TBD Meeting (3080-19)

The monoclonal antibody teplizumab may delay the onset of type 1 diabetes in individuals at high risk, according to research presented at the annual scientific sessions of the American Diabetes Association.

In this study, 76 first-degree relatives of individuals with type 1 diabetes – who did not themselves have the disease but were considered at high risk because of antibodies and abnormal glucose tolerance tests – were randomized to a single two-week outpatient course of intravenous teplizumab or saline placebo. The patients, of whom 72% were 18 years of age or younger, were followed for a median of 745 days and had twice-yearly oral glucose tolerance testing.

Overall, 43% of the 44 patients who received teplizumab were diagnosed with type 1 diabetes during the course of the study, compared with 72% of the 32 who received the placebo. The treatment was associated with a 59% reduction in the hazard ratio for type 1 diabetes, even after adjusting for age, the results of a second oral glucose-tolerance testing before randomization, or the presence of anti-GAD65 antibodies.

The median time to diagnosis was 48.4 months in the teplizumab group and 24.4 months in the placebo group. The greatest effect was seen in the first year after randomization, during which only 7% of the teplizumab group were diagnosed with type 1 diabetes, compared with 44% of the placebo group. The findings were published simultaneously in the New England Journal of Medicine.

“The delay of progression to type 1 diabetes is of clinical importance, particularly for children, in whom the diagnosis is associated with adverse outcomes, and given the challenges of daily management of the condition,” said Dr. Kevan C. Herold, professor of immunobiology and medicine at Yale University, New Haven, Conn., and coauthors.

There were significantly more adverse events in the teplizumab group, compared with placebo, with three-quarters of the 20 grade 3 adverse events being lymphopenia during the first 30 days. In all but one participant, however, the lymphopenia resolved by day 45. Participants receiving teplizumab also reported a higher incidence of dermatologic adverse events, such as a spontaneously-resolving rash that was experienced by just over one-third of the group.

The researchers also looked for evidence of T-cell unresponsiveness, which has been previously seen in patients with new-onset type 1 diabetes who received treatment with teplizumab. They noted an increase in a particular type of CD8+ T cell associated with T-cell unresponsiveness at months 3 and 6 in participants treated with teplizumab.

Teplizumab is an Fc receptor-nonbinding monoclonal antibody that has been shown to reduce the loss of beta-cell function in patients with type 1 diabetes (Diabetes. 2013 Nov;62(11):3766-74).

The study was supported by the National Institutes of Health, the Juvenile Diabetes Research Foundation, and the American Diabetes Association, with the study drug and additional site monitoring provided by MacroGenics. Eight authors declared grants, personal fees, and other support from private industry, with one also declaring income and stock options from MacroGenics.

SOURCE: Herold K et al. NEJM. 2019 Jun 9. doi: 10.1056/NEJMoa1902226*

*Correction, 6/9/2019: An earlier version of this story misstated the doi number for the journal article. The number is 10.1056/NEJMoa1902226.

The monoclonal antibody teplizumab may delay the onset of type 1 diabetes in individuals at high risk, according to research presented at the annual scientific sessions of the American Diabetes Association.

In this study, 76 first-degree relatives of individuals with type 1 diabetes – who did not themselves have the disease but were considered at high risk because of antibodies and abnormal glucose tolerance tests – were randomized to a single two-week outpatient course of intravenous teplizumab or saline placebo. The patients, of whom 72% were 18 years of age or younger, were followed for a median of 745 days and had twice-yearly oral glucose tolerance testing.

Overall, 43% of the 44 patients who received teplizumab were diagnosed with type 1 diabetes during the course of the study, compared with 72% of the 32 who received the placebo. The treatment was associated with a 59% reduction in the hazard ratio for type 1 diabetes, even after adjusting for age, the results of a second oral glucose-tolerance testing before randomization, or the presence of anti-GAD65 antibodies.

The median time to diagnosis was 48.4 months in the teplizumab group and 24.4 months in the placebo group. The greatest effect was seen in the first year after randomization, during which only 7% of the teplizumab group were diagnosed with type 1 diabetes, compared with 44% of the placebo group. The findings were published simultaneously in the New England Journal of Medicine.

“The delay of progression to type 1 diabetes is of clinical importance, particularly for children, in whom the diagnosis is associated with adverse outcomes, and given the challenges of daily management of the condition,” said Dr. Kevan C. Herold, professor of immunobiology and medicine at Yale University, New Haven, Conn., and coauthors.

There were significantly more adverse events in the teplizumab group, compared with placebo, with three-quarters of the 20 grade 3 adverse events being lymphopenia during the first 30 days. In all but one participant, however, the lymphopenia resolved by day 45. Participants receiving teplizumab also reported a higher incidence of dermatologic adverse events, such as a spontaneously-resolving rash that was experienced by just over one-third of the group.

