3.5 kg. It took only 2-3 days before subjects developed systemic and adipose insulin resistance and oxidative stress. No inflammatory or endoplasmic reticulum stress was found.

Digital Vision./Thinkstock

Oxidative stress was linked to extensive oxidation and carbonylation of various proteins within adipose tissue, including carbonylation and loss of glucose transporter type 4 (GLUT4) activity. “The observation of carbonylation in proximity to the GLUT4 glucose transport channel strongly suggested that GLUT4 had become dysfunctional, resulting in insulin resistance and providing a likely causal link between overnutrition and insulin resistance,” the investigators noted.

Find the full study in Science Translational Medicine (doi:10.1126/scitranslmed.aac4765).

[email protected]

A very-high-calorie version of the typical United States diet caused rapid weight gain, along with other adverse side effects, according to Dr. Guenther Boden and his associates.

The study group of six overweight but otherwise healthy men was fed a roughly 6,000-calorie diet representing the average U.S. diet, composed of 50% carbohydrates, 35% protein, and 15% fat. After consuming this high-calorie diet for 1 week, participants gained an average of 3.5 kg. It took only 2-3 days before subjects developed systemic and adipose insulin resistance and oxidative stress. No inflammatory or endoplasmic reticulum stress was found.

Digital Vision./Thinkstock

Oxidative stress was linked to extensive oxidation and carbonylation of various proteins within adipose tissue, including carbonylation and loss of glucose transporter type 4 (GLUT4) activity. “The observation of carbonylation in proximity to the GLUT4 glucose transport channel strongly suggested that GLUT4 had become dysfunctional, resulting in insulin resistance and providing a likely causal link between overnutrition and insulin resistance,” the investigators noted.

Find the full study in Science Translational Medicine (doi:10.1126/scitranslmed.aac4765).

[email protected]

When combined with conventional risk factors, hemoglobin A_1c modestly aids in prediction of atherosclerotic cardiovascular disease risk, according to a retrospective analysis published online Sept. 8 in Circulation: Cardiovascular Quality and Outcomes.

Conventional risk factors for CVD such as sex, age, blood pressure, smoking, or lipid level are important tools used to aid in clinical decision making. However, there is current debate about whether to include hemoglobin A_1c in the algorithms, despite the clear association of CVD with glucose levels, said Jamie A. Jarmul of the University of North Carolina in Chapel Hill, and colleagues.

©janulla/Thinkstock

They used data from the 2011-2012 National Health and Nutrition Examination Survey (NHANES) to analyze CVD risk factors and HbA_1c in 2,000 individuals aged 40-79 years without a history of diabetes or CVD. Utilizing a regression model, the distribution of HbA_1c based on patient characteristics was predicted. The impact of the predicted HbA1c on the 10-year atherosclerotic CVD risk was calculated with the use of example clinical scenarios.

Factors considered significant predictors of HbA_1c were HDL-cholesterol, total cholesterol, current smoking, sex, age, race/ethnicity, and systolic blood pressure. Further, individuals who were of black, Asian, or Hispanic race/ethnicity were associated with prediction of higher HbA_1c.

The investigators noted that by using the final model, they found a modest effect of HbA_1c on post-test atherosclerotic CVD risk in participants with intermediate risk. In the example clinical scenarios, an HbA_1c of more than 6.5% was associated with increase in posttest atherosclerotic CVD risk by 1.0%-2.5% points. An HbA_1c less than 5.7% was associated with a lowering of posttest atherosclerotic CVD risk by 0.4%-2.0% points (Circ Cardiovasc Qual Outcomes. 2015 Sep 8. doi:10.1161/CIRCOUTCOMES.115.001639). The authors note the posttest atherosclerotic CVD risk of having an elevated HbA_1c (greater than 6.5%) is similar to being 5 years older.

“The results we have presented here represent a necessary intermediate step before conducting these more comprehensive analyses assessing the utility of HbA_1c testing in ASCVD [atherosclerotic cardiovascular disease] primary prevention and the larger question of universal screening for abnormal blood glucose levels,” the authors noted.

The National Institutes of Health supported the study. Dr. Pignone reports being a member of the U.S. Preventive Services Task Force (USPSTF).

