Sara Freeman

AMSTERDAM – The multiple sclerosis drug laquinimod did not reduce the risk of relapse in the BRAVO phase III trial, yet the investigational agent delayed the progression of disability to a greater extent than did placebo.

The BRAVO trial also included an open comparator arm against interferon beta-1a (IFNB-1a, Avonex), which proved to reduce brain lesions on MRI to a significantly greater extent relative to placebo than did laquinimod. But even though laquinimod’s effect against active brain inflammation did not appear to be as strong as that of IFNB-1a, it appeared to be potentially neuroprotective because it significantly halted loss of brain volume relative to placebo, whereas IFNB-1a did not.

The 1,331-patient BRAVO (Benefit-Risk Assessment of Avonex and Laquinimod) study is the second of two global phase III trials with laquinimod in patients with relapsing-remitting multiple sclerosis. The first was the 1,106-patient ALLEGRO study, completed earlier this year, in which laquinimod significantly reduced the annualized relapse rate (ARR), the risk of disability progression, and the percentage of total brain volume lost compared with placebo.

Patients in BRAVO had a mean age of about 37 years and were randomized to oral laquinimod 0.6 mg/day (n = 434), daily oral placebo (n = 450), or intramuscular IFNB-1a 30 mcg once per week (n = 447). Only the comparison between oral treatments was conducted in a double-blind fashion, said Dr. Timothy L. Vollmer, professor and director of clinical research in the neurology department at the University of Colorado, Aurora. He presented the study at the joint congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

Although patients in the BRAVO study were generally well matched in terms of baseline characteristics, a higher percentage of patients in the laquinimod arm had gadolinium-enhancing (GdE) T1 lesions than did patients in the placebo or IFNB-1a arms (39.6% vs. 33.4% and 38.1%, respectively). Laquinimod-treated patients also had a greater mean volume of T2 lesions at baseline (9.6 cm³), compared with the placebo (7.9 cm³) and IFNB-1a arms (8.6 cm³).

The 2-year ARR in patients treated with laquinimod was not significantly different from placebo (0.28 vs. 0.34, respectively). But after adjustment for multiple baseline factors, including the prestudy relapse rate, T2 lesion volume on MRI, and GdE T1 lesion status, the difference became significant (0.29 vs. 0.37, P = .03).

Disability progression at 3 months on the Expanded Disability Status Scale was significantly improved with laquinimod on the basis of a 33.5% reduction compared with placebo. In comparison, IFNB-1a reduced disability by 28.7% versus placebo. Laquinimod also significantly reduced the risk for 6-month confirmed disease progression (40.6% reduction vs. placebo), but IFNB-1a did not (28.3% reduction vs. placebo, P = .14).

Exploratory analyses showed that both GdE T1 and new T2 lesions significantly declined following laquinimod treatment versus placebo, although the reduction was less than what was observed in the IFNB-1a arm relative to placebo.

Nevertheless, laquinimod, but not IFNB-1a, appeared to be associated with a reduction in MRI-measured brain volume loss. Brain volume dropped significantly by a mean of –0.83% during treatment with laquinimod, compared with –1.14% for placebo and –1.25% for IFNB-1a. This translated into 27.4% less loss with laquinimod than with placebo, but a 9% increase in brain volume loss with IFNB-1a.

Consistent with the ALLEGRO trial, there were good safety and tolerability, especially when considered alongside existing therapies, Dr. Vollmer said.

There was, however, a higher rate of back pain (10.2%), arthralgia (5.5%), and depression (5.1%) in the laquinimod-treated patients than in the placebo group (7.1%, 4.0%, and 2.7%, respectively) or in the IFNB-1a arm (3.4%, 4.1%, and 4.8%).

During the discussion after his presentation, Dr. Vollmer suggested that laquinimod’s good safety profile and positive effect on disability might make it most useful in combination with other treatments for MS.

"I think the future of MS therapy probably will be combination ... and [laquinimod] is actually quite attractive in that sense – that it’s not a primary immunosuppressant – and so therefore it could be combined with primary immunological therapies, and possibly get an additive, possibly a synergistic effect on the central nervous system as it has its direct effects there."

While the exact mechanism of action of laquinimod is still under investigation, it is thought to target cells resident in the central nervous system such as the oligodendrocytes, astrocytes, and microglia, and have more modest effects on peripheral immune cells.

Dr. Ralf Gold of St. Josef and St. Elizabeth Hospital in Bochum, Germany, noted during a scientific highlights session at the congress that BRAVO was a "carefully executed study," and that the dose of laquinimod used in the study was purposefully quite low.

Laquinimod is a derivative of the failed experimental drug linomide, Dr. Gold explained, and on the basis of experience with that drug, a 0.6-mg dose of laquinimod was used in the BRAVO trial. "Laquinimod seems to be absolutely safe, although there are higher doses currently being tested" he said.

In regard to the possible beneficial effects of laquinimod on brain atrophy, Dr. Gold noted that there appeared to be "dissociation" between the effect of the 0.6-mg dosage on acute inflammation in brain lesions and its effect on neuroprotection, based on its relative preservation of brain volume.

The study was funded by Teva Neuroscience. Dr. Vollmer and Dr. Gold disclosed financial relationships with the company. In addition, Dr. Vollmer disclosed acting as a scientific adviser or receiving institutional research grants now or in the past from Biogen Idec, which manufactures Avonex, and other companies that develop therapies for MS. Dr. Gold disclosed receiving honoraria and research support from Bayer HealthCare, Biogen Idec, Merck Serono, and Novartis.

AMSTERDAM – The multiple sclerosis drug laquinimod did not reduce the risk of relapse in the BRAVO phase III trial, yet the investigational agent delayed the progression of disability to a greater extent than did placebo.

The BRAVO trial also included an open comparator arm against interferon beta-1a (IFNB-1a, Avonex), which proved to reduce brain lesions on MRI to a significantly greater extent relative to placebo than did laquinimod. But even though laquinimod’s effect against active brain inflammation did not appear to be as strong as that of IFNB-1a, it appeared to be potentially neuroprotective because it significantly halted loss of brain volume relative to placebo, whereas IFNB-1a did not.

The 1,331-patient BRAVO (Benefit-Risk Assessment of Avonex and Laquinimod) study is the second of two global phase III trials with laquinimod in patients with relapsing-remitting multiple sclerosis. The first was the 1,106-patient ALLEGRO study, completed earlier this year, in which laquinimod significantly reduced the annualized relapse rate (ARR), the risk of disability progression, and the percentage of total brain volume lost compared with placebo.

Patients in BRAVO had a mean age of about 37 years and were randomized to oral laquinimod 0.6 mg/day (n = 434), daily oral placebo (n = 450), or intramuscular IFNB-1a 30 mcg once per week (n = 447). Only the comparison between oral treatments was conducted in a double-blind fashion, said Dr. Timothy L. Vollmer, professor and director of clinical research in the neurology department at the University of Colorado, Aurora. He presented the study at the joint congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

Although patients in the BRAVO study were generally well matched in terms of baseline characteristics, a higher percentage of patients in the laquinimod arm had gadolinium-enhancing (GdE) T1 lesions than did patients in the placebo or IFNB-1a arms (39.6% vs. 33.4% and 38.1%, respectively). Laquinimod-treated patients also had a greater mean volume of T2 lesions at baseline (9.6 cm³), compared with the placebo (7.9 cm³) and IFNB-1a arms (8.6 cm³).

The 2-year ARR in patients treated with laquinimod was not significantly different from placebo (0.28 vs. 0.34, respectively). But after adjustment for multiple baseline factors, including the prestudy relapse rate, T2 lesion volume on MRI, and GdE T1 lesion status, the difference became significant (0.29 vs. 0.37, P = .03).