The researchers also looked for evidence of T-cell unresponsiveness, which has been previously seen in patients with new-onset type 1 diabetes who received treatment with teplizumab. They noted an increase in a particular type of CD8+ T cell associated with T-cell unresponsiveness at months 3 and 6 in participants treated with teplizumab.

Teplizumab is an Fc receptor-nonbinding monoclonal antibody that has been shown to reduce the loss of beta-cell function in patients with type 1 diabetes (Diabetes. 2013 Nov;62(11):3766-74).

The study was supported by the National Institutes of Health, the Juvenile Diabetes Research Foundation, and the American Diabetes Association, with the study drug and additional site monitoring provided by MacroGenics. Eight authors declared grants, personal fees, and other support from private industry, with one also declaring income and stock options from MacroGenics.

SOURCE: Herold K et al. NEJM. 2019 Jun 9. doi: 10.1056/NEJMoa1902226*

*Correction, 6/9/2019: An earlier version of this story misstated the doi number for the journal article. The number is 10.1056/NEJMoa1902226.

The monoclonal antibody teplizumab may delay the onset of type 1 diabetes in individuals at high risk, according to research presented at the annual scientific sessions of the American Diabetes Association.

In this study, 76 first-degree relatives of individuals with type 1 diabetes – who did not themselves have the disease but were considered at high risk because of antibodies and abnormal glucose tolerance tests – were randomized to a single two-week outpatient course of intravenous teplizumab or saline placebo. The patients, of whom 72% were 18 years of age or younger, were followed for a median of 745 days and had twice-yearly oral glucose tolerance testing.

Overall, 43% of the 44 patients who received teplizumab were diagnosed with type 1 diabetes during the course of the study, compared with 72% of the 32 who received the placebo. The treatment was associated with a 59% reduction in the hazard ratio for type 1 diabetes, even after adjusting for age, the results of a second oral glucose-tolerance testing before randomization, or the presence of anti-GAD65 antibodies.

The median time to diagnosis was 48.4 months in the teplizumab group and 24.4 months in the placebo group. The greatest effect was seen in the first year after randomization, during which only 7% of the teplizumab group were diagnosed with type 1 diabetes, compared with 44% of the placebo group. The findings were published simultaneously in the New England Journal of Medicine.

“The delay of progression to type 1 diabetes is of clinical importance, particularly for children, in whom the diagnosis is associated with adverse outcomes, and given the challenges of daily management of the condition,” said Dr. Kevan C. Herold, professor of immunobiology and medicine at Yale University, New Haven, Conn., and coauthors.

There were significantly more adverse events in the teplizumab group, compared with placebo, with three-quarters of the 20 grade 3 adverse events being lymphopenia during the first 30 days. In all but one participant, however, the lymphopenia resolved by day 45. Participants receiving teplizumab also reported a higher incidence of dermatologic adverse events, such as a spontaneously-resolving rash that was experienced by just over one-third of the group.

The researchers also looked for evidence of T-cell unresponsiveness, which has been previously seen in patients with new-onset type 1 diabetes who received treatment with teplizumab. They noted an increase in a particular type of CD8+ T cell associated with T-cell unresponsiveness at months 3 and 6 in participants treated with teplizumab.

Teplizumab is an Fc receptor-nonbinding monoclonal antibody that has been shown to reduce the loss of beta-cell function in patients with type 1 diabetes (Diabetes. 2013 Nov;62(11):3766-74).

The study was supported by the National Institutes of Health, the Juvenile Diabetes Research Foundation, and the American Diabetes Association, with the study drug and additional site monitoring provided by MacroGenics. Eight authors declared grants, personal fees, and other support from private industry, with one also declaring income and stock options from MacroGenics.

SOURCE: Herold K et al. NEJM. 2019 Jun 9. doi: 10.1056/NEJMoa1902226*

*Correction, 6/9/2019: An earlier version of this story misstated the doi number for the journal article. The number is 10.1056/NEJMoa1902226.

SAN FRANCISCO – Vitamin D supplementation did not significantly reduce the risk of progression from prediabetes to type 2 diabetes, according to the landmark D2d study.

A possible reason why the observed reduction was not statistically significant was that most participants already had acceptable levels of vitamin D. Still, the intervention “did not significantly reduce the risk [of diabetes],” Anastassios G. Pittas, MD, professor of medicine at Tufts Medical Center, Boston, said at the annual scientific sessions of the American Diabetes Association.