When combined with conventional risk factors, hemoglobin A_1c modestly aids in prediction of atherosclerotic cardiovascular disease risk, according to a retrospective analysis published online Sept. 8 in Circulation: Cardiovascular Quality and Outcomes.

Conventional risk factors for CVD such as sex, age, blood pressure, smoking, or lipid level are important tools used to aid in clinical decision making. However, there is current debate about whether to include hemoglobin A_1c in the algorithms, despite the clear association of CVD with glucose levels, said Jamie A. Jarmul of the University of North Carolina in Chapel Hill, and colleagues.

©janulla/Thinkstock

They used data from the 2011-2012 National Health and Nutrition Examination Survey (NHANES) to analyze CVD risk factors and HbA_1c in 2,000 individuals aged 40-79 years without a history of diabetes or CVD. Utilizing a regression model, the distribution of HbA_1c based on patient characteristics was predicted. The impact of the predicted HbA1c on the 10-year atherosclerotic CVD risk was calculated with the use of example clinical scenarios.

Factors considered significant predictors of HbA_1c were HDL-cholesterol, total cholesterol, current smoking, sex, age, race/ethnicity, and systolic blood pressure. Further, individuals who were of black, Asian, or Hispanic race/ethnicity were associated with prediction of higher HbA_1c.

The investigators noted that by using the final model, they found a modest effect of HbA_1c on post-test atherosclerotic CVD risk in participants with intermediate risk. In the example clinical scenarios, an HbA_1c of more than 6.5% was associated with increase in posttest atherosclerotic CVD risk by 1.0%-2.5% points. An HbA_1c less than 5.7% was associated with a lowering of posttest atherosclerotic CVD risk by 0.4%-2.0% points (Circ Cardiovasc Qual Outcomes. 2015 Sep 8. doi:10.1161/CIRCOUTCOMES.115.001639). The authors note the posttest atherosclerotic CVD risk of having an elevated HbA_1c (greater than 6.5%) is similar to being 5 years older.

“The results we have presented here represent a necessary intermediate step before conducting these more comprehensive analyses assessing the utility of HbA_1c testing in ASCVD [atherosclerotic cardiovascular disease] primary prevention and the larger question of universal screening for abnormal blood glucose levels,” the authors noted.

The National Institutes of Health supported the study. Dr. Pignone reports being a member of the U.S. Preventive Services Task Force (USPSTF).

When combined with conventional risk factors, hemoglobin A_1c modestly aids in prediction of atherosclerotic cardiovascular disease risk, according to a retrospective analysis published online Sept. 8 in Circulation: Cardiovascular Quality and Outcomes.

Conventional risk factors for CVD such as sex, age, blood pressure, smoking, or lipid level are important tools used to aid in clinical decision making. However, there is current debate about whether to include hemoglobin A_1c in the algorithms, despite the clear association of CVD with glucose levels, said Jamie A. Jarmul of the University of North Carolina in Chapel Hill, and colleagues.

©janulla/Thinkstock

They used data from the 2011-2012 National Health and Nutrition Examination Survey (NHANES) to analyze CVD risk factors and HbA_1c in 2,000 individuals aged 40-79 years without a history of diabetes or CVD. Utilizing a regression model, the distribution of HbA_1c based on patient characteristics was predicted. The impact of the predicted HbA1c on the 10-year atherosclerotic CVD risk was calculated with the use of example clinical scenarios.

Factors considered significant predictors of HbA_1c were HDL-cholesterol, total cholesterol, current smoking, sex, age, race/ethnicity, and systolic blood pressure. Further, individuals who were of black, Asian, or Hispanic race/ethnicity were associated with prediction of higher HbA_1c.

The investigators noted that by using the final model, they found a modest effect of HbA_1c on post-test atherosclerotic CVD risk in participants with intermediate risk. In the example clinical scenarios, an HbA_1c of more than 6.5% was associated with increase in posttest atherosclerotic CVD risk by 1.0%-2.5% points. An HbA_1c less than 5.7% was associated with a lowering of posttest atherosclerotic CVD risk by 0.4%-2.0% points (Circ Cardiovasc Qual Outcomes. 2015 Sep 8. doi:10.1161/CIRCOUTCOMES.115.001639). The authors note the posttest atherosclerotic CVD risk of having an elevated HbA_1c (greater than 6.5%) is similar to being 5 years older.

