Miriam E. Tucker

MONTREAL — The largest-ever clinical trial in patients with type 2 diabetes is continuing to yield data that are expected to lead to improved prediction of cardiovascular risk in people with diabetes, as well as a better understanding of the relationship between intensive metabolic control and cardiovascular outcomes.

In a symposium lecture at the World Diabetes Congress, Dr. John P. Chalmers summarized data from published and unpublished substudies of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study, a randomized, placebo-controlled trial that examined the effect of both intensive blood glucose and blood pressure control on micro- and macrovascular complications. The trial included a multiethnic cohort of 11,140 patients with type 2 diabetes from 215 centers in 20 countries.

The glucose-lowering arm of ADVANCE, funded by grants from the French pharmaceutical company Servier and the National Health and Medical Research Council of Australia, used modified-release gliclazide along with other glucose-lowering drugs to target a hemoglobin A_1c of 6.5%.

The intensive-treatment group achieved a mean HbA_1c of 6.5%, compared with 7.3% in the standard-treatment group. At a median of 5 years, the intensive group had a 10% relative reduction in the combined outcome of major macro- and microvascular events compared with standard care, primarily as a consequence of a 21% relative reduction in nephropathy. There was a positive trend toward reduction of major cardiovascular events (N. Engl. J. Med. 2008;358:2560–72).

There was no excess mortality, weight gain, or severe hypoglycemic episodes in the intensive group, said Dr. Chalmers, co–principal investigator for ADVANCE.

In the blood pressure control arm, routine administration of a fixed combination of perindopril and indapamide to patients with type 2 diabetes was associated with a 9% reduction in the relative risk of a major macro- or microvascular event (Lancet 2007;370:829–40).

In a new, not-yet-published subgroup analysis of the glucose-lowering arm, the results held true regardless of age, duration of diabetes, sex, body mass index, HbA_1c at study entry, urinary albumin excretion, glomerular filtration rate, or initial glucose-lowering treatment, said Dr. Chalmers, senior director of the George Institute for International Health, Sydney, and emeritus professor of medicine at the University of Sydney and Flinders University, Adelaide, Australia.

Cognitive function, however, was an independent predictor of cardiovascular risk. Both mild and severe cognitive dysfunction, as measured at baseline by the Mini Mental State Examination, increased the risk for major cardiovascular events with hazard ratios of 1.27 and 1.42, respectively. Cardiovascular death was increased by hazard ratios of 1.41 and 1.56 for mild and severe cognitive dysfunction, respectively, and all-cause death by 1.33 and 1.50 (Diabetologia 2009;52:2328–36).

Another new and unpublished analysis showed that the risk for microvascular complications had a strong linear relationship with HbA_1c values all the way down to 6.0%, with each percentage point reduction reducing the risk by 22%. For macrovascular events, cardiovascular death, and all-cause death, the risk reduction was linear down to an HbA_1c of 7.0%, then leveled off between 7% and 6%.

A substudy of 647 participants showed no significant associations between cardiovascular risk and body mass index, but there was a relationship with waist-hip ratio, a better index of visceral fat. Urinary albumin excretion also predicted risk: For every 10-fold increase, there was a 2-fold increase in macrovascular events. Similarly, a halving of glomerular filtration rate was associated with a twofold increased risk for cardiovascular events, Dr. Chalmers said.

Using ADVANCE data regarding predictors of cardiovascular risk, the investigators are working to develop a risk engine that is specific for people with diabetes. Data from two other studies presented at the congress showed that neither Framingham score nor the risk engine derived from the 1998 United Kingdom Prospective Diabetes Study (UKPDS) is an accurate risk predictor for patients receiving modern treatments for glucose, blood pressure, and lipid levels.

Dr. Andre Pascal Kengne, also of the George Institute, presented one of these studies, which found that major cardiovascular risk among 7,502 ADVANCE participants was overestimated by 170% and 202% using two different Framingham equations. Another study, from Greek investigators, also found that Framingham and UKPDS scores overestimated the cardiovascular risk in type 2 diabetes patients receiving modern treatment.

Dr. Kengne also presented a separate paper on the predictive value of a risk engine using the independent predictors age at diagnosis, known duration of diabetes, sex, pulse pressure, treated hypertension, atrial fibrillation, retinopathy, HbA_1c, albumin/creatinine ratio, and non-HDL cholesterol level at baseline. Based on a cutoff for a 4-year predicted risk of 8% and above (equivalent to 10-year predicted risk of 20% and above), it was possible to reliably identify the 21% of 473 ADVANCE participants in whom 46% of all major cardiovascular disease was recorded during the follow-up period.

External validation will be needed to demonstrate the tool's potential for widespread clinical use, Dr. Kengne said.

Dr. Chalmers also discussed those findings in his presentation. “We have a plan in which an individual clinician can plug in the data and get a risk prediction score. This is potentially very useful. The next step is to validate the data in populations other than ADVANCE. We have plans to do that in two or three populations in different parts of the world.”

The ADVANCE investigators are now embarking on the ADVANCE-ON trial, in which the study participants will be observed for 5 years post study in their usual care settings. Primary outcomes will be death from any cause and major macrovascular events.

Dr. Chalmers is on the advisory board for Servier. Dr. Kengne stated that he had no conflicts of interest.

MONTREAL — The largest-ever clinical trial in patients with type 2 diabetes is continuing to yield data that are expected to lead to improved prediction of cardiovascular risk in people with diabetes, as well as a better understanding of the relationship between intensive metabolic control and cardiovascular outcomes.

In a symposium lecture at the World Diabetes Congress, Dr. John P. Chalmers summarized data from published and unpublished substudies of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study, a randomized, placebo-controlled trial that examined the effect of both intensive blood glucose and blood pressure control on micro- and macrovascular complications. The trial included a multiethnic cohort of 11,140 patients with type 2 diabetes from 215 centers in 20 countries.

The glucose-lowering arm of ADVANCE, funded by grants from the French pharmaceutical company Servier and the National Health and Medical Research Council of Australia, used modified-release gliclazide along with other glucose-lowering drugs to target a hemoglobin A_1c of 6.5%.

The intensive-treatment group achieved a mean HbA_1c of 6.5%, compared with 7.3% in the standard-treatment group. At a median of 5 years, the intensive group had a 10% relative reduction in the combined outcome of major macro- and microvascular events compared with standard care, primarily as a consequence of a 21% relative reduction in nephropathy. There was a positive trend toward reduction of major cardiovascular events (N. Engl. J. Med. 2008;358:2560–72).

There was no excess mortality, weight gain, or severe hypoglycemic episodes in the intensive group, said Dr. Chalmers, co–principal investigator for ADVANCE.

In the blood pressure control arm, routine administration of a fixed combination of perindopril and indapamide to patients with type 2 diabetes was associated with a 9% reduction in the relative risk of a major macro- or microvascular event (Lancet 2007;370:829–40).

In a new, not-yet-published subgroup analysis of the glucose-lowering arm, the results held true regardless of age, duration of diabetes, sex, body mass index, HbA_1c at study entry, urinary albumin excretion, glomerular filtration rate, or initial glucose-lowering treatment, said Dr. Chalmers, senior director of the George Institute for International Health, Sydney, and emeritus professor of medicine at the University of Sydney and Flinders University, Adelaide, Australia.

Cognitive function, however, was an independent predictor of cardiovascular risk. Both mild and severe cognitive dysfunction, as measured at baseline by the Mini Mental State Examination, increased the risk for major cardiovascular events with hazard ratios of 1.27 and 1.42, respectively. Cardiovascular death was increased by hazard ratios of 1.41 and 1.56 for mild and severe cognitive dysfunction, respectively, and all-cause death by 1.33 and 1.50 (Diabetologia 2009;52:2328–36).

Another new and unpublished analysis showed that the risk for microvascular complications had a strong linear relationship with HbA_1c values all the way down to 6.0%, with each percentage point reduction reducing the risk by 22%. For macrovascular events, cardiovascular death, and all-cause death, the risk reduction was linear down to an HbA_1c of 7.0%, then leveled off between 7% and 6%.

A substudy of 647 participants showed no significant associations between cardiovascular risk and body mass index, but there was a relationship with waist-hip ratio, a better index of visceral fat. Urinary albumin excretion also predicted risk: For every 10-fold increase, there was a 2-fold increase in macrovascular events. Similarly, a halving of glomerular filtration rate was associated with a twofold increased risk for cardiovascular events, Dr. Chalmers said.

Using ADVANCE data regarding predictors of cardiovascular risk, the investigators are working to develop a risk engine that is specific for people with diabetes. Data from two other studies presented at the congress showed that neither Framingham score nor the risk engine derived from the 1998 United Kingdom Prospective Diabetes Study (UKPDS) is an accurate risk predictor for patients receiving modern treatments for glucose, blood pressure, and lipid levels.

Dr. Andre Pascal Kengne, also of the George Institute, presented one of these studies, which found that major cardiovascular risk among 7,502 ADVANCE participants was overestimated by 170% and 202% using two different Framingham equations. Another study, from Greek investigators, also found that Framingham and UKPDS scores overestimated the cardiovascular risk in type 2 diabetes patients receiving modern treatment.

Dr. Kengne also presented a separate paper on the predictive value of a risk engine using the independent predictors age at diagnosis, known duration of diabetes, sex, pulse pressure, treated hypertension, atrial fibrillation, retinopathy, HbA_1c, albumin/creatinine ratio, and non-HDL cholesterol level at baseline. Based on a cutoff for a 4-year predicted risk of 8% and above (equivalent to 10-year predicted risk of 20% and above), it was possible to reliably identify the 21% of 473 ADVANCE participants in whom 46% of all major cardiovascular disease was recorded during the follow-up period.

External validation will be needed to demonstrate the tool's potential for widespread clinical use, Dr. Kengne said.

Dr. Chalmers also discussed those findings in his presentation. “We have a plan in which an individual clinician can plug in the data and get a risk prediction score. This is potentially very useful. The next step is to validate the data in populations other than ADVANCE. We have plans to do that in two or three populations in different parts of the world.”

The ADVANCE investigators are now embarking on the ADVANCE-ON trial, in which the study participants will be observed for 5 years post study in their usual care settings. Primary outcomes will be death from any cause and major macrovascular events.

Dr. Chalmers is on the advisory board for Servier. Dr. Kengne stated that he had no conflicts of interest.

MONTREAL — The largest-ever clinical trial in patients with type 2 diabetes is continuing to yield data that are expected to lead to improved prediction of cardiovascular risk in people with diabetes, as well as a better understanding of the relationship between intensive metabolic control and cardiovascular outcomes.

In a symposium lecture at the World Diabetes Congress, Dr. John P. Chalmers summarized data from published and unpublished substudies of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study, a randomized, placebo-controlled trial that examined the effect of both intensive blood glucose and blood pressure control on micro- and macrovascular complications. The trial included a multiethnic cohort of 11,140 patients with type 2 diabetes from 215 centers in 20 countries.

The glucose-lowering arm of ADVANCE, funded by grants from the French pharmaceutical company Servier and the National Health and Medical Research Council of Australia, used modified-release gliclazide along with other glucose-lowering drugs to target a hemoglobin A_1c of 6.5%.

The intensive-treatment group achieved a mean HbA_1c of 6.5%, compared with 7.3% in the standard-treatment group. At a median of 5 years, the intensive group had a 10% relative reduction in the combined outcome of major macro- and microvascular events compared with standard care, primarily as a consequence of a 21% relative reduction in nephropathy. There was a positive trend toward reduction of major cardiovascular events (N. Engl. J. Med. 2008;358:2560–72).

There was no excess mortality, weight gain, or severe hypoglycemic episodes in the intensive group, said Dr. Chalmers, co–principal investigator for ADVANCE.

In the blood pressure control arm, routine administration of a fixed combination of perindopril and indapamide to patients with type 2 diabetes was associated with a 9% reduction in the relative risk of a major macro- or microvascular event (Lancet 2007;370:829–40).

In a new, not-yet-published subgroup analysis of the glucose-lowering arm, the results held true regardless of age, duration of diabetes, sex, body mass index, HbA_1c at study entry, urinary albumin excretion, glomerular filtration rate, or initial glucose-lowering treatment, said Dr. Chalmers, senior director of the George Institute for International Health, Sydney, and emeritus professor of medicine at the University of Sydney and Flinders University, Adelaide, Australia.