Vitamin D supplementation has been a hot topic on a range of medical fronts. As a 2016 report noted, “low vitamin D levels are also associated with hypertension, cancer, and cardiovascular disease. In addition, [diabetes] and chronic kidney disease (CKD) are also related to vitamin D levels. Vitamin D deficiency has been linked to onset and progression of [diabetes],” (World J Diabetes. 2016;7[5]:89-100).

However, as the report noted, “evidence regarding vitamin D levels and [diabetes] is contradictory, and well-controlled studies are needed.”

For the D2d study, which was coordinated out of the division of endocrinology at Tufts Medical Center, Dr. Pittas and associates recruited 2,423 patients who were considered to have prediabetes, with at least 2 of 3 ADA criteria: fasting plasma glucose level of 100-125 mg/dL; plasma glucose level 2 hours after a 75-g oral glucose load of 140-199 mg/dL; and hemoglobin A_1c (HbA_1c) level of 5.7%-6.4%.

All of the patients were at least 30 years old with the exception of American Indians, Alaska Natives, Native Hawaiians and other Pacific Islanders who were allowed to be aged 25-30 years. About 22% had low vitamin D levels.

The mean age of the patients was 60 years, mean body mass index was 32, 45% were women, and 33% were non-white. The trial was powered to show a reduction of 25% or more in diabetes risk with vitamin D.

The researchers randomly assigned 1,211 patients to take a once-daily capsule of vitamin D3 (cholecalciferol; 4,000 IU per day); 1,212 received a placebo.

Patients in the vitamin D group greatly boosted their mean serum 25-hydroxyvitamin D levels, from 27.7 ng/mL at baseline to 54.3 ng/mL at 24 months. In contrast, those in the placebo group saw little change, going from 28.2 ng/mL at baseline to 28.8 ng/mL at 24 months.

At a median follow-up of 2.5 years, with 99% of the study participants remaining in the trial, 616 patients developed diabetes (293 in the vitamin D group, 323 in the placebo group).

The risk was lower in the vitamin D group although the difference was not statistically significant. An analysis revealed no clear differences in any of the subgroups (race, age, body mass index, latitude-based geographic location, calcium supplement intake, and others).

However, a post hoc analysis of patients with vitamin D deficiency, which is defined by the National Academy of Medicine as having a 25-hydroxyvitamin D level of less than 12 ng/mL, showed that the vitamin D group had a 62% reduction in risk of diabetes, compared with placebo.

“Response to a nutritional intervention depends on nutritional status at baseline. Thus, if vitamin D has an effect on diabetes prevention, then people with lower levels of serum 25-hydroxyvitamin D would be expected to have a larger effect from supplementation than would those with higher baseline levels,” Dr. Pittas said.

SOURCE: Pittas AG et al. ADA 2019

This article was updated on 6/18/2019.

SAN FRANCISCO – Vitamin D supplementation did not significantly reduce the risk of progression from prediabetes to type 2 diabetes, according to the landmark D2d study.

A possible reason why the observed reduction was not statistically significant was that most participants already had acceptable levels of vitamin D. Still, the intervention “did not significantly reduce the risk [of diabetes],” Anastassios G. Pittas, MD, professor of medicine at Tufts Medical Center, Boston, said at the annual scientific sessions of the American Diabetes Association.

Vitamin D supplementation has been a hot topic on a range of medical fronts. As a 2016 report noted, “low vitamin D levels are also associated with hypertension, cancer, and cardiovascular disease. In addition, [diabetes] and chronic kidney disease (CKD) are also related to vitamin D levels. Vitamin D deficiency has been linked to onset and progression of [diabetes],” (World J Diabetes. 2016;7[5]:89-100).

However, as the report noted, “evidence regarding vitamin D levels and [diabetes] is contradictory, and well-controlled studies are needed.”

For the D2d study, which was coordinated out of the division of endocrinology at Tufts Medical Center, Dr. Pittas and associates recruited 2,423 patients who were considered to have prediabetes, with at least 2 of 3 ADA criteria: fasting plasma glucose level of 100-125 mg/dL; plasma glucose level 2 hours after a 75-g oral glucose load of 140-199 mg/dL; and hemoglobin A_1c (HbA_1c) level of 5.7%-6.4%.

All of the patients were at least 30 years old with the exception of American Indians, Alaska Natives, Native Hawaiians and other Pacific Islanders who were allowed to be aged 25-30 years. About 22% had low vitamin D levels.

The mean age of the patients was 60 years, mean body mass index was 32, 45% were women, and 33% were non-white. The trial was powered to show a reduction of 25% or more in diabetes risk with vitamin D.

The researchers randomly assigned 1,211 patients to take a once-daily capsule of vitamin D3 (cholecalciferol; 4,000 IU per day); 1,212 received a placebo.

