Sara Freeman

PARIS – With an expanding array of treatment choices and no fixed algorithm to decide which to use and when, treatment choice for metastatic breast cancer remains based on a conglomeration of tumor biology, prior therapies, toxicities, patients’ performance status and their choice or preference for treatment, Dr. Sandra M. Swain said during a state-of-the-art lecture on metastatic breast cancer at an international congress on anti-cancer treatment.

Compared to 30 years ago when there were only a few drugs available” to treat metastatic disease, “it’s really gratifying to be able to say to a patient, and really mean it, that ‘this is not your last option: we have a lot of other opportunities after this if this treatment doesn’t work or if you don’t like the toxicities from it’,” said Dr. Swain, director of the Washington Cancer Institute at MedStar Washington Hospital Center and professor of medicine at Georgetown University, Washington.

The past decade has seen several drugs approved by the Food and Drug Administration for use in metastatic breast cancer: eribulin in 2010, pertuzumab and everolimus in 2012, trastuzumab-DM1 in 2013, and most recently palbociclib in 2015, she said.

Although treatment goals largely remain the same – to extend survival and minimize toxicity, as well as maximizing patients’ quality of life – there has been a shift to looking at the value of metastatic cancer treatment, taking all these factors and the cost of treatment into consideration.

Looking at available chemotherapies listed in the National Comprehensive Cancer Network guidelines, Dr. Swain noted that no one regimen was preferred over others and highlighted the multiple choices that were recommended.

“My preference is to use sequential single agents, unless we have a patient who is very sick and we need an immediate response, “Dr. Swain said. Response rates are often higher with combination regimens but quality of life may be worse or there are added toxicities that need to be factored into the equation.

Dr. Swain highlighted that newer is not necessarily better. Results of the federal-sponsored CALGB 40502 study, for example, showed that neither weekly nab-paclitaxel (Abraxane) or ixabepilone (Ixempra) was better than weekly treatment with paclitaxel (J. Clin. Oncol. 2012;30:Abstr. CRA1002).

“I think in the U.S. this was very important because paclitaxel is generic and much easier for many patients to afford,” Dr. Swain said.

Expanding Treatment Choices

Studies in metastatic breast cancer highlighted by Dr. Swain include the Triple Negative Trial (TNT), the Breast Cancer Trial of Oral Everolimus 2 (BOLERO-2), and the Tamoxifen Plus Everolimus (TAMRAD) study.

Results of TNT were presented at the 2014 San Antonio Breast Cancer Symposium and showed that carboplatin might be a better choice than docetaxel for women with triple-negative breast cancer and the BRCA1/2 mutation.

BOLERO-2 showed that combining everolimus with exemestane increased progression-free survival by 64% in women with ER-positive, HER2-negative postmenopausal metastatic breast cancer who were refractory to treatment with other AIs (N. Engl. J. Med. 2012;366:520-9). The clinical implications of these data were that the use of everolimus could overcome resistance to endocrine therapy although stomatitis can occur within the first 3 months of treatment. Studies are looking at preventing this side effect with a steroid mouthwash, Dr. Swain said.

TAMRAD was a phase II study looking at the combination of everolimus and tamoxifen, showing improved response rates and overall survival over tamoxifen alone in postmenopausal women with AI-resistant metastatic breast cancer (J. Clin. Oncol. 2012;30:2718-24).

Dr. Swain also discussed the recent fast-tracked FDA approval of palbociclib, a cyclin-dependent kinase 4/6 inhibitor approved for use in combination with letrozole (Femara) for estrogen receptor–positive, HER2-negative, postmenopausal, metastatic breast cancer.

Approval was based on the results of the PALOMA-1 study (Lancet Oncol. 2015;16:25-­35), which showed “a striking benefit, with a 50% reduction in progression-free survival” with the combination versus letrozole alone, she said.

“The biggest side effect is neutropenia,” Dr. Swain cautioned, with around 50% of patients treated with the combination experiencing grade 3 or 4 neutropenia.

“So that’s what we need to be careful of now that this drug is going to be on the market,” she said. While there were no reports of febrile neutropenia in the trial, she felt that this would be seen in the “real world” and needs to be considered.

Whether using granulocyte colony–stimulating factor to prevent neutropenia would be possible or even safe is a topic for future research.

Several phase III studies with palbociclib have been completed or are ongoing. These include PALOMA-2 in combination with letrozole as first-line treatment for ER-positive, HER2-negative metastatic breast cancer; PALOMA-3 in combination with fulvestrant (Faslodex) in patients who have progressed on hormonal therapy; PENELOPE-B in the postneoadjuvant setting; and PEARL in women with ER-positive metastatic breast cancer that is not responsive to treatment with an aromatase inhibitor.

There are also two other CDK 4/6 inhibitors currently under investigation: abemaciclib and LEE011, both in phase III trials.

Dr. Swain has received research funding from Genentech, Pfizer, Puma Biotechnology, and Roche. She has also acted as an advisor or consultant and served as a steering committee member for Genentech and Roche, uncompensated. She has received honoraria from Genentech/Roche and Clinigen. She has received travel funding from Genentech.

PARIS – With an expanding array of treatment choices and no fixed algorithm to decide which to use and when, treatment choice for metastatic breast cancer remains based on a conglomeration of tumor biology, prior therapies, toxicities, patients’ performance status and their choice or preference for treatment, Dr. Sandra M. Swain said during a state-of-the-art lecture on metastatic breast cancer at an international congress on anti-cancer treatment.

Compared to 30 years ago when there were only a few drugs available” to treat metastatic disease, “it’s really gratifying to be able to say to a patient, and really mean it, that ‘this is not your last option: we have a lot of other opportunities after this if this treatment doesn’t work or if you don’t like the toxicities from it’,” said Dr. Swain, director of the Washington Cancer Institute at MedStar Washington Hospital Center and professor of medicine at Georgetown University, Washington.

The past decade has seen several drugs approved by the Food and Drug Administration for use in metastatic breast cancer: eribulin in 2010, pertuzumab and everolimus in 2012, trastuzumab-DM1 in 2013, and most recently palbociclib in 2015, she said.

Although treatment goals largely remain the same – to extend survival and minimize toxicity, as well as maximizing patients’ quality of life – there has been a shift to looking at the value of metastatic cancer treatment, taking all these factors and the cost of treatment into consideration.

Looking at available chemotherapies listed in the National Comprehensive Cancer Network guidelines, Dr. Swain noted that no one regimen was preferred over others and highlighted the multiple choices that were recommended.

“My preference is to use sequential single agents, unless we have a patient who is very sick and we need an immediate response, “Dr. Swain said. Response rates are often higher with combination regimens but quality of life may be worse or there are added toxicities that need to be factored into the equation.

Dr. Swain highlighted that newer is not necessarily better. Results of the federal-sponsored CALGB 40502 study, for example, showed that neither weekly nab-paclitaxel (Abraxane) or ixabepilone (Ixempra) was better than weekly treatment with paclitaxel (J. Clin. Oncol. 2012;30:Abstr. CRA1002).

“I think in the U.S. this was very important because paclitaxel is generic and much easier for many patients to afford,” Dr. Swain said.

Expanding Treatment Choices

Studies in metastatic breast cancer highlighted by Dr. Swain include the Triple Negative Trial (TNT), the Breast Cancer Trial of Oral Everolimus 2 (BOLERO-2), and the Tamoxifen Plus Everolimus (TAMRAD) study.

Results of TNT were presented at the 2014 San Antonio Breast Cancer Symposium and showed that carboplatin might be a better choice than docetaxel for women with triple-negative breast cancer and the BRCA1/2 mutation.

BOLERO-2 showed that combining everolimus with exemestane increased progression-free survival by 64% in women with ER-positive, HER2-negative postmenopausal metastatic breast cancer who were refractory to treatment with other AIs (N. Engl. J. Med. 2012;366:520-9). The clinical implications of these data were that the use of everolimus could overcome resistance to endocrine therapy although stomatitis can occur within the first 3 months of treatment. Studies are looking at preventing this side effect with a steroid mouthwash, Dr. Swain said.

TAMRAD was a phase II study looking at the combination of everolimus and tamoxifen, showing improved response rates and overall survival over tamoxifen alone in postmenopausal women with AI-resistant metastatic breast cancer (J. Clin. Oncol. 2012;30:2718-24).

Dr. Swain also discussed the recent fast-tracked FDA approval of palbociclib, a cyclin-dependent kinase 4/6 inhibitor approved for use in combination with letrozole (Femara) for estrogen receptor–positive, HER2-negative, postmenopausal, metastatic breast cancer.

Approval was based on the results of the PALOMA-1 study (Lancet Oncol. 2015;16:25-­35), which showed “a striking benefit, with a 50% reduction in progression-free survival” with the combination versus letrozole alone, she said.

“The biggest side effect is neutropenia,” Dr. Swain cautioned, with around 50% of patients treated with the combination experiencing grade 3 or 4 neutropenia.

“So that’s what we need to be careful of now that this drug is going to be on the market,” she said. While there were no reports of febrile neutropenia in the trial, she felt that this would be seen in the “real world” and needs to be considered.

Whether using granulocyte colony–stimulating factor to prevent neutropenia would be possible or even safe is a topic for future research.

Several phase III studies with palbociclib have been completed or are ongoing. These include PALOMA-2 in combination with letrozole as first-line treatment for ER-positive, HER2-negative metastatic breast cancer; PALOMA-3 in combination with fulvestrant (Faslodex) in patients who have progressed on hormonal therapy; PENELOPE-B in the postneoadjuvant setting; and PEARL in women with ER-positive metastatic breast cancer that is not responsive to treatment with an aromatase inhibitor.

There are also two other CDK 4/6 inhibitors currently under investigation: abemaciclib and LEE011, both in phase III trials.

Dr. Swain has received research funding from Genentech, Pfizer, Puma Biotechnology, and Roche. She has also acted as an advisor or consultant and served as a steering committee member for Genentech and Roche, uncompensated. She has received honoraria from Genentech/Roche and Clinigen. She has received travel funding from Genentech.

PARIS – With an expanding array of treatment choices and no fixed algorithm to decide which to use and when, treatment choice for metastatic breast cancer remains based on a conglomeration of tumor biology, prior therapies, toxicities, patients’ performance status and their choice or preference for treatment, Dr. Sandra M. Swain said during a state-of-the-art lecture on metastatic breast cancer at an international congress on anti-cancer treatment.

Compared to 30 years ago when there were only a few drugs available” to treat metastatic disease, “it’s really gratifying to be able to say to a patient, and really mean it, that ‘this is not your last option: we have a lot of other opportunities after this if this treatment doesn’t work or if you don’t like the toxicities from it’,” said Dr. Swain, director of the Washington Cancer Institute at MedStar Washington Hospital Center and professor of medicine at Georgetown University, Washington.

The past decade has seen several drugs approved by the Food and Drug Administration for use in metastatic breast cancer: eribulin in 2010, pertuzumab and everolimus in 2012, trastuzumab-DM1 in 2013, and most recently palbociclib in 2015, she said.

Although treatment goals largely remain the same – to extend survival and minimize toxicity, as well as maximizing patients’ quality of life – there has been a shift to looking at the value of metastatic cancer treatment, taking all these factors and the cost of treatment into consideration.

Looking at available chemotherapies listed in the National Comprehensive Cancer Network guidelines, Dr. Swain noted that no one regimen was preferred over others and highlighted the multiple choices that were recommended.

“My preference is to use sequential single agents, unless we have a patient who is very sick and we need an immediate response, “Dr. Swain said. Response rates are often higher with combination regimens but quality of life may be worse or there are added toxicities that need to be factored into the equation.

Dr. Swain highlighted that newer is not necessarily better. Results of the federal-sponsored CALGB 40502 study, for example, showed that neither weekly nab-paclitaxel (Abraxane) or ixabepilone (Ixempra) was better than weekly treatment with paclitaxel (J. Clin. Oncol. 2012;30:Abstr. CRA1002).

“I think in the U.S. this was very important because paclitaxel is generic and much easier for many patients to afford,” Dr. Swain said.

Expanding Treatment Choices

Studies in metastatic breast cancer highlighted by Dr. Swain include the Triple Negative Trial (TNT), the Breast Cancer Trial of Oral Everolimus 2 (BOLERO-2), and the Tamoxifen Plus Everolimus (TAMRAD) study.

Results of TNT were presented at the 2014 San Antonio Breast Cancer Symposium and showed that carboplatin might be a better choice than docetaxel for women with triple-negative breast cancer and the BRCA1/2 mutation.

BOLERO-2 showed that combining everolimus with exemestane increased progression-free survival by 64% in women with ER-positive, HER2-negative postmenopausal metastatic breast cancer who were refractory to treatment with other AIs (N. Engl. J. Med. 2012;366:520-9). The clinical implications of these data were that the use of everolimus could overcome resistance to endocrine therapy although stomatitis can occur within the first 3 months of treatment. Studies are looking at preventing this side effect with a steroid mouthwash, Dr. Swain said.

TAMRAD was a phase II study looking at the combination of everolimus and tamoxifen, showing improved response rates and overall survival over tamoxifen alone in postmenopausal women with AI-resistant metastatic breast cancer (J. Clin. Oncol. 2012;30:2718-24).

Dr. Swain also discussed the recent fast-tracked FDA approval of palbociclib, a cyclin-dependent kinase 4/6 inhibitor approved for use in combination with letrozole (Femara) for estrogen receptor–positive, HER2-negative, postmenopausal, metastatic breast cancer.

Approval was based on the results of the PALOMA-1 study (Lancet Oncol. 2015;16:25-­35), which showed “a striking benefit, with a 50% reduction in progression-free survival” with the combination versus letrozole alone, she said.

“The biggest side effect is neutropenia,” Dr. Swain cautioned, with around 50% of patients treated with the combination experiencing grade 3 or 4 neutropenia.

“So that’s what we need to be careful of now that this drug is going to be on the market,” she said. While there were no reports of febrile neutropenia in the trial, she felt that this would be seen in the “real world” and needs to be considered.

Whether using granulocyte colony–stimulating factor to prevent neutropenia would be possible or even safe is a topic for future research.

Several phase III studies with palbociclib have been completed or are ongoing. These include PALOMA-2 in combination with letrozole as first-line treatment for ER-positive, HER2-negative metastatic breast cancer; PALOMA-3 in combination with fulvestrant (Faslodex) in patients who have progressed on hormonal therapy; PENELOPE-B in the postneoadjuvant setting; and PEARL in women with ER-positive metastatic breast cancer that is not responsive to treatment with an aromatase inhibitor.

There are also two other CDK 4/6 inhibitors currently under investigation: abemaciclib and LEE011, both in phase III trials.

Dr. Swain has received research funding from Genentech, Pfizer, Puma Biotechnology, and Roche. She has also acted as an advisor or consultant and served as a steering committee member for Genentech and Roche, uncompensated. She has received honoraria from Genentech/Roche and Clinigen. She has received travel funding from Genentech.

PARIS – Using chemotherapy earlier in the treatment of patients with metastatic prostate cancer could maximize its benefits on patients’ overall survival, a leading expert said at an international congress on anticancer treatment.

“Survival benefit is related to the number of life-extending therapies received, and you should not miss the ‘window of opportunity’ to use chemotherapy early,” Dr. Stéphane Oudard of Georges Pompidou Hospital, René Descartes University, Paris, advised attendees during an educational lecture at the  meeting.