“The results we have presented here represent a necessary intermediate step before conducting these more comprehensive analyses assessing the utility of HbA_1c testing in ASCVD [atherosclerotic cardiovascular disease] primary prevention and the larger question of universal screening for abnormal blood glucose levels,” the authors noted.

The National Institutes of Health supported the study. Dr. Pignone reports being a member of the U.S. Preventive Services Task Force (USPSTF).

The prevalence of diabetes in the United States was 12% to 14% in 2011-2012 with higher rates in black, Asian, and Hispanic populations.

Over the past decade, the prevalence of diabetes has increased, placing it as a major cause of mortality and morbidity in the United States.

Andy Menke, Ph.D., of Social & Scientific Systems, a biotechnology company in Silver Spring, Md., and his colleagues sought to estimate the U.S. trends and prevalence of prediabetes, total diabetes, diagnosed diabetes, and undiagnosed diabetes using data from the National Health and Nutrition Examination Survey (NHANES). Their results were published in the Journal of the American Medical Association online Sept. 8.

NHANES is a cross-sectional survey, conducted from 1988 to 1994 and 1999 to 2012. To estimate the most recent prevalence, the investigators sampled 2,781 adults from the 2011-2012 data and included 23,634 adults to estimate the trends from 1988 to 2010.

The prevalence of diabetes was determined based on a diagnosis of diabetes or evidence of based on fasting plasma glucose greater than 126 mg/dL, hemoglobin A_1c of 6.5% or more, or 2-hour post prandial glucose greater than 200 mg/dL. Prediabetes was noted to be based on 2-hour post prandial glucose of 140-199 mg/dL, fasting plasma glucose of 100-125 mg/dL, or hemoglobin A_1c of 5.7%-6.4%.

During 2011-2012, the prevalence of diabetes based on 2-hour post prandial glucose, fasting plasma glucose, or hemoglobin A_1c was 14.3% for total diabetes (diagnosed and undiagnosed). Furthermore, the prevalence was 9.1% for diagnosed, 5.2% for undiagnosed, and 38% for prediabetes.

When compared to white individuals (11.3%), the age-standardized prevalence of diabetes was higher in Hispanic (22.6%, P less than .001), Asian (20.6%, P = .007), and black (21.8%, P less than .001) individuals. Likewise, Hispanics (29.7%, P = .003) and blacks (30.8%, P less than .001) tended to have higher BMIs compared to whites (28.4%). Asians tended to have lower BMIs (24.6%, P less than .001).

The age-standardized prevalence of undiagnosed diabetes was higher in Hispanic (49%, P = .02) and Asian (50.9%, P = .004) individuals than in other groups. However, the age-standardized prevalence of prediabetes was higher in blacks (39.6%) than in Asians (32.2%, P = .05).

When defining diabetes based on hemoglobin A_1c or fasting plasma glucose alone, the authors found fewer people with undiagnosed diabetes. For example, the prevalence was 12.3% for total diabetes with 3.1% undiagnosed and 9.2% diagnosed. Furthermore, 36.5% of the study subjects qualified as prediabetic based on these definitions.

The age-standardized prevalance of diabetes increased from 9.8% to 12.4% during the 1988-1994 and 2011-2012 periods (P less than .001 trend). However, there was not much change in prevalence from 2007-2008 to 2011-2012 (12.5% to 12.4%).

The prevalence of diabetes significantly increased during the study time period in both sexes, all racial groups, education levels, incomes, and ages.

The amount of total diabetes that was undiagnosed decreased in most groups, including sex, racial groups, and most age groups. However, in Mexican American subjects the rate of undiagnosed diabetes actually increased over the study period (5.6% to 5.9%, P = .01). The increased prevalence of diabetes was due to increases in the amount of diagnosed diabetes, the authors wrote.