Cognitive function, however, was an independent predictor of cardiovascular risk. Both mild and severe cognitive dysfunction, as measured at baseline by the Mini Mental State Examination, increased the risk for major cardiovascular events with hazard ratios of 1.27 and 1.42, respectively. Cardiovascular death was increased by hazard ratios of 1.41 and 1.56 for mild and severe cognitive dysfunction, respectively, and all-cause death by 1.33 and 1.50 (Diabetologia 2009;52:2328–36).

Another new and unpublished analysis showed that the risk for microvascular complications had a strong linear relationship with HbA_1c values all the way down to 6.0%, with each percentage point reduction reducing the risk by 22%. For macrovascular events, cardiovascular death, and all-cause death, the risk reduction was linear down to an HbA_1c of 7.0%, then leveled off between 7% and 6%.

A substudy of 647 participants showed no significant associations between cardiovascular risk and body mass index, but there was a relationship with waist-hip ratio, a better index of visceral fat. Urinary albumin excretion also predicted risk: For every 10-fold increase, there was a 2-fold increase in macrovascular events. Similarly, a halving of glomerular filtration rate was associated with a twofold increased risk for cardiovascular events, Dr. Chalmers said.

Using ADVANCE data regarding predictors of cardiovascular risk, the investigators are working to develop a risk engine that is specific for people with diabetes. Data from two other studies presented at the congress showed that neither Framingham score nor the risk engine derived from the 1998 United Kingdom Prospective Diabetes Study (UKPDS) is an accurate risk predictor for patients receiving modern treatments for glucose, blood pressure, and lipid levels.

Dr. Andre Pascal Kengne, also of the George Institute, presented one of these studies, which found that major cardiovascular risk among 7,502 ADVANCE participants was overestimated by 170% and 202% using two different Framingham equations. Another study, from Greek investigators, also found that Framingham and UKPDS scores overestimated the cardiovascular risk in type 2 diabetes patients receiving modern treatment.

Dr. Kengne also presented a separate paper on the predictive value of a risk engine using the independent predictors age at diagnosis, known duration of diabetes, sex, pulse pressure, treated hypertension, atrial fibrillation, retinopathy, HbA_1c, albumin/creatinine ratio, and non-HDL cholesterol level at baseline. Based on a cutoff for a 4-year predicted risk of 8% and above (equivalent to 10-year predicted risk of 20% and above), it was possible to reliably identify the 21% of 473 ADVANCE participants in whom 46% of all major cardiovascular disease was recorded during the follow-up period.

External validation will be needed to demonstrate the tool's potential for widespread clinical use, Dr. Kengne said.

Dr. Chalmers also discussed those findings in his presentation. “We have a plan in which an individual clinician can plug in the data and get a risk prediction score. This is potentially very useful. The next step is to validate the data in populations other than ADVANCE. We have plans to do that in two or three populations in different parts of the world.”

The ADVANCE investigators are now embarking on the ADVANCE-ON trial, in which the study participants will be observed for 5 years post study in their usual care settings. Primary outcomes will be death from any cause and major macrovascular events.

Dr. Chalmers is on the advisory board for Servier. Dr. Kengne stated that he had no conflicts of interest.

The human papillomavirus 16/18 vaccine showed efficacy, sustained immunogenicity, and continued safety for up to 6.4 years in a combination of initial and follow-up placebo-controlled studies involving more than 1,000 women aged 15-26 years.

The human papillomavirus (HPV) vaccine, Cervarix, is now licensed in the United States, Europe, and elsewhere around the world. It contains the HPV types 16 and 18 adjuvanted with ASO4, comprising aluminum salt and an immunostimulatory molecule that has been shown to produce higher antibody titers that are sustained over a longer period of time, compared with the same antigens adjuvanted with aluminum salts alone, according to the GSK Vaccine HPV-007 Study Group, led by Dr. Barbara Romanowski (Lancet 2009 Dec. 3 [doi:10.1016/S0140-6736(09)61567-1]).

Of 1,113 women included in the initial three-country, 27-site study, a total of 700 completed the follow-up study. The total vaccinated cohort included 560 women in the vaccine group and 553 in the placebo group, while the according-to-protocol (ATP) efficacy cohort included 465 in the vaccine group and 454 in the placebo group. At baseline, all had normal cervical cytology and were negative for both HPV-16 and −18.

The mean follow-up period from the start of the initial study was 5.9 years, with a maximum duration of 6.4 years. The study population was racially diverse, with a mean age of 20 years (range 15-26 years) at entry to the initial study and 23 years at the beginning of the follow-up study.

At 6.4 years, vaccine efficacy against incident HPV-16 or HPV-18 infection in the ATP analysis was 95.3%, and long-term efficacy against persistent infection was 100% at both 6 and 12 months. In the total vaccinated cohort analysis, protection against cervical intraepithelial neoplasia grade 1 or higher associated with either vaccine HPV type was 100%. For the nonvaccine types HPV-31 and −45, vaccine efficacy against incident infection was 59.8% and 77.7%, while overall efficacy against any cervical intraepithelial neoplasia grade 2 or higher independent of HPV type was 71.9%, said Dr. Romanowski of the University of Alberta, Edmonton, and her associates.

Almost all vaccine recipients (99%) remained seropositive for anti–HPV-16 and anti–HPV-18 total IgG antibodies. After a peak response at 7 months, geometric mean titers for both antibodies reached a plateau between 18 and 24 months post vaccination, and remained stable thereafter. During months 63-76, antibody concentrations against HPV-16 and HPV-18 were at least 13-fold and 12-fold higher than were concentrations recorded following clearance of a natural infection in a previous study (Lancet 2007;369:2161-70).

Safety profiles of the HPV-16/18 vaccine and placebo were similar, with approximately one-third of each group reporting any adverse event, 10% or fewer reporting a serious adverse event, and less than 10% reporting new-onset chronic diseases. None of the serious adverse events was judged to be related to the vaccine, and there were no deaths.

In an accompanying editorial, Dr. Gary M. Clifford wrote that the data showing no evidence of further decline from 3 to 6 years are “perhaps the most interesting” because they suggest that mean antibody concentrations should remain well above those associated with natural infection long into the future.

The target age of vaccination is a balance between “being early enough to catch girls before sexual debut, but late enough to provide an as yet unknown duration of immunity that protects during as many subsequent years of sexual activity as possible,” wrote Dr. Clifford of the International Agency for Research on Cancer, Lyon, France (Lancet 2009 Dec. 3 [doi:10.1016/S0140-6736(09)61789-X]).

Vitals

Major Finding: At 6.4 years, vaccine efficacy against incident HPV infection was 95% in the according-to-protocol cohort.

Source of Data: A three-country, 27-site study of 1,113 women aged 15-26 years.

Disclosures: The study, led by Dr. Romanowski, was funded by GlaxoSmithKline (GSK) Biologicals, manufacturer of Cervarix. Dr. Clifford declared that he had no conflicts of interest.

The human papillomavirus 16/18 vaccine showed efficacy, sustained immunogenicity, and continued safety for up to 6.4 years in a combination of initial and follow-up placebo-controlled studies involving more than 1,000 women aged 15-26 years.

The human papillomavirus (HPV) vaccine, Cervarix, is now licensed in the United States, Europe, and elsewhere around the world. It contains the HPV types 16 and 18 adjuvanted with ASO4, comprising aluminum salt and an immunostimulatory molecule that has been shown to produce higher antibody titers that are sustained over a longer period of time, compared with the same antigens adjuvanted with aluminum salts alone, according to the GSK Vaccine HPV-007 Study Group, led by Dr. Barbara Romanowski (Lancet 2009 Dec. 3 [doi:10.1016/S0140-6736(09)61567-1]).

Of 1,113 women included in the initial three-country, 27-site study, a total of 700 completed the follow-up study. The total vaccinated cohort included 560 women in the vaccine group and 553 in the placebo group, while the according-to-protocol (ATP) efficacy cohort included 465 in the vaccine group and 454 in the placebo group. At baseline, all had normal cervical cytology and were negative for both HPV-16 and −18.

The mean follow-up period from the start of the initial study was 5.9 years, with a maximum duration of 6.4 years. The study population was racially diverse, with a mean age of 20 years (range 15-26 years) at entry to the initial study and 23 years at the beginning of the follow-up study.

At 6.4 years, vaccine efficacy against incident HPV-16 or HPV-18 infection in the ATP analysis was 95.3%, and long-term efficacy against persistent infection was 100% at both 6 and 12 months. In the total vaccinated cohort analysis, protection against cervical intraepithelial neoplasia grade 1 or higher associated with either vaccine HPV type was 100%. For the nonvaccine types HPV-31 and −45, vaccine efficacy against incident infection was 59.8% and 77.7%, while overall efficacy against any cervical intraepithelial neoplasia grade 2 or higher independent of HPV type was 71.9%, said Dr. Romanowski of the University of Alberta, Edmonton, and her associates.

Almost all vaccine recipients (99%) remained seropositive for anti–HPV-16 and anti–HPV-18 total IgG antibodies. After a peak response at 7 months, geometric mean titers for both antibodies reached a plateau between 18 and 24 months post vaccination, and remained stable thereafter. During months 63-76, antibody concentrations against HPV-16 and HPV-18 were at least 13-fold and 12-fold higher than were concentrations recorded following clearance of a natural infection in a previous study (Lancet 2007;369:2161-70).

Safety profiles of the HPV-16/18 vaccine and placebo were similar, with approximately one-third of each group reporting any adverse event, 10% or fewer reporting a serious adverse event, and less than 10% reporting new-onset chronic diseases. None of the serious adverse events was judged to be related to the vaccine, and there were no deaths.

In an accompanying editorial, Dr. Gary M. Clifford wrote that the data showing no evidence of further decline from 3 to 6 years are “perhaps the most interesting” because they suggest that mean antibody concentrations should remain well above those associated with natural infection long into the future.

The target age of vaccination is a balance between “being early enough to catch girls before sexual debut, but late enough to provide an as yet unknown duration of immunity that protects during as many subsequent years of sexual activity as possible,” wrote Dr. Clifford of the International Agency for Research on Cancer, Lyon, France (Lancet 2009 Dec. 3 [doi:10.1016/S0140-6736(09)61789-X]).

Vitals

Major Finding: At 6.4 years, vaccine efficacy against incident HPV infection was 95% in the according-to-protocol cohort.

Source of Data: A three-country, 27-site study of 1,113 women aged 15-26 years.

Disclosures: The study, led by Dr. Romanowski, was funded by GlaxoSmithKline (GSK) Biologicals, manufacturer of Cervarix. Dr. Clifford declared that he had no conflicts of interest.

The human papillomavirus 16/18 vaccine showed efficacy, sustained immunogenicity, and continued safety for up to 6.4 years in a combination of initial and follow-up placebo-controlled studies involving more than 1,000 women aged 15-26 years.

The human papillomavirus (HPV) vaccine, Cervarix, is now licensed in the United States, Europe, and elsewhere around the world. It contains the HPV types 16 and 18 adjuvanted with ASO4, comprising aluminum salt and an immunostimulatory molecule that has been shown to produce higher antibody titers that are sustained over a longer period of time, compared with the same antigens adjuvanted with aluminum salts alone, according to the GSK Vaccine HPV-007 Study Group, led by Dr. Barbara Romanowski (Lancet 2009 Dec. 3 [doi:10.1016/S0140-6736(09)61567-1]).

Of 1,113 women included in the initial three-country, 27-site study, a total of 700 completed the follow-up study. The total vaccinated cohort included 560 women in the vaccine group and 553 in the placebo group, while the according-to-protocol (ATP) efficacy cohort included 465 in the vaccine group and 454 in the placebo group. At baseline, all had normal cervical cytology and were negative for both HPV-16 and −18.

The mean follow-up period from the start of the initial study was 5.9 years, with a maximum duration of 6.4 years. The study population was racially diverse, with a mean age of 20 years (range 15-26 years) at entry to the initial study and 23 years at the beginning of the follow-up study.