Disability progression at 3 months on the Expanded Disability Status Scale was significantly improved with laquinimod on the basis of a 33.5% reduction compared with placebo. In comparison, IFNB-1a reduced disability by 28.7% versus placebo. Laquinimod also significantly reduced the risk for 6-month confirmed disease progression (40.6% reduction vs. placebo), but IFNB-1a did not (28.3% reduction vs. placebo, P = .14).

Exploratory analyses showed that both GdE T1 and new T2 lesions significantly declined following laquinimod treatment versus placebo, although the reduction was less than what was observed in the IFNB-1a arm relative to placebo.

Nevertheless, laquinimod, but not IFNB-1a, appeared to be associated with a reduction in MRI-measured brain volume loss. Brain volume dropped significantly by a mean of –0.83% during treatment with laquinimod, compared with –1.14% for placebo and –1.25% for IFNB-1a. This translated into 27.4% less loss with laquinimod than with placebo, but a 9% increase in brain volume loss with IFNB-1a.

Consistent with the ALLEGRO trial, there were good safety and tolerability, especially when considered alongside existing therapies, Dr. Vollmer said.

There was, however, a higher rate of back pain (10.2%), arthralgia (5.5%), and depression (5.1%) in the laquinimod-treated patients than in the placebo group (7.1%, 4.0%, and 2.7%, respectively) or in the IFNB-1a arm (3.4%, 4.1%, and 4.8%).

During the discussion after his presentation, Dr. Vollmer suggested that laquinimod’s good safety profile and positive effect on disability might make it most useful in combination with other treatments for MS.

"I think the future of MS therapy probably will be combination ... and [laquinimod] is actually quite attractive in that sense – that it’s not a primary immunosuppressant – and so therefore it could be combined with primary immunological therapies, and possibly get an additive, possibly a synergistic effect on the central nervous system as it has its direct effects there."

While the exact mechanism of action of laquinimod is still under investigation, it is thought to target cells resident in the central nervous system such as the oligodendrocytes, astrocytes, and microglia, and have more modest effects on peripheral immune cells.

Dr. Ralf Gold of St. Josef and St. Elizabeth Hospital in Bochum, Germany, noted during a scientific highlights session at the congress that BRAVO was a "carefully executed study," and that the dose of laquinimod used in the study was purposefully quite low.

Laquinimod is a derivative of the failed experimental drug linomide, Dr. Gold explained, and on the basis of experience with that drug, a 0.6-mg dose of laquinimod was used in the BRAVO trial. "Laquinimod seems to be absolutely safe, although there are higher doses currently being tested" he said.

In regard to the possible beneficial effects of laquinimod on brain atrophy, Dr. Gold noted that there appeared to be "dissociation" between the effect of the 0.6-mg dosage on acute inflammation in brain lesions and its effect on neuroprotection, based on its relative preservation of brain volume.

The study was funded by Teva Neuroscience. Dr. Vollmer and Dr. Gold disclosed financial relationships with the company. In addition, Dr. Vollmer disclosed acting as a scientific adviser or receiving institutional research grants now or in the past from Biogen Idec, which manufactures Avonex, and other companies that develop therapies for MS. Dr. Gold disclosed receiving honoraria and research support from Bayer HealthCare, Biogen Idec, Merck Serono, and Novartis.

AMSTERDAM – The multiple sclerosis drug laquinimod did not reduce the risk of relapse in the BRAVO phase III trial, yet the investigational agent delayed the progression of disability to a greater extent than did placebo.

The BRAVO trial also included an open comparator arm against interferon beta-1a (IFNB-1a, Avonex), which proved to reduce brain lesions on MRI to a significantly greater extent relative to placebo than did laquinimod. But even though laquinimod’s effect against active brain inflammation did not appear to be as strong as that of IFNB-1a, it appeared to be potentially neuroprotective because it significantly halted loss of brain volume relative to placebo, whereas IFNB-1a did not.

The 1,331-patient BRAVO (Benefit-Risk Assessment of Avonex and Laquinimod) study is the second of two global phase III trials with laquinimod in patients with relapsing-remitting multiple sclerosis. The first was the 1,106-patient ALLEGRO study, completed earlier this year, in which laquinimod significantly reduced the annualized relapse rate (ARR), the risk of disability progression, and the percentage of total brain volume lost compared with placebo.

Patients in BRAVO had a mean age of about 37 years and were randomized to oral laquinimod 0.6 mg/day (n = 434), daily oral placebo (n = 450), or intramuscular IFNB-1a 30 mcg once per week (n = 447). Only the comparison between oral treatments was conducted in a double-blind fashion, said Dr. Timothy L. Vollmer, professor and director of clinical research in the neurology department at the University of Colorado, Aurora. He presented the study at the joint congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

Although patients in the BRAVO study were generally well matched in terms of baseline characteristics, a higher percentage of patients in the laquinimod arm had gadolinium-enhancing (GdE) T1 lesions than did patients in the placebo or IFNB-1a arms (39.6% vs. 33.4% and 38.1%, respectively). Laquinimod-treated patients also had a greater mean volume of T2 lesions at baseline (9.6 cm³), compared with the placebo (7.9 cm³) and IFNB-1a arms (8.6 cm³).

The 2-year ARR in patients treated with laquinimod was not significantly different from placebo (0.28 vs. 0.34, respectively). But after adjustment for multiple baseline factors, including the prestudy relapse rate, T2 lesion volume on MRI, and GdE T1 lesion status, the difference became significant (0.29 vs. 0.37, P = .03).

Disability progression at 3 months on the Expanded Disability Status Scale was significantly improved with laquinimod on the basis of a 33.5% reduction compared with placebo. In comparison, IFNB-1a reduced disability by 28.7% versus placebo. Laquinimod also significantly reduced the risk for 6-month confirmed disease progression (40.6% reduction vs. placebo), but IFNB-1a did not (28.3% reduction vs. placebo, P = .14).

Exploratory analyses showed that both GdE T1 and new T2 lesions significantly declined following laquinimod treatment versus placebo, although the reduction was less than what was observed in the IFNB-1a arm relative to placebo.

Nevertheless, laquinimod, but not IFNB-1a, appeared to be associated with a reduction in MRI-measured brain volume loss. Brain volume dropped significantly by a mean of –0.83% during treatment with laquinimod, compared with –1.14% for placebo and –1.25% for IFNB-1a. This translated into 27.4% less loss with laquinimod than with placebo, but a 9% increase in brain volume loss with IFNB-1a.

Consistent with the ALLEGRO trial, there were good safety and tolerability, especially when considered alongside existing therapies, Dr. Vollmer said.

There was, however, a higher rate of back pain (10.2%), arthralgia (5.5%), and depression (5.1%) in the laquinimod-treated patients than in the placebo group (7.1%, 4.0%, and 2.7%, respectively) or in the IFNB-1a arm (3.4%, 4.1%, and 4.8%).

During the discussion after his presentation, Dr. Vollmer suggested that laquinimod’s good safety profile and positive effect on disability might make it most useful in combination with other treatments for MS.

"I think the future of MS therapy probably will be combination ... and [laquinimod] is actually quite attractive in that sense – that it’s not a primary immunosuppressant – and so therefore it could be combined with primary immunological therapies, and possibly get an additive, possibly a synergistic effect on the central nervous system as it has its direct effects there."

While the exact mechanism of action of laquinimod is still under investigation, it is thought to target cells resident in the central nervous system such as the oligodendrocytes, astrocytes, and microglia, and have more modest effects on peripheral immune cells.

Dr. Ralf Gold of St. Josef and St. Elizabeth Hospital in Bochum, Germany, noted during a scientific highlights session at the congress that BRAVO was a "carefully executed study," and that the dose of laquinimod used in the study was purposefully quite low.

Laquinimod is a derivative of the failed experimental drug linomide, Dr. Gold explained, and on the basis of experience with that drug, a 0.6-mg dose of laquinimod was used in the BRAVO trial. "Laquinimod seems to be absolutely safe, although there are higher doses currently being tested" he said.

