Rapid HbA1c Rise in a Child? Intensify Treatment Fast

PHILADELPHIA – Getting a firm, early grip on blood glucose confers the best chance for durable glycemic control in children with type 2 diabetes.

Any rapid increase in hemoglobin A_1c after initial stabilization probably signals the need to quickly gear up treatment, Dr. Sonia Caprio said at the annual scientific sessions of the American Diabetes Association.

"The best single predictor of treatment failure – regardless of therapy – is baseline [hemoglobin A_1c], even if it’s in the nondiabetic range" after stabilization, said Dr. Caprio, a professor of pediatric endocrinology at Yale University in New Haven, Conn. "A rapidly rising HbA_1c, even if it’s still in the normal range, is associated with failure, and suggests the need for more intense treatment."

These new findings from the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study mean that physicians may need new treatment markers for diabetes regimens in youth, she said. "We need to identify specific thresholds for intensifying therapy, perhaps at diagnosis, perhaps after a certain period of treatment, or when the patient reaches a certain HbA_1c threshold."

Dr. Caprio joined other TODAY investigators in a lively discussion of the study. TODAY’s primary end points were released in April; the ADA presentation not only broke down predictors of treatment failure, but pointed up a disturbing scenario of the medical comorbidities that already haunt children with type 2 diabetes.

Hypertension, enlarged hearts, retinopathy, dyslipidemia, and incipient kidney dysfunction were all common among the 699 children who participated in the study, said Dr. Neil White of Washington University, St. Louis. The problems occurred early and frequently.

"Within 7-8 months after diagnosis, 14% already had nonproliferative retinopathy. That number is similar to the amount found in the Diabetes Prevention Program study, for a population that was an average of 55 years old. These subjects are getting the signs of disease during childhood that older adults have."

TODAY examined three different treatment regimens among 699 children with newly diagnosed type 2 diabetes: metformin alone, metformin plus lifestyle modifications, and metformin plus rosiglitazone (N. Engl. J. Med. 2012 April 29 [doi:10.1056/NEJMoa1109333]).

The 60-month trial started all patients aged 10-17 years on metformin 2,000 mg/day. Randomization occurred after HbA_1c stabilized at 8% or lower with metformin therapy. The primary end point was time to the failure of glycemic control (defined as an HbA_1c of at least 8% for 6 months, or sustained metabolic decompensation that required insulin treatment).

Overall, nearly half of the cohort (46%) failed to maintain glycemic control; the median time to failure was 11 months. However, compared with the combination therapy group, significantly more of those taking metformin alone failed glycemic control (52% vs. 39%). The failure rate in the lifestyle intervention group was 47% – not significantly different from that of the metformin mono- or combination therapy groups.

The new analyses examined predictors of response, and looked at medical comorbidities among the patients. A seemingly innocuous increase in HbA_1c during the initial 6-month stabilization phase was the strongest predictor of whether a child would achieve a durable response to the long-term therapy, said Dr. Kenneth Copeland, a TODAY investigator and the Milburn Endowed Chair of Pediatrics at the University of Oklahoma Health Sciences Center, Oklahoma City.

In a univariate analysis, a number of baseline factors were associated with failure, including race (with blacks doing significantly worse than whites); the presence of depression; lower household income; lower insulinogenic index, and lower HbA_1c.

The baseline difference in HbA_1c was statistically significant, but still apparently small, he said. After initial stabilization, those who maintained and failed control still had blood glucose levels in the nondiabetic range (5.7% vs. 6.4%)

But in a multivariate model, only baseline HbA_1c strongly predicted response to long-term therapy. Those who maintained glucose control had very moderate HbA_1c increases, from a median of 6.4% to about 7% by the end of the study. Those who failed therapy had a much steeper increase, rising from 5.7% at baseline to about 7.3% at the end.

"Baseline HbA_1c appears to be the best predictor of failure, regardless of whether it is still in the nondiabetic range. A rapidly rising level – even in the normal range – is associated with incipient failure and may suggest the need to intensify treatment early."

The increases in blood sugar that arose during stabilization and treatment probably signaled beta-cell decline in an increasingly stressed pancreas, Dr. Caprio said. The analysis used two algorithms to assess beta-cell function: the insulinogenic index (the difference in blood glucose before and after insulin administration) and the oral disposition index (a measure of beta-cell function relative to insulin). The baseline for this analysis was the point of randomization, when glucose was stabilized at 8% or lower after 6 months of treatment.