At 6.4 years, vaccine efficacy against incident HPV-16 or HPV-18 infection in the ATP analysis was 95.3%, and long-term efficacy against persistent infection was 100% at both 6 and 12 months. In the total vaccinated cohort analysis, protection against cervical intraepithelial neoplasia grade 1 or higher associated with either vaccine HPV type was 100%. For the nonvaccine types HPV-31 and −45, vaccine efficacy against incident infection was 59.8% and 77.7%, while overall efficacy against any cervical intraepithelial neoplasia grade 2 or higher independent of HPV type was 71.9%, said Dr. Romanowski of the University of Alberta, Edmonton, and her associates.

Almost all vaccine recipients (99%) remained seropositive for anti–HPV-16 and anti–HPV-18 total IgG antibodies. After a peak response at 7 months, geometric mean titers for both antibodies reached a plateau between 18 and 24 months post vaccination, and remained stable thereafter. During months 63-76, antibody concentrations against HPV-16 and HPV-18 were at least 13-fold and 12-fold higher than were concentrations recorded following clearance of a natural infection in a previous study (Lancet 2007;369:2161-70).

Safety profiles of the HPV-16/18 vaccine and placebo were similar, with approximately one-third of each group reporting any adverse event, 10% or fewer reporting a serious adverse event, and less than 10% reporting new-onset chronic diseases. None of the serious adverse events was judged to be related to the vaccine, and there were no deaths.

In an accompanying editorial, Dr. Gary M. Clifford wrote that the data showing no evidence of further decline from 3 to 6 years are “perhaps the most interesting” because they suggest that mean antibody concentrations should remain well above those associated with natural infection long into the future.

The target age of vaccination is a balance between “being early enough to catch girls before sexual debut, but late enough to provide an as yet unknown duration of immunity that protects during as many subsequent years of sexual activity as possible,” wrote Dr. Clifford of the International Agency for Research on Cancer, Lyon, France (Lancet 2009 Dec. 3 [doi:10.1016/S0140-6736(09)61789-X]).

Vitals

Major Finding: At 6.4 years, vaccine efficacy against incident HPV infection was 95% in the according-to-protocol cohort.

Source of Data: A three-country, 27-site study of 1,113 women aged 15-26 years.

Disclosures: The study, led by Dr. Romanowski, was funded by GlaxoSmithKline (GSK) Biologicals, manufacturer of Cervarix. Dr. Clifford declared that he had no conflicts of interest.

MONTREAL — No difference in mortality was found at 4 years between baseline hemoglobin A_1c levels of less than 6.5% and levels of 6.5%-7.0% in a prospective observational study of nearly 3,000 unselected patients with type 2 diabetes.

However, the Diabetes in Germany study also found a dramatically increased risk of mortality for those with baseline HbA_1c levels greater than 8%, compared with those who began the study with lower HbA_1c values. Other baseline predictors of mortality included age, smoking, cardiovascular disease, and systolic blood pressure, Dr. Markolf Hanefeld reported at the World Diabetes Congress.

“In a diabetes population rather well controlled for hemoglobin A_1c, smoking status and good blood pressure control are of utmost importance for survival. However, at a level greater than 8%, [the degree of] glucose control becomes a serious risk factor for all-cause mortality,” said Dr. Hanefeld of the Center for Clinical Studies, Technical University, Dresden, Germany.

Of an initial 4,020 unselected patients aged 35-80 years with type 2 diabetes in Germany, 2,784 completed the study at a median of 3.7 years; 175 died during that time. Most (86%) had no history of major cardiovascular events (MACE) at baseline; 251 (8.5%) reported a first MACE during follow-up. Average baseline HbA_1c for the entire group was 7.0%. Thirty-seven percent met the International Diabetes Federation's and American Association of Clinical Endocrinologists' target HbA_1c of less than 6.5%; 57% met the American Diabetes Association's target of less than 7.0%. But 29% had values above 7.5%. The average HbA_1c level for the entire group did not change over the 4-year period, Dr. Hanefeld said.

Among those who died during the study period, 6% had baseline HbA_1c values of less than 6.5%; 5.3% had values of 6.5%-6.9%; 5.1% had values of 7.0%-7.9%; and 7.6% had values of 8% or higher. The same trend was seen in MACE.

In a multivariate analysis, the most significant factor predicting mortality was MACE at baseline, conferring a twofold greater risk. Also significant were smoking, age, and systolic blood pressure. Female gender cut the risk by half. Hemoglobin A_1c did not contribute significantly to mortality, he said.

A comparison of these findings with the standard care arms of the randomized, controlled glucose-lowering trials ADVANCE, ACCORD, and VADT shows no link between HbA_1c and mortality.

Dr. Hanefeld stated that he had no conflicts of interest.

MONTREAL — No difference in mortality was found at 4 years between baseline hemoglobin A_1c levels of less than 6.5% and levels of 6.5%-7.0% in a prospective observational study of nearly 3,000 unselected patients with type 2 diabetes.

However, the Diabetes in Germany study also found a dramatically increased risk of mortality for those with baseline HbA_1c levels greater than 8%, compared with those who began the study with lower HbA_1c values. Other baseline predictors of mortality included age, smoking, cardiovascular disease, and systolic blood pressure, Dr. Markolf Hanefeld reported at the World Diabetes Congress.

“In a diabetes population rather well controlled for hemoglobin A_1c, smoking status and good blood pressure control are of utmost importance for survival. However, at a level greater than 8%, [the degree of] glucose control becomes a serious risk factor for all-cause mortality,” said Dr. Hanefeld of the Center for Clinical Studies, Technical University, Dresden, Germany.

Of an initial 4,020 unselected patients aged 35-80 years with type 2 diabetes in Germany, 2,784 completed the study at a median of 3.7 years; 175 died during that time. Most (86%) had no history of major cardiovascular events (MACE) at baseline; 251 (8.5%) reported a first MACE during follow-up. Average baseline HbA_1c for the entire group was 7.0%. Thirty-seven percent met the International Diabetes Federation's and American Association of Clinical Endocrinologists' target HbA_1c of less than 6.5%; 57% met the American Diabetes Association's target of less than 7.0%. But 29% had values above 7.5%. The average HbA_1c level for the entire group did not change over the 4-year period, Dr. Hanefeld said.

Among those who died during the study period, 6% had baseline HbA_1c values of less than 6.5%; 5.3% had values of 6.5%-6.9%; 5.1% had values of 7.0%-7.9%; and 7.6% had values of 8% or higher. The same trend was seen in MACE.

In a multivariate analysis, the most significant factor predicting mortality was MACE at baseline, conferring a twofold greater risk. Also significant were smoking, age, and systolic blood pressure. Female gender cut the risk by half. Hemoglobin A_1c did not contribute significantly to mortality, he said.

A comparison of these findings with the standard care arms of the randomized, controlled glucose-lowering trials ADVANCE, ACCORD, and VADT shows no link between HbA_1c and mortality.

Dr. Hanefeld stated that he had no conflicts of interest.

MONTREAL — No difference in mortality was found at 4 years between baseline hemoglobin A_1c levels of less than 6.5% and levels of 6.5%-7.0% in a prospective observational study of nearly 3,000 unselected patients with type 2 diabetes.

However, the Diabetes in Germany study also found a dramatically increased risk of mortality for those with baseline HbA_1c levels greater than 8%, compared with those who began the study with lower HbA_1c values. Other baseline predictors of mortality included age, smoking, cardiovascular disease, and systolic blood pressure, Dr. Markolf Hanefeld reported at the World Diabetes Congress.

“In a diabetes population rather well controlled for hemoglobin A_1c, smoking status and good blood pressure control are of utmost importance for survival. However, at a level greater than 8%, [the degree of] glucose control becomes a serious risk factor for all-cause mortality,” said Dr. Hanefeld of the Center for Clinical Studies, Technical University, Dresden, Germany.

Of an initial 4,020 unselected patients aged 35-80 years with type 2 diabetes in Germany, 2,784 completed the study at a median of 3.7 years; 175 died during that time. Most (86%) had no history of major cardiovascular events (MACE) at baseline; 251 (8.5%) reported a first MACE during follow-up. Average baseline HbA_1c for the entire group was 7.0%. Thirty-seven percent met the International Diabetes Federation's and American Association of Clinical Endocrinologists' target HbA_1c of less than 6.5%; 57% met the American Diabetes Association's target of less than 7.0%. But 29% had values above 7.5%. The average HbA_1c level for the entire group did not change over the 4-year period, Dr. Hanefeld said.

Among those who died during the study period, 6% had baseline HbA_1c values of less than 6.5%; 5.3% had values of 6.5%-6.9%; 5.1% had values of 7.0%-7.9%; and 7.6% had values of 8% or higher. The same trend was seen in MACE.

In a multivariate analysis, the most significant factor predicting mortality was MACE at baseline, conferring a twofold greater risk. Also significant were smoking, age, and systolic blood pressure. Female gender cut the risk by half. Hemoglobin A_1c did not contribute significantly to mortality, he said.

A comparison of these findings with the standard care arms of the randomized, controlled glucose-lowering trials ADVANCE, ACCORD, and VADT shows no link between HbA_1c and mortality.

Dr. Hanefeld stated that he had no conflicts of interest.

MONTREAL — The age-adjusted prevalence of visual impairment among people with diabetes in the United States had a relative decline of more than 20% between 1997 and 2008, despite a sharp rise in the number of people diagnosed with the disease during that time.

The findings, calculated from National Health Interview Survey data, were presented in a poster by Dr. Nilka Rios Burrows at the World Diabetes Congress.

Visual impairment was defined as an affirmative response to the question, “Do you have trouble seeing even with glasses or contacts?”

The number of adults aged 18 and older with both self-reported diabetes and visual impairment increased from 2.6 million in 1997 to 3.6 million in 2008. Throughout the period, the prevalence of visual impairment was greater with increasing age, and was higher for women than men. But no racial or ethnic disparities were seen, said Dr. Burrows of the Centers for Disease Control and Prevention, Atlanta.

The prevalence of visual impairment declined steadily and significantly during the study period. Overall prevalence declined from 26% in 1997 to 22% in 2008, while the age-adjusted prevalence dropped from 24% to 19%, with an average annual relative change of 2.7%. The similarity of the crude and age-adjusted prevalences suggests that aging had little effect on the trends, she said.

The decline may be due in part to a reduction in ocular risk factors, improved detection and treatment of eye problems, or better health in the diabetes population overall. The increase in the number of new diabetes cases since the 1990s may have led to a large number of people who have not had diabetes long enough to develop visual impairment, Dr. Burrows and her associates noted in the poster.

Reported annual contact with eye care providers remained suboptimal among people with diabetes regardless of their visual status: Half of those surveyed reported having seen an eye doctor in 2008.

“Effective strategies are needed to increase awareness about eye health and improve rates of routine eye examinations among people with diabetes,” the authors concluded.

Dr. Burrows declared that she had no conflicts of interest.

MONTREAL — The age-adjusted prevalence of visual impairment among people with diabetes in the United States had a relative decline of more than 20% between 1997 and 2008, despite a sharp rise in the number of people diagnosed with the disease during that time.

The findings, calculated from National Health Interview Survey data, were presented in a poster by Dr. Nilka Rios Burrows at the World Diabetes Congress.

Visual impairment was defined as an affirmative response to the question, “Do you have trouble seeing even with glasses or contacts?”

The number of adults aged 18 and older with both self-reported diabetes and visual impairment increased from 2.6 million in 1997 to 3.6 million in 2008. Throughout the period, the prevalence of visual impairment was greater with increasing age, and was higher for women than men. But no racial or ethnic disparities were seen, said Dr. Burrows of the Centers for Disease Control and Prevention, Atlanta.

The prevalence of visual impairment declined steadily and significantly during the study period. Overall prevalence declined from 26% in 1997 to 22% in 2008, while the age-adjusted prevalence dropped from 24% to 19%, with an average annual relative change of 2.7%. The similarity of the crude and age-adjusted prevalences suggests that aging had little effect on the trends, she said.

The decline may be due in part to a reduction in ocular risk factors, improved detection and treatment of eye problems, or better health in the diabetes population overall. The increase in the number of new diabetes cases since the 1990s may have led to a large number of people who have not had diabetes long enough to develop visual impairment, Dr. Burrows and her associates noted in the poster.