In regard to the possible beneficial effects of laquinimod on brain atrophy, Dr. Gold noted that there appeared to be "dissociation" between the effect of the 0.6-mg dosage on acute inflammation in brain lesions and its effect on neuroprotection, based on its relative preservation of brain volume.

The study was funded by Teva Neuroscience. Dr. Vollmer and Dr. Gold disclosed financial relationships with the company. In addition, Dr. Vollmer disclosed acting as a scientific adviser or receiving institutional research grants now or in the past from Biogen Idec, which manufactures Avonex, and other companies that develop therapies for MS. Dr. Gold disclosed receiving honoraria and research support from Bayer HealthCare, Biogen Idec, Merck Serono, and Novartis.

AMSTERDAM – Alemtuzumab, a drug currently licensed to treat chronic lymphocytic leukemia and T-cell lymphomas, reduced the risk of relapse by 55% in early-stage multiple sclerosis when compared with a current standard of therapy in a phase III trial.

Despite positive results in reducing the risk of relapse – a primary end point of the trial – there was no difference between the treatments in the second primary end point of 6-month sustained accumulated disability (SAD). That result and long-term safety concerns about alemtuzumab could dampen enthusiasm for its widespread use.

In the randomized, multicenter, placebo-controlled study of 563 patients with previously untreated relapsing–remitting multiple sclerosis, the annualized risk of relapse at 2 years (primary end point) was 0.18 for alemtuzumab-treated patients and 0.39 for interferon beta-1a (IFNB-1a, Rebif)-treated patients (P less than .0001).

At 2 years, 78% of 376 patients treated with alemtuzumab and 59% of 187 treated with IFNB-1a remained relapse free (P less than .0001), Dr. Alasdair J. Coles reported at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

Alemtuzumab is a humanized monoclonal antibody that targets the CD52 antigen on the surface of T and B cells. The U.S. Food and Drug Administration has already granted the investigational agent fast track designation and its manufacturer, Genzyme, hopes to file for regulatory approval in early in 2012. Alemtuzumab is known as Campath for its oncologic indications but is being re-branded for MS as Lemtrada.

The CARE-MS I (Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis) study is the first of two phase III trials comparing the effects of the drug against an active comparator in patients with relapsing–remitting multiple sclerosis. In CARE-MS I, patients have received no prior treatment for MS and are at a relatively early stage in their disease course (less than 5 years). In the second trial, CARE-MS II, the drugs’ effects are being compared in patients who have relapsed following treatment with IFN-B1a or glatiramer acetate (Copaxone).

SAD at 6 months occurred in 8% in the alemtuzumab arm and 11% in the IFNB-1a arm (P less than .22). SAD was defined as a 1-point or greater increase in Expanded Disability Status Scale (EDSS) score lasting at least 6 months, or a 1.5-point or greater increase if the baseline EDSS score was less than 1. There was no difference between treatments in any EDSS-based end points.

"[These results] may be helpful in counseling patients considering treatment with alemtuzumab."

However, the trial’s design had assumed that 20%, not 11%, of patients treated with the active comparator would meet the disability end point. "So we can conclude that the power of our study to discriminate a treatment effect has been undermined by the unexpectedly low rate of disability events in the active comparator arm," said Dr. Coles, a senior lecturer at the University of Cambridge (England).

Alemtuzumab had more favorable effects on secondary end points than IFNB-1a, including significant improvements in MS Functional Composite scores and visual acuity, reductions in new lesion formation, and significant slowing of brain atrophy.

A similar rate of general adverse events was noted with alemtuzumab and IFNB-1a (96% vs. 92%), although patients treated with alemtuzumab had a higher rate of infections, which were mostly mild to moderate (67% vs. 46%). More patients treated with IFNB-1a than with alemtuzumab experienced adverse events that led to treatment discontinuation (5.9% vs. 1.3%) or withdrawal (2.7% vs. 0%).

Autoimmune side effects were more common among patients who took alemtuzumab than among those who took IFNB-1a. Thyroid disorders, mainly hyperthyroid disease, were reported in 18.1% vs. 6.4%, respectively, and immune thrombocytopenic purpura (ITP) occurred in 0.8% and 0.5%, respectively.

"I don’t think the thyroid disease is really an issue in the grand scheme of things," Dr. Cole said in an interview. ITP, however, is more of a potential concern. All cases of ITP that occurred with alemtuzumab were considered serious adverse events and were managed with medical treatment including steroids, intravenous immunoglobulin, or rituximab.

In an interview, Dr. Daniel Kantor, president of the Florida Society of Neurology and director of the Neurologique Foundation in Ponte Vedra Beach, Fla., agreed that alemtuzumab’s efficacy in reducing relapse may be more important than in preserving thyroid function. "You can replace thyroid, but you can’t replace neurons."

Dr. Kantor, who was not involved in the study, also worried that alemtuzumab could potentially worsen patients’ adherence to treatment because it involves only a short course of treatment each year. Patients promise to return for follow-up visits, but sometimes they do not as they don’t feel the need for further treatment, he observed.

In the CARE-MS I study, alemtuzumab was given at an initial intravenous dose of 12 mg/day once daily for 5 consecutive days, followed by 12 mg/day for 3 consecutive days 1 year later. INFB-1a was administered as a 44-mcg subcutaneous injection given three times per week for 2 years.

Other research, presented by Dr. Joanne Jones of the University of Cambridge, suggests that a predictive test could perhaps be developed to identify the 20% to 30% of patients who may develop autoimmunity following treatment with alemtuzumab.

The experimental test is based on detecting pretreatment levels of interleukin (IL)-21 and IL-7 in the blood. People who experience autoimmune side effects with alemtuzumab have increased IL-21 levels and decreased IL-7 levels.

"It appears that we can ‘pull out’ a group of patients who are [at] very low risk of developing autoimmunity," Dr. Jones said. These results are of course preliminary, but "may be helpful in counseling patients considering treatment with alemtuzumab," Dr. Jones suggested.

The CARE-MS I study was funded by Genzyme (a subsidiary of Sanofi-Aventis) and Bayer HealthCare. Dr. Coles disclosed receiving consulting fees, lecture fees, and institutional grant support from Genzyme, Merck Serono, and UCB-Celltech. Dr. Jones said she had no disclosures. Dr. Kantor has acted as an investigator or had commercial relationships with Acorda, Avanir, Biogen Idec, Genzyme, Novartis, and Teva Neuroscience.

AMSTERDAM – Alemtuzumab, a drug currently licensed to treat chronic lymphocytic leukemia and T-cell lymphomas, reduced the risk of relapse by 55% in early-stage multiple sclerosis when compared with a current standard of therapy in a phase III trial.

Despite positive results in reducing the risk of relapse – a primary end point of the trial – there was no difference between the treatments in the second primary end point of 6-month sustained accumulated disability (SAD). That result and long-term safety concerns about alemtuzumab could dampen enthusiasm for its widespread use.

In the randomized, multicenter, placebo-controlled study of 563 patients with previously untreated relapsing–remitting multiple sclerosis, the annualized risk of relapse at 2 years (primary end point) was 0.18 for alemtuzumab-treated patients and 0.39 for interferon beta-1a (IFNB-1a, Rebif)-treated patients (P less than .0001).

At 2 years, 78% of 376 patients treated with alemtuzumab and 59% of 187 treated with IFNB-1a remained relapse free (P less than .0001), Dr. Alasdair J. Coles reported at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

Alemtuzumab is a humanized monoclonal antibody that targets the CD52 antigen on the surface of T and B cells. The U.S. Food and Drug Administration has already granted the investigational agent fast track designation and its manufacturer, Genzyme, hopes to file for regulatory approval in early in 2012. Alemtuzumab is known as Campath for its oncologic indications but is being re-branded for MS as Lemtrada.