© alexdans/Thinkstock

The treatment of advanced prostate cancer usually starts with hormonal or antiandrogen therapies before the disease becomes castrate resistant. Chemotherapy with docetaxel is then a standard first-line choice and cabazitaxel a second-line chemotherapy option when the disease becomes castrate resistant.

The prostate cancer vaccine sipuleucel-T (Provenge) can also be used first-line, with abiraterone (Zytiga), enzalutamide (Xtandi), and radium-223 possible other first- or second-line choices. All of these treatments have different targets and have been shown in phase III clinical trials to increase survival by around 3-5 months more than control treatments have.

Evidence suggests that overall survival may be at its highest, however, when docetaxel is used first before abiraterone, enzalutamide, and cabazitaxel in the metastatic castration-resistant prostate cancer (mCRPC) setting. Furthermore, recent findings of the CHAARTED trial (J. Clin. Oncol. 2014;32-5s: Abstr, LBA2) suggest that combining docetaxel with androgen deprivation therapy (ADT) in castrate-sensitive disease could dramatically up overall survival by around 14 months vs. ADT alone.

Tailoring treatment in mCRPC

During his talk, Dr. Oudard generally discussed how clinicians might interpret available clinical trial data to help them decide which treatment approach to use for individual patients.

First, he looked at post hoc analysis data from the IMPACT study (Urology 2013;81:1297-302) with sipuleucel-T. In this trial, immunotherapy-treated patients had a median overall survival gain of 13 months over controls, when their baseline prostate-specific antigen (PSA) levels were 22.1 mg/mL or lower. As PSA levels increased, however, survival gains were substantially decreased, with a gain of just 2.8 months when PSA was over 134.1 ng/mL.

“So it means if you want to use immunotherapy you perhaps need to use it in asymptomatic patients with a low disease burden,” Dr. Oudard suggested.

Predicting response to treatment

Looking at the use of abiraterone acetate and enzalutamide after docetaxel, he noted that primary resistance to these agents develops in one-third to one-quarter of patients. This usually happens at around the 3-month mark, so it would be advisable to stop using androgen receptor (AR)-targeted agents at this point and find an alternative approach.

Combining AR-targeted agents might seem like a potential option, but data suggest that this approach does not overcome primary resistance, and research has focused on trying to determine which patients will and will not respond to AR-targeted agents.

Results of this research suggest that the duration of response to first-line ADT might be predictive of the risk for primary resistance to AR-targeted agents, with a shorter (12 months) ADT response, but not the duration of hormonal therapy, being associated with a lower response to subsequent ADT.

Another interesting parameter that might help predict response and outcome to treatment is the neutrophil/lymphocyte ratio, with the higher the ratio, the lower the overall survival to abiraterone, docetaxel, and cabazitaxel.

High residual baseline testosterone, below the level of castration, also seems a promising way to predict better response to endocrine therapies, Dr. Oudard observed, but this requires further validation.

And the presence of a genetic anomaly (the AR-V7 splice variant) in circulating tumor cells is “very promising but requires methodology validation” for use as a marker of abiraterone and enzalutamide resistance (N. Engl. J. Med. 2014;371:1028-38).

Treating refractory patients

So what are the options for patients who are refractory to first-line treatments? Data suggest that better overall survival can be achieved if patients who are “truly refractory to docetaxel” are treated with cabazitaxel rather than an AR-targeted agent, Dr. Oudard said.

It also appears that overall survival is better if docetaxel is used before abiraterone than if it is used after, and “interesting” in vitro data show that cabazitaxel seems to have greater antitumor activity than does docetaxel in enzalutamide-resistant xenografts.

Dr. Oudard also presented data showing that the PSA response achieved with cabazitaxel does not appear to be influenced by the prior use of AR-targeted agents.

Higher overall survival can be achieved in the post-docetaxel setting if cabazitaxel is used before abiraterone than if it was used after, he observed, His own data have shown a trend for better survival if the sequence of treatment starts with docetaxel, changes to cabazitaxel, and then goes to abiraterone rather than if patients receive abiraterone before cabazitaxel. The sequence of these three drugs also seems preferable rather than using docetaxel followed by cabazitaxel, he said. Large retrospective or observational studies need to address these points.

“We need to think about the sequence of treatment as early as possible,” Dr. Oudard concluded. Considering the CHAARTED study findings, he added: “We maybe need to propose chemotherapy much earlier” in order to overcome resistance. “The difference in using docetaxel much earlier is huge in terms of overall survival outcome.”

Dr. Oudard has consulting agreements with Bayer, GSK, Janssen, Keocyt, Novartis, Pfizer, Roche, Sanofi, and Takeda.

PARIS – Using chemotherapy earlier in the treatment of patients with metastatic prostate cancer could maximize its benefits on patients’ overall survival, a leading expert said at an international congress on anticancer treatment.

“Survival benefit is related to the number of life-extending therapies received, and you should not miss the ‘window of opportunity’ to use chemotherapy early,” Dr. Stéphane Oudard of Georges Pompidou Hospital, René Descartes University, Paris, advised attendees during an educational lecture at the  meeting.

© alexdans/Thinkstock

The treatment of advanced prostate cancer usually starts with hormonal or antiandrogen therapies before the disease becomes castrate resistant. Chemotherapy with docetaxel is then a standard first-line choice and cabazitaxel a second-line chemotherapy option when the disease becomes castrate resistant.

The prostate cancer vaccine sipuleucel-T (Provenge) can also be used first-line, with abiraterone (Zytiga), enzalutamide (Xtandi), and radium-223 possible other first- or second-line choices. All of these treatments have different targets and have been shown in phase III clinical trials to increase survival by around 3-5 months more than control treatments have.

Evidence suggests that overall survival may be at its highest, however, when docetaxel is used first before abiraterone, enzalutamide, and cabazitaxel in the metastatic castration-resistant prostate cancer (mCRPC) setting. Furthermore, recent findings of the CHAARTED trial (J. Clin. Oncol. 2014;32-5s: Abstr, LBA2) suggest that combining docetaxel with androgen deprivation therapy (ADT) in castrate-sensitive disease could dramatically up overall survival by around 14 months vs. ADT alone.

Tailoring treatment in mCRPC

During his talk, Dr. Oudard generally discussed how clinicians might interpret available clinical trial data to help them decide which treatment approach to use for individual patients.

First, he looked at post hoc analysis data from the IMPACT study (Urology 2013;81:1297-302) with sipuleucel-T. In this trial, immunotherapy-treated patients had a median overall survival gain of 13 months over controls, when their baseline prostate-specific antigen (PSA) levels were 22.1 mg/mL or lower. As PSA levels increased, however, survival gains were substantially decreased, with a gain of just 2.8 months when PSA was over 134.1 ng/mL.

“So it means if you want to use immunotherapy you perhaps need to use it in asymptomatic patients with a low disease burden,” Dr. Oudard suggested.

Predicting response to treatment

Looking at the use of abiraterone acetate and enzalutamide after docetaxel, he noted that primary resistance to these agents develops in one-third to one-quarter of patients. This usually happens at around the 3-month mark, so it would be advisable to stop using androgen receptor (AR)-targeted agents at this point and find an alternative approach.

Combining AR-targeted agents might seem like a potential option, but data suggest that this approach does not overcome primary resistance, and research has focused on trying to determine which patients will and will not respond to AR-targeted agents.

Results of this research suggest that the duration of response to first-line ADT might be predictive of the risk for primary resistance to AR-targeted agents, with a shorter (12 months) ADT response, but not the duration of hormonal therapy, being associated with a lower response to subsequent ADT.

Another interesting parameter that might help predict response and outcome to treatment is the neutrophil/lymphocyte ratio, with the higher the ratio, the lower the overall survival to abiraterone, docetaxel, and cabazitaxel.

High residual baseline testosterone, below the level of castration, also seems a promising way to predict better response to endocrine therapies, Dr. Oudard observed, but this requires further validation.

And the presence of a genetic anomaly (the AR-V7 splice variant) in circulating tumor cells is “very promising but requires methodology validation” for use as a marker of abiraterone and enzalutamide resistance (N. Engl. J. Med. 2014;371:1028-38).

Treating refractory patients

So what are the options for patients who are refractory to first-line treatments? Data suggest that better overall survival can be achieved if patients who are “truly refractory to docetaxel” are treated with cabazitaxel rather than an AR-targeted agent, Dr. Oudard said.

It also appears that overall survival is better if docetaxel is used before abiraterone than if it is used after, and “interesting” in vitro data show that cabazitaxel seems to have greater antitumor activity than does docetaxel in enzalutamide-resistant xenografts.

Dr. Oudard also presented data showing that the PSA response achieved with cabazitaxel does not appear to be influenced by the prior use of AR-targeted agents.

Higher overall survival can be achieved in the post-docetaxel setting if cabazitaxel is used before abiraterone than if it was used after, he observed, His own data have shown a trend for better survival if the sequence of treatment starts with docetaxel, changes to cabazitaxel, and then goes to abiraterone rather than if patients receive abiraterone before cabazitaxel. The sequence of these three drugs also seems preferable rather than using docetaxel followed by cabazitaxel, he said. Large retrospective or observational studies need to address these points.

“We need to think about the sequence of treatment as early as possible,” Dr. Oudard concluded. Considering the CHAARTED study findings, he added: “We maybe need to propose chemotherapy much earlier” in order to overcome resistance. “The difference in using docetaxel much earlier is huge in terms of overall survival outcome.”

Dr. Oudard has consulting agreements with Bayer, GSK, Janssen, Keocyt, Novartis, Pfizer, Roche, Sanofi, and Takeda.

PARIS – Using chemotherapy earlier in the treatment of patients with metastatic prostate cancer could maximize its benefits on patients’ overall survival, a leading expert said at an international congress on anticancer treatment.

“Survival benefit is related to the number of life-extending therapies received, and you should not miss the ‘window of opportunity’ to use chemotherapy early,” Dr. Stéphane Oudard of Georges Pompidou Hospital, René Descartes University, Paris, advised attendees during an educational lecture at the  meeting.

© alexdans/Thinkstock

The treatment of advanced prostate cancer usually starts with hormonal or antiandrogen therapies before the disease becomes castrate resistant. Chemotherapy with docetaxel is then a standard first-line choice and cabazitaxel a second-line chemotherapy option when the disease becomes castrate resistant.

The prostate cancer vaccine sipuleucel-T (Provenge) can also be used first-line, with abiraterone (Zytiga), enzalutamide (Xtandi), and radium-223 possible other first- or second-line choices. All of these treatments have different targets and have been shown in phase III clinical trials to increase survival by around 3-5 months more than control treatments have.

Evidence suggests that overall survival may be at its highest, however, when docetaxel is used first before abiraterone, enzalutamide, and cabazitaxel in the metastatic castration-resistant prostate cancer (mCRPC) setting. Furthermore, recent findings of the CHAARTED trial (J. Clin. Oncol. 2014;32-5s: Abstr, LBA2) suggest that combining docetaxel with androgen deprivation therapy (ADT) in castrate-sensitive disease could dramatically up overall survival by around 14 months vs. ADT alone.

Tailoring treatment in mCRPC

During his talk, Dr. Oudard generally discussed how clinicians might interpret available clinical trial data to help them decide which treatment approach to use for individual patients.

First, he looked at post hoc analysis data from the IMPACT study (Urology 2013;81:1297-302) with sipuleucel-T. In this trial, immunotherapy-treated patients had a median overall survival gain of 13 months over controls, when their baseline prostate-specific antigen (PSA) levels were 22.1 mg/mL or lower. As PSA levels increased, however, survival gains were substantially decreased, with a gain of just 2.8 months when PSA was over 134.1 ng/mL.

“So it means if you want to use immunotherapy you perhaps need to use it in asymptomatic patients with a low disease burden,” Dr. Oudard suggested.

Predicting response to treatment

Looking at the use of abiraterone acetate and enzalutamide after docetaxel, he noted that primary resistance to these agents develops in one-third to one-quarter of patients. This usually happens at around the 3-month mark, so it would be advisable to stop using androgen receptor (AR)-targeted agents at this point and find an alternative approach.

Combining AR-targeted agents might seem like a potential option, but data suggest that this approach does not overcome primary resistance, and research has focused on trying to determine which patients will and will not respond to AR-targeted agents.

Results of this research suggest that the duration of response to first-line ADT might be predictive of the risk for primary resistance to AR-targeted agents, with a shorter (12 months) ADT response, but not the duration of hormonal therapy, being associated with a lower response to subsequent ADT.

Another interesting parameter that might help predict response and outcome to treatment is the neutrophil/lymphocyte ratio, with the higher the ratio, the lower the overall survival to abiraterone, docetaxel, and cabazitaxel.

High residual baseline testosterone, below the level of castration, also seems a promising way to predict better response to endocrine therapies, Dr. Oudard observed, but this requires further validation.

And the presence of a genetic anomaly (the AR-V7 splice variant) in circulating tumor cells is “very promising but requires methodology validation” for use as a marker of abiraterone and enzalutamide resistance (N. Engl. J. Med. 2014;371:1028-38).

Treating refractory patients

So what are the options for patients who are refractory to first-line treatments? Data suggest that better overall survival can be achieved if patients who are “truly refractory to docetaxel” are treated with cabazitaxel rather than an AR-targeted agent, Dr. Oudard said.

It also appears that overall survival is better if docetaxel is used before abiraterone than if it is used after, and “interesting” in vitro data show that cabazitaxel seems to have greater antitumor activity than does docetaxel in enzalutamide-resistant xenografts.

Dr. Oudard also presented data showing that the PSA response achieved with cabazitaxel does not appear to be influenced by the prior use of AR-targeted agents.

Higher overall survival can be achieved in the post-docetaxel setting if cabazitaxel is used before abiraterone than if it was used after, he observed, His own data have shown a trend for better survival if the sequence of treatment starts with docetaxel, changes to cabazitaxel, and then goes to abiraterone rather than if patients receive abiraterone before cabazitaxel. The sequence of these three drugs also seems preferable rather than using docetaxel followed by cabazitaxel, he said. Large retrospective or observational studies need to address these points.

“We need to think about the sequence of treatment as early as possible,” Dr. Oudard concluded. Considering the CHAARTED study findings, he added: “We maybe need to propose chemotherapy much earlier” in order to overcome resistance. “The difference in using docetaxel much earlier is huge in terms of overall survival outcome.”

Dr. Oudard has consulting agreements with Bayer, GSK, Janssen, Keocyt, Novartis, Pfizer, Roche, Sanofi, and Takeda.

VIENNA – A hemoglobin A_1c of less than 7% was achieved by 78% patients with type 2 diabetes when insulin degludec (IDeg) was added to oral antidiabetic drug therapy in a randomized, double blind, phase III study.

In comparison, 36% of patients treated with the glucagon-like peptide 1 (GLP-1) agonist liraglutide (Victoza, Novo Nordisk) on top of metformin achieved this blood glucose target, with an odds ratio favoring treatment intensification of 7.79.

Furthermore, after about 6 months of treatment, HbA_1c was 0.92% lower in the insulin-added arm than in the control arm, with mean end-of-treatment values of 6.5% versus 7.5% (P < .0001), respectively.

“This treatment approach also resulted in lower fasting plasma glucose [FPG] … and overall low rates of hypoglycemia,” Dr. Vanita Aroda of MedStar Health Research Institute in Hyattsville, Md., said at the annual meeting of the European Association for the Study of Diabetes.

IDeg (Tresiba, Novo Nordisk) is an ultra-long-acting basal insulin analogue currently approved for use in Europe and some other countries around the world. A dual, once-daily, single-injection formulation of IDeg and liraglutide (Xultophy, Novo Nordisk) also is under investigation.