Finally, the age-standardized prevalence of total diabetes for subjects aged 40-74 years was 15.9%, 18.1%, and 18% during 1988-1994, 2005-2006, and 2011-2012, respectively (P = .01 for trend).

“Between 1988-1994 and 2011-2012, the prevalence of diabetes increased significantly among the overall population and among each age group, both sexes, every racial/ethnic group, every education level, and every income level, with a particularly rapid increase among non-Hispanic black and Mexican American participants. The proportion of people who had undiagnosed diabetes significantly decreased,” the authors noted.

The authors further clarified that the lower rates of undiagnosed diabetes over time may be secondary to improved survival in patients with diabetes and better screening.

The National Institute of Diabetes and Digestive and Kidney Diseases supported the study. The authors reported no conflicts of interests.

The prevalence of diabetes in the United States was 12% to 14% in 2011-2012 with higher rates in black, Asian, and Hispanic populations.

Over the past decade, the prevalence of diabetes has increased, placing it as a major cause of mortality and morbidity in the United States.

Andy Menke, Ph.D., of Social & Scientific Systems, a biotechnology company in Silver Spring, Md., and his colleagues sought to estimate the U.S. trends and prevalence of prediabetes, total diabetes, diagnosed diabetes, and undiagnosed diabetes using data from the National Health and Nutrition Examination Survey (NHANES). Their results were published in the Journal of the American Medical Association online Sept. 8.

NHANES is a cross-sectional survey, conducted from 1988 to 1994 and 1999 to 2012. To estimate the most recent prevalence, the investigators sampled 2,781 adults from the 2011-2012 data and included 23,634 adults to estimate the trends from 1988 to 2010.

The prevalence of diabetes was determined based on a diagnosis of diabetes or evidence of based on fasting plasma glucose greater than 126 mg/dL, hemoglobin A_1c of 6.5% or more, or 2-hour post prandial glucose greater than 200 mg/dL. Prediabetes was noted to be based on 2-hour post prandial glucose of 140-199 mg/dL, fasting plasma glucose of 100-125 mg/dL, or hemoglobin A_1c of 5.7%-6.4%.

During 2011-2012, the prevalence of diabetes based on 2-hour post prandial glucose, fasting plasma glucose, or hemoglobin A_1c was 14.3% for total diabetes (diagnosed and undiagnosed). Furthermore, the prevalence was 9.1% for diagnosed, 5.2% for undiagnosed, and 38% for prediabetes.

When compared to white individuals (11.3%), the age-standardized prevalence of diabetes was higher in Hispanic (22.6%, P less than .001), Asian (20.6%, P = .007), and black (21.8%, P less than .001) individuals. Likewise, Hispanics (29.7%, P = .003) and blacks (30.8%, P less than .001) tended to have higher BMIs compared to whites (28.4%). Asians tended to have lower BMIs (24.6%, P less than .001).

The age-standardized prevalence of undiagnosed diabetes was higher in Hispanic (49%, P = .02) and Asian (50.9%, P = .004) individuals than in other groups. However, the age-standardized prevalence of prediabetes was higher in blacks (39.6%) than in Asians (32.2%, P = .05).

When defining diabetes based on hemoglobin A_1c or fasting plasma glucose alone, the authors found fewer people with undiagnosed diabetes. For example, the prevalence was 12.3% for total diabetes with 3.1% undiagnosed and 9.2% diagnosed. Furthermore, 36.5% of the study subjects qualified as prediabetic based on these definitions.

The age-standardized prevalance of diabetes increased from 9.8% to 12.4% during the 1988-1994 and 2011-2012 periods (P less than .001 trend). However, there was not much change in prevalence from 2007-2008 to 2011-2012 (12.5% to 12.4%).

The prevalence of diabetes significantly increased during the study time period in both sexes, all racial groups, education levels, incomes, and ages.

The amount of total diabetes that was undiagnosed decreased in most groups, including sex, racial groups, and most age groups. However, in Mexican American subjects the rate of undiagnosed diabetes actually increased over the study period (5.6% to 5.9%, P = .01). The increased prevalence of diabetes was due to increases in the amount of diagnosed diabetes, the authors wrote.