The CARE-MS I (Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis) study is the first of two phase III trials comparing the effects of the drug against an active comparator in patients with relapsing–remitting multiple sclerosis. In CARE-MS I, patients have received no prior treatment for MS and are at a relatively early stage in their disease course (less than 5 years). In the second trial, CARE-MS II, the drugs’ effects are being compared in patients who have relapsed following treatment with IFN-B1a or glatiramer acetate (Copaxone).

SAD at 6 months occurred in 8% in the alemtuzumab arm and 11% in the IFNB-1a arm (P less than .22). SAD was defined as a 1-point or greater increase in Expanded Disability Status Scale (EDSS) score lasting at least 6 months, or a 1.5-point or greater increase if the baseline EDSS score was less than 1. There was no difference between treatments in any EDSS-based end points.

"[These results] may be helpful in counseling patients considering treatment with alemtuzumab."

However, the trial’s design had assumed that 20%, not 11%, of patients treated with the active comparator would meet the disability end point. "So we can conclude that the power of our study to discriminate a treatment effect has been undermined by the unexpectedly low rate of disability events in the active comparator arm," said Dr. Coles, a senior lecturer at the University of Cambridge (England).

Alemtuzumab had more favorable effects on secondary end points than IFNB-1a, including significant improvements in MS Functional Composite scores and visual acuity, reductions in new lesion formation, and significant slowing of brain atrophy.

A similar rate of general adverse events was noted with alemtuzumab and IFNB-1a (96% vs. 92%), although patients treated with alemtuzumab had a higher rate of infections, which were mostly mild to moderate (67% vs. 46%). More patients treated with IFNB-1a than with alemtuzumab experienced adverse events that led to treatment discontinuation (5.9% vs. 1.3%) or withdrawal (2.7% vs. 0%).

Autoimmune side effects were more common among patients who took alemtuzumab than among those who took IFNB-1a. Thyroid disorders, mainly hyperthyroid disease, were reported in 18.1% vs. 6.4%, respectively, and immune thrombocytopenic purpura (ITP) occurred in 0.8% and 0.5%, respectively.

"I don’t think the thyroid disease is really an issue in the grand scheme of things," Dr. Cole said in an interview. ITP, however, is more of a potential concern. All cases of ITP that occurred with alemtuzumab were considered serious adverse events and were managed with medical treatment including steroids, intravenous immunoglobulin, or rituximab.

In an interview, Dr. Daniel Kantor, president of the Florida Society of Neurology and director of the Neurologique Foundation in Ponte Vedra Beach, Fla., agreed that alemtuzumab’s efficacy in reducing relapse may be more important than in preserving thyroid function. "You can replace thyroid, but you can’t replace neurons."

Dr. Kantor, who was not involved in the study, also worried that alemtuzumab could potentially worsen patients’ adherence to treatment because it involves only a short course of treatment each year. Patients promise to return for follow-up visits, but sometimes they do not as they don’t feel the need for further treatment, he observed.

In the CARE-MS I study, alemtuzumab was given at an initial intravenous dose of 12 mg/day once daily for 5 consecutive days, followed by 12 mg/day for 3 consecutive days 1 year later. INFB-1a was administered as a 44-mcg subcutaneous injection given three times per week for 2 years.

Other research, presented by Dr. Joanne Jones of the University of Cambridge, suggests that a predictive test could perhaps be developed to identify the 20% to 30% of patients who may develop autoimmunity following treatment with alemtuzumab.

The experimental test is based on detecting pretreatment levels of interleukin (IL)-21 and IL-7 in the blood. People who experience autoimmune side effects with alemtuzumab have increased IL-21 levels and decreased IL-7 levels.

"It appears that we can ‘pull out’ a group of patients who are [at] very low risk of developing autoimmunity," Dr. Jones said. These results are of course preliminary, but "may be helpful in counseling patients considering treatment with alemtuzumab," Dr. Jones suggested.

The CARE-MS I study was funded by Genzyme (a subsidiary of Sanofi-Aventis) and Bayer HealthCare. Dr. Coles disclosed receiving consulting fees, lecture fees, and institutional grant support from Genzyme, Merck Serono, and UCB-Celltech. Dr. Jones said she had no disclosures. Dr. Kantor has acted as an investigator or had commercial relationships with Acorda, Avanir, Biogen Idec, Genzyme, Novartis, and Teva Neuroscience.

AMSTERDAM – Alemtuzumab, a drug currently licensed to treat chronic lymphocytic leukemia and T-cell lymphomas, reduced the risk of relapse by 55% in early-stage multiple sclerosis when compared with a current standard of therapy in a phase III trial.

Despite positive results in reducing the risk of relapse – a primary end point of the trial – there was no difference between the treatments in the second primary end point of 6-month sustained accumulated disability (SAD). That result and long-term safety concerns about alemtuzumab could dampen enthusiasm for its widespread use.

In the randomized, multicenter, placebo-controlled study of 563 patients with previously untreated relapsing–remitting multiple sclerosis, the annualized risk of relapse at 2 years (primary end point) was 0.18 for alemtuzumab-treated patients and 0.39 for interferon beta-1a (IFNB-1a, Rebif)-treated patients (P less than .0001).

At 2 years, 78% of 376 patients treated with alemtuzumab and 59% of 187 treated with IFNB-1a remained relapse free (P less than .0001), Dr. Alasdair J. Coles reported at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

Alemtuzumab is a humanized monoclonal antibody that targets the CD52 antigen on the surface of T and B cells. The U.S. Food and Drug Administration has already granted the investigational agent fast track designation and its manufacturer, Genzyme, hopes to file for regulatory approval in early in 2012. Alemtuzumab is known as Campath for its oncologic indications but is being re-branded for MS as Lemtrada.

The CARE-MS I (Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis) study is the first of two phase III trials comparing the effects of the drug against an active comparator in patients with relapsing–remitting multiple sclerosis. In CARE-MS I, patients have received no prior treatment for MS and are at a relatively early stage in their disease course (less than 5 years). In the second trial, CARE-MS II, the drugs’ effects are being compared in patients who have relapsed following treatment with IFN-B1a or glatiramer acetate (Copaxone).

SAD at 6 months occurred in 8% in the alemtuzumab arm and 11% in the IFNB-1a arm (P less than .22). SAD was defined as a 1-point or greater increase in Expanded Disability Status Scale (EDSS) score lasting at least 6 months, or a 1.5-point or greater increase if the baseline EDSS score was less than 1. There was no difference between treatments in any EDSS-based end points.

"[These results] may be helpful in counseling patients considering treatment with alemtuzumab."

However, the trial’s design had assumed that 20%, not 11%, of patients treated with the active comparator would meet the disability end point. "So we can conclude that the power of our study to discriminate a treatment effect has been undermined by the unexpectedly low rate of disability events in the active comparator arm," said Dr. Coles, a senior lecturer at the University of Cambridge (England).

Alemtuzumab had more favorable effects on secondary end points than IFNB-1a, including significant improvements in MS Functional Composite scores and visual acuity, reductions in new lesion formation, and significant slowing of brain atrophy.

A similar rate of general adverse events was noted with alemtuzumab and IFNB-1a (96% vs. 92%), although patients treated with alemtuzumab had a higher rate of infections, which were mostly mild to moderate (67% vs. 46%). More patients treated with IFNB-1a than with alemtuzumab experienced adverse events that led to treatment discontinuation (5.9% vs. 1.3%) or withdrawal (2.7% vs. 0%).

Autoimmune side effects were more common among patients who took alemtuzumab than among those who took IFNB-1a. Thyroid disorders, mainly hyperthyroid disease, were reported in 18.1% vs. 6.4%, respectively, and immune thrombocytopenic purpura (ITP) occurred in 0.8% and 0.5%, respectively.

"I don’t think the thyroid disease is really an issue in the grand scheme of things," Dr. Cole said in an interview. ITP, however, is more of a potential concern. All cases of ITP that occurred with alemtuzumab were considered serious adverse events and were managed with medical treatment including steroids, intravenous immunoglobulin, or rituximab.