Results from the DUAL (Dual Action of Liraglutide and Insulin Degludec in Type 2 Diabetes) program with the fixed dose combination were reported elsewhere at the EASD annual meeting and recently reported (Lancet Diabetes Endocrinol. 2014 Sept. 2 [doi:10.1016/S2213-8587(14)70174-3]).

In the present study, Dr. Aroda and her associates aimed to confirm the efficacy and safety of IDeg given separately but in combination with liraglutide and metformin versus these oral antidiabetic drugs (OADs) plus an injected insulin placebo.

A total of 1,504 patients with diabetes of at least 6 months’ duration, being treated with metformin or other OADs but not insulin, and in need of treatment intensification were screen for possible inclusion in the trial.

After a 15-week run-in period, during which time the dose of liraglutide was titrated up to 1.5 mg, 346 patients were randomized to receive liraglutide plus metformin and either IDeg or an injectable placebo.

Ninety-two percent of the 174 patients randomized to IDeg plus liraglutide and metformin completed the 26-week trial, as did 76% of the 172 randomized to the placebo arm. Baseline characteristics of the two groups of patients were similar, with a mean age of 57 years, 9 years’ diabetes duration, and a starting HbA_1c of about 7.5%.

FPG values at baseline were 8.7 mmol/L in the intensified arm and 9.1 mmol/L in the placebo arm. These decreased to 8.8 and 6.1 mmol/L, respectively, with an end-of-treatment difference of –2.55 mmol/L favoring the intensified arm, a highly significant difference.

Daily insulin doses at the end of treatment were 51 units in the intensified arm and the equivalent of 105 units in the placebo arm.

Mean body weight was lower in the IDeg-supplemented arm than in the placebo arm at baseline (90.7 kg vs. 94.2 kg), and there was an average weight gain of 2 kg and weight loss of 1.3 kg in each arm, respectively, over the study period, such that the mean body weight at the end of the trial was the same, at 92.7 kg.

No cases of severe hypoglycemia were reported, and there was no significant difference in the number of confirmed nocturnal hypoglycemia cases (four events in three patients with IDeg versus two events in two patients with placebo). The rate of confirmed hypoglycemia was significantly higher in insulin-treated patients (17.3% vs 4.7%); otherwise, both regimens studied were well tolerated.

Dr. Julio Rosenstock of Dallas Diabetes & Endocrine Center, who chaired the session, said that these results were “impressive” and that the study was much better designed than was a similar study with insulin detemir (Levemir, Novo Nordisk) added to liraglutide.

“This is better because you have a control injectable,” he said. “In the previous study with detemir the A_1c came down to 7.1% after 6 months, as reported by DeVries [Diabetes Care 2012;35:1446-54], and to 7.2%, as we reported, after 1 year [J. Diabetes Complications 2013;27:492-500].

“In that previous study the dose of detemir was 39 units, here it was 51 units, so the question is, are the better results because of a higher insulin dose, or because of a difference in the insulin?”

Dr. Rosenstock suggested that a head-to-head trial of insulin detemir and IDeg would be needed to determine the answer. Dr. Aroda agreed.

Dr. Aroda and Dr. Rosenstock disclosed ties with Novo Nordisk, which funded the study, and with other companies that manufacture diabetes medications and devices.

VIENNA – A hemoglobin A_1c of less than 7% was achieved by 78% patients with type 2 diabetes when insulin degludec (IDeg) was added to oral antidiabetic drug therapy in a randomized, double blind, phase III study.

In comparison, 36% of patients treated with the glucagon-like peptide 1 (GLP-1) agonist liraglutide (Victoza, Novo Nordisk) on top of metformin achieved this blood glucose target, with an odds ratio favoring treatment intensification of 7.79.

Furthermore, after about 6 months of treatment, HbA_1c was 0.92% lower in the insulin-added arm than in the control arm, with mean end-of-treatment values of 6.5% versus 7.5% (P < .0001), respectively.

“This treatment approach also resulted in lower fasting plasma glucose [FPG] … and overall low rates of hypoglycemia,” Dr. Vanita Aroda of MedStar Health Research Institute in Hyattsville, Md., said at the annual meeting of the European Association for the Study of Diabetes.

IDeg (Tresiba, Novo Nordisk) is an ultra-long-acting basal insulin analogue currently approved for use in Europe and some other countries around the world. A dual, once-daily, single-injection formulation of IDeg and liraglutide (Xultophy, Novo Nordisk) also is under investigation.

Results from the DUAL (Dual Action of Liraglutide and Insulin Degludec in Type 2 Diabetes) program with the fixed dose combination were reported elsewhere at the EASD annual meeting and recently reported (Lancet Diabetes Endocrinol. 2014 Sept. 2 [doi:10.1016/S2213-8587(14)70174-3]).

In the present study, Dr. Aroda and her associates aimed to confirm the efficacy and safety of IDeg given separately but in combination with liraglutide and metformin versus these oral antidiabetic drugs (OADs) plus an injected insulin placebo.

A total of 1,504 patients with diabetes of at least 6 months’ duration, being treated with metformin or other OADs but not insulin, and in need of treatment intensification were screen for possible inclusion in the trial.

After a 15-week run-in period, during which time the dose of liraglutide was titrated up to 1.5 mg, 346 patients were randomized to receive liraglutide plus metformin and either IDeg or an injectable placebo.

Ninety-two percent of the 174 patients randomized to IDeg plus liraglutide and metformin completed the 26-week trial, as did 76% of the 172 randomized to the placebo arm. Baseline characteristics of the two groups of patients were similar, with a mean age of 57 years, 9 years’ diabetes duration, and a starting HbA_1c of about 7.5%.

FPG values at baseline were 8.7 mmol/L in the intensified arm and 9.1 mmol/L in the placebo arm. These decreased to 8.8 and 6.1 mmol/L, respectively, with an end-of-treatment difference of –2.55 mmol/L favoring the intensified arm, a highly significant difference.

Daily insulin doses at the end of treatment were 51 units in the intensified arm and the equivalent of 105 units in the placebo arm.

Mean body weight was lower in the IDeg-supplemented arm than in the placebo arm at baseline (90.7 kg vs. 94.2 kg), and there was an average weight gain of 2 kg and weight loss of 1.3 kg in each arm, respectively, over the study period, such that the mean body weight at the end of the trial was the same, at 92.7 kg.

No cases of severe hypoglycemia were reported, and there was no significant difference in the number of confirmed nocturnal hypoglycemia cases (four events in three patients with IDeg versus two events in two patients with placebo). The rate of confirmed hypoglycemia was significantly higher in insulin-treated patients (17.3% vs 4.7%); otherwise, both regimens studied were well tolerated.

Dr. Julio Rosenstock of Dallas Diabetes & Endocrine Center, who chaired the session, said that these results were “impressive” and that the study was much better designed than was a similar study with insulin detemir (Levemir, Novo Nordisk) added to liraglutide.

“This is better because you have a control injectable,” he said. “In the previous study with detemir the A_1c came down to 7.1% after 6 months, as reported by DeVries [Diabetes Care 2012;35:1446-54], and to 7.2%, as we reported, after 1 year [J. Diabetes Complications 2013;27:492-500].

“In that previous study the dose of detemir was 39 units, here it was 51 units, so the question is, are the better results because of a higher insulin dose, or because of a difference in the insulin?”

Dr. Rosenstock suggested that a head-to-head trial of insulin detemir and IDeg would be needed to determine the answer. Dr. Aroda agreed.

Dr. Aroda and Dr. Rosenstock disclosed ties with Novo Nordisk, which funded the study, and with other companies that manufacture diabetes medications and devices.

VIENNA – A hemoglobin A_1c of less than 7% was achieved by 78% patients with type 2 diabetes when insulin degludec (IDeg) was added to oral antidiabetic drug therapy in a randomized, double blind, phase III study.

In comparison, 36% of patients treated with the glucagon-like peptide 1 (GLP-1) agonist liraglutide (Victoza, Novo Nordisk) on top of metformin achieved this blood glucose target, with an odds ratio favoring treatment intensification of 7.79.

Furthermore, after about 6 months of treatment, HbA_1c was 0.92% lower in the insulin-added arm than in the control arm, with mean end-of-treatment values of 6.5% versus 7.5% (P < .0001), respectively.

“This treatment approach also resulted in lower fasting plasma glucose [FPG] … and overall low rates of hypoglycemia,” Dr. Vanita Aroda of MedStar Health Research Institute in Hyattsville, Md., said at the annual meeting of the European Association for the Study of Diabetes.

IDeg (Tresiba, Novo Nordisk) is an ultra-long-acting basal insulin analogue currently approved for use in Europe and some other countries around the world. A dual, once-daily, single-injection formulation of IDeg and liraglutide (Xultophy, Novo Nordisk) also is under investigation.

Results from the DUAL (Dual Action of Liraglutide and Insulin Degludec in Type 2 Diabetes) program with the fixed dose combination were reported elsewhere at the EASD annual meeting and recently reported (Lancet Diabetes Endocrinol. 2014 Sept. 2 [doi:10.1016/S2213-8587(14)70174-3]).

In the present study, Dr. Aroda and her associates aimed to confirm the efficacy and safety of IDeg given separately but in combination with liraglutide and metformin versus these oral antidiabetic drugs (OADs) plus an injected insulin placebo.

A total of 1,504 patients with diabetes of at least 6 months’ duration, being treated with metformin or other OADs but not insulin, and in need of treatment intensification were screen for possible inclusion in the trial.

After a 15-week run-in period, during which time the dose of liraglutide was titrated up to 1.5 mg, 346 patients were randomized to receive liraglutide plus metformin and either IDeg or an injectable placebo.

Ninety-two percent of the 174 patients randomized to IDeg plus liraglutide and metformin completed the 26-week trial, as did 76% of the 172 randomized to the placebo arm. Baseline characteristics of the two groups of patients were similar, with a mean age of 57 years, 9 years’ diabetes duration, and a starting HbA_1c of about 7.5%.

FPG values at baseline were 8.7 mmol/L in the intensified arm and 9.1 mmol/L in the placebo arm. These decreased to 8.8 and 6.1 mmol/L, respectively, with an end-of-treatment difference of –2.55 mmol/L favoring the intensified arm, a highly significant difference.

Daily insulin doses at the end of treatment were 51 units in the intensified arm and the equivalent of 105 units in the placebo arm.

Mean body weight was lower in the IDeg-supplemented arm than in the placebo arm at baseline (90.7 kg vs. 94.2 kg), and there was an average weight gain of 2 kg and weight loss of 1.3 kg in each arm, respectively, over the study period, such that the mean body weight at the end of the trial was the same, at 92.7 kg.

No cases of severe hypoglycemia were reported, and there was no significant difference in the number of confirmed nocturnal hypoglycemia cases (four events in three patients with IDeg versus two events in two patients with placebo). The rate of confirmed hypoglycemia was significantly higher in insulin-treated patients (17.3% vs 4.7%); otherwise, both regimens studied were well tolerated.

Dr. Julio Rosenstock of Dallas Diabetes & Endocrine Center, who chaired the session, said that these results were “impressive” and that the study was much better designed than was a similar study with insulin detemir (Levemir, Novo Nordisk) added to liraglutide.

“This is better because you have a control injectable,” he said. “In the previous study with detemir the A_1c came down to 7.1% after 6 months, as reported by DeVries [Diabetes Care 2012;35:1446-54], and to 7.2%, as we reported, after 1 year [J. Diabetes Complications 2013;27:492-500].

“In that previous study the dose of detemir was 39 units, here it was 51 units, so the question is, are the better results because of a higher insulin dose, or because of a difference in the insulin?”

Dr. Rosenstock suggested that a head-to-head trial of insulin detemir and IDeg would be needed to determine the answer. Dr. Aroda agreed.

Dr. Aroda and Dr. Rosenstock disclosed ties with Novo Nordisk, which funded the study, and with other companies that manufacture diabetes medications and devices.

VIENNA – Metformin will be tested for its ability to prevent cardiovascular events in the upcoming Glucose Lowering in Non-diabetic Hyperglycemia Trial (GLINT).

The researchers for the U.K.-based trial plan to recruit 11,834 men and women aged 40 years or older who are at increased risk for type 2 diabetes and have a 20% risk of developing CV disease in the next 10 years.

“Metformin is now the most widely prescribed oral antidiabetic drug in the world,” Dr. Rury Holman, director of the University of Oxford Diabetes Trials Unit (DTU) and one of the driving forces behind the new trial, said during a press briefing held at the annual meeting of the European Association for the Study of Diabetes.

This will be “the first large-scale randomized controlled outcome trial of this drug since the UKPDS [United Kingdom Prospective Diabetes Study], and is looking specifically at cardiovascular disease and cancer,” added Dr. Holman, who also is the chief investigator of the landmark UKPDS trial.

In the original UKPDS trial (Lancet 1998;352:854–65), there were reductions of 39% in heart attacks and 36% in the risk of death in patients treated with metformin versus conventional therapy, Dr. Holman observed. The effect was sustained, albeit slightly reduced, in the 10-year post-trial follow-up (N. Engl. J. Med. 2008;359:1577-89), but only 753 patients were studied in this analysis.

While there have been plenty of observational data to back up the UKPDS findings, no further randomized controlled trials have been conducted, which is why GLINT is now being conducted to resolve the uncertainty. As to why it is has taken so long to do a second study, Dr. Holman observed that metformin is off patent, and raising the funding to perform the much needed trial has taken time.

GLINT will be a pragmatic, primary prevention study conducted in multiple centers in the United Kingdom and jointly coordinated by Dr. Holman at the DTU and Dr. Nicholas Wareham at the University of Cambridge. A feasibility study is underway, recruiting an expected 500 patients. If it is successful, the study population will be expanded to almost 12,000 U.K. individuals, who will be randomly allocated to double-blind treatment with either an extended-release formulation of metformin (Glucophage, Merck Serono) or placebo. Follow-up will continue for 5 and 7 years, with the results likely to be available in 2022.

While the primary purpose is to look at metformin’s effects on cardiovascular outcome reduction versus placebo, the trial will also look at whether the drug can reduce the risk for cancer. Observational data have suggested that metformin may reduce cancer risk (Diabetes Care 2009;32:1620–5), while meta-analyses of randomized controlled trials have suggested that there is no benefit (Diabetologia 2012;55:2593–603).

Metformin has been used to treat type 2 diabetes for more than 50 years, with the first clinical trial published in 1957 leading to its approval for use in England in 1958. However, it took almost another 20 years for the drug to be licensed in Canada in 1972, with the U.S. Food and Drug Administration approving metformin for the treatment of diabetes only in 1994.

“It’s amazing that, more than five decades after it was introduced in the U.K., we remain unclear about the benefits and risks of the most widely used antidiabetic drug,” Dr. Holman said. “Hopefully, GLINT will bring much needed clarity by providing robust evidence for metformin’s effects.”

GLINT is sponsored by the University of Cambridge and funded by the National Institute for Health Research Health Technology Assessment program. Merck Serono is donating the study drug, Glucophage XR. Dr. Holman has received research funding and honoraria from Bayer, BMS, and MSD, and additional honoraria from Amgen, Elcelyx, Janssen, Novartis, and Novo Nordisk.

VIENNA – Metformin will be tested for its ability to prevent cardiovascular events in the upcoming Glucose Lowering in Non-diabetic Hyperglycemia Trial (GLINT).

The researchers for the U.K.-based trial plan to recruit 11,834 men and women aged 40 years or older who are at increased risk for type 2 diabetes and have a 20% risk of developing CV disease in the next 10 years.