"At 6 months, we saw a dramatic difference between the rosiglitazone/metformin arm and the other arms," with a 20% increase in insulin sensitivity compared with no change in the other groups. Thereafter, however, insulin sensitivity started to decrease in the rosiglitazone group, until it plateaued.

By the end of the study, beta-cell function was also similar between the groups, but those in the rosiglitazone group showed a slower decline during the treatment period. This indicated that rosiglitazone was able to stabilize function for at least a period of time. "In contrast, we saw a dramatic fall-off in the beta-cell function in the other two groups, although by 24 months there were no differences among any of them."

"The favorable changes relative to insulin sensitivity were responsible for the observed reduced failure rate in the rosiglitazone group; telling is that this profound degree of insulin resistance in obese youth with type 2 diabetes is unresponsive to the effect of metformin, alone or with lifestyle therapy," Dr. Caprio said.

Because metformin failed those children, the better alternative appears to be more aggressive treatment early in the disease. "The introduction of such aggressive therapy early in the course of the disease appears to slow the decline of beta-cell adaptation and improve the chance or durable control."

Children in TODAY were plagued with much the same medical issues as are adults with type 2 diabetes, said Dr. Neil White, chairman of the TODAY data safety and monitoring committee.

The subjects had a very short duration of diabetes, having been diagnosed 5-7 months before the metformin stabilization period. At that point, 34% already had hypertension. Abnormal LDL cholesterol levels were present in 10%, and high triglycerides in 54%. Some 20% had microalbuminuria, suggesting possible progression to kidney disease.

All of the children, regardless of their treatment group or outcome, showed somewhat abnormal left ventricular and right auricular measurements, noted Dr. White, who is also director of the pediatric clinical research unit at Washington University.

Echocardiography showed that the children had a left auricular diameter of up to 2.4 cm/m height, greater than the population median. All also had a left ventricular mass greater than the population median of 30 g/m², with some reaching almost 45 g/m².

"These youngsters had big hearts that are going to predispose them to heart disease in the future," Dr. White said.

At the end of the study, most children (523) underwent fundus photography to evaluate retinopathy. About 14% of them had some degree of nonproliferative retinopathy, putting the young group’s prevalence squarely in line with prevalence in adults with type 2 diabetes.

"This profound insulin resistance was a culprit ... against which metformin had no effect at all," Dr. Caprio said. "Even with the two best drugs we had at the time of this study – metformin and rosiglitazone – we were not able to improve outcomes in 50% of these kids."

Dr. Copeland agreed.

"The finding that 50% of our children failed therapy indicates that this is an incredibly tough disease to treat by any modality we have. Our target as a society needs to be ‘How do we prevent diabetes in children?’ because once they get it, it’s going to be really tough to intervene effectively."

TODAY was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. All of the presenters disclosed financial relationships with Daiichi Sankyo, but said these were not relevant to the TODAY study.

PHILADELPHIA – Getting a firm, early grip on blood glucose confers the best chance for durable glycemic control in children with type 2 diabetes.

Any rapid increase in hemoglobin A_1c after initial stabilization probably signals the need to quickly gear up treatment, Dr. Sonia Caprio said at the annual scientific sessions of the American Diabetes Association.

"The best single predictor of treatment failure – regardless of therapy – is baseline [hemoglobin A_1c], even if it’s in the nondiabetic range" after stabilization, said Dr. Caprio, a professor of pediatric endocrinology at Yale University in New Haven, Conn. "A rapidly rising HbA_1c, even if it’s still in the normal range, is associated with failure, and suggests the need for more intense treatment."

These new findings from the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study mean that physicians may need new treatment markers for diabetes regimens in youth, she said. "We need to identify specific thresholds for intensifying therapy, perhaps at diagnosis, perhaps after a certain period of treatment, or when the patient reaches a certain HbA_1c threshold."

Dr. Caprio joined other TODAY investigators in a lively discussion of the study. TODAY’s primary end points were released in April; the ADA presentation not only broke down predictors of treatment failure, but pointed up a disturbing scenario of the medical comorbidities that already haunt children with type 2 diabetes.

Hypertension, enlarged hearts, retinopathy, dyslipidemia, and incipient kidney dysfunction were all common among the 699 children who participated in the study, said Dr. Neil White of Washington University, St. Louis. The problems occurred early and frequently.