In an interview, Dr. Daniel Kantor, president of the Florida Society of Neurology and director of the Neurologique Foundation in Ponte Vedra Beach, Fla., agreed that alemtuzumab’s efficacy in reducing relapse may be more important than in preserving thyroid function. "You can replace thyroid, but you can’t replace neurons."

Dr. Kantor, who was not involved in the study, also worried that alemtuzumab could potentially worsen patients’ adherence to treatment because it involves only a short course of treatment each year. Patients promise to return for follow-up visits, but sometimes they do not as they don’t feel the need for further treatment, he observed.

In the CARE-MS I study, alemtuzumab was given at an initial intravenous dose of 12 mg/day once daily for 5 consecutive days, followed by 12 mg/day for 3 consecutive days 1 year later. INFB-1a was administered as a 44-mcg subcutaneous injection given three times per week for 2 years.

Other research, presented by Dr. Joanne Jones of the University of Cambridge, suggests that a predictive test could perhaps be developed to identify the 20% to 30% of patients who may develop autoimmunity following treatment with alemtuzumab.

The experimental test is based on detecting pretreatment levels of interleukin (IL)-21 and IL-7 in the blood. People who experience autoimmune side effects with alemtuzumab have increased IL-21 levels and decreased IL-7 levels.

"It appears that we can ‘pull out’ a group of patients who are [at] very low risk of developing autoimmunity," Dr. Jones said. These results are of course preliminary, but "may be helpful in counseling patients considering treatment with alemtuzumab," Dr. Jones suggested.

The CARE-MS I study was funded by Genzyme (a subsidiary of Sanofi-Aventis) and Bayer HealthCare. Dr. Coles disclosed receiving consulting fees, lecture fees, and institutional grant support from Genzyme, Merck Serono, and UCB-Celltech. Dr. Jones said she had no disclosures. Dr. Kantor has acted as an investigator or had commercial relationships with Acorda, Avanir, Biogen Idec, Genzyme, Novartis, and Teva Neuroscience.

LISBON – The possibility that incretin-based therapies for type 2 diabetes can cause cancer warrants further investigation, a leading clinical diabetologist has said.

"Pancreatitis and pancreatic cancer are reported in excess with exenatide and sitagliptin therapy in the FDA AERS [Food and Drug Administration’s Adverse Events Reporting System database] in comparison to other diabetes medications," Dr. Peter Butler said at the annual meeting of the European Association for the Study of Diabetes.

Using the database, Dr. Butler and his associates recently found that treatment with exenatide (Byetta) and sitagliptin (Januvia) significantly increased the risk of pancreatitis more than sixfold, with odds ratios (ORs) of 10.7 and 6.7, respectively, compared with four control drugs – rosiglitazone (Avandia), nateglinide (Starlix), repaglinide (Prandin), and glipizide (Glucotrol) – (P less than 10^-16 for both comparisons) (Gastroenterology 2011;141:150-6). These data are somewhat alarming, as many experts now believe that pancreatitis may be a precursor to malignancy.

Furthermore, the risk of pancreatic cancer was more than doubled, compared with control treatments, with statistically significant odds ratios of 2.9 (P = 9 x 10^-5) for exenatide and 2.7 for sitagliptin (P = .008). Thyroid cancer risk was also significantly elevated by exenatide, with an odds ratio of 4.7, (P = 4 x 10^-16), but not by sitagliptin (OR = 1.5, P = .65).

The risk of other cancers did not seem to be elevated by the incretin-based therapies. Exenatide, a glucagon-like peptide–1 (GLP-1) receptor agonist, stimulates insulin secretion when glucose levels are high; sitagliptin, a dipeptidyl peptidase–4 (DPP-4) inhibitor, acts to lower glucose levels by prolonging the activity of GLP-1.

Dr. Butler, professor of medicine and chief of the division of endocrinology, diabetes, and hypertension at the University of California, Los Angeles, noted that there is also evidence that GLP-1–based therapy induces proliferative changes in the pancreatic ducts of rodents. GLP-1 receptors are also expressed in a very high percentage of premalignant and malignant pancreatic lesions in humans.

While he admitted that he would be happy to be proved wrong, Dr. Butler stated during a debate on GLP-1–based treatment and cancer that the association must be thoroughly investigated, as it was important to ensure the overall safety of patients using these drugs.

"For now, this analysis of the FDA database does not establish that pancreatitis, [and] pancreatic and thyroid cancer are caused by GLP-1–based therapy," Dr. Butler said, citing the concluding sentences of the recently published paper. "It simply raises the level of concern that they may be and that the appropriate prospective studies are required to rule them out."

Clinical Trials May Not Be Feasible

It might not be possible to conduct such studies because of the sheer number of patients that would need to be involved, suggested Dr. Michael Nuack of the Diabetes Center, Bad Lauterberg, Germany.

"In the case of pancreatitis ... we have around 5 cases per 1,000 patient years," Dr. Nuack observed. "If you want to exclude a rise in risk by 25% you would need to do a study with 80,000 patients per arm, and I think we are all pretty sure that this will never be tested in a prospective, randomized trial."

According to Dr. Nuack, there is not enough strong evidence for or against the notion that GLP-1–based therapy can cause cancer, and using the FDA AERS database to investigate any associated risk is significantly flawed for several reasons.

Severe adverse events are more likely to be reported than are less-severe events, he suggested, and newer drugs may receive more attention than older, more established medications. Overreporting could also occur because of rumors of a cancer link, and diagnoses may not be accurate or recorded in the same way by physicians.

More importantly, the FDA AERS review included years when exenatide and sitagliptin were not available and excluded data from 2010, when more adverse events associated with the two drugs would have been available.

"Talking about cancer and malignant disease in general, based on this analysis, some forms of cancer or malignant disease are reduced," Dr. Nuack observed. For exenatide this included reduced cases of lung cancer, prostate cancer, sarcoma, lymphoma, and multiple myeloma. For sitagliptin it included colon cancer and prostate cancer.

Change in Practice Not Necessary

There is no need to change current practice, Dr. Nuack advised. "I think we can say today that there is not a single case report of pancreatic cancer in patients treated with DPP-4 inhibitors or GLP-1 receptor agonists."

Reading a statement from the European Association for the Study of Diabetes on the matter, the society’s past president, Dr. Ulf Smith, agreed that for now, no changes to treatment should be made.

"There is no immediate need for action, and patients should under no circumstances stop taking any medication, and should consult their physicians to be advised on their diabetes therapy," observed Dr. Smith of Sahlgrenska University Hospital, Gothenburg, Sweden.

"Although there are important questions which currently need to be answered with respect to the safety of incretin-based medications, there is no definitive evidence pointing to an increased cancer risk. The only robust way of measuring comparative risk is with randomized, controlled trials that record adverse events."

Dr. Butler noted that because of a possibly protective effect of metformin in relation to the development of cancer, GLP-1–based therapies should always be prescribed in association with the drug, which is in accordance with current diabetes treatment guidelines.

The FDA AERS database review was supported by the Larry L. Hillblom Foundation. Dr. Butler and Dr. Smith stated they had no conflicts of interest Dr. Nuack has received research support via his institution and acted as an advisory board member, consultant, or speaker for multiple pharmaceutical companies including the manufacturers of incretin-based therapies.

LISBON – The possibility that incretin-based therapies for type 2 diabetes can cause cancer warrants further investigation, a leading clinical diabetologist has said.

"Pancreatitis and pancreatic cancer are reported in excess with exenatide and sitagliptin therapy in the FDA AERS [Food and Drug Administration’s Adverse Events Reporting System database] in comparison to other diabetes medications," Dr. Peter Butler said at the annual meeting of the European Association for the Study of Diabetes.