“Metformin is now the most widely prescribed oral antidiabetic drug in the world,” Dr. Rury Holman, director of the University of Oxford Diabetes Trials Unit (DTU) and one of the driving forces behind the new trial, said during a press briefing held at the annual meeting of the European Association for the Study of Diabetes.

This will be “the first large-scale randomized controlled outcome trial of this drug since the UKPDS [United Kingdom Prospective Diabetes Study], and is looking specifically at cardiovascular disease and cancer,” added Dr. Holman, who also is the chief investigator of the landmark UKPDS trial.

In the original UKPDS trial (Lancet 1998;352:854–65), there were reductions of 39% in heart attacks and 36% in the risk of death in patients treated with metformin versus conventional therapy, Dr. Holman observed. The effect was sustained, albeit slightly reduced, in the 10-year post-trial follow-up (N. Engl. J. Med. 2008;359:1577-89), but only 753 patients were studied in this analysis.

While there have been plenty of observational data to back up the UKPDS findings, no further randomized controlled trials have been conducted, which is why GLINT is now being conducted to resolve the uncertainty. As to why it is has taken so long to do a second study, Dr. Holman observed that metformin is off patent, and raising the funding to perform the much needed trial has taken time.

GLINT will be a pragmatic, primary prevention study conducted in multiple centers in the United Kingdom and jointly coordinated by Dr. Holman at the DTU and Dr. Nicholas Wareham at the University of Cambridge. A feasibility study is underway, recruiting an expected 500 patients. If it is successful, the study population will be expanded to almost 12,000 U.K. individuals, who will be randomly allocated to double-blind treatment with either an extended-release formulation of metformin (Glucophage, Merck Serono) or placebo. Follow-up will continue for 5 and 7 years, with the results likely to be available in 2022.

While the primary purpose is to look at metformin’s effects on cardiovascular outcome reduction versus placebo, the trial will also look at whether the drug can reduce the risk for cancer. Observational data have suggested that metformin may reduce cancer risk (Diabetes Care 2009;32:1620–5), while meta-analyses of randomized controlled trials have suggested that there is no benefit (Diabetologia 2012;55:2593–603).

Metformin has been used to treat type 2 diabetes for more than 50 years, with the first clinical trial published in 1957 leading to its approval for use in England in 1958. However, it took almost another 20 years for the drug to be licensed in Canada in 1972, with the U.S. Food and Drug Administration approving metformin for the treatment of diabetes only in 1994.

“It’s amazing that, more than five decades after it was introduced in the U.K., we remain unclear about the benefits and risks of the most widely used antidiabetic drug,” Dr. Holman said. “Hopefully, GLINT will bring much needed clarity by providing robust evidence for metformin’s effects.”

GLINT is sponsored by the University of Cambridge and funded by the National Institute for Health Research Health Technology Assessment program. Merck Serono is donating the study drug, Glucophage XR. Dr. Holman has received research funding and honoraria from Bayer, BMS, and MSD, and additional honoraria from Amgen, Elcelyx, Janssen, Novartis, and Novo Nordisk.

VIENNA – Metformin will be tested for its ability to prevent cardiovascular events in the upcoming Glucose Lowering in Non-diabetic Hyperglycemia Trial (GLINT).

The researchers for the U.K.-based trial plan to recruit 11,834 men and women aged 40 years or older who are at increased risk for type 2 diabetes and have a 20% risk of developing CV disease in the next 10 years.

“Metformin is now the most widely prescribed oral antidiabetic drug in the world,” Dr. Rury Holman, director of the University of Oxford Diabetes Trials Unit (DTU) and one of the driving forces behind the new trial, said during a press briefing held at the annual meeting of the European Association for the Study of Diabetes.

This will be “the first large-scale randomized controlled outcome trial of this drug since the UKPDS [United Kingdom Prospective Diabetes Study], and is looking specifically at cardiovascular disease and cancer,” added Dr. Holman, who also is the chief investigator of the landmark UKPDS trial.

In the original UKPDS trial (Lancet 1998;352:854–65), there were reductions of 39% in heart attacks and 36% in the risk of death in patients treated with metformin versus conventional therapy, Dr. Holman observed. The effect was sustained, albeit slightly reduced, in the 10-year post-trial follow-up (N. Engl. J. Med. 2008;359:1577-89), but only 753 patients were studied in this analysis.

While there have been plenty of observational data to back up the UKPDS findings, no further randomized controlled trials have been conducted, which is why GLINT is now being conducted to resolve the uncertainty. As to why it is has taken so long to do a second study, Dr. Holman observed that metformin is off patent, and raising the funding to perform the much needed trial has taken time.

GLINT will be a pragmatic, primary prevention study conducted in multiple centers in the United Kingdom and jointly coordinated by Dr. Holman at the DTU and Dr. Nicholas Wareham at the University of Cambridge. A feasibility study is underway, recruiting an expected 500 patients. If it is successful, the study population will be expanded to almost 12,000 U.K. individuals, who will be randomly allocated to double-blind treatment with either an extended-release formulation of metformin (Glucophage, Merck Serono) or placebo. Follow-up will continue for 5 and 7 years, with the results likely to be available in 2022.

While the primary purpose is to look at metformin’s effects on cardiovascular outcome reduction versus placebo, the trial will also look at whether the drug can reduce the risk for cancer. Observational data have suggested that metformin may reduce cancer risk (Diabetes Care 2009;32:1620–5), while meta-analyses of randomized controlled trials have suggested that there is no benefit (Diabetologia 2012;55:2593–603).

Metformin has been used to treat type 2 diabetes for more than 50 years, with the first clinical trial published in 1957 leading to its approval for use in England in 1958. However, it took almost another 20 years for the drug to be licensed in Canada in 1972, with the U.S. Food and Drug Administration approving metformin for the treatment of diabetes only in 1994.

“It’s amazing that, more than five decades after it was introduced in the U.K., we remain unclear about the benefits and risks of the most widely used antidiabetic drug,” Dr. Holman said. “Hopefully, GLINT will bring much needed clarity by providing robust evidence for metformin’s effects.”

GLINT is sponsored by the University of Cambridge and funded by the National Institute for Health Research Health Technology Assessment program. Merck Serono is donating the study drug, Glucophage XR. Dr. Holman has received research funding and honoraria from Bayer, BMS, and MSD, and additional honoraria from Amgen, Elcelyx, Janssen, Novartis, and Novo Nordisk.

VIENNA – Two separate analyses of data from the Dutch-based, longitudinal Diabetes Care System cohort show that there are four distinct, but not necessarily related, subgroups of patients with type 2 diabetes based on hemoglobin A1C and systolic blood pressure over time.

Both analyses showed that, on the whole, most patients with type 2 diabetes are well controlled, with 83% hitting a European guideline–directed A1C target of 7% or less and 86% achieving adequate (140 mm Hg or lower) systolic blood pressure (SBP) control, both after a mean follow-up of 5.7 years.

However, there were two distinct subgroups of patients in both analyses who did not achieve good A1C or SBP control, with a fourth group showing a delayed response to therapy.

“This is the start of a new analysis,” said Dr. Giel Nijpels of the VU University Medical Center in Amsterdam where the research was coordinated. “We plan to do dynamic prediction models,” he added, with the aim of “more individualized prediction of patient level of risk.”

Patients with type 2 diabetes are at increased risk for both micro- and macrovascular complications, Dr. Nijpels said at the annual meeting of the European Association for the Study of Diabetes. However, “what every doctor knows, especially primary care physicians, is that not every patient with type 2 diabetes has the same risk.”

Guidelines do not take the individual characteristics into account and recommend fixed targets for both glucose and blood pressure control. These targets are based on randomized, controlled trial data, which do not reflect “real world” clinical practice, he observed. Since type 2 diabetes is a heterogeneous disease, and clearly “one size does not fit all,” there was a need to look at the trajectories of both blood glucose and blood pressure control, to see if there are any changes over time that may help to identify patients that may need a little extra help to achieve their personalized targets.

The Diabetes Care System cohort was initiated in 1998 and is a centrally organized diabetes care system. There are currently 9,849 patients with types 2 diabetes registered in the system, who were included anytime from the start of the program until 2012. Patients undergo a physical examination at recruitment and glycemic, blood pressure, and other key parameters are recorded at this baseline. Patients are then checked annually, providing a longitudinal source of real-world data.

For the analysis of blood glucose control, which Dr. Nijpels presented, patients had to have at least two A1C follow-up measurements; 5,423 patients were included. For the analysis of blood pressure control, presented by his college Dr. Iris Walraven, at least two SBP follow-up measurements were needed; 5,711 patients fulfilled this criteria.

The four subgroups of patients based on glycemic control were labeled “good glycemic control,” “fast responders,” “reduced glycemic control,” and “nonresponders.” There were 83.1%, 8.2%, 5.2%, and 3.4% in each group, respectively. The good glycemic control group maintained a target A1C of 7% or lower throughout the follow-up period, which was up to a maximum of 9 years. As the name suggests, the 8.2% of patients in the fast responders group experienced a rapid drop in A1C in the first 2 years of treatment, and then maintained a target A1C for the duration of follow-up. The 5.2% of patients with reduced glycemic control exhibited an initial A1C decrease very close to target, but this subsequently rose further away from the desired target during follow-up, and the 3.4% who were “nonresponders” failed to achieved a target A1C throughout the course of their treatment.

Analysis showed that the fast responders tended to have significantly higher A1C values at baseline, compared with the reduced glycemic control or nonresponsive subgroups, with comparable A1C to those in the “good glycemic control” subgroup. Patients in the reduced control and nonresponder subgroups tended to be younger (under 60 years of age) and have a longer diabetes duration (more than 1 year), with a higher prevalence of microvascular complications than the good or fast control groups, Dr. Nijpels reported.

In terms of treatment, most patients were “doing well” on metformin alone, sulfonylurea monotherapy, or on both of those, with about a quarter of patients using insulin.

Four subgroups of patients with distinct SBP control over time were also identified, although they were not directly linked to the four glycemic control subgroups, said Dr. Walraven in an interview. She noted that while the majority (85.6%) of patients fell into the “adequate SBP control” group, achieving a guideline-recommend systolic blood pressure of 140 mm Hg or lower, 5.6% were “delayed responders,” 3.4% were “insufficient responders,” and 3.4% were “nonresponders.”

When the delayed responders were compared with the adequate responders, they tended to be older (66 vs. 59 years) and have higher body mass indexes (31 kg/m² vs. 29 kg/m²). The insufficient responders were also older and had higher body weight, and were also more likely to be female than male (68% vs. 47%), compared with the adequate responders). Nonresponders were also more likely to be women, of older age, and have a longer diabetes duration (2 vs. 0.9 years).

Dr. Walraven reported that patients with insufficient SBP control had almost a twofold increased risk for cardiovascular disease. “Subgroups with inferior SBP control are important to target in order to eventually improve BP management,” she observed.

Patients’ adherence to medication was questioned in the discussions following both presentations. Although this was not directly measured, Dr. Nijpels responded that, certainly with regard to glucose-lowering agents, that he was “convinced that everyone in this cohort took their medication.”

Dr. Nijpels and Dr. Walraven had no conflicts of interest.

VIENNA – Two separate analyses of data from the Dutch-based, longitudinal Diabetes Care System cohort show that there are four distinct, but not necessarily related, subgroups of patients with type 2 diabetes based on hemoglobin A1C and systolic blood pressure over time.

Both analyses showed that, on the whole, most patients with type 2 diabetes are well controlled, with 83% hitting a European guideline–directed A1C target of 7% or less and 86% achieving adequate (140 mm Hg or lower) systolic blood pressure (SBP) control, both after a mean follow-up of 5.7 years.

However, there were two distinct subgroups of patients in both analyses who did not achieve good A1C or SBP control, with a fourth group showing a delayed response to therapy.

“This is the start of a new analysis,” said Dr. Giel Nijpels of the VU University Medical Center in Amsterdam where the research was coordinated. “We plan to do dynamic prediction models,” he added, with the aim of “more individualized prediction of patient level of risk.”

Patients with type 2 diabetes are at increased risk for both micro- and macrovascular complications, Dr. Nijpels said at the annual meeting of the European Association for the Study of Diabetes. However, “what every doctor knows, especially primary care physicians, is that not every patient with type 2 diabetes has the same risk.”

Guidelines do not take the individual characteristics into account and recommend fixed targets for both glucose and blood pressure control. These targets are based on randomized, controlled trial data, which do not reflect “real world” clinical practice, he observed. Since type 2 diabetes is a heterogeneous disease, and clearly “one size does not fit all,” there was a need to look at the trajectories of both blood glucose and blood pressure control, to see if there are any changes over time that may help to identify patients that may need a little extra help to achieve their personalized targets.

The Diabetes Care System cohort was initiated in 1998 and is a centrally organized diabetes care system. There are currently 9,849 patients with types 2 diabetes registered in the system, who were included anytime from the start of the program until 2012. Patients undergo a physical examination at recruitment and glycemic, blood pressure, and other key parameters are recorded at this baseline. Patients are then checked annually, providing a longitudinal source of real-world data.

For the analysis of blood glucose control, which Dr. Nijpels presented, patients had to have at least two A1C follow-up measurements; 5,423 patients were included. For the analysis of blood pressure control, presented by his college Dr. Iris Walraven, at least two SBP follow-up measurements were needed; 5,711 patients fulfilled this criteria.

The four subgroups of patients based on glycemic control were labeled “good glycemic control,” “fast responders,” “reduced glycemic control,” and “nonresponders.” There were 83.1%, 8.2%, 5.2%, and 3.4% in each group, respectively. The good glycemic control group maintained a target A1C of 7% or lower throughout the follow-up period, which was up to a maximum of 9 years. As the name suggests, the 8.2% of patients in the fast responders group experienced a rapid drop in A1C in the first 2 years of treatment, and then maintained a target A1C for the duration of follow-up. The 5.2% of patients with reduced glycemic control exhibited an initial A1C decrease very close to target, but this subsequently rose further away from the desired target during follow-up, and the 3.4% who were “nonresponders” failed to achieved a target A1C throughout the course of their treatment.

Analysis showed that the fast responders tended to have significantly higher A1C values at baseline, compared with the reduced glycemic control or nonresponsive subgroups, with comparable A1C to those in the “good glycemic control” subgroup. Patients in the reduced control and nonresponder subgroups tended to be younger (under 60 years of age) and have a longer diabetes duration (more than 1 year), with a higher prevalence of microvascular complications than the good or fast control groups, Dr. Nijpels reported.

In terms of treatment, most patients were “doing well” on metformin alone, sulfonylurea monotherapy, or on both of those, with about a quarter of patients using insulin.

Four subgroups of patients with distinct SBP control over time were also identified, although they were not directly linked to the four glycemic control subgroups, said Dr. Walraven in an interview. She noted that while the majority (85.6%) of patients fell into the “adequate SBP control” group, achieving a guideline-recommend systolic blood pressure of 140 mm Hg or lower, 5.6% were “delayed responders,” 3.4% were “insufficient responders,” and 3.4% were “nonresponders.”

When the delayed responders were compared with the adequate responders, they tended to be older (66 vs. 59 years) and have higher body mass indexes (31 kg/m² vs. 29 kg/m²). The insufficient responders were also older and had higher body weight, and were also more likely to be female than male (68% vs. 47%), compared with the adequate responders). Nonresponders were also more likely to be women, of older age, and have a longer diabetes duration (2 vs. 0.9 years).