Reported annual contact with eye care providers remained suboptimal among people with diabetes regardless of their visual status: Half of those surveyed reported having seen an eye doctor in 2008.

“Effective strategies are needed to increase awareness about eye health and improve rates of routine eye examinations among people with diabetes,” the authors concluded.

Dr. Burrows declared that she had no conflicts of interest.

MONTREAL — The age-adjusted prevalence of visual impairment among people with diabetes in the United States had a relative decline of more than 20% between 1997 and 2008, despite a sharp rise in the number of people diagnosed with the disease during that time.

The findings, calculated from National Health Interview Survey data, were presented in a poster by Dr. Nilka Rios Burrows at the World Diabetes Congress.

Visual impairment was defined as an affirmative response to the question, “Do you have trouble seeing even with glasses or contacts?”

The number of adults aged 18 and older with both self-reported diabetes and visual impairment increased from 2.6 million in 1997 to 3.6 million in 2008. Throughout the period, the prevalence of visual impairment was greater with increasing age, and was higher for women than men. But no racial or ethnic disparities were seen, said Dr. Burrows of the Centers for Disease Control and Prevention, Atlanta.

The prevalence of visual impairment declined steadily and significantly during the study period. Overall prevalence declined from 26% in 1997 to 22% in 2008, while the age-adjusted prevalence dropped from 24% to 19%, with an average annual relative change of 2.7%. The similarity of the crude and age-adjusted prevalences suggests that aging had little effect on the trends, she said.

The decline may be due in part to a reduction in ocular risk factors, improved detection and treatment of eye problems, or better health in the diabetes population overall. The increase in the number of new diabetes cases since the 1990s may have led to a large number of people who have not had diabetes long enough to develop visual impairment, Dr. Burrows and her associates noted in the poster.

Reported annual contact with eye care providers remained suboptimal among people with diabetes regardless of their visual status: Half of those surveyed reported having seen an eye doctor in 2008.

“Effective strategies are needed to increase awareness about eye health and improve rates of routine eye examinations among people with diabetes,” the authors concluded.

Dr. Burrows declared that she had no conflicts of interest.

MONTREAL — At the onset of autoimmune diabetes, nearly half of African American children and almost one in five white children seen at Children's Hospital of Pittsburgh during 2004-2006 were overweight.

Those figures represent dramatic increases from the 1980s, when just 7% of African American and 3% of white children seen at the hospital were overweight at onset of autoimmune (type 1A) diabetes, Dr. Ingrid Libman reported in a poster presentation at the World Diabetes Congress.

Dr. Libman, a pediatric endocrinologist at the hospital, and her associates reported earlier that among children treated with insulin, the prevalence of overweight (body mass index of 85th percentile or greater) increased from 13% during 1979-1989 to 37% during 1990-1998 in white children, and from 22% to 55% during those two study periods in black children (Diabetes Care 2003;26:2871-5). In those with at least one antibody, the prevalence of overweight rose from 5% to 24%.

This time, they compared the period 1999-2006 (excluding 2003) with the previous two study periods. Data were available for 298 children out of 376 diagnosed with diabetes and treated with insulin during that time. Overall, the prevalence of overweight had more than tripled since 1979-1989, to 41%. Mean BMI percentile rose from 40.4 during 1979-1989 to 58.8 in 1990-1998 to 60.4 in 1999-2006.

Among 219 children for whom beta-cell antibody levels were available during all three periods, 173 (79%) were positive for at least one. This proportion was similar in each of the three time periods, Dr. Libman noted.

Of the 173 children with one or more antibodies, the proportions who were overweight rose from 5% to 25% to 31% during the three time periods. In contrast, the proportions overweight among the 46 with no antibodies—i.e., presumably with type 2 diabetes—were 46%, 70%, and 75%, respectively. The increase in overweight was more noticeable in the African American children with autoimmunity—from 7% to 38% to 46%, respectively, compared with 3%, 14%, and 19% of the white children.

Experts believe that weight excess plays an “accelerator” role in the ongoing increase in type 1A diabetes, Dr. Libman said in an interview.

Dr. Libman indicated that she had no conflicts of interest.

MONTREAL — At the onset of autoimmune diabetes, nearly half of African American children and almost one in five white children seen at Children's Hospital of Pittsburgh during 2004-2006 were overweight.

Those figures represent dramatic increases from the 1980s, when just 7% of African American and 3% of white children seen at the hospital were overweight at onset of autoimmune (type 1A) diabetes, Dr. Ingrid Libman reported in a poster presentation at the World Diabetes Congress.

Dr. Libman, a pediatric endocrinologist at the hospital, and her associates reported earlier that among children treated with insulin, the prevalence of overweight (body mass index of 85th percentile or greater) increased from 13% during 1979-1989 to 37% during 1990-1998 in white children, and from 22% to 55% during those two study periods in black children (Diabetes Care 2003;26:2871-5). In those with at least one antibody, the prevalence of overweight rose from 5% to 24%.

This time, they compared the period 1999-2006 (excluding 2003) with the previous two study periods. Data were available for 298 children out of 376 diagnosed with diabetes and treated with insulin during that time. Overall, the prevalence of overweight had more than tripled since 1979-1989, to 41%. Mean BMI percentile rose from 40.4 during 1979-1989 to 58.8 in 1990-1998 to 60.4 in 1999-2006.

Among 219 children for whom beta-cell antibody levels were available during all three periods, 173 (79%) were positive for at least one. This proportion was similar in each of the three time periods, Dr. Libman noted.

Of the 173 children with one or more antibodies, the proportions who were overweight rose from 5% to 25% to 31% during the three time periods. In contrast, the proportions overweight among the 46 with no antibodies—i.e., presumably with type 2 diabetes—were 46%, 70%, and 75%, respectively. The increase in overweight was more noticeable in the African American children with autoimmunity—from 7% to 38% to 46%, respectively, compared with 3%, 14%, and 19% of the white children.

Experts believe that weight excess plays an “accelerator” role in the ongoing increase in type 1A diabetes, Dr. Libman said in an interview.

Dr. Libman indicated that she had no conflicts of interest.

MONTREAL — At the onset of autoimmune diabetes, nearly half of African American children and almost one in five white children seen at Children's Hospital of Pittsburgh during 2004-2006 were overweight.

Those figures represent dramatic increases from the 1980s, when just 7% of African American and 3% of white children seen at the hospital were overweight at onset of autoimmune (type 1A) diabetes, Dr. Ingrid Libman reported in a poster presentation at the World Diabetes Congress.

Dr. Libman, a pediatric endocrinologist at the hospital, and her associates reported earlier that among children treated with insulin, the prevalence of overweight (body mass index of 85th percentile or greater) increased from 13% during 1979-1989 to 37% during 1990-1998 in white children, and from 22% to 55% during those two study periods in black children (Diabetes Care 2003;26:2871-5). In those with at least one antibody, the prevalence of overweight rose from 5% to 24%.

This time, they compared the period 1999-2006 (excluding 2003) with the previous two study periods. Data were available for 298 children out of 376 diagnosed with diabetes and treated with insulin during that time. Overall, the prevalence of overweight had more than tripled since 1979-1989, to 41%. Mean BMI percentile rose from 40.4 during 1979-1989 to 58.8 in 1990-1998 to 60.4 in 1999-2006.

Among 219 children for whom beta-cell antibody levels were available during all three periods, 173 (79%) were positive for at least one. This proportion was similar in each of the three time periods, Dr. Libman noted.

Of the 173 children with one or more antibodies, the proportions who were overweight rose from 5% to 25% to 31% during the three time periods. In contrast, the proportions overweight among the 46 with no antibodies—i.e., presumably with type 2 diabetes—were 46%, 70%, and 75%, respectively. The increase in overweight was more noticeable in the African American children with autoimmunity—from 7% to 38% to 46%, respectively, compared with 3%, 14%, and 19% of the white children.

Experts believe that weight excess plays an “accelerator” role in the ongoing increase in type 1A diabetes, Dr. Libman said in an interview.

Dr. Libman indicated that she had no conflicts of interest.

NEW YORK — There is no reason to test overweight or obese children for insulin resistance, according to an international committee of experts in pediatric endocrinology and diabetes.

Five of its members presented the conclusions at a joint meeting of the Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology. The evidence-based document, which the presenters intended to submitt for publication in October, will address the definition, measurement, risk assessment, treatment, and prevention of insulin resistance in children.

It is expected that the document will recommend against the use of fasting insulin levels—or any laboratory test—to screen for insulin resistance in children, and against the use of medication to treat children with insulin resistance in the absence of specific diagnoses such as type 2 diabetes or polycystic ovarian syndrome.

In adults, insulin resistance has been strongly linked to obesity, type 2 diabetes, and cardiovascular disease, and there is also some evidence linking it with a risk for those conditions among children, said Dr. Franco Chiarelli, panel cochair.

“But unfortunately for us pediatricians, there is a lack of clarity as to what insulin resistance means in childhood, how it is best assessed, what clinical disorders occur, and its consequences. And, there is debate on how to treat and possibly prevent insulin resistance in children,” said Dr. Chiarelli, professor and head of pediatrics at the University of Chieti (Italy).

Dr. Claire Levy-Marchal, another panel cochair, said that population data on the distribution of normal insulin levels is fairly well characterized in adults but not in children, in whom fasting insulin levels vary by weight, nutrition, activity, gender, developmental stage, ethnicity, and other factors. Thus, there is no clear cutoff between normal and abnormal, said Dr. Levy-Marchal, of Robert Debre Hospital, Paris.

The strong stance against testing for insulin resistance was needed because the practice is common, Dr. Silva Arslanian, a panel member, said in an interview. “We get a lot of referrals of children with a 'high insulin level' and meanwhile the child is obese and the parent was never told that the child is obese. … That's why the insulin level is high.”

Measuring insulin levels is an unnecessary health care expenditure, added Dr. Arslanian, the Richard L. Day Endowed Professor of Pediatrics at the University of Pittsburgh. “Why do that when your eyes can tell you—or the body mass index can tell you. If you're obese, the insulin level will be higher. You treat the obesity and the insulin comes down. You don't treat the insulin.”

She reviewed the literature regarding risk factors for insulin resistance in children, including obesity, high BMI, and high waist circumference. African American children are at greater risk, as are those entering puberty, when insulin sensitivity declines an average of 30%. PCOS also confers an increased risk as does intrauterine exposure to a mother's diabetes during pregnancy, she said.

Dr. Chiarelli summarized the group's recommendation for prevention of insulin resistance in children, which include efforts to reduce maternal and childhood obesity, and the promotion of breast-feeding as a means of reducing obesity for the child later in life. The breast-feeding recommendation sparked some debate and received only a “C” level of evidence, but there are data to support it, he said.

The statement has been endorsed by seven specialty societies and is financially supported by the Institut National de la Santé et de la Recherche Médicale (INSERM) and an unrestricted educational grant from the French pharmaceutical company Ipsen.

The strong stance against testing for insulin resistance was needed because the practice is common.

Source DR. ARSLANIAN

NEW YORK — There is no reason to test overweight or obese children for insulin resistance, according to an international committee of experts in pediatric endocrinology and diabetes.

Five of its members presented the conclusions at a joint meeting of the Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology. The evidence-based document, which the presenters intended to submitt for publication in October, will address the definition, measurement, risk assessment, treatment, and prevention of insulin resistance in children.

It is expected that the document will recommend against the use of fasting insulin levels—or any laboratory test—to screen for insulin resistance in children, and against the use of medication to treat children with insulin resistance in the absence of specific diagnoses such as type 2 diabetes or polycystic ovarian syndrome.

In adults, insulin resistance has been strongly linked to obesity, type 2 diabetes, and cardiovascular disease, and there is also some evidence linking it with a risk for those conditions among children, said Dr. Franco Chiarelli, panel cochair.

“But unfortunately for us pediatricians, there is a lack of clarity as to what insulin resistance means in childhood, how it is best assessed, what clinical disorders occur, and its consequences. And, there is debate on how to treat and possibly prevent insulin resistance in children,” said Dr. Chiarelli, professor and head of pediatrics at the University of Chieti (Italy).