Using the database, Dr. Butler and his associates recently found that treatment with exenatide (Byetta) and sitagliptin (Januvia) significantly increased the risk of pancreatitis more than sixfold, with odds ratios (ORs) of 10.7 and 6.7, respectively, compared with four control drugs – rosiglitazone (Avandia), nateglinide (Starlix), repaglinide (Prandin), and glipizide (Glucotrol) – (P less than 10^-16 for both comparisons) (Gastroenterology 2011;141:150-6). These data are somewhat alarming, as many experts now believe that pancreatitis may be a precursor to malignancy.

Furthermore, the risk of pancreatic cancer was more than doubled, compared with control treatments, with statistically significant odds ratios of 2.9 (P = 9 x 10^-5) for exenatide and 2.7 for sitagliptin (P = .008). Thyroid cancer risk was also significantly elevated by exenatide, with an odds ratio of 4.7, (P = 4 x 10^-16), but not by sitagliptin (OR = 1.5, P = .65).

The risk of other cancers did not seem to be elevated by the incretin-based therapies. Exenatide, a glucagon-like peptide–1 (GLP-1) receptor agonist, stimulates insulin secretion when glucose levels are high; sitagliptin, a dipeptidyl peptidase–4 (DPP-4) inhibitor, acts to lower glucose levels by prolonging the activity of GLP-1.

Dr. Butler, professor of medicine and chief of the division of endocrinology, diabetes, and hypertension at the University of California, Los Angeles, noted that there is also evidence that GLP-1–based therapy induces proliferative changes in the pancreatic ducts of rodents. GLP-1 receptors are also expressed in a very high percentage of premalignant and malignant pancreatic lesions in humans.

While he admitted that he would be happy to be proved wrong, Dr. Butler stated during a debate on GLP-1–based treatment and cancer that the association must be thoroughly investigated, as it was important to ensure the overall safety of patients using these drugs.

"For now, this analysis of the FDA database does not establish that pancreatitis, [and] pancreatic and thyroid cancer are caused by GLP-1–based therapy," Dr. Butler said, citing the concluding sentences of the recently published paper. "It simply raises the level of concern that they may be and that the appropriate prospective studies are required to rule them out."

Clinical Trials May Not Be Feasible

It might not be possible to conduct such studies because of the sheer number of patients that would need to be involved, suggested Dr. Michael Nuack of the Diabetes Center, Bad Lauterberg, Germany.

"In the case of pancreatitis ... we have around 5 cases per 1,000 patient years," Dr. Nuack observed. "If you want to exclude a rise in risk by 25% you would need to do a study with 80,000 patients per arm, and I think we are all pretty sure that this will never be tested in a prospective, randomized trial."

According to Dr. Nuack, there is not enough strong evidence for or against the notion that GLP-1–based therapy can cause cancer, and using the FDA AERS database to investigate any associated risk is significantly flawed for several reasons.

Severe adverse events are more likely to be reported than are less-severe events, he suggested, and newer drugs may receive more attention than older, more established medications. Overreporting could also occur because of rumors of a cancer link, and diagnoses may not be accurate or recorded in the same way by physicians.

More importantly, the FDA AERS review included years when exenatide and sitagliptin were not available and excluded data from 2010, when more adverse events associated with the two drugs would have been available.

"Talking about cancer and malignant disease in general, based on this analysis, some forms of cancer or malignant disease are reduced," Dr. Nuack observed. For exenatide this included reduced cases of lung cancer, prostate cancer, sarcoma, lymphoma, and multiple myeloma. For sitagliptin it included colon cancer and prostate cancer.

Change in Practice Not Necessary

There is no need to change current practice, Dr. Nuack advised. "I think we can say today that there is not a single case report of pancreatic cancer in patients treated with DPP-4 inhibitors or GLP-1 receptor agonists."

Reading a statement from the European Association for the Study of Diabetes on the matter, the society’s past president, Dr. Ulf Smith, agreed that for now, no changes to treatment should be made.

"There is no immediate need for action, and patients should under no circumstances stop taking any medication, and should consult their physicians to be advised on their diabetes therapy," observed Dr. Smith of Sahlgrenska University Hospital, Gothenburg, Sweden.

"Although there are important questions which currently need to be answered with respect to the safety of incretin-based medications, there is no definitive evidence pointing to an increased cancer risk. The only robust way of measuring comparative risk is with randomized, controlled trials that record adverse events."

Dr. Butler noted that because of a possibly protective effect of metformin in relation to the development of cancer, GLP-1–based therapies should always be prescribed in association with the drug, which is in accordance with current diabetes treatment guidelines.

The FDA AERS database review was supported by the Larry L. Hillblom Foundation. Dr. Butler and Dr. Smith stated they had no conflicts of interest Dr. Nuack has received research support via his institution and acted as an advisory board member, consultant, or speaker for multiple pharmaceutical companies including the manufacturers of incretin-based therapies.

LISBON – The possibility that incretin-based therapies for type 2 diabetes can cause cancer warrants further investigation, a leading clinical diabetologist has said.

"Pancreatitis and pancreatic cancer are reported in excess with exenatide and sitagliptin therapy in the FDA AERS [Food and Drug Administration’s Adverse Events Reporting System database] in comparison to other diabetes medications," Dr. Peter Butler said at the annual meeting of the European Association for the Study of Diabetes.

Using the database, Dr. Butler and his associates recently found that treatment with exenatide (Byetta) and sitagliptin (Januvia) significantly increased the risk of pancreatitis more than sixfold, with odds ratios (ORs) of 10.7 and 6.7, respectively, compared with four control drugs – rosiglitazone (Avandia), nateglinide (Starlix), repaglinide (Prandin), and glipizide (Glucotrol) – (P less than 10^-16 for both comparisons) (Gastroenterology 2011;141:150-6). These data are somewhat alarming, as many experts now believe that pancreatitis may be a precursor to malignancy.

Furthermore, the risk of pancreatic cancer was more than doubled, compared with control treatments, with statistically significant odds ratios of 2.9 (P = 9 x 10^-5) for exenatide and 2.7 for sitagliptin (P = .008). Thyroid cancer risk was also significantly elevated by exenatide, with an odds ratio of 4.7, (P = 4 x 10^-16), but not by sitagliptin (OR = 1.5, P = .65).

The risk of other cancers did not seem to be elevated by the incretin-based therapies. Exenatide, a glucagon-like peptide–1 (GLP-1) receptor agonist, stimulates insulin secretion when glucose levels are high; sitagliptin, a dipeptidyl peptidase–4 (DPP-4) inhibitor, acts to lower glucose levels by prolonging the activity of GLP-1.

Dr. Butler, professor of medicine and chief of the division of endocrinology, diabetes, and hypertension at the University of California, Los Angeles, noted that there is also evidence that GLP-1–based therapy induces proliferative changes in the pancreatic ducts of rodents. GLP-1 receptors are also expressed in a very high percentage of premalignant and malignant pancreatic lesions in humans.

While he admitted that he would be happy to be proved wrong, Dr. Butler stated during a debate on GLP-1–based treatment and cancer that the association must be thoroughly investigated, as it was important to ensure the overall safety of patients using these drugs.

"For now, this analysis of the FDA database does not establish that pancreatitis, [and] pancreatic and thyroid cancer are caused by GLP-1–based therapy," Dr. Butler said, citing the concluding sentences of the recently published paper. "It simply raises the level of concern that they may be and that the appropriate prospective studies are required to rule them out."

Clinical Trials May Not Be Feasible

It might not be possible to conduct such studies because of the sheer number of patients that would need to be involved, suggested Dr. Michael Nuack of the Diabetes Center, Bad Lauterberg, Germany.

"In the case of pancreatitis ... we have around 5 cases per 1,000 patient years," Dr. Nuack observed. "If you want to exclude a rise in risk by 25% you would need to do a study with 80,000 patients per arm, and I think we are all pretty sure that this will never be tested in a prospective, randomized trial."

According to Dr. Nuack, there is not enough strong evidence for or against the notion that GLP-1–based therapy can cause cancer, and using the FDA AERS database to investigate any associated risk is significantly flawed for several reasons.