"Within 7-8 months after diagnosis, 14% already had nonproliferative retinopathy. That number is similar to the amount found in the Diabetes Prevention Program study, for a population that was an average of 55 years old. These subjects are getting the signs of disease during childhood that older adults have."

TODAY examined three different treatment regimens among 699 children with newly diagnosed type 2 diabetes: metformin alone, metformin plus lifestyle modifications, and metformin plus rosiglitazone (N. Engl. J. Med. 2012 April 29 [doi:10.1056/NEJMoa1109333]).

The 60-month trial started all patients aged 10-17 years on metformin 2,000 mg/day. Randomization occurred after HbA_1c stabilized at 8% or lower with metformin therapy. The primary end point was time to the failure of glycemic control (defined as an HbA_1c of at least 8% for 6 months, or sustained metabolic decompensation that required insulin treatment).

Overall, nearly half of the cohort (46%) failed to maintain glycemic control; the median time to failure was 11 months. However, compared with the combination therapy group, significantly more of those taking metformin alone failed glycemic control (52% vs. 39%). The failure rate in the lifestyle intervention group was 47% – not significantly different from that of the metformin mono- or combination therapy groups.

The new analyses examined predictors of response, and looked at medical comorbidities among the patients. A seemingly innocuous increase in HbA_1c during the initial 6-month stabilization phase was the strongest predictor of whether a child would achieve a durable response to the long-term therapy, said Dr. Kenneth Copeland, a TODAY investigator and the Milburn Endowed Chair of Pediatrics at the University of Oklahoma Health Sciences Center, Oklahoma City.

In a univariate analysis, a number of baseline factors were associated with failure, including race (with blacks doing significantly worse than whites); the presence of depression; lower household income; lower insulinogenic index, and lower HbA_1c.

The baseline difference in HbA_1c was statistically significant, but still apparently small, he said. After initial stabilization, those who maintained and failed control still had blood glucose levels in the nondiabetic range (5.7% vs. 6.4%)

But in a multivariate model, only baseline HbA_1c strongly predicted response to long-term therapy. Those who maintained glucose control had very moderate HbA_1c increases, from a median of 6.4% to about 7% by the end of the study. Those who failed therapy had a much steeper increase, rising from 5.7% at baseline to about 7.3% at the end.

"Baseline HbA_1c appears to be the best predictor of failure, regardless of whether it is still in the nondiabetic range. A rapidly rising level – even in the normal range – is associated with incipient failure and may suggest the need to intensify treatment early."

The increases in blood sugar that arose during stabilization and treatment probably signaled beta-cell decline in an increasingly stressed pancreas, Dr. Caprio said. The analysis used two algorithms to assess beta-cell function: the insulinogenic index (the difference in blood glucose before and after insulin administration) and the oral disposition index (a measure of beta-cell function relative to insulin). The baseline for this analysis was the point of randomization, when glucose was stabilized at 8% or lower after 6 months of treatment.

"At 6 months, we saw a dramatic difference between the rosiglitazone/metformin arm and the other arms," with a 20% increase in insulin sensitivity compared with no change in the other groups. Thereafter, however, insulin sensitivity started to decrease in the rosiglitazone group, until it plateaued.

By the end of the study, beta-cell function was also similar between the groups, but those in the rosiglitazone group showed a slower decline during the treatment period. This indicated that rosiglitazone was able to stabilize function for at least a period of time. "In contrast, we saw a dramatic fall-off in the beta-cell function in the other two groups, although by 24 months there were no differences among any of them."

"The favorable changes relative to insulin sensitivity were responsible for the observed reduced failure rate in the rosiglitazone group; telling is that this profound degree of insulin resistance in obese youth with type 2 diabetes is unresponsive to the effect of metformin, alone or with lifestyle therapy," Dr. Caprio said.

Because metformin failed those children, the better alternative appears to be more aggressive treatment early in the disease. "The introduction of such aggressive therapy early in the course of the disease appears to slow the decline of beta-cell adaptation and improve the chance or durable control."

Children in TODAY were plagued with much the same medical issues as are adults with type 2 diabetes, said Dr. Neil White, chairman of the TODAY data safety and monitoring committee.