Dr. Claire Levy-Marchal, another panel cochair, said that population data on the distribution of normal insulin levels is fairly well characterized in adults but not in children, in whom fasting insulin levels vary by weight, nutrition, activity, gender, developmental stage, ethnicity, and other factors. Thus, there is no clear cutoff between normal and abnormal, said Dr. Levy-Marchal, of Robert Debre Hospital, Paris.

The strong stance against testing for insulin resistance was needed because the practice is common, Dr. Silva Arslanian, a panel member, said in an interview. “We get a lot of referrals of children with a 'high insulin level' and meanwhile the child is obese and the parent was never told that the child is obese. … That's why the insulin level is high.”

Measuring insulin levels is an unnecessary health care expenditure, added Dr. Arslanian, the Richard L. Day Endowed Professor of Pediatrics at the University of Pittsburgh. “Why do that when your eyes can tell you—or the body mass index can tell you. If you're obese, the insulin level will be higher. You treat the obesity and the insulin comes down. You don't treat the insulin.”

She reviewed the literature regarding risk factors for insulin resistance in children, including obesity, high BMI, and high waist circumference. African American children are at greater risk, as are those entering puberty, when insulin sensitivity declines an average of 30%. PCOS also confers an increased risk as does intrauterine exposure to a mother's diabetes during pregnancy, she said.

Dr. Chiarelli summarized the group's recommendation for prevention of insulin resistance in children, which include efforts to reduce maternal and childhood obesity, and the promotion of breast-feeding as a means of reducing obesity for the child later in life. The breast-feeding recommendation sparked some debate and received only a “C” level of evidence, but there are data to support it, he said.

The statement has been endorsed by seven specialty societies and is financially supported by the Institut National de la Santé et de la Recherche Médicale (INSERM) and an unrestricted educational grant from the French pharmaceutical company Ipsen.

The strong stance against testing for insulin resistance was needed because the practice is common.

Source DR. ARSLANIAN

NEW YORK — There is no reason to test overweight or obese children for insulin resistance, according to an international committee of experts in pediatric endocrinology and diabetes.

Five of its members presented the conclusions at a joint meeting of the Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology. The evidence-based document, which the presenters intended to submitt for publication in October, will address the definition, measurement, risk assessment, treatment, and prevention of insulin resistance in children.

It is expected that the document will recommend against the use of fasting insulin levels—or any laboratory test—to screen for insulin resistance in children, and against the use of medication to treat children with insulin resistance in the absence of specific diagnoses such as type 2 diabetes or polycystic ovarian syndrome.

In adults, insulin resistance has been strongly linked to obesity, type 2 diabetes, and cardiovascular disease, and there is also some evidence linking it with a risk for those conditions among children, said Dr. Franco Chiarelli, panel cochair.

“But unfortunately for us pediatricians, there is a lack of clarity as to what insulin resistance means in childhood, how it is best assessed, what clinical disorders occur, and its consequences. And, there is debate on how to treat and possibly prevent insulin resistance in children,” said Dr. Chiarelli, professor and head of pediatrics at the University of Chieti (Italy).

Dr. Claire Levy-Marchal, another panel cochair, said that population data on the distribution of normal insulin levels is fairly well characterized in adults but not in children, in whom fasting insulin levels vary by weight, nutrition, activity, gender, developmental stage, ethnicity, and other factors. Thus, there is no clear cutoff between normal and abnormal, said Dr. Levy-Marchal, of Robert Debre Hospital, Paris.

The strong stance against testing for insulin resistance was needed because the practice is common, Dr. Silva Arslanian, a panel member, said in an interview. “We get a lot of referrals of children with a 'high insulin level' and meanwhile the child is obese and the parent was never told that the child is obese. … That's why the insulin level is high.”

Measuring insulin levels is an unnecessary health care expenditure, added Dr. Arslanian, the Richard L. Day Endowed Professor of Pediatrics at the University of Pittsburgh. “Why do that when your eyes can tell you—or the body mass index can tell you. If you're obese, the insulin level will be higher. You treat the obesity and the insulin comes down. You don't treat the insulin.”

She reviewed the literature regarding risk factors for insulin resistance in children, including obesity, high BMI, and high waist circumference. African American children are at greater risk, as are those entering puberty, when insulin sensitivity declines an average of 30%. PCOS also confers an increased risk as does intrauterine exposure to a mother's diabetes during pregnancy, she said.

Dr. Chiarelli summarized the group's recommendation for prevention of insulin resistance in children, which include efforts to reduce maternal and childhood obesity, and the promotion of breast-feeding as a means of reducing obesity for the child later in life. The breast-feeding recommendation sparked some debate and received only a “C” level of evidence, but there are data to support it, he said.

The statement has been endorsed by seven specialty societies and is financially supported by the Institut National de la Santé et de la Recherche Médicale (INSERM) and an unrestricted educational grant from the French pharmaceutical company Ipsen.

The strong stance against testing for insulin resistance was needed because the practice is common.

Source DR. ARSLANIAN

BETHESDA, MD. — Monitoring of influenza A(H1N1) vaccine safety in studies conducted across multiple U.S. government agencies have shown no safety signals of concern so far, nationally or internationally.

The multiple data collection efforts—some preexisting and others a result of the pandemic H1N1 outbreak—represent “strengthened collaboration and communication among government agencies and internationally, with enhanced capacity for timely signal detection, strengthening, and confirmation,” Dr. Hector Izurieta told the Food and Drug Administration's Vaccines and Related Biological Products Advisory Committee.

In addition to the FDA, other participating agencies include the Centers for Disease Control and Prevention, the Department of Defense, the Department of Veterans Affairs, the Centers for Medicare and Medicaid Services, and the Indian Health Service, Dr. Izurieta, chief of the FDA's analytic epidemiology branch, said in an interview.

For example, the CDC is currently evaluating 205 reports of serious adverse events following H1N1 vaccine in the Vaccine Adverse Events Reporting System (VAERS). Of those, 70 are among pregnant females. All but 13 were nonserious and none involved maternal death.

Eight deaths following receipt of H1N1 vaccine have been reported to VAERS, including two following live attenuated (intranasal) vaccine and six after inactivated (injected) vaccine. The three that have been evaluated so far had severe underlying conditions. There have been 29 reported cases of anaphylaxis, which is consistent with published estimates following other vaccinations, he said.

Two cases of “possible or probable” Guillain-Barré syndrome have been reported within 1 day of H1N1 vaccine receipt. The short interval “decreases but does not eliminate” the possibility that H1N1 vaccine caused the event. However, to date the rate of reported GBS cases is less than the background rate in the population, Dr. Izurieta said.

Dr. Claudia Vellozzi of the CDC's Immunization Safety Office described the Vaccine Safety Datalink (VSD), an active surveillance program of both the CDC and managed care plans that cover more than 9.5 million people, or 3.1% of the U.S. population, and is used to follow up on safety “signals” obtained from VAERS.

VSD analyses of pregnant women and of 10 GBS cases identified so far have shown no significant associations with either H1N1 or seasonal vaccine, although it's still early, she said.

Dr. Richard Platt of Harvard Pilgrim Health Care and Harvard Medical School, Boston, described a new safety analysis that his institution will conduct in collaboration with health plans covering approximately 25 million people and nine state immunization registries comprising a total population of 14 million; it is called Post-Licensure Rapid Immunization Safety Monitoring.

BETHESDA, MD. — Monitoring of influenza A(H1N1) vaccine safety in studies conducted across multiple U.S. government agencies have shown no safety signals of concern so far, nationally or internationally.

The multiple data collection efforts—some preexisting and others a result of the pandemic H1N1 outbreak—represent “strengthened collaboration and communication among government agencies and internationally, with enhanced capacity for timely signal detection, strengthening, and confirmation,” Dr. Hector Izurieta told the Food and Drug Administration's Vaccines and Related Biological Products Advisory Committee.

In addition to the FDA, other participating agencies include the Centers for Disease Control and Prevention, the Department of Defense, the Department of Veterans Affairs, the Centers for Medicare and Medicaid Services, and the Indian Health Service, Dr. Izurieta, chief of the FDA's analytic epidemiology branch, said in an interview.

For example, the CDC is currently evaluating 205 reports of serious adverse events following H1N1 vaccine in the Vaccine Adverse Events Reporting System (VAERS). Of those, 70 are among pregnant females. All but 13 were nonserious and none involved maternal death.

Eight deaths following receipt of H1N1 vaccine have been reported to VAERS, including two following live attenuated (intranasal) vaccine and six after inactivated (injected) vaccine. The three that have been evaluated so far had severe underlying conditions. There have been 29 reported cases of anaphylaxis, which is consistent with published estimates following other vaccinations, he said.

Two cases of “possible or probable” Guillain-Barré syndrome have been reported within 1 day of H1N1 vaccine receipt. The short interval “decreases but does not eliminate” the possibility that H1N1 vaccine caused the event. However, to date the rate of reported GBS cases is less than the background rate in the population, Dr. Izurieta said.

Dr. Claudia Vellozzi of the CDC's Immunization Safety Office described the Vaccine Safety Datalink (VSD), an active surveillance program of both the CDC and managed care plans that cover more than 9.5 million people, or 3.1% of the U.S. population, and is used to follow up on safety “signals” obtained from VAERS.

VSD analyses of pregnant women and of 10 GBS cases identified so far have shown no significant associations with either H1N1 or seasonal vaccine, although it's still early, she said.

Dr. Richard Platt of Harvard Pilgrim Health Care and Harvard Medical School, Boston, described a new safety analysis that his institution will conduct in collaboration with health plans covering approximately 25 million people and nine state immunization registries comprising a total population of 14 million; it is called Post-Licensure Rapid Immunization Safety Monitoring.

BETHESDA, MD. — Monitoring of influenza A(H1N1) vaccine safety in studies conducted across multiple U.S. government agencies have shown no safety signals of concern so far, nationally or internationally.

The multiple data collection efforts—some preexisting and others a result of the pandemic H1N1 outbreak—represent “strengthened collaboration and communication among government agencies and internationally, with enhanced capacity for timely signal detection, strengthening, and confirmation,” Dr. Hector Izurieta told the Food and Drug Administration's Vaccines and Related Biological Products Advisory Committee.

In addition to the FDA, other participating agencies include the Centers for Disease Control and Prevention, the Department of Defense, the Department of Veterans Affairs, the Centers for Medicare and Medicaid Services, and the Indian Health Service, Dr. Izurieta, chief of the FDA's analytic epidemiology branch, said in an interview.

For example, the CDC is currently evaluating 205 reports of serious adverse events following H1N1 vaccine in the Vaccine Adverse Events Reporting System (VAERS). Of those, 70 are among pregnant females. All but 13 were nonserious and none involved maternal death.

Eight deaths following receipt of H1N1 vaccine have been reported to VAERS, including two following live attenuated (intranasal) vaccine and six after inactivated (injected) vaccine. The three that have been evaluated so far had severe underlying conditions. There have been 29 reported cases of anaphylaxis, which is consistent with published estimates following other vaccinations, he said.

Two cases of “possible or probable” Guillain-Barré syndrome have been reported within 1 day of H1N1 vaccine receipt. The short interval “decreases but does not eliminate” the possibility that H1N1 vaccine caused the event. However, to date the rate of reported GBS cases is less than the background rate in the population, Dr. Izurieta said.

Dr. Claudia Vellozzi of the CDC's Immunization Safety Office described the Vaccine Safety Datalink (VSD), an active surveillance program of both the CDC and managed care plans that cover more than 9.5 million people, or 3.1% of the U.S. population, and is used to follow up on safety “signals” obtained from VAERS.

VSD analyses of pregnant women and of 10 GBS cases identified so far have shown no significant associations with either H1N1 or seasonal vaccine, although it's still early, she said.

Dr. Richard Platt of Harvard Pilgrim Health Care and Harvard Medical School, Boston, described a new safety analysis that his institution will conduct in collaboration with health plans covering approximately 25 million people and nine state immunization registries comprising a total population of 14 million; it is called Post-Licensure Rapid Immunization Safety Monitoring.

NATIONAL HARBOR, MD. — Children with inflammatory bowel diseases have a significantly increased risk for other immune-mediated diseases, according to a large cross-sectional study.