Dr. Walraven reported that patients with insufficient SBP control had almost a twofold increased risk for cardiovascular disease. “Subgroups with inferior SBP control are important to target in order to eventually improve BP management,” she observed.

Patients’ adherence to medication was questioned in the discussions following both presentations. Although this was not directly measured, Dr. Nijpels responded that, certainly with regard to glucose-lowering agents, that he was “convinced that everyone in this cohort took their medication.”

Dr. Nijpels and Dr. Walraven had no conflicts of interest.

VIENNA – Two separate analyses of data from the Dutch-based, longitudinal Diabetes Care System cohort show that there are four distinct, but not necessarily related, subgroups of patients with type 2 diabetes based on hemoglobin A1C and systolic blood pressure over time.

Both analyses showed that, on the whole, most patients with type 2 diabetes are well controlled, with 83% hitting a European guideline–directed A1C target of 7% or less and 86% achieving adequate (140 mm Hg or lower) systolic blood pressure (SBP) control, both after a mean follow-up of 5.7 years.

However, there were two distinct subgroups of patients in both analyses who did not achieve good A1C or SBP control, with a fourth group showing a delayed response to therapy.

“This is the start of a new analysis,” said Dr. Giel Nijpels of the VU University Medical Center in Amsterdam where the research was coordinated. “We plan to do dynamic prediction models,” he added, with the aim of “more individualized prediction of patient level of risk.”

Patients with type 2 diabetes are at increased risk for both micro- and macrovascular complications, Dr. Nijpels said at the annual meeting of the European Association for the Study of Diabetes. However, “what every doctor knows, especially primary care physicians, is that not every patient with type 2 diabetes has the same risk.”

Guidelines do not take the individual characteristics into account and recommend fixed targets for both glucose and blood pressure control. These targets are based on randomized, controlled trial data, which do not reflect “real world” clinical practice, he observed. Since type 2 diabetes is a heterogeneous disease, and clearly “one size does not fit all,” there was a need to look at the trajectories of both blood glucose and blood pressure control, to see if there are any changes over time that may help to identify patients that may need a little extra help to achieve their personalized targets.

The Diabetes Care System cohort was initiated in 1998 and is a centrally organized diabetes care system. There are currently 9,849 patients with types 2 diabetes registered in the system, who were included anytime from the start of the program until 2012. Patients undergo a physical examination at recruitment and glycemic, blood pressure, and other key parameters are recorded at this baseline. Patients are then checked annually, providing a longitudinal source of real-world data.

For the analysis of blood glucose control, which Dr. Nijpels presented, patients had to have at least two A1C follow-up measurements; 5,423 patients were included. For the analysis of blood pressure control, presented by his college Dr. Iris Walraven, at least two SBP follow-up measurements were needed; 5,711 patients fulfilled this criteria.

The four subgroups of patients based on glycemic control were labeled “good glycemic control,” “fast responders,” “reduced glycemic control,” and “nonresponders.” There were 83.1%, 8.2%, 5.2%, and 3.4% in each group, respectively. The good glycemic control group maintained a target A1C of 7% or lower throughout the follow-up period, which was up to a maximum of 9 years. As the name suggests, the 8.2% of patients in the fast responders group experienced a rapid drop in A1C in the first 2 years of treatment, and then maintained a target A1C for the duration of follow-up. The 5.2% of patients with reduced glycemic control exhibited an initial A1C decrease very close to target, but this subsequently rose further away from the desired target during follow-up, and the 3.4% who were “nonresponders” failed to achieved a target A1C throughout the course of their treatment.

Analysis showed that the fast responders tended to have significantly higher A1C values at baseline, compared with the reduced glycemic control or nonresponsive subgroups, with comparable A1C to those in the “good glycemic control” subgroup. Patients in the reduced control and nonresponder subgroups tended to be younger (under 60 years of age) and have a longer diabetes duration (more than 1 year), with a higher prevalence of microvascular complications than the good or fast control groups, Dr. Nijpels reported.

In terms of treatment, most patients were “doing well” on metformin alone, sulfonylurea monotherapy, or on both of those, with about a quarter of patients using insulin.

Four subgroups of patients with distinct SBP control over time were also identified, although they were not directly linked to the four glycemic control subgroups, said Dr. Walraven in an interview. She noted that while the majority (85.6%) of patients fell into the “adequate SBP control” group, achieving a guideline-recommend systolic blood pressure of 140 mm Hg or lower, 5.6% were “delayed responders,” 3.4% were “insufficient responders,” and 3.4% were “nonresponders.”

When the delayed responders were compared with the adequate responders, they tended to be older (66 vs. 59 years) and have higher body mass indexes (31 kg/m² vs. 29 kg/m²). The insufficient responders were also older and had higher body weight, and were also more likely to be female than male (68% vs. 47%), compared with the adequate responders). Nonresponders were also more likely to be women, of older age, and have a longer diabetes duration (2 vs. 0.9 years).

Dr. Walraven reported that patients with insufficient SBP control had almost a twofold increased risk for cardiovascular disease. “Subgroups with inferior SBP control are important to target in order to eventually improve BP management,” she observed.

Patients’ adherence to medication was questioned in the discussions following both presentations. Although this was not directly measured, Dr. Nijpels responded that, certainly with regard to glucose-lowering agents, that he was “convinced that everyone in this cohort took their medication.”

Dr. Nijpels and Dr. Walraven had no conflicts of interest.

VIENNA – Two separate analyses of data from the Dutch-based, longitudinal Diabetes Care System cohort show that there are four distinct, but not necessarily related, subgroups of patients with type 2 diabetes based on hemoglobin A1c and systolic blood pressure over time.

Both analyses showed that, on the whole, most patients with type 2 diabetes are well controlled, with 83% hitting a European guideline–directed HbA1c target of 7% or less and 86% achieving adequate (140 mm Hg or lower) systolic blood pressure (SBP) control, both after a mean follow-up of 5.7 years.

However, there were two distinct subgroups of patients in both analyses who did not achieve good HbA1c or SBP control, with a fourth group showing a delayed response to therapy.

“This is the start of a new analysis,” said Dr. Giel Nijpels of the VU University Medical Center in Amsterdam where the research was coordinated. “We plan to do dynamic prediction models,” he added, with the aim of “more individualized prediction of patient level of risk.”

Patients with type 2 diabetes are at increased risk for both micro- and macrovascular complications, Dr. Nijpels said at the annual meeting of the European Association for the Study of Diabetes. However, “what every doctor knows, especially primary care physicians, is that not every patient with type 2 diabetes has the same risk.”

Guidelines do not take the individual characteristics into account and recommend fixed targets for both glucose and blood pressure control. These targets are based on randomized, controlled trial data, which do not reflect “real world” clinical practice, he observed. Since type 2 diabetes is a heterogeneous disease, and clearly “one size does not fit all,” there was a need to look at the trajectories of both blood glucose and blood pressure control, to see if there are any changes over time that may help to identify patients that may need a little extra help to achieve their personalized targets.

The Diabetes Care System cohort was initiated in 1998 and is a centrally organized diabetes care system. There are currently 9,849 patients with types 2 diabetes registered in the system, who were included anytime from the start of the program until 2012. Patients undergo a physical examination at recruitment and glycemic, blood pressure, and other key parameters are recorded at this baseline. Patients are then checked annually, providing a longitudinal source of real-world data.

For the analysis of blood glucose control, which Dr. Nijpels presented, patients had to have at least two HbA1c follow-up measurements; 5,423 patients were included. For the analysis of blood pressure control, presented by his college Dr. Iris Walraven, at least two SBP follow-up measurements were needed; 5,711 patients fulfilled this criteria.

The four subgroups of patients based on glycemic control were labeled “good glycemic control,” “fast responders,” “reduced glycemic control,” and “nonresponders.” There were 83.1%, 8.2%, 5.2%, and 3.4% in each group, respectively. The good glycemic control group maintained a target HbA1c of 7% or lower throughout the follow-up period, which was up to a maximum of 9 years. As the name suggests, the 8.2% of patients in the fast responders group experienced a rapid drop in HbA1c in the first 2 years of treatment, and then maintained a target HbA_1c for the duration of follow-up. The 5.2% of patients with reduced glycemic control exhibited an initial HbA_1c decrease very close to target, but this subsequently rose further away from the desired target during follow-up, and the 3.4% who were “nonresponders” failed to achieved a target HbA_1c throughout the course of their treatment.

Analysis showed that the fast responders tended to have significantly higher HbA_1c values at baseline, compared with the reduced glycemic control or nonresponsive subgroups, with comparable HbA_1c to those in the “good glycemic control” subgroup. Patients in the reduced control and nonresponder subgroups tended to be younger (under 60 years of age) and have a longer diabetes duration (more than 1 year), with a higher prevalence of microvascular complications than the good or fast control groups, Dr. Nijpels reported.

In terms of treatment, most patients were “doing well” on metformin alone, sulfonylurea monotherapy, or on both of those, with about a quarter of patients using insulin.

Four subgroups of patients with distinct SBP control over time were also identified, although they were not directly linked to the four glycemic control subgroups, said Dr. Walraven in an interview. She noted that while the majority (85.6%) of patients fell into the “adequate SBP control” group, achieving a guideline-recommend systolic blood pressure of 140 mm Hg or lower, 5.6% were “delayed responders,” 3.4% were “insufficient responders,” and 3.4% were “nonresponders.”

When the delayed responders were compared with the adequate responders, they tended to be older (66 vs. 59 years) and have higher body mass indexes (31 kg/m² vs. 29 kg/m²). The insufficient responders were also older and had higher body weight, and were also more likely to be female than male (68% vs. 47%), compared with the adequate responders). Nonresponders were also more likely to be women, of older age, and have a longer diabetes duration (2 vs. 0.9 years).

Dr. Walraven reported that patients with insufficient SBP control had almost a twofold increased risk for cardiovascular disease. “Subgroups with inferior SBP control are important to target in order to eventually improve BP management,” she observed.

Patients’ adherence to medication was questioned in the discussions following both presentations. Although this was not directly measured, Dr. Nijpels responded that, certainly with regard to glucose-lowering agents, that he was “convinced that everyone in this cohort took their medication.”

Dr. Nijpels and Dr. Walraven had no conflicts of interest.

VIENNA – Two separate analyses of data from the Dutch-based, longitudinal Diabetes Care System cohort show that there are four distinct, but not necessarily related, subgroups of patients with type 2 diabetes based on hemoglobin A1c and systolic blood pressure over time.

Both analyses showed that, on the whole, most patients with type 2 diabetes are well controlled, with 83% hitting a European guideline–directed HbA1c target of 7% or less and 86% achieving adequate (140 mm Hg or lower) systolic blood pressure (SBP) control, both after a mean follow-up of 5.7 years.

However, there were two distinct subgroups of patients in both analyses who did not achieve good HbA1c or SBP control, with a fourth group showing a delayed response to therapy.

“This is the start of a new analysis,” said Dr. Giel Nijpels of the VU University Medical Center in Amsterdam where the research was coordinated. “We plan to do dynamic prediction models,” he added, with the aim of “more individualized prediction of patient level of risk.”

Patients with type 2 diabetes are at increased risk for both micro- and macrovascular complications, Dr. Nijpels said at the annual meeting of the European Association for the Study of Diabetes. However, “what every doctor knows, especially primary care physicians, is that not every patient with type 2 diabetes has the same risk.”

Guidelines do not take the individual characteristics into account and recommend fixed targets for both glucose and blood pressure control. These targets are based on randomized, controlled trial data, which do not reflect “real world” clinical practice, he observed. Since type 2 diabetes is a heterogeneous disease, and clearly “one size does not fit all,” there was a need to look at the trajectories of both blood glucose and blood pressure control, to see if there are any changes over time that may help to identify patients that may need a little extra help to achieve their personalized targets.

The Diabetes Care System cohort was initiated in 1998 and is a centrally organized diabetes care system. There are currently 9,849 patients with types 2 diabetes registered in the system, who were included anytime from the start of the program until 2012. Patients undergo a physical examination at recruitment and glycemic, blood pressure, and other key parameters are recorded at this baseline. Patients are then checked annually, providing a longitudinal source of real-world data.

For the analysis of blood glucose control, which Dr. Nijpels presented, patients had to have at least two HbA1c follow-up measurements; 5,423 patients were included. For the analysis of blood pressure control, presented by his college Dr. Iris Walraven, at least two SBP follow-up measurements were needed; 5,711 patients fulfilled this criteria.

The four subgroups of patients based on glycemic control were labeled “good glycemic control,” “fast responders,” “reduced glycemic control,” and “nonresponders.” There were 83.1%, 8.2%, 5.2%, and 3.4% in each group, respectively. The good glycemic control group maintained a target HbA1c of 7% or lower throughout the follow-up period, which was up to a maximum of 9 years. As the name suggests, the 8.2% of patients in the fast responders group experienced a rapid drop in HbA1c in the first 2 years of treatment, and then maintained a target HbA_1c for the duration of follow-up. The 5.2% of patients with reduced glycemic control exhibited an initial HbA_1c decrease very close to target, but this subsequently rose further away from the desired target during follow-up, and the 3.4% who were “nonresponders” failed to achieved a target HbA_1c throughout the course of their treatment.

Analysis showed that the fast responders tended to have significantly higher HbA_1c values at baseline, compared with the reduced glycemic control or nonresponsive subgroups, with comparable HbA_1c to those in the “good glycemic control” subgroup. Patients in the reduced control and nonresponder subgroups tended to be younger (under 60 years of age) and have a longer diabetes duration (more than 1 year), with a higher prevalence of microvascular complications than the good or fast control groups, Dr. Nijpels reported.

In terms of treatment, most patients were “doing well” on metformin alone, sulfonylurea monotherapy, or on both of those, with about a quarter of patients using insulin.

Four subgroups of patients with distinct SBP control over time were also identified, although they were not directly linked to the four glycemic control subgroups, said Dr. Walraven in an interview. She noted that while the majority (85.6%) of patients fell into the “adequate SBP control” group, achieving a guideline-recommend systolic blood pressure of 140 mm Hg or lower, 5.6% were “delayed responders,” 3.4% were “insufficient responders,” and 3.4% were “nonresponders.”

When the delayed responders were compared with the adequate responders, they tended to be older (66 vs. 59 years) and have higher body mass indexes (31 kg/m² vs. 29 kg/m²). The insufficient responders were also older and had higher body weight, and were also more likely to be female than male (68% vs. 47%), compared with the adequate responders). Nonresponders were also more likely to be women, of older age, and have a longer diabetes duration (2 vs. 0.9 years).

Dr. Walraven reported that patients with insufficient SBP control had almost a twofold increased risk for cardiovascular disease. “Subgroups with inferior SBP control are important to target in order to eventually improve BP management,” she observed.

Patients’ adherence to medication was questioned in the discussions following both presentations. Although this was not directly measured, Dr. Nijpels responded that, certainly with regard to glucose-lowering agents, that he was “convinced that everyone in this cohort took their medication.”

Dr. Nijpels and Dr. Walraven had no conflicts of interest.

VIENNA – Two separate analyses of data from the Dutch-based, longitudinal Diabetes Care System cohort show that there are four distinct, but not necessarily related, subgroups of patients with type 2 diabetes based on hemoglobin A1c and systolic blood pressure over time.

Both analyses showed that, on the whole, most patients with type 2 diabetes are well controlled, with 83% hitting a European guideline–directed HbA1c target of 7% or less and 86% achieving adequate (140 mm Hg or lower) systolic blood pressure (SBP) control, both after a mean follow-up of 5.7 years.