The subjects had a very short duration of diabetes, having been diagnosed 5-7 months before the metformin stabilization period. At that point, 34% already had hypertension. Abnormal LDL cholesterol levels were present in 10%, and high triglycerides in 54%. Some 20% had microalbuminuria, suggesting possible progression to kidney disease.

All of the children, regardless of their treatment group or outcome, showed somewhat abnormal left ventricular and right auricular measurements, noted Dr. White, who is also director of the pediatric clinical research unit at Washington University.

Echocardiography showed that the children had a left auricular diameter of up to 2.4 cm/m height, greater than the population median. All also had a left ventricular mass greater than the population median of 30 g/m², with some reaching almost 45 g/m².

"These youngsters had big hearts that are going to predispose them to heart disease in the future," Dr. White said.

At the end of the study, most children (523) underwent fundus photography to evaluate retinopathy. About 14% of them had some degree of nonproliferative retinopathy, putting the young group’s prevalence squarely in line with prevalence in adults with type 2 diabetes.

"This profound insulin resistance was a culprit ... against which metformin had no effect at all," Dr. Caprio said. "Even with the two best drugs we had at the time of this study – metformin and rosiglitazone – we were not able to improve outcomes in 50% of these kids."

Dr. Copeland agreed.

"The finding that 50% of our children failed therapy indicates that this is an incredibly tough disease to treat by any modality we have. Our target as a society needs to be ‘How do we prevent diabetes in children?’ because once they get it, it’s going to be really tough to intervene effectively."

TODAY was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. All of the presenters disclosed financial relationships with Daiichi Sankyo, but said these were not relevant to the TODAY study.

PHILADELPHIA – Getting a firm, early grip on blood glucose confers the best chance for durable glycemic control in children with type 2 diabetes.

Any rapid increase in hemoglobin A_1c after initial stabilization probably signals the need to quickly gear up treatment, Dr. Sonia Caprio said at the annual scientific sessions of the American Diabetes Association.

"The best single predictor of treatment failure – regardless of therapy – is baseline [hemoglobin A_1c], even if it’s in the nondiabetic range" after stabilization, said Dr. Caprio, a professor of pediatric endocrinology at Yale University in New Haven, Conn. "A rapidly rising HbA_1c, even if it’s still in the normal range, is associated with failure, and suggests the need for more intense treatment."

These new findings from the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study mean that physicians may need new treatment markers for diabetes regimens in youth, she said. "We need to identify specific thresholds for intensifying therapy, perhaps at diagnosis, perhaps after a certain period of treatment, or when the patient reaches a certain HbA_1c threshold."

Dr. Caprio joined other TODAY investigators in a lively discussion of the study. TODAY’s primary end points were released in April; the ADA presentation not only broke down predictors of treatment failure, but pointed up a disturbing scenario of the medical comorbidities that already haunt children with type 2 diabetes.

Hypertension, enlarged hearts, retinopathy, dyslipidemia, and incipient kidney dysfunction were all common among the 699 children who participated in the study, said Dr. Neil White of Washington University, St. Louis. The problems occurred early and frequently.

"Within 7-8 months after diagnosis, 14% already had nonproliferative retinopathy. That number is similar to the amount found in the Diabetes Prevention Program study, for a population that was an average of 55 years old. These subjects are getting the signs of disease during childhood that older adults have."

TODAY examined three different treatment regimens among 699 children with newly diagnosed type 2 diabetes: metformin alone, metformin plus lifestyle modifications, and metformin plus rosiglitazone (N. Engl. J. Med. 2012 April 29 [doi:10.1056/NEJMoa1109333]).

The 60-month trial started all patients aged 10-17 years on metformin 2,000 mg/day. Randomization occurred after HbA_1c stabilized at 8% or lower with metformin therapy. The primary end point was time to the failure of glycemic control (defined as an HbA_1c of at least 8% for 6 months, or sustained metabolic decompensation that required insulin treatment).

Overall, nearly half of the cohort (46%) failed to maintain glycemic control; the median time to failure was 11 months. However, compared with the combination therapy group, significantly more of those taking metformin alone failed glycemic control (52% vs. 39%). The failure rate in the lifestyle intervention group was 47% – not significantly different from that of the metformin mono- or combination therapy groups.

The new analyses examined predictors of response, and looked at medical comorbidities among the patients. A seemingly innocuous increase in HbA_1c during the initial 6-month stabilization phase was the strongest predictor of whether a child would achieve a durable response to the long-term therapy, said Dr. Kenneth Copeland, a TODAY investigator and the Milburn Endowed Chair of Pediatrics at the University of Oklahoma Health Sciences Center, Oklahoma City.