Finally, the age-standardized prevalence of total diabetes for subjects aged 40-74 years was 15.9%, 18.1%, and 18% during 1988-1994, 2005-2006, and 2011-2012, respectively (P = .01 for trend).

“Between 1988-1994 and 2011-2012, the prevalence of diabetes increased significantly among the overall population and among each age group, both sexes, every racial/ethnic group, every education level, and every income level, with a particularly rapid increase among non-Hispanic black and Mexican American participants. The proportion of people who had undiagnosed diabetes significantly decreased,” the authors noted.

The authors further clarified that the lower rates of undiagnosed diabetes over time may be secondary to improved survival in patients with diabetes and better screening.

The National Institute of Diabetes and Digestive and Kidney Diseases supported the study. The authors reported no conflicts of interests.

The prevalence of diabetes in the United States was 12% to 14% in 2011-2012 with higher rates in black, Asian, and Hispanic populations.

Over the past decade, the prevalence of diabetes has increased, placing it as a major cause of mortality and morbidity in the United States.

Andy Menke, Ph.D., of Social & Scientific Systems, a biotechnology company in Silver Spring, Md., and his colleagues sought to estimate the U.S. trends and prevalence of prediabetes, total diabetes, diagnosed diabetes, and undiagnosed diabetes using data from the National Health and Nutrition Examination Survey (NHANES). Their results were published in the Journal of the American Medical Association online Sept. 8.

NHANES is a cross-sectional survey, conducted from 1988 to 1994 and 1999 to 2012. To estimate the most recent prevalence, the investigators sampled 2,781 adults from the 2011-2012 data and included 23,634 adults to estimate the trends from 1988 to 2010.

The prevalence of diabetes was determined based on a diagnosis of diabetes or evidence of based on fasting plasma glucose greater than 126 mg/dL, hemoglobin A_1c of 6.5% or more, or 2-hour post prandial glucose greater than 200 mg/dL. Prediabetes was noted to be based on 2-hour post prandial glucose of 140-199 mg/dL, fasting plasma glucose of 100-125 mg/dL, or hemoglobin A_1c of 5.7%-6.4%.

During 2011-2012, the prevalence of diabetes based on 2-hour post prandial glucose, fasting plasma glucose, or hemoglobin A_1c was 14.3% for total diabetes (diagnosed and undiagnosed). Furthermore, the prevalence was 9.1% for diagnosed, 5.2% for undiagnosed, and 38% for prediabetes.

When compared to white individuals (11.3%), the age-standardized prevalence of diabetes was higher in Hispanic (22.6%, P less than .001), Asian (20.6%, P = .007), and black (21.8%, P less than .001) individuals. Likewise, Hispanics (29.7%, P = .003) and blacks (30.8%, P less than .001) tended to have higher BMIs compared to whites (28.4%). Asians tended to have lower BMIs (24.6%, P less than .001).

The age-standardized prevalence of undiagnosed diabetes was higher in Hispanic (49%, P = .02) and Asian (50.9%, P = .004) individuals than in other groups. However, the age-standardized prevalence of prediabetes was higher in blacks (39.6%) than in Asians (32.2%, P = .05).

When defining diabetes based on hemoglobin A_1c or fasting plasma glucose alone, the authors found fewer people with undiagnosed diabetes. For example, the prevalence was 12.3% for total diabetes with 3.1% undiagnosed and 9.2% diagnosed. Furthermore, 36.5% of the study subjects qualified as prediabetic based on these definitions.

The age-standardized prevalance of diabetes increased from 9.8% to 12.4% during the 1988-1994 and 2011-2012 periods (P less than .001 trend). However, there was not much change in prevalence from 2007-2008 to 2011-2012 (12.5% to 12.4%).

The prevalence of diabetes significantly increased during the study time period in both sexes, all racial groups, education levels, incomes, and ages.

The amount of total diabetes that was undiagnosed decreased in most groups, including sex, racial groups, and most age groups. However, in Mexican American subjects the rate of undiagnosed diabetes actually increased over the study period (5.6% to 5.9%, P = .01). The increased prevalence of diabetes was due to increases in the amount of diagnosed diabetes, the authors wrote.