Previous studies in adults have demonstrated associations between inflammatory bowel disease (IBD) and comorbid rheumatologic, autoimmune, and atopic conditions, but this is the first population-based study to examine those links in children with inflammatory bowel diseases, Dr. Michael Kappelman said at the annual meeting of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN).

The associations between pediatric IBD and both rheumatoid arthritis and lupus were particularly strong, and of a higher magnitude than previously demonstrated in studies of adult IBD comorbidity. “The burden of IBD in children is quite substantial and involves not only the gastrointestinal burden but also the extraintestinal burden, including comorbidities,” Dr. Kappelman, a pediatric gastroenterologist at the University of North Carolina at Chapel Hill, said in an interview.

“When managing these children, you have to maintain a high level of suspicion for associated conditions.” The study involved an administrative data analysis of 1,242 children with IBD and 3,353 matched controls who were enrolled continuously in 87 health plans in 33 states during 2003-2004. They had a mean age of 15 years, and slightly more than half (55%) were male.

The study sample included 737 children with Crohn's disease and 488 with ulcerative colitis. Each child with IBD was matched with three controls on the basis of age, sex, health plan, and geographic region.

Eight specific immune-mediated comorbid diagnoses were examined, grouped into four categories: rheumatologic (rheumatoid arthritis and lupus); autoimmune (type 1 diabetes and hypothyroidism); atopic (asthma, eczema, and allergic rhinitis); and other inflammatory (psoriasis).

The strongest relationship with IBD was seen with lupus, with an odds ratio of 21.7, compared with controls. Rheumatoid arthritis was also significantly greater among the IBD children, with an odds ratio of 9.6. The relationship with both RA and lupus was statistically significant for children with Crohn's, while not quite reaching statistical significance for those with ulcerative colitis.

In contrast, the odds ratios for the association between IBD and rheumatoid arthritis from three adult studies ranged from 1.4 to 2.4, while one study looking at IBD and lupus in adults showed an odds ratio of just 1.3.

There was also an elevated risk for autoimmune disorders among the children with IBD, with odds ratios of 2.6 for hypothyroidism and 1.9 for type 1 diabetes. The associations reached statistical significance for Crohn's disease and thyroid disease and for ulcerative colitis and diabetes. Weaker associations were seen with the atopic conditions, with odds ratios of 1.1 for asthma, 1.3 for eczema, and 1.3 for allergic rhinitis. The associations between Crohn's and ulcerative colitis and Crohn's and allergic rhinitis did reach statistical significance, but just barely. The association was insignificant for psoriasis, with an odds ratio of 1.2.

In contrast to the rheumatologic disorders, studies of adults with IBD have found associations of similar or slightly greater strength than among children with the other immune-mediated disorders, including odds ratios of 1.1-1.3 for hypothyroid disease, 1.4-1.5 for asthma, and 1.5-1.7 for psoriasis.

The reason for the adult-child differences isn't known. “Obviously it has something to do with the disease etiology and pathogenesis, which is currently a black box. We talk about early-onset disease being different from later-onset disease. Moreover, [Crohn's] and [ulcerative colitis] are probably not 2 diseases but more like 50 different diseases. Right now we're just not sophisticated enough to subtype appropriately,” he said.

This study was funded in part by a grant from the National Institutes of Health. Dr. Kappelman stated that he had no relevant financial disclosures.

NATIONAL HARBOR, MD. — Children with inflammatory bowel diseases have a significantly increased risk for other immune-mediated diseases, according to a large cross-sectional study.

Previous studies in adults have demonstrated associations between inflammatory bowel disease (IBD) and comorbid rheumatologic, autoimmune, and atopic conditions, but this is the first population-based study to examine those links in children with inflammatory bowel diseases, Dr. Michael Kappelman said at the annual meeting of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN).

The associations between pediatric IBD and both rheumatoid arthritis and lupus were particularly strong, and of a higher magnitude than previously demonstrated in studies of adult IBD comorbidity. “The burden of IBD in children is quite substantial and involves not only the gastrointestinal burden but also the extraintestinal burden, including comorbidities,” Dr. Kappelman, a pediatric gastroenterologist at the University of North Carolina at Chapel Hill, said in an interview.

“When managing these children, you have to maintain a high level of suspicion for associated conditions.” The study involved an administrative data analysis of 1,242 children with IBD and 3,353 matched controls who were enrolled continuously in 87 health plans in 33 states during 2003-2004. They had a mean age of 15 years, and slightly more than half (55%) were male.

The study sample included 737 children with Crohn's disease and 488 with ulcerative colitis. Each child with IBD was matched with three controls on the basis of age, sex, health plan, and geographic region.

Eight specific immune-mediated comorbid diagnoses were examined, grouped into four categories: rheumatologic (rheumatoid arthritis and lupus); autoimmune (type 1 diabetes and hypothyroidism); atopic (asthma, eczema, and allergic rhinitis); and other inflammatory (psoriasis).

The strongest relationship with IBD was seen with lupus, with an odds ratio of 21.7, compared with controls. Rheumatoid arthritis was also significantly greater among the IBD children, with an odds ratio of 9.6. The relationship with both RA and lupus was statistically significant for children with Crohn's, while not quite reaching statistical significance for those with ulcerative colitis.

In contrast, the odds ratios for the association between IBD and rheumatoid arthritis from three adult studies ranged from 1.4 to 2.4, while one study looking at IBD and lupus in adults showed an odds ratio of just 1.3.

There was also an elevated risk for autoimmune disorders among the children with IBD, with odds ratios of 2.6 for hypothyroidism and 1.9 for type 1 diabetes. The associations reached statistical significance for Crohn's disease and thyroid disease and for ulcerative colitis and diabetes. Weaker associations were seen with the atopic conditions, with odds ratios of 1.1 for asthma, 1.3 for eczema, and 1.3 for allergic rhinitis. The associations between Crohn's and ulcerative colitis and Crohn's and allergic rhinitis did reach statistical significance, but just barely. The association was insignificant for psoriasis, with an odds ratio of 1.2.

In contrast to the rheumatologic disorders, studies of adults with IBD have found associations of similar or slightly greater strength than among children with the other immune-mediated disorders, including odds ratios of 1.1-1.3 for hypothyroid disease, 1.4-1.5 for asthma, and 1.5-1.7 for psoriasis.

The reason for the adult-child differences isn't known. “Obviously it has something to do with the disease etiology and pathogenesis, which is currently a black box. We talk about early-onset disease being different from later-onset disease. Moreover, [Crohn's] and [ulcerative colitis] are probably not 2 diseases but more like 50 different diseases. Right now we're just not sophisticated enough to subtype appropriately,” he said.

This study was funded in part by a grant from the National Institutes of Health. Dr. Kappelman stated that he had no relevant financial disclosures.

NATIONAL HARBOR, MD. — Children with inflammatory bowel diseases have a significantly increased risk for other immune-mediated diseases, according to a large cross-sectional study.

Previous studies in adults have demonstrated associations between inflammatory bowel disease (IBD) and comorbid rheumatologic, autoimmune, and atopic conditions, but this is the first population-based study to examine those links in children with inflammatory bowel diseases, Dr. Michael Kappelman said at the annual meeting of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN).

The associations between pediatric IBD and both rheumatoid arthritis and lupus were particularly strong, and of a higher magnitude than previously demonstrated in studies of adult IBD comorbidity. “The burden of IBD in children is quite substantial and involves not only the gastrointestinal burden but also the extraintestinal burden, including comorbidities,” Dr. Kappelman, a pediatric gastroenterologist at the University of North Carolina at Chapel Hill, said in an interview.

“When managing these children, you have to maintain a high level of suspicion for associated conditions.” The study involved an administrative data analysis of 1,242 children with IBD and 3,353 matched controls who were enrolled continuously in 87 health plans in 33 states during 2003-2004. They had a mean age of 15 years, and slightly more than half (55%) were male.

The study sample included 737 children with Crohn's disease and 488 with ulcerative colitis. Each child with IBD was matched with three controls on the basis of age, sex, health plan, and geographic region.

Eight specific immune-mediated comorbid diagnoses were examined, grouped into four categories: rheumatologic (rheumatoid arthritis and lupus); autoimmune (type 1 diabetes and hypothyroidism); atopic (asthma, eczema, and allergic rhinitis); and other inflammatory (psoriasis).

The strongest relationship with IBD was seen with lupus, with an odds ratio of 21.7, compared with controls. Rheumatoid arthritis was also significantly greater among the IBD children, with an odds ratio of 9.6. The relationship with both RA and lupus was statistically significant for children with Crohn's, while not quite reaching statistical significance for those with ulcerative colitis.

In contrast, the odds ratios for the association between IBD and rheumatoid arthritis from three adult studies ranged from 1.4 to 2.4, while one study looking at IBD and lupus in adults showed an odds ratio of just 1.3.

There was also an elevated risk for autoimmune disorders among the children with IBD, with odds ratios of 2.6 for hypothyroidism and 1.9 for type 1 diabetes. The associations reached statistical significance for Crohn's disease and thyroid disease and for ulcerative colitis and diabetes. Weaker associations were seen with the atopic conditions, with odds ratios of 1.1 for asthma, 1.3 for eczema, and 1.3 for allergic rhinitis. The associations between Crohn's and ulcerative colitis and Crohn's and allergic rhinitis did reach statistical significance, but just barely. The association was insignificant for psoriasis, with an odds ratio of 1.2.

In contrast to the rheumatologic disorders, studies of adults with IBD have found associations of similar or slightly greater strength than among children with the other immune-mediated disorders, including odds ratios of 1.1-1.3 for hypothyroid disease, 1.4-1.5 for asthma, and 1.5-1.7 for psoriasis.

The reason for the adult-child differences isn't known. “Obviously it has something to do with the disease etiology and pathogenesis, which is currently a black box. We talk about early-onset disease being different from later-onset disease. Moreover, [Crohn's] and [ulcerative colitis] are probably not 2 diseases but more like 50 different diseases. Right now we're just not sophisticated enough to subtype appropriately,” he said.

This study was funded in part by a grant from the National Institutes of Health. Dr. Kappelman stated that he had no relevant financial disclosures.

BETHESDA, MD. — Monitoring of influenza A(H1N1) vaccine safety in studies conducted across multiple U.S. government agencies have shown no safety signals of concern so far, nationally or internationally.

The multiple data collection efforts—some pre-existing and others a result of the pandemic H1N1 outbreak—represent “strengthened collaboration and communication among government agencies and internationally, with enhanced capacity for timely signal detection, strengthening, and confirmation,” Dr. Hector Izurieta told the Food and Drug Administration's Vaccines and Related Biological Products Advisory Committee.

In addition to the FDA, other participating agencies include the Centers for Disease Control and Prevention, the Department of Defense, the Department of Veterans Affairs, the Centers for Medicare and Medicaid Services, and the Indian Health Service, said Dr. Izurieta, who is chief of the FDA's analytic epidemiology branch.

“Not every system has the same degree of sophistication, or of populations served. The studies are complementary, and also provide redundancy that is helpful in detecting signals,” he said in an interview.

For example, the CDC is currently evaluating 205 reports of serious adverse events following H1N1 vaccine from in the Vaccine Adverse Events Reporting System (VAERS). Of those, 70 are among pregnant females. All but 13 were nonserious and none involve maternal death.

Eight deaths following receipt of H1N1 vaccine have been reported to VAERS, including two following live attenuated (intranasal) vaccine and six after inactivated (injected) vaccine.

The three that have been evaluated so far had severe underlying conditions. There have been 29 reported cases of anaphylaxis, which is consistent with published estimates following other vaccinations, he said.

Two cases of “possible or probable” Guillain-Barre syndrome have been reported within one day of H1N1 vaccine receipt. The short interval “decreases but does not eliminate” the possibility that H1N1 vaccine caused the event. However, to date the rate of reported GBS cases is less than the background rate in the population, Dr. Izurieta said.

Dr. Claudia Vellozzi, of the CDC's Immunization Safety Office, described the Vaccine Safety Datalink, an active surveillance program of both the CDC and managed care plans that cover more than 9.5 million people, or 3.1% of the U.S. population, is used to follow up on safety “signals” obtained from VAERS.