In a univariate analysis, a number of baseline factors were associated with failure, including race (with blacks doing significantly worse than whites); the presence of depression; lower household income; lower insulinogenic index, and lower HbA_1c.

The baseline difference in HbA_1c was statistically significant, but still apparently small, he said. After initial stabilization, those who maintained and failed control still had blood glucose levels in the nondiabetic range (5.7% vs. 6.4%)

But in a multivariate model, only baseline HbA_1c strongly predicted response to long-term therapy. Those who maintained glucose control had very moderate HbA_1c increases, from a median of 6.4% to about 7% by the end of the study. Those who failed therapy had a much steeper increase, rising from 5.7% at baseline to about 7.3% at the end.

"Baseline HbA_1c appears to be the best predictor of failure, regardless of whether it is still in the nondiabetic range. A rapidly rising level – even in the normal range – is associated with incipient failure and may suggest the need to intensify treatment early."

The increases in blood sugar that arose during stabilization and treatment probably signaled beta-cell decline in an increasingly stressed pancreas, Dr. Caprio said. The analysis used two algorithms to assess beta-cell function: the insulinogenic index (the difference in blood glucose before and after insulin administration) and the oral disposition index (a measure of beta-cell function relative to insulin). The baseline for this analysis was the point of randomization, when glucose was stabilized at 8% or lower after 6 months of treatment.

"At 6 months, we saw a dramatic difference between the rosiglitazone/metformin arm and the other arms," with a 20% increase in insulin sensitivity compared with no change in the other groups. Thereafter, however, insulin sensitivity started to decrease in the rosiglitazone group, until it plateaued.

By the end of the study, beta-cell function was also similar between the groups, but those in the rosiglitazone group showed a slower decline during the treatment period. This indicated that rosiglitazone was able to stabilize function for at least a period of time. "In contrast, we saw a dramatic fall-off in the beta-cell function in the other two groups, although by 24 months there were no differences among any of them."

"The favorable changes relative to insulin sensitivity were responsible for the observed reduced failure rate in the rosiglitazone group; telling is that this profound degree of insulin resistance in obese youth with type 2 diabetes is unresponsive to the effect of metformin, alone or with lifestyle therapy," Dr. Caprio said.

Because metformin failed those children, the better alternative appears to be more aggressive treatment early in the disease. "The introduction of such aggressive therapy early in the course of the disease appears to slow the decline of beta-cell adaptation and improve the chance or durable control."

Children in TODAY were plagued with much the same medical issues as are adults with type 2 diabetes, said Dr. Neil White, chairman of the TODAY data safety and monitoring committee.

The subjects had a very short duration of diabetes, having been diagnosed 5-7 months before the metformin stabilization period. At that point, 34% already had hypertension. Abnormal LDL cholesterol levels were present in 10%, and high triglycerides in 54%. Some 20% had microalbuminuria, suggesting possible progression to kidney disease.

All of the children, regardless of their treatment group or outcome, showed somewhat abnormal left ventricular and right auricular measurements, noted Dr. White, who is also director of the pediatric clinical research unit at Washington University.

Echocardiography showed that the children had a left auricular diameter of up to 2.4 cm/m height, greater than the population median. All also had a left ventricular mass greater than the population median of 30 g/m², with some reaching almost 45 g/m².

"These youngsters had big hearts that are going to predispose them to heart disease in the future," Dr. White said.

At the end of the study, most children (523) underwent fundus photography to evaluate retinopathy. About 14% of them had some degree of nonproliferative retinopathy, putting the young group’s prevalence squarely in line with prevalence in adults with type 2 diabetes.

"This profound insulin resistance was a culprit ... against which metformin had no effect at all," Dr. Caprio said. "Even with the two best drugs we had at the time of this study – metformin and rosiglitazone – we were not able to improve outcomes in 50% of these kids."

Dr. Copeland agreed.

"The finding that 50% of our children failed therapy indicates that this is an incredibly tough disease to treat by any modality we have. Our target as a society needs to be ‘How do we prevent diabetes in children?’ because once they get it, it’s going to be really tough to intervene effectively."

TODAY was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. All of the presenters disclosed financial relationships with Daiichi Sankyo, but said these were not relevant to the TODAY study.