Finally, the age-standardized prevalence of total diabetes for subjects aged 40-74 years was 15.9%, 18.1%, and 18% during 1988-1994, 2005-2006, and 2011-2012, respectively (P = .01 for trend).

“Between 1988-1994 and 2011-2012, the prevalence of diabetes increased significantly among the overall population and among each age group, both sexes, every racial/ethnic group, every education level, and every income level, with a particularly rapid increase among non-Hispanic black and Mexican American participants. The proportion of people who had undiagnosed diabetes significantly decreased,” the authors noted.

The authors further clarified that the lower rates of undiagnosed diabetes over time may be secondary to improved survival in patients with diabetes and better screening.

The National Institute of Diabetes and Digestive and Kidney Diseases supported the study. The authors reported no conflicts of interests.

Diabetes affects over 9% of Americans and is expected to double in prevalence in the next 25 years. In a country where 37% of adults are at risk for developing type 2 diabetes, programs to prevent diabetes are necessary to address the costs, morbidity, and mortality associated with this disease. Diet and exercise programs to prevent diabetes are targeted to patients with a glycosylated hemoglobin A_1c level between 5.7% and 6.4% or a fasting blood glucose of 100-125 mg/dL. Many studies have shown the benefit of intensive diet and exercise programs in preventing progression to diabetes and improving weight reduction. Based on the results of a systematic review published in Annals of Internal Medicine in July 2015, the Community Preventive Services Task Force published a clinical guideline recommending the use of combined diet and exercise programs for all patients at increased risk of developing type 2 diabetes (Ann Intern Med. 2015 Jul 14. doi: 10.7326/M15-0452.).

Description of diet and exercise programs

The task force identified several critical components of successful programs: a minimum of 3 months’ duration; well-trained providers and facilitators; a mix of counseling, coaching, and extended support outside of scheduled sessions; and multiple sessions of varied content and delivery methods.

Interventions commonly featured at least one of a few other components. Most programs set a clear goal for weight loss, and many programs included goals for physical activity and diet. Many programs used a variety of different team members such as doctors, nurses, dietitians, diabetes educators, personal trainers, trained health coaches, and physiotherapists. A series of maintenance sessions after the initial intervention was noted in many of the studies. Often times, the studies modeled their intervention based upon the well-known National Diabetes Prevention Program curriculum. These materials are available free on the Centers for Disease Control and Prevention’s website. Of the 66 programs reviewed, all were live programs using some combination of individual and group sessions. Seven programs were virtual programs using a variety of modalities such as websites and apps. Two studies were conducted with groups of adolescents.

Program outcomes

The task force recommendation was based upon a systematic review of 53 studies that evaluated 66 intensive diet and exercise education programs from 1991 to 2015. The studies were conducted over 3 months to 6 years with an average length of 12 months. Only five were less than 6 months. They included randomized controlled trials, prospective nonrandomized comparison trials, and prospective single-group studies. Some were compared with usual care and some with less intensive counseling.

The systematic review supported a decrease in the risk of developing type 2 diabetes and improved hyperglycemia, blood pressure, and lipid panels. The data were not sufficient to directly comment on long-term outcomes like cardiovascular disease, diabetic compilations, or death.

It was clear that more intense programs that included more sessions, more personnel, and more individual sessions had better weight loss and diabetes prevention outcomes.

Economics

A review of 28 studies showed that these programs are cost effective. Twelve programs provided program costs, including identifying patients at risk and program costs. The average cost per participant was $653, with a range of $383-$1,160. Group-based programs were more cost effective.

Next steps

There is a large amount of evidence to support the recommendation of diet and exercise programs in the prevention of type 2 diabetes. The cost of such programs is small in comparison with the costs incurred from the long-term health effects of type 2 diabetes, but we do not yet know which components of these programs are most important. The data support that higher-intensity programs are more successful, but, at the same time, more expensive. In an era in which virtual tools are prevalent, data are currently insufficient to support their use. Identifying a structure for maintenance visits, causes of program attrition, and long-term follow-up of existing programs also may help to craft the ideal program for diabetes prevention.