Thus far, VSD analyses of pregnant women and of 10 GBS cases identified so far show no significant associations with either H1N1 or seasonal vaccine, although it's still early. The VSD will continue to monitor both vaccines on a weekly basis, she said.

Dr. Richard Platt of Harvard Pilgrim Health Care and Harvard Medical School, Boston, described a new safety analysis that his institution will conduct in collaboration with health plans covering approximately 25 million people and nine state immunization registries comprising a total population of 14 million.

That system, called Post-Licensure Rapid Immunization Safety Monitoring (PRISM), is looking specifically for Guillan-Barre syndrome, as well as other neurologic problems and pregnancy complications following receipt of H1N1 vaccine, Dr. Platt said.

Another new effort, within the Indian Health Service, will use electronic health records to monitor selected health events following vaccine receipt among a population of 1.4 million, Dr. Izurieta said.

In all, these efforts have coalesced as a result of the H1N1 vaccine outbreak but are expected to continue beyond to monitor safety of all vaccines given to the U.S. population as well as populations worldwide, he said in the interview.

“We are investing ourselves with the idea that this goes beyond H1N1. This is for vaccine safety in general, going well beyond passive surveillance.”

BETHESDA, MD. — Monitoring of influenza A(H1N1) vaccine safety in studies conducted across multiple U.S. government agencies have shown no safety signals of concern so far, nationally or internationally.

The multiple data collection efforts—some pre-existing and others a result of the pandemic H1N1 outbreak—represent “strengthened collaboration and communication among government agencies and internationally, with enhanced capacity for timely signal detection, strengthening, and confirmation,” Dr. Hector Izurieta told the Food and Drug Administration's Vaccines and Related Biological Products Advisory Committee.

In addition to the FDA, other participating agencies include the Centers for Disease Control and Prevention, the Department of Defense, the Department of Veterans Affairs, the Centers for Medicare and Medicaid Services, and the Indian Health Service, said Dr. Izurieta, who is chief of the FDA's analytic epidemiology branch.

“Not every system has the same degree of sophistication, or of populations served. The studies are complementary, and also provide redundancy that is helpful in detecting signals,” he said in an interview.

For example, the CDC is currently evaluating 205 reports of serious adverse events following H1N1 vaccine from in the Vaccine Adverse Events Reporting System (VAERS). Of those, 70 are among pregnant females. All but 13 were nonserious and none involve maternal death.

Eight deaths following receipt of H1N1 vaccine have been reported to VAERS, including two following live attenuated (intranasal) vaccine and six after inactivated (injected) vaccine.

The three that have been evaluated so far had severe underlying conditions. There have been 29 reported cases of anaphylaxis, which is consistent with published estimates following other vaccinations, he said.

Two cases of “possible or probable” Guillain-Barre syndrome have been reported within one day of H1N1 vaccine receipt. The short interval “decreases but does not eliminate” the possibility that H1N1 vaccine caused the event. However, to date the rate of reported GBS cases is less than the background rate in the population, Dr. Izurieta said.

Dr. Claudia Vellozzi, of the CDC's Immunization Safety Office, described the Vaccine Safety Datalink, an active surveillance program of both the CDC and managed care plans that cover more than 9.5 million people, or 3.1% of the U.S. population, is used to follow up on safety “signals” obtained from VAERS.

Thus far, VSD analyses of pregnant women and of 10 GBS cases identified so far show no significant associations with either H1N1 or seasonal vaccine, although it's still early. The VSD will continue to monitor both vaccines on a weekly basis, she said.

Dr. Richard Platt of Harvard Pilgrim Health Care and Harvard Medical School, Boston, described a new safety analysis that his institution will conduct in collaboration with health plans covering approximately 25 million people and nine state immunization registries comprising a total population of 14 million.

That system, called Post-Licensure Rapid Immunization Safety Monitoring (PRISM), is looking specifically for Guillan-Barre syndrome, as well as other neurologic problems and pregnancy complications following receipt of H1N1 vaccine, Dr. Platt said.

Another new effort, within the Indian Health Service, will use electronic health records to monitor selected health events following vaccine receipt among a population of 1.4 million, Dr. Izurieta said.

In all, these efforts have coalesced as a result of the H1N1 vaccine outbreak but are expected to continue beyond to monitor safety of all vaccines given to the U.S. population as well as populations worldwide, he said in the interview.

“We are investing ourselves with the idea that this goes beyond H1N1. This is for vaccine safety in general, going well beyond passive surveillance.”

BETHESDA, MD. — Monitoring of influenza A(H1N1) vaccine safety in studies conducted across multiple U.S. government agencies have shown no safety signals of concern so far, nationally or internationally.

The multiple data collection efforts—some pre-existing and others a result of the pandemic H1N1 outbreak—represent “strengthened collaboration and communication among government agencies and internationally, with enhanced capacity for timely signal detection, strengthening, and confirmation,” Dr. Hector Izurieta told the Food and Drug Administration's Vaccines and Related Biological Products Advisory Committee.

In addition to the FDA, other participating agencies include the Centers for Disease Control and Prevention, the Department of Defense, the Department of Veterans Affairs, the Centers for Medicare and Medicaid Services, and the Indian Health Service, said Dr. Izurieta, who is chief of the FDA's analytic epidemiology branch.

“Not every system has the same degree of sophistication, or of populations served. The studies are complementary, and also provide redundancy that is helpful in detecting signals,” he said in an interview.

For example, the CDC is currently evaluating 205 reports of serious adverse events following H1N1 vaccine from in the Vaccine Adverse Events Reporting System (VAERS). Of those, 70 are among pregnant females. All but 13 were nonserious and none involve maternal death.

Eight deaths following receipt of H1N1 vaccine have been reported to VAERS, including two following live attenuated (intranasal) vaccine and six after inactivated (injected) vaccine.

The three that have been evaluated so far had severe underlying conditions. There have been 29 reported cases of anaphylaxis, which is consistent with published estimates following other vaccinations, he said.

Two cases of “possible or probable” Guillain-Barre syndrome have been reported within one day of H1N1 vaccine receipt. The short interval “decreases but does not eliminate” the possibility that H1N1 vaccine caused the event. However, to date the rate of reported GBS cases is less than the background rate in the population, Dr. Izurieta said.

Dr. Claudia Vellozzi, of the CDC's Immunization Safety Office, described the Vaccine Safety Datalink, an active surveillance program of both the CDC and managed care plans that cover more than 9.5 million people, or 3.1% of the U.S. population, is used to follow up on safety “signals” obtained from VAERS.

Thus far, VSD analyses of pregnant women and of 10 GBS cases identified so far show no significant associations with either H1N1 or seasonal vaccine, although it's still early. The VSD will continue to monitor both vaccines on a weekly basis, she said.

Dr. Richard Platt of Harvard Pilgrim Health Care and Harvard Medical School, Boston, described a new safety analysis that his institution will conduct in collaboration with health plans covering approximately 25 million people and nine state immunization registries comprising a total population of 14 million.

That system, called Post-Licensure Rapid Immunization Safety Monitoring (PRISM), is looking specifically for Guillan-Barre syndrome, as well as other neurologic problems and pregnancy complications following receipt of H1N1 vaccine, Dr. Platt said.

Another new effort, within the Indian Health Service, will use electronic health records to monitor selected health events following vaccine receipt among a population of 1.4 million, Dr. Izurieta said.

In all, these efforts have coalesced as a result of the H1N1 vaccine outbreak but are expected to continue beyond to monitor safety of all vaccines given to the U.S. population as well as populations worldwide, he said in the interview.

“We are investing ourselves with the idea that this goes beyond H1N1. This is for vaccine safety in general, going well beyond passive surveillance.”

A new one-page treatment algorithm for type 2 diabetes from the American Association of Clinical Endocrinologists is aimed at assisting physicians in choosing appropriate therapy from among all the approved classes of glucose-lowering medications.

The algorithm stratifies treatment by the patient's hemoglobin A_1c level, with separate treatment pathways for those with levels of 6.5%-7.5%, 7.6%-9.0%, and greater than 9.0% (Endocrine Practice 2009;15:541-59).

In general, patients with HbA_1c values of 7.5% or lower can start with monotherapy, with metformin considered the “cornerstone” but with three other drug classes included as alternatives. Patients with levels of 7.6%-9.0% typically require dual therapy. The algorithm advises insulin for patients with values higher than 9% who already are receiving other treatments or who are drug-naive and symptomatic. For patients with values higher than 9% who are drug-naive but asymptomatic, dual or triple combination therapies can be used.

“This is an authoritative, up-to-date, practical, and simple algorithm which should provide meaningful guidance to physicians as they make their therapeutic decisions,” said Dr. Helena W. Rodbard, cochair of the consensus panel that developed the algorithm, which is officially a publication of both AACE and its educational branch, the American College of Endocrinology (ACE).

“It's an easily-readable clinical point-of-care tool designed to assist endocrinologists, primary care physicians, and others involved in the care of patients with type 2 diabetes,” said Dr. Paul S. Jellinger, panel cochair who, like Dr. Rodbard, is a former president of both AACE and ACE.

Both Dr. Jellinger and Dr. Rodbard emphasized that this algorithm—written by a panel of 14 practicing endocrinologists—very accurately represents the way a majority of experienced endocrinologists approach the treatment of type 2 diabetes.

In contrast to a recently-revised algorithm from the American Diabetes Association and the European Association for the Study of Diabetes (Diabetes Care 2009;32:193-203), the AACE/ACE algorithm fully incorporates all classes of drugs approved to treat type 2 diabetes and places less emphasis on their cost.

“Most previous algorithms placed an undue emphasis on the cost of medications. Drugs can be expensive, but the cost of medications is only about 11% of the total cost of care of the population with diabetes. We need to consider the total cost of care, which is overwhelmingly driven by the cost of complications,” said Dr. Rodbard, an endocrinologist in Rockville, Md.

Dr. Jellinger said, “We placed a big emphasis on safety, particularly in terms of hypoglycemia. We included GLP-1 mimetics, DPP4 inhibitors and TZDs, along with metformin, since those classes have no potential for hypoglycemia. At the same time, we have down-graded the use of sulfonylureas due to their increased risk for hypoglycemia. By avoiding hypoglycemia, you avoid hospitalizations which are far more expensive than the medicine.”

But Dr. David M. Nathan, chair of the ADA/EASD consensus panel, said he doesn't believe it makes sense to include the additional agents as alternatives to metformin for first-line therapy or to list so many drug classes at every level. “The ADA/EASD guidelines were specifically formulated to help busy nonspecialists make informed choices from the large number of treatments that have become available in the last decade. With that in mind, the ADA/EASD consensus committee tried to narrow the choices, based on effectiveness, safety, tolerability/acceptability, and cost.”

“AACE has taken a different tack and included all approved medications. Their more complex algorithm offers more choices but, in our opinion, doesn't help the busy clinician make the best choices,” said Dr. Nathan, professor of medicine at Harvard University and director of the diabetes center at Massachusetts General Hospital, Boston.

He added, “The TZD, DPP-4, and AGI they recommend are manyfold more expensive than metformin, have far less clinical experience than with metformin, are no safer—and probably less safe for TZD—and have the same frequency or far more side-effects.”

Accompanying the AACE algorithm is a text document that explains the rationale for each of the treatment options along with the algorithm's underlying principles, which include the following:

▸ Lifestyle—dietary and exercise—modifications are essential for all patients with diabetes, but delaying pharmacotherapy to allow for lifestyle modifications to take effect is likely to be inadequate. Counseling regarding lifestyle should be initiated along with diabetes self-management education and medications.

▸ Achieving a hemoglobin A_1c of 6.5% is the primary goal, but this goal must be individualized based on factors such as comorbid conditions, hypoglycemia history/unawareness, and limited life expectancy.

▸ Effectiveness of therapy must be evaluated frequently, typically every 2-3 months.

▸ Rapid-acting insulin analogs are a better, superior alternative to “regular human insulin.” Similarly, long-acting synthetic analogs glargine and insulin detemir yield better reproducibility and consistency as basal insulins than does NPH, which is not recommended.

▸ The algorithm should conform as nearly as possible to consensus of expert endocrinologists who manage patients with type 2 diabetes, and should provide specific guidance to physicians with prioritization and rationale for the selection of any particular regimen.

