Metformin Monotherapy Fails 50% of Children With Type 2 Diabetes

BOSTON – For about half of children with type 2 diabetes, metformin alone is not enough to produce durable glycemic control, a study has shown.

The TODAY trial found that 52% of children failed monotherapy – many by 11 months, Dr. Phil Zeitler said at the annual meeting of the Pediatric Academic Societies.

And although the addition of rosiglitazone to metformin did improve results, the take-home message about monotherapy is clear, he said: Many young people with type 2 diabetes are going to need multiple medications, or insulin, within a few years of diagnosis.

"Metformin is not as good a medicine as we all thought it was. This is a much more rapid loss of control than we see in adults, in which metformin failure is about 6%-10% per year. And while the addition of rosiglitazone reduced the loss of glycemic control by 23%, the time to failure was unchanged," said Dr. Zeitler, a lead investigator in the Treatment Options for Type 2 Diabetes in Adolescents and Youth trial.

The study’s third arm – a combination of metformin and lifestyle modification – was not significantly different than either monotherapy or dual therapy. Patients using the combination of nutritional and activity counseling plus medication did lose significantly more weight than did those in the medication-only arms, but that did not translate into a longer period of glycemic control.

The study was simultaneously publishedin the online edition of the New England Journal of Medicine (2012 April 29 [doi:10.1056/NEJMoa1109333]).

The 60-month trial started 699 patients aged 10-17 years on 2,000 mg/day metformin; this treatment was continued until hemoglobin A_1c stabilized at 8%. The group was then randomized to one of the three treatment arms. The primary end point was time to the failure of glycemic control, defined as an HbA_1c level 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 for metformin monotherapy or combination therapy.

Physiology rather than compliance probably drove the differences, said Dr. Zeitler, head of pediatric endocrinology at the Children’s Hospital Colorado, Aurora.

"There was no reason to suspect that differences [in any of the results] were due to lack of adherence," he said. "In fact, if we look at a comparison of those who failed compared to those who did not, adherence was generally better in those who failed, which might have reflected the efforts of the sites to enforce adherence as the HbA_1C levels began to rise."

However, Dr. Zeitler said, the results differed significantly between sexes and racial/ethnic groups. For girls, metformin plus rosiglitazone was significantly better than monotherapy or the combination of metformin and lifestyle modification. For boys, the combination of metformin and lifestyle changes was significantly better than for the other groups.

"Metformin is not as good a medicine as we all thought it was."

"While we saw distinct gender differences in the response, we can only speculate about the reasons behind that," Dr. Zeitler said.

Blacks responded especially poorly to metformin alone, he said, "such that by 12 months, almost 50% had failed treatment. We saw increased [statistically significant] efficacy with the addition of either rosiglitazone or lifestyle changes."

Among Hispanics, there were no statistically significant differences between any of the treatment arms, although Dr. Zeitler said that lifestyle intervention tended to be less effective than drug therapy.

Among whites, there was no difference between metformin and metformin with lifestyle changes. These patients had a better response with the addition of rosiglitazone, but it was not statistically significant, he said.

"These very distinct differences in gender and ethnicity suggest that there is something biologic going on here. But we need to analyze a variety of things that could also be factors, including adherence, socioeconomic status, site location, depression, and other things. We do have those data, and those analyses will be forthcoming," Dr. Zeitler said.

Despite the benefit rosiglitazone conferred to some patients, it can’t be recommended as an add-on therapy for young people with type 2 diabetes, he said in an interview. "It’s been shown to increase cardiovascular events in adults, although we don’t know how it would affect young people who are typically more cardiovascularly healthy."

TODAY made it clear that metformin alone isn’t enough for about half of these young patients. However, Dr. Zeitler said, this glass is not just half-empty.

"Half of the youngsters do seem to maintain long-term control irrespective of treatment, and this is something we don’t want to lose sight of," he said. "This suggests there are two cohorts of patients: One that will continue to do well on monotherapy, and one that will fail very rapidly. If we could predict who those children will be at the time of diagnosis, that could have a substantial effect on our choice of treatment."

The study was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Zeitler said he had no relevant financial disclosures. However, several of the coauthors did note financial relationships with various pharmaceutical companies, including Daiichi-Sankyo, Merck, Bristol-Meyers-Squibb, Jenny Craig/Nestle, and Medtronic.