The Bottom Line

Combined programs of diet and exercise promotion are very successful and cost effective in preventing patients with prediabetes from progressing to type 2 diabetes. Higher-intensity programs with more sessions, more personnel, and individual counseling are more effective but also are more expensive. All patients with an increased risk for type 2 diabetes should participate in a combined diet and exercise program.

Dr. Skolnik is associate director of the family medicine residency program at Abington (Pa.) Memorial Hospital and professor of family and community medicine at Temple University in Philadelphia. Dr. Fidler is attending physician and assistant director in the family practice residency program at Abington Memorial Hospital.

Diabetes affects over 9% of Americans and is expected to double in prevalence in the next 25 years. In a country where 37% of adults are at risk for developing type 2 diabetes, programs to prevent diabetes are necessary to address the costs, morbidity, and mortality associated with this disease. Diet and exercise programs to prevent diabetes are targeted to patients with a glycosylated hemoglobin A_1c level between 5.7% and 6.4% or a fasting blood glucose of 100-125 mg/dL. Many studies have shown the benefit of intensive diet and exercise programs in preventing progression to diabetes and improving weight reduction. Based on the results of a systematic review published in Annals of Internal Medicine in July 2015, the Community Preventive Services Task Force published a clinical guideline recommending the use of combined diet and exercise programs for all patients at increased risk of developing type 2 diabetes (Ann Intern Med. 2015 Jul 14. doi: 10.7326/M15-0452.).

Description of diet and exercise programs

The task force identified several critical components of successful programs: a minimum of 3 months’ duration; well-trained providers and facilitators; a mix of counseling, coaching, and extended support outside of scheduled sessions; and multiple sessions of varied content and delivery methods.

Interventions commonly featured at least one of a few other components. Most programs set a clear goal for weight loss, and many programs included goals for physical activity and diet. Many programs used a variety of different team members such as doctors, nurses, dietitians, diabetes educators, personal trainers, trained health coaches, and physiotherapists. A series of maintenance sessions after the initial intervention was noted in many of the studies. Often times, the studies modeled their intervention based upon the well-known National Diabetes Prevention Program curriculum. These materials are available free on the Centers for Disease Control and Prevention’s website. Of the 66 programs reviewed, all were live programs using some combination of individual and group sessions. Seven programs were virtual programs using a variety of modalities such as websites and apps. Two studies were conducted with groups of adolescents.

Program outcomes

The task force recommendation was based upon a systematic review of 53 studies that evaluated 66 intensive diet and exercise education programs from 1991 to 2015. The studies were conducted over 3 months to 6 years with an average length of 12 months. Only five were less than 6 months. They included randomized controlled trials, prospective nonrandomized comparison trials, and prospective single-group studies. Some were compared with usual care and some with less intensive counseling.

The systematic review supported a decrease in the risk of developing type 2 diabetes and improved hyperglycemia, blood pressure, and lipid panels. The data were not sufficient to directly comment on long-term outcomes like cardiovascular disease, diabetic compilations, or death.

It was clear that more intense programs that included more sessions, more personnel, and more individual sessions had better weight loss and diabetes prevention outcomes.

Economics

A review of 28 studies showed that these programs are cost effective. Twelve programs provided program costs, including identifying patients at risk and program costs. The average cost per participant was $653, with a range of $383-$1,160. Group-based programs were more cost effective.

Next steps

There is a large amount of evidence to support the recommendation of diet and exercise programs in the prevention of type 2 diabetes. The cost of such programs is small in comparison with the costs incurred from the long-term health effects of type 2 diabetes, but we do not yet know which components of these programs are most important. The data support that higher-intensity programs are more successful, but, at the same time, more expensive. In an era in which virtual tools are prevalent, data are currently insufficient to support their use. Identifying a structure for maintenance visits, causes of program attrition, and long-term follow-up of existing programs also may help to craft the ideal program for diabetes prevention.

The Bottom Line

Combined programs of diet and exercise promotion are very successful and cost effective in preventing patients with prediabetes from progressing to type 2 diabetes. Higher-intensity programs with more sessions, more personnel, and individual counseling are more effective but also are more expensive. All patients with an increased risk for type 2 diabetes should participate in a combined diet and exercise program.