Severe adverse events are more likely to be reported than are less-severe events, he suggested, and newer drugs may receive more attention than older, more established medications. Overreporting could also occur because of rumors of a cancer link, and diagnoses may not be accurate or recorded in the same way by physicians.

More importantly, the FDA AERS review included years when exenatide and sitagliptin were not available and excluded data from 2010, when more adverse events associated with the two drugs would have been available.

"Talking about cancer and malignant disease in general, based on this analysis, some forms of cancer or malignant disease are reduced," Dr. Nuack observed. For exenatide this included reduced cases of lung cancer, prostate cancer, sarcoma, lymphoma, and multiple myeloma. For sitagliptin it included colon cancer and prostate cancer.

Change in Practice Not Necessary

There is no need to change current practice, Dr. Nuack advised. "I think we can say today that there is not a single case report of pancreatic cancer in patients treated with DPP-4 inhibitors or GLP-1 receptor agonists."

Reading a statement from the European Association for the Study of Diabetes on the matter, the society’s past president, Dr. Ulf Smith, agreed that for now, no changes to treatment should be made.

"There is no immediate need for action, and patients should under no circumstances stop taking any medication, and should consult their physicians to be advised on their diabetes therapy," observed Dr. Smith of Sahlgrenska University Hospital, Gothenburg, Sweden.

"Although there are important questions which currently need to be answered with respect to the safety of incretin-based medications, there is no definitive evidence pointing to an increased cancer risk. The only robust way of measuring comparative risk is with randomized, controlled trials that record adverse events."

Dr. Butler noted that because of a possibly protective effect of metformin in relation to the development of cancer, GLP-1–based therapies should always be prescribed in association with the drug, which is in accordance with current diabetes treatment guidelines.

The FDA AERS database review was supported by the Larry L. Hillblom Foundation. Dr. Butler and Dr. Smith stated they had no conflicts of interest Dr. Nuack has received research support via his institution and acted as an advisory board member, consultant, or speaker for multiple pharmaceutical companies including the manufacturers of incretin-based therapies.

AMSTERDAM – Treatment with the investigational oral drug dimethyl fumarate reduced the risk of relapse by up to 50%, compared with placebo, in patients with relapsing–remitting multiple sclerosis in a phase III trial.

In the multicenter, randomized, double-blind trial of 1,234 patients, placebo-treated patients had a cumulative probability of relapse of 46% at 2 years, which was significantly higher than the rates of 27% and 26% recorded in patients who received dimethyl fumarate at 240 mg twice daily or 240 mg three times daily, respectively. These rates for the primary end point of the trial corresponded to hazard ratios for relapse of 0.51 and 0.50, respectively.

Those 2-year relapse rates translated to annualized relapse rates of 0.364 for placebo and 0.172 for 240 mg dimethyl fumarate twice daily and 0.189 for 240 mg three times daily.

The possibly of using a fumaric acid ester (FAE) such as dimethyl fumarate (also known as BG-12) in the treatment for MS was first suggested about 10 years ago, although FAEs have been used for the treatment of psoriasis for some years in Europe, said Dr. Ralf Gold of St. Josef and St. Elizabeth Hospital in Bochum, Germany. He presented the results of the DEFINE (Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS) study at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

BG-12 is thought to defend the brain against oxidative stress and recent experimental evidence suggests that it may have dual effects – acting as both an anti-inflammatory and as a neuroprotective agent (Brain 2011;134:678-92).

Findings from a phase II study of BG-12 showed that it reduced MRI-detected disease activity in MS by about 69% from week 12 to 24, compared with placebo (Lancet 2008;372:1463-72), but the current findings from DEFINE suggest a greater reduction in MRI lesions may be possible.

Dr. Gold reported data from an MRI substudy of DEFINE that involved 540 patients. BG-12 was associated with a 73%-98% reduction in gadolinium-enhancing (GdE) lesions and a 74%-85% reduction in new or newly enlarging T2 hyperintense lesions on MRI at 2 years, depending on the dosing regimen used.

Coinvestigator Dr. Douglas Arnold of the Montreal Neurological Institute and Hospital at McGill University commented in an interview that these MRI results are impressive if you consider what can be achieved with other therapies.

"I think everybody was pleasantly surprised at how effective [BG-12] was on the MRI," Dr. Arnold said. "The suppression of the GdE lesions is 90% – that’s a stronger effect than any medication that’s available currently for the treatment for MS." The reduction of GdE lesions is as low as 30% for some agents, although it as high as 89% for others such as natalizumab (Tysabri), he said.

BG-12 reduced the risk of disability progression at 12 weeks by 38% with twice daily dosing and by 34% with three times daily dosing as measured by scores on the Expanded Disability Status Scale.

The safety and tolerability of BG-12 did not appear to differ greatly from placebo. Serious adverse events were reported in fewer BG-12 than placebo-treated patients (16%-18% vs. 21%), with two deaths – both unrelated to treatment – occurring in the BG-12 groups.

Flushing and gastrointestinal adverse events were reported more frequently in the BG-12 groups, although Dr. Gold observed that most cases of flushing were mild or moderate in severity and their incidence decreased substantially after the first month of treatment. Opportunistic infections were seen only in placebo-treated patients, and there was no increased risk of other serious infections or malignancies with BG-12.

MS patients who took BG-12 also benefited from higher quality of life scores after 2 years on physical and mental functioning, as well as higher general well-being scores, than did patients who received placebo.

In addition to efficacy, the safety of BG-12 in the study is reassuring, Dr. Paul O’Connor, director of the MS Clinic at St. Michael’s Hospital in Toronto, said in an interview. He noted that data from a second ongoing phase III trial, called CONFIRM, would be needed before any firm conclusions could be drawn. CONFIRM is comparing BG-12 with an active comparator, glatiramer acetate (Copaxone).

"The safety data are very encouraging because there have been various new treatments over the past 4 or 5 years that looked to have a more powerful effect than our conventional treatments, but all of them have come with significant safety problems," Dr. Neil Scolding of the University of Bristol (United Kingdom), said in an interview.

Dr. Daniel Kantor, president of the Florida Society of Neurology and director of the Neurologique Foundation in Ponte Vedra Beach, Fla., said after the study’s presentation that "I think I speak for many people when I say, ‘wow.’ "

"Right now, as it stands, the data from the phase III trial are better than the phase II trial, which is not normally the case," Dr. Kantor said. He hoped that the CONFIRM trial can replicate the results of DEFINE and noted that no previous trial has compared an active drug against glatiramer acetate.

The study was supported by Biogen Idec. Dr. Gold disclosed receiving honoraria and research support from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience. Dr. Arnold has received consulting fees from Bayer HealthCare, Biogen Idec, Genentech, Merck Serono, NeuroRx Research, Roche, Schering-Plough, and Teva Neuroscience. Dr. O’Connor has received consulting fees and honoraria from Bayer, Biogen Idec, EMD Serono, Genentech, Novartis, Roche, Sanofi-Aventis, and Teva. Dr. Scolding had nothing to disclose. Dr. Kantor disclosed acting as an investigator or having commercial relationships with Acorda, Avanir, Biogen Idec (although not in relation to BG-12), Genzyme, Novartis, and Teva Neuroscience.

AMSTERDAM – Treatment with the investigational oral drug dimethyl fumarate reduced the risk of relapse by up to 50%, compared with placebo, in patients with relapsing–remitting multiple sclerosis in a phase III trial.

In the multicenter, randomized, double-blind trial of 1,234 patients, placebo-treated patients had a cumulative probability of relapse of 46% at 2 years, which was significantly higher than the rates of 27% and 26% recorded in patients who received dimethyl fumarate at 240 mg twice daily or 240 mg three times daily, respectively. These rates for the primary end point of the trial corresponded to hazard ratios for relapse of 0.51 and 0.50, respectively.