BOSTON – For about half of children with type 2 diabetes, metformin alone is not enough to produce durable glycemic control, a study has shown.

The TODAY trial found that 52% of children failed monotherapy – many by 11 months, Dr. Phil Zeitler said at the annual meeting of the Pediatric Academic Societies.

And although the addition of rosiglitazone to metformin did improve results, the take-home message about monotherapy is clear, he said: Many young people with type 2 diabetes are going to need multiple medications, or insulin, within a few years of diagnosis.

"Metformin is not as good a medicine as we all thought it was. This is a much more rapid loss of control than we see in adults, in which metformin failure is about 6%-10% per year. And while the addition of rosiglitazone reduced the loss of glycemic control by 23%, the time to failure was unchanged," said Dr. Zeitler, a lead investigator in the Treatment Options for Type 2 Diabetes in Adolescents and Youth trial.

The study’s third arm – a combination of metformin and lifestyle modification – was not significantly different than either monotherapy or dual therapy. Patients using the combination of nutritional and activity counseling plus medication did lose significantly more weight than did those in the medication-only arms, but that did not translate into a longer period of glycemic control.

The study was simultaneously publishedin the online edition of the New England Journal of Medicine (2012 April 29 [doi:10.1056/NEJMoa1109333]).

The 60-month trial started 699 patients aged 10-17 years on 2,000 mg/day metformin; this treatment was continued until hemoglobin A_1c stabilized at 8%. The group was then randomized to one of the three treatment arms. The primary end point was time to the failure of glycemic control, defined as an HbA_1c level 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 for metformin monotherapy or combination therapy.

Physiology rather than compliance probably drove the differences, said Dr. Zeitler, head of pediatric endocrinology at the Children’s Hospital Colorado, Aurora.

"There was no reason to suspect that differences [in any of the results] were due to lack of adherence," he said. "In fact, if we look at a comparison of those who failed compared to those who did not, adherence was generally better in those who failed, which might have reflected the efforts of the sites to enforce adherence as the HbA_1C levels began to rise."

However, Dr. Zeitler said, the results differed significantly between sexes and racial/ethnic groups. For girls, metformin plus rosiglitazone was significantly better than monotherapy or the combination of metformin and lifestyle modification. For boys, the combination of metformin and lifestyle changes was significantly better than for the other groups.

"Metformin is not as good a medicine as we all thought it was."

"While we saw distinct gender differences in the response, we can only speculate about the reasons behind that," Dr. Zeitler said.

Blacks responded especially poorly to metformin alone, he said, "such that by 12 months, almost 50% had failed treatment. We saw increased [statistically significant] efficacy with the addition of either rosiglitazone or lifestyle changes."

Among Hispanics, there were no statistically significant differences between any of the treatment arms, although Dr. Zeitler said that lifestyle intervention tended to be less effective than drug therapy.

Among whites, there was no difference between metformin and metformin with lifestyle changes. These patients had a better response with the addition of rosiglitazone, but it was not statistically significant, he said.

"These very distinct differences in gender and ethnicity suggest that there is something biologic going on here. But we need to analyze a variety of things that could also be factors, including adherence, socioeconomic status, site location, depression, and other things. We do have those data, and those analyses will be forthcoming," Dr. Zeitler said.

Despite the benefit rosiglitazone conferred to some patients, it can’t be recommended as an add-on therapy for young people with type 2 diabetes, he said in an interview. "It’s been shown to increase cardiovascular events in adults, although we don’t know how it would affect young people who are typically more cardiovascularly healthy."

TODAY made it clear that metformin alone isn’t enough for about half of these young patients. However, Dr. Zeitler said, this glass is not just half-empty.

"Half of the youngsters do seem to maintain long-term control irrespective of treatment, and this is something we don’t want to lose sight of," he said. "This suggests there are two cohorts of patients: One that will continue to do well on monotherapy, and one that will fail very rapidly. If we could predict who those children will be at the time of diagnosis, that could have a substantial effect on our choice of treatment."

The study was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Zeitler said he had no relevant financial disclosures. However, several of the coauthors did note financial relationships with various pharmaceutical companies, including Daiichi-Sankyo, Merck, Bristol-Meyers-Squibb, Jenny Craig/Nestle, and Medtronic.