Dr. Skolnik is associate director of the family medicine residency program at Abington (Pa.) Memorial Hospital and professor of family and community medicine at Temple University in Philadelphia. Dr. Fidler is attending physician and assistant director in the family practice residency program at Abington Memorial Hospital.

Diabetes affects over 9% of Americans and is expected to double in prevalence in the next 25 years. In a country where 37% of adults are at risk for developing type 2 diabetes, programs to prevent diabetes are necessary to address the costs, morbidity, and mortality associated with this disease. Diet and exercise programs to prevent diabetes are targeted to patients with a glycosylated hemoglobin A_1c level between 5.7% and 6.4% or a fasting blood glucose of 100-125 mg/dL. Many studies have shown the benefit of intensive diet and exercise programs in preventing progression to diabetes and improving weight reduction. Based on the results of a systematic review published in Annals of Internal Medicine in July 2015, the Community Preventive Services Task Force published a clinical guideline recommending the use of combined diet and exercise programs for all patients at increased risk of developing type 2 diabetes (Ann Intern Med. 2015 Jul 14. doi: 10.7326/M15-0452.).

Description of diet and exercise programs

The task force identified several critical components of successful programs: a minimum of 3 months’ duration; well-trained providers and facilitators; a mix of counseling, coaching, and extended support outside of scheduled sessions; and multiple sessions of varied content and delivery methods.

Interventions commonly featured at least one of a few other components. Most programs set a clear goal for weight loss, and many programs included goals for physical activity and diet. Many programs used a variety of different team members such as doctors, nurses, dietitians, diabetes educators, personal trainers, trained health coaches, and physiotherapists. A series of maintenance sessions after the initial intervention was noted in many of the studies. Often times, the studies modeled their intervention based upon the well-known National Diabetes Prevention Program curriculum. These materials are available free on the Centers for Disease Control and Prevention’s website. Of the 66 programs reviewed, all were live programs using some combination of individual and group sessions. Seven programs were virtual programs using a variety of modalities such as websites and apps. Two studies were conducted with groups of adolescents.

Program outcomes

The task force recommendation was based upon a systematic review of 53 studies that evaluated 66 intensive diet and exercise education programs from 1991 to 2015. The studies were conducted over 3 months to 6 years with an average length of 12 months. Only five were less than 6 months. They included randomized controlled trials, prospective nonrandomized comparison trials, and prospective single-group studies. Some were compared with usual care and some with less intensive counseling.

The systematic review supported a decrease in the risk of developing type 2 diabetes and improved hyperglycemia, blood pressure, and lipid panels. The data were not sufficient to directly comment on long-term outcomes like cardiovascular disease, diabetic compilations, or death.

It was clear that more intense programs that included more sessions, more personnel, and more individual sessions had better weight loss and diabetes prevention outcomes.

Economics

A review of 28 studies showed that these programs are cost effective. Twelve programs provided program costs, including identifying patients at risk and program costs. The average cost per participant was $653, with a range of $383-$1,160. Group-based programs were more cost effective.

Next steps

There is a large amount of evidence to support the recommendation of diet and exercise programs in the prevention of type 2 diabetes. The cost of such programs is small in comparison with the costs incurred from the long-term health effects of type 2 diabetes, but we do not yet know which components of these programs are most important. The data support that higher-intensity programs are more successful, but, at the same time, more expensive. In an era in which virtual tools are prevalent, data are currently insufficient to support their use. Identifying a structure for maintenance visits, causes of program attrition, and long-term follow-up of existing programs also may help to craft the ideal program for diabetes prevention.

The Bottom Line

Combined programs of diet and exercise promotion are very successful and cost effective in preventing patients with prediabetes from progressing to type 2 diabetes. Higher-intensity programs with more sessions, more personnel, and individual counseling are more effective but also are more expensive. All patients with an increased risk for type 2 diabetes should participate in a combined diet and exercise program.

Dr. Skolnik is associate director of the family medicine residency program at Abington (Pa.) Memorial Hospital and professor of family and community medicine at Temple University in Philadelphia. Dr. Fidler is attending physician and assistant director in the family practice residency program at Abington Memorial Hospital.