Dr. Rodbard has received consultant honoraria from Abbott Laboratories, AstraZeneca Pharmaceuticals LP, Biodel Inc., GlaxoSmithKline, MannKind Corp., Merck & Co., Novo Nordisk Inc., Sanofi-Aventis U.S., and Takeda Pharmaceuticals America Inc. She also receives speaker honoraria and/or research grant support from some of those companies, as well as from Amylin Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly, and MacroGenics Inc.

Dr. Jellinger has received speaker honoraria from Amylin, Lilly, Merck, Novo-Nordisk, Sanofi-Aventis, and Takeda, and consultant honoraria from Daiichi Sankyo Inc., MannKind, and Tethys Bioscience.

Dr. Nathan has received a research grant for investigator-initiated research support from Sanofi-Aventis and support for educational programs from GlaxoSmithKline.

'We need to consider the total cost of care, which is overwhelmingly driven by the cost of complications.'

Source DR. RODBARD

A new one-page treatment algorithm for type 2 diabetes from the American Association of Clinical Endocrinologists is aimed at assisting physicians in choosing appropriate therapy from among all the approved classes of glucose-lowering medications.

The algorithm stratifies treatment by the patient's hemoglobin A_1c level, with separate treatment pathways for those with levels of 6.5%-7.5%, 7.6%-9.0%, and greater than 9.0% (Endocrine Practice 2009;15:541-59).

In general, patients with HbA_1c values of 7.5% or lower can start with monotherapy, with metformin considered the “cornerstone” but with three other drug classes included as alternatives. Patients with levels of 7.6%-9.0% typically require dual therapy. The algorithm advises insulin for patients with values higher than 9% who already are receiving other treatments or who are drug-naive and symptomatic. For patients with values higher than 9% who are drug-naive but asymptomatic, dual or triple combination therapies can be used.

“This is an authoritative, up-to-date, practical, and simple algorithm which should provide meaningful guidance to physicians as they make their therapeutic decisions,” said Dr. Helena W. Rodbard, cochair of the consensus panel that developed the algorithm, which is officially a publication of both AACE and its educational branch, the American College of Endocrinology (ACE).

“It's an easily-readable clinical point-of-care tool designed to assist endocrinologists, primary care physicians, and others involved in the care of patients with type 2 diabetes,” said Dr. Paul S. Jellinger, panel cochair who, like Dr. Rodbard, is a former president of both AACE and ACE.

Both Dr. Jellinger and Dr. Rodbard emphasized that this algorithm—written by a panel of 14 practicing endocrinologists—very accurately represents the way a majority of experienced endocrinologists approach the treatment of type 2 diabetes.

In contrast to a recently-revised algorithm from the American Diabetes Association and the European Association for the Study of Diabetes (Diabetes Care 2009;32:193-203), the AACE/ACE algorithm fully incorporates all classes of drugs approved to treat type 2 diabetes and places less emphasis on their cost.

“Most previous algorithms placed an undue emphasis on the cost of medications. Drugs can be expensive, but the cost of medications is only about 11% of the total cost of care of the population with diabetes. We need to consider the total cost of care, which is overwhelmingly driven by the cost of complications,” said Dr. Rodbard, an endocrinologist in Rockville, Md.

Dr. Jellinger said, “We placed a big emphasis on safety, particularly in terms of hypoglycemia. We included GLP-1 mimetics, DPP4 inhibitors and TZDs, along with metformin, since those classes have no potential for hypoglycemia. At the same time, we have down-graded the use of sulfonylureas due to their increased risk for hypoglycemia. By avoiding hypoglycemia, you avoid hospitalizations which are far more expensive than the medicine.”

But Dr. David M. Nathan, chair of the ADA/EASD consensus panel, said he doesn't believe it makes sense to include the additional agents as alternatives to metformin for first-line therapy or to list so many drug classes at every level. “The ADA/EASD guidelines were specifically formulated to help busy nonspecialists make informed choices from the large number of treatments that have become available in the last decade. With that in mind, the ADA/EASD consensus committee tried to narrow the choices, based on effectiveness, safety, tolerability/acceptability, and cost.”

“AACE has taken a different tack and included all approved medications. Their more complex algorithm offers more choices but, in our opinion, doesn't help the busy clinician make the best choices,” said Dr. Nathan, professor of medicine at Harvard University and director of the diabetes center at Massachusetts General Hospital, Boston.

He added, “The TZD, DPP-4, and AGI they recommend are manyfold more expensive than metformin, have far less clinical experience than with metformin, are no safer—and probably less safe for TZD—and have the same frequency or far more side-effects.”

Accompanying the AACE algorithm is a text document that explains the rationale for each of the treatment options along with the algorithm's underlying principles, which include the following:

▸ Lifestyle—dietary and exercise—modifications are essential for all patients with diabetes, but delaying pharmacotherapy to allow for lifestyle modifications to take effect is likely to be inadequate. Counseling regarding lifestyle should be initiated along with diabetes self-management education and medications.

▸ Achieving a hemoglobin A_1c of 6.5% is the primary goal, but this goal must be individualized based on factors such as comorbid conditions, hypoglycemia history/unawareness, and limited life expectancy.

▸ Effectiveness of therapy must be evaluated frequently, typically every 2-3 months.

▸ Rapid-acting insulin analogs are a better, superior alternative to “regular human insulin.” Similarly, long-acting synthetic analogs glargine and insulin detemir yield better reproducibility and consistency as basal insulins than does NPH, which is not recommended.

▸ The algorithm should conform as nearly as possible to consensus of expert endocrinologists who manage patients with type 2 diabetes, and should provide specific guidance to physicians with prioritization and rationale for the selection of any particular regimen.

Dr. Rodbard has received consultant honoraria from Abbott Laboratories, AstraZeneca Pharmaceuticals LP, Biodel Inc., GlaxoSmithKline, MannKind Corp., Merck & Co., Novo Nordisk Inc., Sanofi-Aventis U.S., and Takeda Pharmaceuticals America Inc. She also receives speaker honoraria and/or research grant support from some of those companies, as well as from Amylin Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly, and MacroGenics Inc.

Dr. Jellinger has received speaker honoraria from Amylin, Lilly, Merck, Novo-Nordisk, Sanofi-Aventis, and Takeda, and consultant honoraria from Daiichi Sankyo Inc., MannKind, and Tethys Bioscience.

Dr. Nathan has received a research grant for investigator-initiated research support from Sanofi-Aventis and support for educational programs from GlaxoSmithKline.

'We need to consider the total cost of care, which is overwhelmingly driven by the cost of complications.'

Source DR. RODBARD

A new one-page treatment algorithm for type 2 diabetes from the American Association of Clinical Endocrinologists is aimed at assisting physicians in choosing appropriate therapy from among all the approved classes of glucose-lowering medications.

The algorithm stratifies treatment by the patient's hemoglobin A_1c level, with separate treatment pathways for those with levels of 6.5%-7.5%, 7.6%-9.0%, and greater than 9.0% (Endocrine Practice 2009;15:541-59).

In general, patients with HbA_1c values of 7.5% or lower can start with monotherapy, with metformin considered the “cornerstone” but with three other drug classes included as alternatives. Patients with levels of 7.6%-9.0% typically require dual therapy. The algorithm advises insulin for patients with values higher than 9% who already are receiving other treatments or who are drug-naive and symptomatic. For patients with values higher than 9% who are drug-naive but asymptomatic, dual or triple combination therapies can be used.

“This is an authoritative, up-to-date, practical, and simple algorithm which should provide meaningful guidance to physicians as they make their therapeutic decisions,” said Dr. Helena W. Rodbard, cochair of the consensus panel that developed the algorithm, which is officially a publication of both AACE and its educational branch, the American College of Endocrinology (ACE).

“It's an easily-readable clinical point-of-care tool designed to assist endocrinologists, primary care physicians, and others involved in the care of patients with type 2 diabetes,” said Dr. Paul S. Jellinger, panel cochair who, like Dr. Rodbard, is a former president of both AACE and ACE.

Both Dr. Jellinger and Dr. Rodbard emphasized that this algorithm—written by a panel of 14 practicing endocrinologists—very accurately represents the way a majority of experienced endocrinologists approach the treatment of type 2 diabetes.

In contrast to a recently-revised algorithm from the American Diabetes Association and the European Association for the Study of Diabetes (Diabetes Care 2009;32:193-203), the AACE/ACE algorithm fully incorporates all classes of drugs approved to treat type 2 diabetes and places less emphasis on their cost.

“Most previous algorithms placed an undue emphasis on the cost of medications. Drugs can be expensive, but the cost of medications is only about 11% of the total cost of care of the population with diabetes. We need to consider the total cost of care, which is overwhelmingly driven by the cost of complications,” said Dr. Rodbard, an endocrinologist in Rockville, Md.

Dr. Jellinger said, “We placed a big emphasis on safety, particularly in terms of hypoglycemia. We included GLP-1 mimetics, DPP4 inhibitors and TZDs, along with metformin, since those classes have no potential for hypoglycemia. At the same time, we have down-graded the use of sulfonylureas due to their increased risk for hypoglycemia. By avoiding hypoglycemia, you avoid hospitalizations which are far more expensive than the medicine.”

But Dr. David M. Nathan, chair of the ADA/EASD consensus panel, said he doesn't believe it makes sense to include the additional agents as alternatives to metformin for first-line therapy or to list so many drug classes at every level. “The ADA/EASD guidelines were specifically formulated to help busy nonspecialists make informed choices from the large number of treatments that have become available in the last decade. With that in mind, the ADA/EASD consensus committee tried to narrow the choices, based on effectiveness, safety, tolerability/acceptability, and cost.”

“AACE has taken a different tack and included all approved medications. Their more complex algorithm offers more choices but, in our opinion, doesn't help the busy clinician make the best choices,” said Dr. Nathan, professor of medicine at Harvard University and director of the diabetes center at Massachusetts General Hospital, Boston.

He added, “The TZD, DPP-4, and AGI they recommend are manyfold more expensive than metformin, have far less clinical experience than with metformin, are no safer—and probably less safe for TZD—and have the same frequency or far more side-effects.”

Accompanying the AACE algorithm is a text document that explains the rationale for each of the treatment options along with the algorithm's underlying principles, which include the following:

▸ Lifestyle—dietary and exercise—modifications are essential for all patients with diabetes, but delaying pharmacotherapy to allow for lifestyle modifications to take effect is likely to be inadequate. Counseling regarding lifestyle should be initiated along with diabetes self-management education and medications.

▸ Achieving a hemoglobin A_1c of 6.5% is the primary goal, but this goal must be individualized based on factors such as comorbid conditions, hypoglycemia history/unawareness, and limited life expectancy.

▸ Effectiveness of therapy must be evaluated frequently, typically every 2-3 months.

▸ Rapid-acting insulin analogs are a better, superior alternative to “regular human insulin.” Similarly, long-acting synthetic analogs glargine and insulin detemir yield better reproducibility and consistency as basal insulins than does NPH, which is not recommended.

▸ The algorithm should conform as nearly as possible to consensus of expert endocrinologists who manage patients with type 2 diabetes, and should provide specific guidance to physicians with prioritization and rationale for the selection of any particular regimen.

Dr. Rodbard has received consultant honoraria from Abbott Laboratories, AstraZeneca Pharmaceuticals LP, Biodel Inc., GlaxoSmithKline, MannKind Corp., Merck & Co., Novo Nordisk Inc., Sanofi-Aventis U.S., and Takeda Pharmaceuticals America Inc. She also receives speaker honoraria and/or research grant support from some of those companies, as well as from Amylin Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly, and MacroGenics Inc.

Dr. Jellinger has received speaker honoraria from Amylin, Lilly, Merck, Novo-Nordisk, Sanofi-Aventis, and Takeda, and consultant honoraria from Daiichi Sankyo Inc., MannKind, and Tethys Bioscience.

Dr. Nathan has received a research grant for investigator-initiated research support from Sanofi-Aventis and support for educational programs from GlaxoSmithKline.

'We need to consider the total cost of care, which is overwhelmingly driven by the cost of complications.'

Source DR. RODBARD