However, there were two distinct subgroups of patients in both analyses who did not achieve good HbA1c or SBP control, with a fourth group showing a delayed response to therapy.

“This is the start of a new analysis,” said Dr. Giel Nijpels of the VU University Medical Center in Amsterdam where the research was coordinated. “We plan to do dynamic prediction models,” he added, with the aim of “more individualized prediction of patient level of risk.”

Patients with type 2 diabetes are at increased risk for both micro- and macrovascular complications, Dr. Nijpels said at the annual meeting of the European Association for the Study of Diabetes. However, “what every doctor knows, especially primary care physicians, is that not every patient with type 2 diabetes has the same risk.”

Guidelines do not take the individual characteristics into account and recommend fixed targets for both glucose and blood pressure control. These targets are based on randomized, controlled trial data, which do not reflect “real world” clinical practice, he observed. Since type 2 diabetes is a heterogeneous disease, and clearly “one size does not fit all,” there was a need to look at the trajectories of both blood glucose and blood pressure control, to see if there are any changes over time that may help to identify patients that may need a little extra help to achieve their personalized targets.

The Diabetes Care System cohort was initiated in 1998 and is a centrally organized diabetes care system. There are currently 9,849 patients with types 2 diabetes registered in the system, who were included anytime from the start of the program until 2012. Patients undergo a physical examination at recruitment and glycemic, blood pressure, and other key parameters are recorded at this baseline. Patients are then checked annually, providing a longitudinal source of real-world data.

For the analysis of blood glucose control, which Dr. Nijpels presented, patients had to have at least two HbA1c follow-up measurements; 5,423 patients were included. For the analysis of blood pressure control, presented by his college Dr. Iris Walraven, at least two SBP follow-up measurements were needed; 5,711 patients fulfilled this criteria.

The four subgroups of patients based on glycemic control were labeled “good glycemic control,” “fast responders,” “reduced glycemic control,” and “nonresponders.” There were 83.1%, 8.2%, 5.2%, and 3.4% in each group, respectively. The good glycemic control group maintained a target HbA1c of 7% or lower throughout the follow-up period, which was up to a maximum of 9 years. As the name suggests, the 8.2% of patients in the fast responders group experienced a rapid drop in HbA1c in the first 2 years of treatment, and then maintained a target HbA_1c for the duration of follow-up. The 5.2% of patients with reduced glycemic control exhibited an initial HbA_1c decrease very close to target, but this subsequently rose further away from the desired target during follow-up, and the 3.4% who were “nonresponders” failed to achieved a target HbA_1c throughout the course of their treatment.

Analysis showed that the fast responders tended to have significantly higher HbA_1c values at baseline, compared with the reduced glycemic control or nonresponsive subgroups, with comparable HbA_1c to those in the “good glycemic control” subgroup. Patients in the reduced control and nonresponder subgroups tended to be younger (under 60 years of age) and have a longer diabetes duration (more than 1 year), with a higher prevalence of microvascular complications than the good or fast control groups, Dr. Nijpels reported.

In terms of treatment, most patients were “doing well” on metformin alone, sulfonylurea monotherapy, or on both of those, with about a quarter of patients using insulin.

Four subgroups of patients with distinct SBP control over time were also identified, although they were not directly linked to the four glycemic control subgroups, said Dr. Walraven in an interview. She noted that while the majority (85.6%) of patients fell into the “adequate SBP control” group, achieving a guideline-recommend systolic blood pressure of 140 mm Hg or lower, 5.6% were “delayed responders,” 3.4% were “insufficient responders,” and 3.4% were “nonresponders.”

When the delayed responders were compared with the adequate responders, they tended to be older (66 vs. 59 years) and have higher body mass indexes (31 kg/m² vs. 29 kg/m²). The insufficient responders were also older and had higher body weight, and were also more likely to be female than male (68% vs. 47%), compared with the adequate responders). Nonresponders were also more likely to be women, of older age, and have a longer diabetes duration (2 vs. 0.9 years).

Dr. Walraven reported that patients with insufficient SBP control had almost a twofold increased risk for cardiovascular disease. “Subgroups with inferior SBP control are important to target in order to eventually improve BP management,” she observed.

Patients’ adherence to medication was questioned in the discussions following both presentations. Although this was not directly measured, Dr. Nijpels responded that, certainly with regard to glucose-lowering agents, that he was “convinced that everyone in this cohort took their medication.”

Dr. Nijpels and Dr. Walraven had no conflicts of interest.

VIENNA – A risk model based on a single assessment of hemoglobin A_1c and other parameters was able to differentiate well between patients who had a low and high risk for progression of sight-threatening diabetic retinopathy, researchers reported at the annual meeting of the European Association for the Study of Diabetes.

Although further validation is needed, the risk model “would be suitable for personalized screening intervals,” said presenting author Dr. Irene Stratton of the Gloucestershire (England) Hospitals NHS Foundation Trust. In England, the current recommendation is to screen everyone with diabetes annually using digital retinal photography.

Because of the increasing numbers of patients that require annual screening, health budgets for diabetic eye screening are being stretched and alternatives are desirable. In England, such screening considers both retinopathy and macropathology, Dr. Stratton said.

The risk model was derived and tested based on data from 14,000 patients with no or mild nonproliferative retinopathy treated in the Gloucestershire area. The investigators looked at HbA_1c levels in the 12 months prior to diabetic eye screening to determine if they could predict which patients did and did not develop sight-threatening retinopathy. The risk model also considered the baseline retinopathy status in both eyes of patients; systolic and diastolic blood pressure; measures of kidney function and lipids; the time to develop retinopathy from diagnosis; and the type of diabetes.

“We found that the most important piece of information that went into the model was the grading at the baseline screening episode,” Dr. Stratton said. “So patients who had no retinopathy in either eye were at lowest risk, patients with background retinopathy in one eye had about a doubling of risk, and patients with background retinopathy in both eyes were at a much higher level of risk.”

The next most important parameters were the time since the first mention of a diagnosis of diabetes and HbA_1c in the year prior to screening. Total cholesterol in the year prior to screening also was a factor for consideration.

Hazard ratios for the development of diabetic retinopathy were 7.13 for patients with mild retinopathy in both eyes at baseline and 2.56 for those with mild retinopathy in one eye. The hazard ratios increased by 1.28 for every 10-mmol/mol increase in HbA_1c in the past 12 months, by 1.20 for every 5-year increase in the duration of diabetes, and by 1.12 for every 1-mmol/L increase in total serum cholesterol.

Three study populations, which altogether comprised almost 20,000 patients with diabetes, were used to validate the model; the largest population included more than 17,000 individuals. The main difference between the screening programs was the ethnic mix, Dr. Stratton highlighted. White patients dominated in the largest screening cohort, at 98%, but to a lesser extent in the other cohorts, at 47% (of 1,223 patients) and 81% (of 1,083). About half the patients in the cohorts were women, and the duration of diabetes ranged from 2.9 to 4.5 years. The majority (95%) of patients screened had type 1 diabetes. HbA_1c ranged from 6.3% to 8.2% overall.

The investigators stratified patients according to quintiles of risk using the model, and found that the quintiles correlated very well with the chances of patients developing sight-threatening eye disease in each of the three validation cohorts. Comparing the lowest- with the highest-risk quintiles, the rate of progression to sight-threatening retinopathy was 1-3 and 55-79 per 1,000 per patient-years, respectively. The overall event rate was around 20 per 1,000 patient years.

“Further validation in other screening programs and ethnic groups is required,” Dr. Stratton concluded.

The study was funded by a grant from the U.K. National Institute for Health Research, Health Technology Assessment Programme; and the Gloucestershire Hospitals National Health Service Foundation Trust. Dr. Stratton had no conflicts of interest.

VIENNA – A risk model based on a single assessment of hemoglobin A_1c and other parameters was able to differentiate well between patients who had a low and high risk for progression of sight-threatening diabetic retinopathy, researchers reported at the annual meeting of the European Association for the Study of Diabetes.

Although further validation is needed, the risk model “would be suitable for personalized screening intervals,” said presenting author Dr. Irene Stratton of the Gloucestershire (England) Hospitals NHS Foundation Trust. In England, the current recommendation is to screen everyone with diabetes annually using digital retinal photography.

Because of the increasing numbers of patients that require annual screening, health budgets for diabetic eye screening are being stretched and alternatives are desirable. In England, such screening considers both retinopathy and macropathology, Dr. Stratton said.

The risk model was derived and tested based on data from 14,000 patients with no or mild nonproliferative retinopathy treated in the Gloucestershire area. The investigators looked at HbA_1c levels in the 12 months prior to diabetic eye screening to determine if they could predict which patients did and did not develop sight-threatening retinopathy. The risk model also considered the baseline retinopathy status in both eyes of patients; systolic and diastolic blood pressure; measures of kidney function and lipids; the time to develop retinopathy from diagnosis; and the type of diabetes.

“We found that the most important piece of information that went into the model was the grading at the baseline screening episode,” Dr. Stratton said. “So patients who had no retinopathy in either eye were at lowest risk, patients with background retinopathy in one eye had about a doubling of risk, and patients with background retinopathy in both eyes were at a much higher level of risk.”

The next most important parameters were the time since the first mention of a diagnosis of diabetes and HbA_1c in the year prior to screening. Total cholesterol in the year prior to screening also was a factor for consideration.

Hazard ratios for the development of diabetic retinopathy were 7.13 for patients with mild retinopathy in both eyes at baseline and 2.56 for those with mild retinopathy in one eye. The hazard ratios increased by 1.28 for every 10-mmol/mol increase in HbA_1c in the past 12 months, by 1.20 for every 5-year increase in the duration of diabetes, and by 1.12 for every 1-mmol/L increase in total serum cholesterol.

Three study populations, which altogether comprised almost 20,000 patients with diabetes, were used to validate the model; the largest population included more than 17,000 individuals. The main difference between the screening programs was the ethnic mix, Dr. Stratton highlighted. White patients dominated in the largest screening cohort, at 98%, but to a lesser extent in the other cohorts, at 47% (of 1,223 patients) and 81% (of 1,083). About half the patients in the cohorts were women, and the duration of diabetes ranged from 2.9 to 4.5 years. The majority (95%) of patients screened had type 1 diabetes. HbA_1c ranged from 6.3% to 8.2% overall.

The investigators stratified patients according to quintiles of risk using the model, and found that the quintiles correlated very well with the chances of patients developing sight-threatening eye disease in each of the three validation cohorts. Comparing the lowest- with the highest-risk quintiles, the rate of progression to sight-threatening retinopathy was 1-3 and 55-79 per 1,000 per patient-years, respectively. The overall event rate was around 20 per 1,000 patient years.

“Further validation in other screening programs and ethnic groups is required,” Dr. Stratton concluded.

The study was funded by a grant from the U.K. National Institute for Health Research, Health Technology Assessment Programme; and the Gloucestershire Hospitals National Health Service Foundation Trust. Dr. Stratton had no conflicts of interest.

VIENNA – A risk model based on a single assessment of hemoglobin A_1c and other parameters was able to differentiate well between patients who had a low and high risk for progression of sight-threatening diabetic retinopathy, researchers reported at the annual meeting of the European Association for the Study of Diabetes.

Although further validation is needed, the risk model “would be suitable for personalized screening intervals,” said presenting author Dr. Irene Stratton of the Gloucestershire (England) Hospitals NHS Foundation Trust. In England, the current recommendation is to screen everyone with diabetes annually using digital retinal photography.

Because of the increasing numbers of patients that require annual screening, health budgets for diabetic eye screening are being stretched and alternatives are desirable. In England, such screening considers both retinopathy and macropathology, Dr. Stratton said.

The risk model was derived and tested based on data from 14,000 patients with no or mild nonproliferative retinopathy treated in the Gloucestershire area. The investigators looked at HbA_1c levels in the 12 months prior to diabetic eye screening to determine if they could predict which patients did and did not develop sight-threatening retinopathy. The risk model also considered the baseline retinopathy status in both eyes of patients; systolic and diastolic blood pressure; measures of kidney function and lipids; the time to develop retinopathy from diagnosis; and the type of diabetes.

“We found that the most important piece of information that went into the model was the grading at the baseline screening episode,” Dr. Stratton said. “So patients who had no retinopathy in either eye were at lowest risk, patients with background retinopathy in one eye had about a doubling of risk, and patients with background retinopathy in both eyes were at a much higher level of risk.”

The next most important parameters were the time since the first mention of a diagnosis of diabetes and HbA_1c in the year prior to screening. Total cholesterol in the year prior to screening also was a factor for consideration.

Hazard ratios for the development of diabetic retinopathy were 7.13 for patients with mild retinopathy in both eyes at baseline and 2.56 for those with mild retinopathy in one eye. The hazard ratios increased by 1.28 for every 10-mmol/mol increase in HbA_1c in the past 12 months, by 1.20 for every 5-year increase in the duration of diabetes, and by 1.12 for every 1-mmol/L increase in total serum cholesterol.

Three study populations, which altogether comprised almost 20,000 patients with diabetes, were used to validate the model; the largest population included more than 17,000 individuals. The main difference between the screening programs was the ethnic mix, Dr. Stratton highlighted. White patients dominated in the largest screening cohort, at 98%, but to a lesser extent in the other cohorts, at 47% (of 1,223 patients) and 81% (of 1,083). About half the patients in the cohorts were women, and the duration of diabetes ranged from 2.9 to 4.5 years. The majority (95%) of patients screened had type 1 diabetes. HbA_1c ranged from 6.3% to 8.2% overall.

The investigators stratified patients according to quintiles of risk using the model, and found that the quintiles correlated very well with the chances of patients developing sight-threatening eye disease in each of the three validation cohorts. Comparing the lowest- with the highest-risk quintiles, the rate of progression to sight-threatening retinopathy was 1-3 and 55-79 per 1,000 per patient-years, respectively. The overall event rate was around 20 per 1,000 patient years.

“Further validation in other screening programs and ethnic groups is required,” Dr. Stratton concluded.

The study was funded by a grant from the U.K. National Institute for Health Research, Health Technology Assessment Programme; and the Gloucestershire Hospitals National Health Service Foundation Trust. Dr. Stratton had no conflicts of interest.

VIENNA – Pretreating cannulas with a recombinant human hyaluronidase reduces the risk of hypoglycemia in patients with type 1 diabetes using insulin pumps, according to the results of a phase IV study.

In CONSISTENT-1 (Continuous Subcutaneous Insulin Infusion Study Enrolling Type 1), there were 23% fewer hypoglycemic events, defined as a blood glucose level below 56 mg/dL, and 21% fewer nocturnal hypoglycemic events in patients who received the infusion site pretreatment, compared with those who did not.

Importantly, the primary endpoint of noninferiority for glycemic control after 6 months was achieved, with comparable final mean and mean change from baseline hemoglobin A_1c results.

“Current rapid-acting analogue insulin preparations are too slow to mimic the physiologic insulin meal response,” Dr. Jay Skyler, a study investigator with the University of Miami, explained at the annual meeting of the European Association for the Study of Diabetes.

He noted that hyaluronidase has been used for more than 60 years and recombinant human hyaluronidase (rHuPH20) is approved by the Food and Drug Administration as a means of improving the dispersion and absorption of injected or infused drugs. “Previously, we have demonstrated that adding recombinant human hyaluronidase [Halozyme Therapeutics’ Hylex] to rapid-acting insulin preparations accelerates the absorption and action of insulin,” Dr. Skyler said.