Patients in the vitamin D group greatly boosted their mean serum 25-hydroxyvitamin D levels, from 27.7 ng/mL at baseline to 54.3 ng/mL at 24 months. In contrast, those in the placebo group saw little change, going from 28.2 ng/mL at baseline to 28.8 ng/mL at 24 months.

At a median follow-up of 2.5 years, with 99% of the study participants remaining in the trial, 616 patients developed diabetes (293 in the vitamin D group, 323 in the placebo group).

The risk was lower in the vitamin D group although the difference was not statistically significant. An analysis revealed no clear differences in any of the subgroups (race, age, body mass index, latitude-based geographic location, calcium supplement intake, and others).

However, a post hoc analysis of patients with vitamin D deficiency, which is defined by the National Academy of Medicine as having a 25-hydroxyvitamin D level of less than 12 ng/mL, showed that the vitamin D group had a 62% reduction in risk of diabetes, compared with placebo.

“Response to a nutritional intervention depends on nutritional status at baseline. Thus, if vitamin D has an effect on diabetes prevention, then people with lower levels of serum 25-hydroxyvitamin D would be expected to have a larger effect from supplementation than would those with higher baseline levels,” Dr. Pittas said.

SOURCE: Pittas AG et al. ADA 2019

This article was updated on 6/18/2019.

SAN FRANCISCO – Vitamin D supplementation did not significantly reduce the risk of progression from prediabetes to type 2 diabetes, according to the landmark D2d study.

A possible reason why the observed reduction was not statistically significant was that most participants already had acceptable levels of vitamin D. Still, the intervention “did not significantly reduce the risk [of diabetes],” Anastassios G. Pittas, MD, professor of medicine at Tufts Medical Center, Boston, said at the annual scientific sessions of the American Diabetes Association.

Vitamin D supplementation has been a hot topic on a range of medical fronts. As a 2016 report noted, “low vitamin D levels are also associated with hypertension, cancer, and cardiovascular disease. In addition, [diabetes] and chronic kidney disease (CKD) are also related to vitamin D levels. Vitamin D deficiency has been linked to onset and progression of [diabetes],” (World J Diabetes. 2016;7[5]:89-100).

However, as the report noted, “evidence regarding vitamin D levels and [diabetes] is contradictory, and well-controlled studies are needed.”

For the D2d study, which was coordinated out of the division of endocrinology at Tufts Medical Center, Dr. Pittas and associates recruited 2,423 patients who were considered to have prediabetes, with at least 2 of 3 ADA criteria: fasting plasma glucose level of 100-125 mg/dL; plasma glucose level 2 hours after a 75-g oral glucose load of 140-199 mg/dL; and hemoglobin A_1c (HbA_1c) level of 5.7%-6.4%.

All of the patients were at least 30 years old with the exception of American Indians, Alaska Natives, Native Hawaiians and other Pacific Islanders who were allowed to be aged 25-30 years. About 22% had low vitamin D levels.

The mean age of the patients was 60 years, mean body mass index was 32, 45% were women, and 33% were non-white. The trial was powered to show a reduction of 25% or more in diabetes risk with vitamin D.

The researchers randomly assigned 1,211 patients to take a once-daily capsule of vitamin D3 (cholecalciferol; 4,000 IU per day); 1,212 received a placebo.

Patients in the vitamin D group greatly boosted their mean serum 25-hydroxyvitamin D levels, from 27.7 ng/mL at baseline to 54.3 ng/mL at 24 months. In contrast, those in the placebo group saw little change, going from 28.2 ng/mL at baseline to 28.8 ng/mL at 24 months.

At a median follow-up of 2.5 years, with 99% of the study participants remaining in the trial, 616 patients developed diabetes (293 in the vitamin D group, 323 in the placebo group).

The risk was lower in the vitamin D group although the difference was not statistically significant. An analysis revealed no clear differences in any of the subgroups (race, age, body mass index, latitude-based geographic location, calcium supplement intake, and others).

However, a post hoc analysis of patients with vitamin D deficiency, which is defined by the National Academy of Medicine as having a 25-hydroxyvitamin D level of less than 12 ng/mL, showed that the vitamin D group had a 62% reduction in risk of diabetes, compared with placebo.

“Response to a nutritional intervention depends on nutritional status at baseline. Thus, if vitamin D has an effect on diabetes prevention, then people with lower levels of serum 25-hydroxyvitamin D would be expected to have a larger effect from supplementation than would those with higher baseline levels,” Dr. Pittas said.

SOURCE: Pittas AG et al. ADA 2019

This article was updated on 6/18/2019.