BOSTON – For about half of children with type 2 diabetes, metformin alone is not enough to produce durable glycemic control, a study has shown.

The TODAY trial found that 52% of children failed monotherapy – many by 11 months, Dr. Phil Zeitler said at the annual meeting of the Pediatric Academic Societies.

And although the addition of rosiglitazone to metformin did improve results, the take-home message about monotherapy is clear, he said: Many young people with type 2 diabetes are going to need multiple medications, or insulin, within a few years of diagnosis.

"Metformin is not as good a medicine as we all thought it was. This is a much more rapid loss of control than we see in adults, in which metformin failure is about 6%-10% per year. And while the addition of rosiglitazone reduced the loss of glycemic control by 23%, the time to failure was unchanged," said Dr. Zeitler, a lead investigator in the Treatment Options for Type 2 Diabetes in Adolescents and Youth trial.

The study’s third arm – a combination of metformin and lifestyle modification – was not significantly different than either monotherapy or dual therapy. Patients using the combination of nutritional and activity counseling plus medication did lose significantly more weight than did those in the medication-only arms, but that did not translate into a longer period of glycemic control.

The study was simultaneously publishedin the online edition of the New England Journal of Medicine (2012 April 29 [doi:10.1056/NEJMoa1109333]).

The 60-month trial started 699 patients aged 10-17 years on 2,000 mg/day metformin; this treatment was continued until hemoglobin A_1c stabilized at 8%. The group was then randomized to one of the three treatment arms. The primary end point was time to the failure of glycemic control, defined as an HbA_1c level 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 for metformin monotherapy or combination therapy.

Physiology rather than compliance probably drove the differences, said Dr. Zeitler, head of pediatric endocrinology at the Children’s Hospital Colorado, Aurora.

"There was no reason to suspect that differences [in any of the results] were due to lack of adherence," he said. "In fact, if we look at a comparison of those who failed compared to those who did not, adherence was generally better in those who failed, which might have reflected the efforts of the sites to enforce adherence as the HbA_1C levels began to rise."

However, Dr. Zeitler said, the results differed significantly between sexes and racial/ethnic groups. For girls, metformin plus rosiglitazone was significantly better than monotherapy or the combination of metformin and lifestyle modification. For boys, the combination of metformin and lifestyle changes was significantly better than for the other groups.

"Metformin is not as good a medicine as we all thought it was."

"While we saw distinct gender differences in the response, we can only speculate about the reasons behind that," Dr. Zeitler said.

Blacks responded especially poorly to metformin alone, he said, "such that by 12 months, almost 50% had failed treatment. We saw increased [statistically significant] efficacy with the addition of either rosiglitazone or lifestyle changes."

Among Hispanics, there were no statistically significant differences between any of the treatment arms, although Dr. Zeitler said that lifestyle intervention tended to be less effective than drug therapy.

Among whites, there was no difference between metformin and metformin with lifestyle changes. These patients had a better response with the addition of rosiglitazone, but it was not statistically significant, he said.

"These very distinct differences in gender and ethnicity suggest that there is something biologic going on here. But we need to analyze a variety of things that could also be factors, including adherence, socioeconomic status, site location, depression, and other things. We do have those data, and those analyses will be forthcoming," Dr. Zeitler said.

Despite the benefit rosiglitazone conferred to some patients, it can’t be recommended as an add-on therapy for young people with type 2 diabetes, he said in an interview. "It’s been shown to increase cardiovascular events in adults, although we don’t know how it would affect young people who are typically more cardiovascularly healthy."

TODAY made it clear that metformin alone isn’t enough for about half of these young patients. However, Dr. Zeitler said, this glass is not just half-empty.

"Half of the youngsters do seem to maintain long-term control irrespective of treatment, and this is something we don’t want to lose sight of," he said. "This suggests there are two cohorts of patients: One that will continue to do well on monotherapy, and one that will fail very rapidly. If we could predict who those children will be at the time of diagnosis, that could have a substantial effect on our choice of treatment."

The study was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Zeitler said he had no relevant financial disclosures. However, several of the coauthors did note financial relationships with various pharmaceutical companies, including Daiichi-Sankyo, Merck, Bristol-Meyers-Squibb, Jenny Craig/Nestle, and Medtronic.