In this study, rHuPH20 was given in a single injection into the cannula prior to the placement of a pump for continuous subcutaneous insulin infusion (CSII), but Dr. Skyler observed that it could also be coformulated with insulin for use in pens or vials.

The aim of CONSISTENT-1 was to assess the metabolic outcomes and safety of rHuPH20 after 6 months. The trial was open label, and 456 patients with type 1 diabetes were randomized, in a 3 to 1 ratio, to pretreatment with rHuPH20 or to standard CSII without rHuPH20.

The mean age of participants was 47 years in the rHuPH20 arm and 50 years in the CSII-alone arm. Around a quarter of patients in each group used continuous glucose monitors (CGMs), and 77% had used an insulin pump for more than 5 years. Patients had been using insulin pumps for a mean of about 10 years in both groups.

The number of hypoglycemic events per month was 13.8 in the rHuPH20-pretreated group and 12.1 in the CSII-only group when a blood glucose cutoff of 70 mg/dL or lower was used, representing a nonsignificant 12% reduction. However, when the lower threshold of 56 mg/dL or lower was used, there were fewer hypoglycemia events per month (4.0 vs. 3.1; P = .02).

While the difference in the number of nocturnal hypoglycemic events per month between the rHuPH20 and CSII-only groups was also significant (2.1 vs. 1.7; P = .02), the rate of severe hypoglycemic events per 100 subject-years was only numerically lower (19 vs. 7; P = .08) in the rHuPH20 group.

Subgroup analysis showed that the timing of bolus dosing was important, with fewer blood glucose excursions and hypoglycemic events if insulin was dosed within 15 minutes before a meal than if it was dosed within 15 minutes after a meal.

Looking at CGM profiles for breakfast, lunch, and dinner, there were fewer glucose excursions in the patients who had received rHuPH20, and, stating that it was the reason for performing the study, Dr. Skyler said there were fewer excursions on subsequent days.

In terms of safety, he noted that there was an increase in injection-site reactions in the rHuPH20-pretreated group, with pain, discomfort, or paresthesia in 15.5%, compared with 6.2% in the CSII-only patients. In addition, hematoma, bruising, or hemorrhage occurred in 3.8% of the rHuPH20 group vs. 0.0% of the standard CSII group. There was no “meaningful immunogenicity,” and adverse events were otherwise well balanced between the groups.

Dr. Skyler said that a 1.5-year extension study is in progress and that the current findings “demonstrate that rHuPH20 pretreatment eliminates the systemic variability in glucose control that naturally occurs as infusion sites age.

“This should allow for improved diabetes control since insulin responses will occur more predictably.”

Halozyme supported the study. Dr. Skyler has been an adviser for Halozyme and has consulted for other companies with an interest in insulin pump therapy.

VIENNA – Pretreating cannulas with a recombinant human hyaluronidase reduces the risk of hypoglycemia in patients with type 1 diabetes using insulin pumps, according to the results of a phase IV study.

In CONSISTENT-1 (Continuous Subcutaneous Insulin Infusion Study Enrolling Type 1), there were 23% fewer hypoglycemic events, defined as a blood glucose level below 56 mg/dL, and 21% fewer nocturnal hypoglycemic events in patients who received the infusion site pretreatment, compared with those who did not.

Importantly, the primary endpoint of noninferiority for glycemic control after 6 months was achieved, with comparable final mean and mean change from baseline hemoglobin A_1c results.

“Current rapid-acting analogue insulin preparations are too slow to mimic the physiologic insulin meal response,” Dr. Jay Skyler, a study investigator with the University of Miami, explained at the annual meeting of the European Association for the Study of Diabetes.

He noted that hyaluronidase has been used for more than 60 years and recombinant human hyaluronidase (rHuPH20) is approved by the Food and Drug Administration as a means of improving the dispersion and absorption of injected or infused drugs. “Previously, we have demonstrated that adding recombinant human hyaluronidase [Halozyme Therapeutics’ Hylex] to rapid-acting insulin preparations accelerates the absorption and action of insulin,” Dr. Skyler said.

In this study, rHuPH20 was given in a single injection into the cannula prior to the placement of a pump for continuous subcutaneous insulin infusion (CSII), but Dr. Skyler observed that it could also be coformulated with insulin for use in pens or vials.

The aim of CONSISTENT-1 was to assess the metabolic outcomes and safety of rHuPH20 after 6 months. The trial was open label, and 456 patients with type 1 diabetes were randomized, in a 3 to 1 ratio, to pretreatment with rHuPH20 or to standard CSII without rHuPH20.

The mean age of participants was 47 years in the rHuPH20 arm and 50 years in the CSII-alone arm. Around a quarter of patients in each group used continuous glucose monitors (CGMs), and 77% had used an insulin pump for more than 5 years. Patients had been using insulin pumps for a mean of about 10 years in both groups.

The number of hypoglycemic events per month was 13.8 in the rHuPH20-pretreated group and 12.1 in the CSII-only group when a blood glucose cutoff of 70 mg/dL or lower was used, representing a nonsignificant 12% reduction. However, when the lower threshold of 56 mg/dL or lower was used, there were fewer hypoglycemia events per month (4.0 vs. 3.1; P = .02).

While the difference in the number of nocturnal hypoglycemic events per month between the rHuPH20 and CSII-only groups was also significant (2.1 vs. 1.7; P = .02), the rate of severe hypoglycemic events per 100 subject-years was only numerically lower (19 vs. 7; P = .08) in the rHuPH20 group.

Subgroup analysis showed that the timing of bolus dosing was important, with fewer blood glucose excursions and hypoglycemic events if insulin was dosed within 15 minutes before a meal than if it was dosed within 15 minutes after a meal.

Looking at CGM profiles for breakfast, lunch, and dinner, there were fewer glucose excursions in the patients who had received rHuPH20, and, stating that it was the reason for performing the study, Dr. Skyler said there were fewer excursions on subsequent days.

In terms of safety, he noted that there was an increase in injection-site reactions in the rHuPH20-pretreated group, with pain, discomfort, or paresthesia in 15.5%, compared with 6.2% in the CSII-only patients. In addition, hematoma, bruising, or hemorrhage occurred in 3.8% of the rHuPH20 group vs. 0.0% of the standard CSII group. There was no “meaningful immunogenicity,” and adverse events were otherwise well balanced between the groups.

Dr. Skyler said that a 1.5-year extension study is in progress and that the current findings “demonstrate that rHuPH20 pretreatment eliminates the systemic variability in glucose control that naturally occurs as infusion sites age.

“This should allow for improved diabetes control since insulin responses will occur more predictably.”

Halozyme supported the study. Dr. Skyler has been an adviser for Halozyme and has consulted for other companies with an interest in insulin pump therapy.

VIENNA – Pretreating cannulas with a recombinant human hyaluronidase reduces the risk of hypoglycemia in patients with type 1 diabetes using insulin pumps, according to the results of a phase IV study.

In CONSISTENT-1 (Continuous Subcutaneous Insulin Infusion Study Enrolling Type 1), there were 23% fewer hypoglycemic events, defined as a blood glucose level below 56 mg/dL, and 21% fewer nocturnal hypoglycemic events in patients who received the infusion site pretreatment, compared with those who did not.

Importantly, the primary endpoint of noninferiority for glycemic control after 6 months was achieved, with comparable final mean and mean change from baseline hemoglobin A_1c results.

“Current rapid-acting analogue insulin preparations are too slow to mimic the physiologic insulin meal response,” Dr. Jay Skyler, a study investigator with the University of Miami, explained at the annual meeting of the European Association for the Study of Diabetes.

He noted that hyaluronidase has been used for more than 60 years and recombinant human hyaluronidase (rHuPH20) is approved by the Food and Drug Administration as a means of improving the dispersion and absorption of injected or infused drugs. “Previously, we have demonstrated that adding recombinant human hyaluronidase [Halozyme Therapeutics’ Hylex] to rapid-acting insulin preparations accelerates the absorption and action of insulin,” Dr. Skyler said.

In this study, rHuPH20 was given in a single injection into the cannula prior to the placement of a pump for continuous subcutaneous insulin infusion (CSII), but Dr. Skyler observed that it could also be coformulated with insulin for use in pens or vials.

The aim of CONSISTENT-1 was to assess the metabolic outcomes and safety of rHuPH20 after 6 months. The trial was open label, and 456 patients with type 1 diabetes were randomized, in a 3 to 1 ratio, to pretreatment with rHuPH20 or to standard CSII without rHuPH20.

The mean age of participants was 47 years in the rHuPH20 arm and 50 years in the CSII-alone arm. Around a quarter of patients in each group used continuous glucose monitors (CGMs), and 77% had used an insulin pump for more than 5 years. Patients had been using insulin pumps for a mean of about 10 years in both groups.

The number of hypoglycemic events per month was 13.8 in the rHuPH20-pretreated group and 12.1 in the CSII-only group when a blood glucose cutoff of 70 mg/dL or lower was used, representing a nonsignificant 12% reduction. However, when the lower threshold of 56 mg/dL or lower was used, there were fewer hypoglycemia events per month (4.0 vs. 3.1; P = .02).

While the difference in the number of nocturnal hypoglycemic events per month between the rHuPH20 and CSII-only groups was also significant (2.1 vs. 1.7; P = .02), the rate of severe hypoglycemic events per 100 subject-years was only numerically lower (19 vs. 7; P = .08) in the rHuPH20 group.

Subgroup analysis showed that the timing of bolus dosing was important, with fewer blood glucose excursions and hypoglycemic events if insulin was dosed within 15 minutes before a meal than if it was dosed within 15 minutes after a meal.

Looking at CGM profiles for breakfast, lunch, and dinner, there were fewer glucose excursions in the patients who had received rHuPH20, and, stating that it was the reason for performing the study, Dr. Skyler said there were fewer excursions on subsequent days.

In terms of safety, he noted that there was an increase in injection-site reactions in the rHuPH20-pretreated group, with pain, discomfort, or paresthesia in 15.5%, compared with 6.2% in the CSII-only patients. In addition, hematoma, bruising, or hemorrhage occurred in 3.8% of the rHuPH20 group vs. 0.0% of the standard CSII group. There was no “meaningful immunogenicity,” and adverse events were otherwise well balanced between the groups.

Dr. Skyler said that a 1.5-year extension study is in progress and that the current findings “demonstrate that rHuPH20 pretreatment eliminates the systemic variability in glucose control that naturally occurs as infusion sites age.

“This should allow for improved diabetes control since insulin responses will occur more predictably.”

Halozyme supported the study. Dr. Skyler has been an adviser for Halozyme and has consulted for other companies with an interest in insulin pump therapy.

VIENNA – Long-term use of antidepressant medication does not appear to cause diabetes, according to findings from a longitudinal study.

The team, from the Institut National de la Santé et de la Recherche Médicale (INSERM) in Villejuif, France, found no association between fasting plasma glucose (FPG) or hemoglobin A1c levels measured over a 9-year study period and the use of antidepressants.

“Several studies have shown an association between antidepressant use and the risk of type 2 diabetes,” reported Marine Azevedo Da Silva at the annual meeting of the European Association for the Study of Diabetes.

The reason for this remains unclear, so the hypothesis for the study was that “if antidepressant use is causally associated with type 2 diabetes, then it should also be associated with glucose dysregulation,” said Ms. Azevedo Da Silva, a doctoral student at the Versailles (France) Saint-Quentin-en-Yvelines University.

While other research teams have examined this hypothesis, the results have been inconsistent, Ms. Azevedo Da Silva added. To solve some of the methodological issues of the prior studies, she and her colleagues used data from an epidemiological study on the insulin resistance syndrome (DESIR). This is a longitudinal cohort of 5,212 men and women without diabetes who were aged 30-60 years at recruitment.

Health assessments, including antidepressant use, FPG, and hemoglobin A1c, were performed at four time points: at recruitment in 1994 to 1996, and then at 3-year intervals between 1997-1999, 2000-2002, and 2003-2005. Data on 4,869 participants who did not have diabetes at baseline were available for analysis. Diabetes was defined as an FPG of less than 7 mmol/L (126 mg/dL) and no use of glucose-lowering medication. The majority (96%) of participants were not using antidepressants at baseline.

Baseline mean FPG and hemoglobin A1c levels were similar among antidepressant and non–antidepressant users, at 5.22 mmol/L (96 mg/dL) and 5.22%, versus 5.32 mmol/L (96 mg/dL) and 5.35%, respectively. Among the 4% of subjects who used antidepressants, there was no difference in these blood glucose measures according to the type of antidepressant used.

There were similar increases in both FPG and hemoglobin A1c in the two groups over time, at 0.02 mmol/L (0.36 mg/dL) per year for FPG in both antidepressant users and nonusers, and 0.01% per year for hemoglobin A1c.

Results had been adjusted for multiple confounding factors, including gender, age, marital status, education, and employment status; and several other health factors, such as alcohol use, smoking, body mass index, family diabetes history, hypertension, and other medication use.

Antidepressant use was self-reported, noted Ms. Azevedo Da Silva, which was one of the main limitations of the study. There was also a lack of information on the actual antidepressants used and the doses taken. In addition, there is the possibility of “confounding depression,” she acknowledged.

Nevertheless, this is a large observational, longitudinal cohort with an extended period of follow-up. FPG and hemoglobin A1c were robust clinical measures, and the team was able to study a large number of participants.

“Our results suggest that the association highlighted in recent studies between antidepressant use and type 2 diabetes may not be causal,” Ms. Azevedo Da Silva concluded.

This study is the fourth to find no association between antidepressant use and glucose dysregulation (Biol. Psych. 2011;70:978-84; Ann. Med. 2012;44:279-88; Psychopharmacology 2013;227:467-77), with only two other studies suggesting that there might be a link (Int. J. Clin. Pharm. 2011;33:484-92; PloS One 2011;6:e21551).

There is now a need to look at other reasons that might be responsible for the purported association, such as insulin resistance, she said.

The Ministry of French Research supported the study. Ms. Azevedo Da Silva had no conflicts of interest.

VIENNA – Long-term use of antidepressant medication does not appear to cause diabetes, according to findings from a longitudinal study.

The team, from the Institut National de la Santé et de la Recherche Médicale (INSERM) in Villejuif, France, found no association between fasting plasma glucose (FPG) or hemoglobin A1c levels measured over a 9-year study period and the use of antidepressants.

“Several studies have shown an association between antidepressant use and the risk of type 2 diabetes,” reported Marine Azevedo Da Silva at the annual meeting of the European Association for the Study of Diabetes.

The reason for this remains unclear, so the hypothesis for the study was that “if antidepressant use is causally associated with type 2 diabetes, then it should also be associated with glucose dysregulation,” said Ms. Azevedo Da Silva, a doctoral student at the Versailles (France) Saint-Quentin-en-Yvelines University.

While other research teams have examined this hypothesis, the results have been inconsistent, Ms. Azevedo Da Silva added. To solve some of the methodological issues of the prior studies, she and her colleagues used data from an epidemiological study on the insulin resistance syndrome (DESIR). This is a longitudinal cohort of 5,212 men and women without diabetes who were aged 30-60 years at recruitment.

Health assessments, including antidepressant use, FPG, and hemoglobin A1c, were performed at four time points: at recruitment in 1994 to 1996, and then at 3-year intervals between 1997-1999, 2000-2002, and 2003-2005. Data on 4,869 participants who did not have diabetes at baseline were available for analysis. Diabetes was defined as an FPG of less than 7 mmol/L (126 mg/dL) and no use of glucose-lowering medication. The majority (96%) of participants were not using antidepressants at baseline.

Baseline mean FPG and hemoglobin A1c levels were similar among antidepressant and non–antidepressant users, at 5.22 mmol/L (96 mg/dL) and 5.22%, versus 5.32 mmol/L (96 mg/dL) and 5.35%, respectively. Among the 4% of subjects who used antidepressants, there was no difference in these blood glucose measures according to the type of antidepressant used.

There were similar increases in both FPG and hemoglobin A1c in the two groups over time, at 0.02 mmol/L (0.36 mg/dL) per year for FPG in both antidepressant users and nonusers, and 0.01% per year for hemoglobin A1c.

Results had been adjusted for multiple confounding factors, including gender, age, marital status, education, and employment status; and several other health factors, such as alcohol use, smoking, body mass index, family diabetes history, hypertension, and other medication use.

Antidepressant use was self-reported, noted Ms. Azevedo Da Silva, which was one of the main limitations of the study. There was also a lack of information on the actual antidepressants used and the doses taken. In addition, there is the possibility of “confounding depression,” she acknowledged.

Nevertheless, this is a large observational, longitudinal cohort with an extended period of follow-up. FPG and hemoglobin A1c were robust clinical measures, and the team was able to study a large number of participants.

“Our results suggest that the association highlighted in recent studies between antidepressant use and type 2 diabetes may not be causal,” Ms. Azevedo Da Silva concluded.

This study is the fourth to find no association between antidepressant use and glucose dysregulation (Biol. Psych. 2011;70:978-84; Ann. Med. 2012;44:279-88; Psychopharmacology 2013;227:467-77), with only two other studies suggesting that there might be a link (Int. J. Clin. Pharm. 2011;33:484-92; PloS One 2011;6:e21551).

There is now a need to look at other reasons that might be responsible for the purported association, such as insulin resistance, she said.

The Ministry of French Research supported the study. Ms. Azevedo Da Silva had no conflicts of interest.

VIENNA – Long-term use of antidepressant medication does not appear to cause diabetes, according to findings from a longitudinal study.

The team, from the Institut National de la Santé et de la Recherche Médicale (INSERM) in Villejuif, France, found no association between fasting plasma glucose (FPG) or hemoglobin A1c levels measured over a 9-year study period and the use of antidepressants.

“Several studies have shown an association between antidepressant use and the risk of type 2 diabetes,” reported Marine Azevedo Da Silva at the annual meeting of the European Association for the Study of Diabetes.

The reason for this remains unclear, so the hypothesis for the study was that “if antidepressant use is causally associated with type 2 diabetes, then it should also be associated with glucose dysregulation,” said Ms. Azevedo Da Silva, a doctoral student at the Versailles (France) Saint-Quentin-en-Yvelines University.

While other research teams have examined this hypothesis, the results have been inconsistent, Ms. Azevedo Da Silva added. To solve some of the methodological issues of the prior studies, she and her colleagues used data from an epidemiological study on the insulin resistance syndrome (DESIR). This is a longitudinal cohort of 5,212 men and women without diabetes who were aged 30-60 years at recruitment.

Health assessments, including antidepressant use, FPG, and hemoglobin A1c, were performed at four time points: at recruitment in 1994 to 1996, and then at 3-year intervals between 1997-1999, 2000-2002, and 2003-2005. Data on 4,869 participants who did not have diabetes at baseline were available for analysis. Diabetes was defined as an FPG of less than 7 mmol/L (126 mg/dL) and no use of glucose-lowering medication. The majority (96%) of participants were not using antidepressants at baseline.

Baseline mean FPG and hemoglobin A1c levels were similar among antidepressant and non–antidepressant users, at 5.22 mmol/L (96 mg/dL) and 5.22%, versus 5.32 mmol/L (96 mg/dL) and 5.35%, respectively. Among the 4% of subjects who used antidepressants, there was no difference in these blood glucose measures according to the type of antidepressant used.

There were similar increases in both FPG and hemoglobin A1c in the two groups over time, at 0.02 mmol/L (0.36 mg/dL) per year for FPG in both antidepressant users and nonusers, and 0.01% per year for hemoglobin A1c.

Results had been adjusted for multiple confounding factors, including gender, age, marital status, education, and employment status; and several other health factors, such as alcohol use, smoking, body mass index, family diabetes history, hypertension, and other medication use.

Antidepressant use was self-reported, noted Ms. Azevedo Da Silva, which was one of the main limitations of the study. There was also a lack of information on the actual antidepressants used and the doses taken. In addition, there is the possibility of “confounding depression,” she acknowledged.

Nevertheless, this is a large observational, longitudinal cohort with an extended period of follow-up. FPG and hemoglobin A1c were robust clinical measures, and the team was able to study a large number of participants.

“Our results suggest that the association highlighted in recent studies between antidepressant use and type 2 diabetes may not be causal,” Ms. Azevedo Da Silva concluded.

This study is the fourth to find no association between antidepressant use and glucose dysregulation (Biol. Psych. 2011;70:978-84; Ann. Med. 2012;44:279-88; Psychopharmacology 2013;227:467-77), with only two other studies suggesting that there might be a link (Int. J. Clin. Pharm. 2011;33:484-92; PloS One 2011;6:e21551).

There is now a need to look at other reasons that might be responsible for the purported association, such as insulin resistance, she said.

The Ministry of French Research supported the study. Ms. Azevedo Da Silva had no conflicts of interest.

VIENNA – Long-term use of antidepressant medication does not appear to cause diabetes, according to findings from a longitudinal study.

The team, from the Institut National de la Santé et de la Recherche Médicale (INSERM) in Villejuif, France, found no association between fasting plasma glucose (FPG) or hemoglobin A1c levels measured over a 9-year study period and the use of antidepressants.

“Several studies have shown an association between antidepressant use and the risk of type 2 diabetes,” reported Marine Azevedo Da Silva at the annual meeting of the European Association for the Study of Diabetes.

The reason for this remains unclear, so the hypothesis for the study was that “if antidepressant use is causally associated with type 2 diabetes, then it should also be associated with glucose dysregulation,” said Ms. Azevedo Da Silva, a doctoral student at the Versailles (France) Saint-Quentin-en-Yvelines University.

While other research teams have examined this hypothesis, the results have been inconsistent, Ms. Azevedo Da Silva added. To solve some of the methodological issues of the prior studies, she and her colleagues used data from an epidemiological study on the insulin resistance syndrome (DESIR). This is a longitudinal cohort of 5,212 men and women without diabetes who were aged 30-60 years at recruitment.

Health assessments, including antidepressant use, FPG, and hemoglobin A1c, were performed at four time points: at recruitment in 1994 to 1996, and then at 3-year intervals between 1997-1999, 2000-2002, and 2003-2005. Data on 4,869 participants who did not have diabetes at baseline were available for analysis. Diabetes was defined as an FPG of less than 7 mmol/L (126 mg/dL) and no use of glucose-lowering medication. The majority (96%) of participants were not using antidepressants at baseline.

Baseline mean FPG and hemoglobin A1c levels were similar among antidepressant and non–antidepressant users, at 5.22 mmol/L (96 mg/dL) and 5.22%, versus 5.32 mmol/L (96 mg/dL) and 5.35%, respectively. Among the 4% of subjects who used antidepressants, there was no difference in these blood glucose measures according to the type of antidepressant used.

There were similar increases in both FPG and hemoglobin A1c in the two groups over time, at 0.02 mmol/L (0.36 mg/dL) per year for FPG in both antidepressant users and nonusers, and 0.01% per year for hemoglobin A1c.

Results had been adjusted for multiple confounding factors, including gender, age, marital status, education, and employment status; and several other health factors, such as alcohol use, smoking, body mass index, family diabetes history, hypertension, and other medication use.

Antidepressant use was self-reported, noted Ms. Azevedo Da Silva, which was one of the main limitations of the study. There was also a lack of information on the actual antidepressants used and the doses taken. In addition, there is the possibility of “confounding depression,” she acknowledged.

Nevertheless, this is a large observational, longitudinal cohort with an extended period of follow-up. FPG and hemoglobin A1c were robust clinical measures, and the team was able to study a large number of participants.

“Our results suggest that the association highlighted in recent studies between antidepressant use and type 2 diabetes may not be causal,” Ms. Azevedo Da Silva concluded.

This study is the fourth to find no association between antidepressant use and glucose dysregulation (Biol. Psych. 2011;70:978-84; Ann. Med. 2012;44:279-88; Psychopharmacology 2013;227:467-77), with only two other studies suggesting that there might be a link (Int. J. Clin. Pharm. 2011;33:484-92; PloS One 2011;6:e21551).

There is now a need to look at other reasons that might be responsible for the purported association, such as insulin resistance, she said.

The Ministry of French Research supported the study. Ms. Azevedo Da Silva had no conflicts of interest.

VIENNA – Long-term use of antidepressant medication does not appear to cause diabetes, according to findings from a longitudinal study.

The team, from the Institut National de la Santé et de la Recherche Médicale (INSERM) in Villejuif, France, found no association between fasting plasma glucose (FPG) or hemoglobin A1c levels measured over a 9-year study period and the use of antidepressants.

“Several studies have shown an association between antidepressant use and the risk of type 2 diabetes,” reported Marine Azevedo Da Silva at the annual meeting of the European Association for the Study of Diabetes.

The reason for this remains unclear, so the hypothesis for the study was that “if antidepressant use is causally associated with type 2 diabetes, then it should also be associated with glucose dysregulation,” said Ms. Azevedo Da Silva, a doctoral student at the Versailles (France) Saint-Quentin-en-Yvelines University.

While other research teams have examined this hypothesis, the results have been inconsistent, Ms. Azevedo Da Silva added. To solve some of the methodological issues of the prior studies, she and her colleagues used data from an epidemiological study on the insulin resistance syndrome (DESIR). This is a longitudinal cohort of 5,212 men and women without diabetes who were aged 30-60 years at recruitment.

Health assessments, including antidepressant use, FPG, and hemoglobin A1c, were performed at four time points: at recruitment in 1994 to 1996, and then at 3-year intervals between 1997-1999, 2000-2002, and 2003-2005. Data on 4,869 participants who did not have diabetes at baseline were available for analysis. Diabetes was defined as an FPG of less than 7 mmol/L (126 mg/dL) and no use of glucose-lowering medication. The majority (96%) of participants were not using antidepressants at baseline.

Baseline mean FPG and hemoglobin A1c levels were similar among antidepressant and non–antidepressant users, at 5.22 mmol/L (96 mg/dL) and 5.22%, versus 5.32 mmol/L (96 mg/dL) and 5.35%, respectively. Among the 4% of subjects who used antidepressants, there was no difference in these blood glucose measures according to the type of antidepressant used.

There were similar increases in both FPG and hemoglobin A1c in the two groups over time, at 0.02 mmol/L (0.36 mg/dL) per year for FPG in both antidepressant users and nonusers, and 0.01% per year for hemoglobin A1c.

Results had been adjusted for multiple confounding factors, including gender, age, marital status, education, and employment status; and several other health factors, such as alcohol use, smoking, body mass index, family diabetes history, hypertension, and other medication use.

Antidepressant use was self-reported, noted Ms. Azevedo Da Silva, which was one of the main limitations of the study. There was also a lack of information on the actual antidepressants used and the doses taken. In addition, there is the possibility of “confounding depression,” she acknowledged.

Nevertheless, this is a large observational, longitudinal cohort with an extended period of follow-up. FPG and hemoglobin A1c were robust clinical measures, and the team was able to study a large number of participants.

“Our results suggest that the association highlighted in recent studies between antidepressant use and type 2 diabetes may not be causal,” Ms. Azevedo Da Silva concluded.

This study is the fourth to find no association between antidepressant use and glucose dysregulation (Biol. Psych. 2011;70:978-84; Ann. Med. 2012;44:279-88; Psychopharmacology 2013;227:467-77), with only two other studies suggesting that there might be a link (Int. J. Clin. Pharm. 2011;33:484-92; PloS One 2011;6:e21551).

There is now a need to look at other reasons that might be responsible for the purported association, such as insulin resistance, she said.

The Ministry of French Research supported the study. Ms. Azevedo Da Silva had no conflicts of interest.

VIENNA – Long-term use of antidepressant medication does not appear to cause diabetes, according to findings from a longitudinal study.

The team, from the Institut National de la Santé et de la Recherche Médicale (INSERM) in Villejuif, France, found no association between fasting plasma glucose (FPG) or hemoglobin A1c levels measured over a 9-year study period and the use of antidepressants.

“Several studies have shown an association between antidepressant use and the risk of type 2 diabetes,” reported Marine Azevedo Da Silva at the annual meeting of the European Association for the Study of Diabetes.

The reason for this remains unclear, so the hypothesis for the study was that “if antidepressant use is causally associated with type 2 diabetes, then it should also be associated with glucose dysregulation,” said Ms. Azevedo Da Silva, a doctoral student at the Versailles (France) Saint-Quentin-en-Yvelines University.

While other research teams have examined this hypothesis, the results have been inconsistent, Ms. Azevedo Da Silva added. To solve some of the methodological issues of the prior studies, she and her colleagues used data from an epidemiological study on the insulin resistance syndrome (DESIR). This is a longitudinal cohort of 5,212 men and women without diabetes who were aged 30-60 years at recruitment.

Health assessments, including antidepressant use, FPG, and hemoglobin A1c, were performed at four time points: at recruitment in 1994 to 1996, and then at 3-year intervals between 1997-1999, 2000-2002, and 2003-2005. Data on 4,869 participants who did not have diabetes at baseline were available for analysis. Diabetes was defined as an FPG of less than 7 mmol/L (126 mg/dL) and no use of glucose-lowering medication. The majority (96%) of participants were not using antidepressants at baseline.

Baseline mean FPG and hemoglobin A1c levels were similar among antidepressant and non–antidepressant users, at 5.22 mmol/L (96 mg/dL) and 5.22%, versus 5.32 mmol/L (96 mg/dL) and 5.35%, respectively. Among the 4% of subjects who used antidepressants, there was no difference in these blood glucose measures according to the type of antidepressant used.

There were similar increases in both FPG and hemoglobin A1c in the two groups over time, at 0.02 mmol/L (0.36 mg/dL) per year for FPG in both antidepressant users and nonusers, and 0.01% per year for hemoglobin A1c.

Results had been adjusted for multiple confounding factors, including gender, age, marital status, education, and employment status; and several other health factors, such as alcohol use, smoking, body mass index, family diabetes history, hypertension, and other medication use.

Antidepressant use was self-reported, noted Ms. Azevedo Da Silva, which was one of the main limitations of the study. There was also a lack of information on the actual antidepressants used and the doses taken. In addition, there is the possibility of “confounding depression,” she acknowledged.

Nevertheless, this is a large observational, longitudinal cohort with an extended period of follow-up. FPG and hemoglobin A1c were robust clinical measures, and the team was able to study a large number of participants.

“Our results suggest that the association highlighted in recent studies between antidepressant use and type 2 diabetes may not be causal,” Ms. Azevedo Da Silva concluded.

This study is the fourth to find no association between antidepressant use and glucose dysregulation (Biol. Psych. 2011;70:978-84; Ann. Med. 2012;44:279-88; Psychopharmacology 2013;227:467-77), with only two other studies suggesting that there might be a link (Int. J. Clin. Pharm. 2011;33:484-92; PloS One 2011;6:e21551).

There is now a need to look at other reasons that might be responsible for the purported association, such as insulin resistance, she said.

The Ministry of French Research supported the study. Ms. Azevedo Da Silva had no conflicts of interest.