Those 2-year relapse rates translated to annualized relapse rates of 0.364 for placebo and 0.172 for 240 mg dimethyl fumarate twice daily and 0.189 for 240 mg three times daily.

The possibly of using a fumaric acid ester (FAE) such as dimethyl fumarate (also known as BG-12) in the treatment for MS was first suggested about 10 years ago, although FAEs have been used for the treatment of psoriasis for some years in Europe, said Dr. Ralf Gold of St. Josef and St. Elizabeth Hospital in Bochum, Germany. He presented the results of the DEFINE (Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS) study at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

BG-12 is thought to defend the brain against oxidative stress and recent experimental evidence suggests that it may have dual effects – acting as both an anti-inflammatory and as a neuroprotective agent (Brain 2011;134:678-92).

Findings from a phase II study of BG-12 showed that it reduced MRI-detected disease activity in MS by about 69% from week 12 to 24, compared with placebo (Lancet 2008;372:1463-72), but the current findings from DEFINE suggest a greater reduction in MRI lesions may be possible.

Dr. Gold reported data from an MRI substudy of DEFINE that involved 540 patients. BG-12 was associated with a 73%-98% reduction in gadolinium-enhancing (GdE) lesions and a 74%-85% reduction in new or newly enlarging T2 hyperintense lesions on MRI at 2 years, depending on the dosing regimen used.

Coinvestigator Dr. Douglas Arnold of the Montreal Neurological Institute and Hospital at McGill University commented in an interview that these MRI results are impressive if you consider what can be achieved with other therapies.

"I think everybody was pleasantly surprised at how effective [BG-12] was on the MRI," Dr. Arnold said. "The suppression of the GdE lesions is 90% – that’s a stronger effect than any medication that’s available currently for the treatment for MS." The reduction of GdE lesions is as low as 30% for some agents, although it as high as 89% for others such as natalizumab (Tysabri), he said.

BG-12 reduced the risk of disability progression at 12 weeks by 38% with twice daily dosing and by 34% with three times daily dosing as measured by scores on the Expanded Disability Status Scale.

The safety and tolerability of BG-12 did not appear to differ greatly from placebo. Serious adverse events were reported in fewer BG-12 than placebo-treated patients (16%-18% vs. 21%), with two deaths – both unrelated to treatment – occurring in the BG-12 groups.

Flushing and gastrointestinal adverse events were reported more frequently in the BG-12 groups, although Dr. Gold observed that most cases of flushing were mild or moderate in severity and their incidence decreased substantially after the first month of treatment. Opportunistic infections were seen only in placebo-treated patients, and there was no increased risk of other serious infections or malignancies with BG-12.

MS patients who took BG-12 also benefited from higher quality of life scores after 2 years on physical and mental functioning, as well as higher general well-being scores, than did patients who received placebo.

In addition to efficacy, the safety of BG-12 in the study is reassuring, Dr. Paul O’Connor, director of the MS Clinic at St. Michael’s Hospital in Toronto, said in an interview. He noted that data from a second ongoing phase III trial, called CONFIRM, would be needed before any firm conclusions could be drawn. CONFIRM is comparing BG-12 with an active comparator, glatiramer acetate (Copaxone).

"The safety data are very encouraging because there have been various new treatments over the past 4 or 5 years that looked to have a more powerful effect than our conventional treatments, but all of them have come with significant safety problems," Dr. Neil Scolding of the University of Bristol (United Kingdom), said in an interview.

Dr. Daniel Kantor, president of the Florida Society of Neurology and director of the Neurologique Foundation in Ponte Vedra Beach, Fla., said after the study’s presentation that "I think I speak for many people when I say, ‘wow.’ "

"Right now, as it stands, the data from the phase III trial are better than the phase II trial, which is not normally the case," Dr. Kantor said. He hoped that the CONFIRM trial can replicate the results of DEFINE and noted that no previous trial has compared an active drug against glatiramer acetate.

The study was supported by Biogen Idec. Dr. Gold disclosed receiving honoraria and research support from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience. Dr. Arnold has received consulting fees from Bayer HealthCare, Biogen Idec, Genentech, Merck Serono, NeuroRx Research, Roche, Schering-Plough, and Teva Neuroscience. Dr. O’Connor has received consulting fees and honoraria from Bayer, Biogen Idec, EMD Serono, Genentech, Novartis, Roche, Sanofi-Aventis, and Teva. Dr. Scolding had nothing to disclose. Dr. Kantor disclosed acting as an investigator or having commercial relationships with Acorda, Avanir, Biogen Idec (although not in relation to BG-12), Genzyme, Novartis, and Teva Neuroscience.

AMSTERDAM – Treatment with the investigational oral drug dimethyl fumarate reduced the risk of relapse by up to 50%, compared with placebo, in patients with relapsing–remitting multiple sclerosis in a phase III trial.

In the multicenter, randomized, double-blind trial of 1,234 patients, placebo-treated patients had a cumulative probability of relapse of 46% at 2 years, which was significantly higher than the rates of 27% and 26% recorded in patients who received dimethyl fumarate at 240 mg twice daily or 240 mg three times daily, respectively. These rates for the primary end point of the trial corresponded to hazard ratios for relapse of 0.51 and 0.50, respectively.

Those 2-year relapse rates translated to annualized relapse rates of 0.364 for placebo and 0.172 for 240 mg dimethyl fumarate twice daily and 0.189 for 240 mg three times daily.

The possibly of using a fumaric acid ester (FAE) such as dimethyl fumarate (also known as BG-12) in the treatment for MS was first suggested about 10 years ago, although FAEs have been used for the treatment of psoriasis for some years in Europe, said Dr. Ralf Gold of St. Josef and St. Elizabeth Hospital in Bochum, Germany. He presented the results of the DEFINE (Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS) study at the joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

BG-12 is thought to defend the brain against oxidative stress and recent experimental evidence suggests that it may have dual effects – acting as both an anti-inflammatory and as a neuroprotective agent (Brain 2011;134:678-92).

Findings from a phase II study of BG-12 showed that it reduced MRI-detected disease activity in MS by about 69% from week 12 to 24, compared with placebo (Lancet 2008;372:1463-72), but the current findings from DEFINE suggest a greater reduction in MRI lesions may be possible.

Dr. Gold reported data from an MRI substudy of DEFINE that involved 540 patients. BG-12 was associated with a 73%-98% reduction in gadolinium-enhancing (GdE) lesions and a 74%-85% reduction in new or newly enlarging T2 hyperintense lesions on MRI at 2 years, depending on the dosing regimen used.

Coinvestigator Dr. Douglas Arnold of the Montreal Neurological Institute and Hospital at McGill University commented in an interview that these MRI results are impressive if you consider what can be achieved with other therapies.

"I think everybody was pleasantly surprised at how effective [BG-12] was on the MRI," Dr. Arnold said. "The suppression of the GdE lesions is 90% – that’s a stronger effect than any medication that’s available currently for the treatment for MS." The reduction of GdE lesions is as low as 30% for some agents, although it as high as 89% for others such as natalizumab (Tysabri), he said.

BG-12 reduced the risk of disability progression at 12 weeks by 38% with twice daily dosing and by 34% with three times daily dosing as measured by scores on the Expanded Disability Status Scale.

The safety and tolerability of BG-12 did not appear to differ greatly from placebo. Serious adverse events were reported in fewer BG-12 than placebo-treated patients (16%-18% vs. 21%), with two deaths – both unrelated to treatment – occurring in the BG-12 groups.

Flushing and gastrointestinal adverse events were reported more frequently in the BG-12 groups, although Dr. Gold observed that most cases of flushing were mild or moderate in severity and their incidence decreased substantially after the first month of treatment. Opportunistic infections were seen only in placebo-treated patients, and there was no increased risk of other serious infections or malignancies with BG-12.

MS patients who took BG-12 also benefited from higher quality of life scores after 2 years on physical and mental functioning, as well as higher general well-being scores, than did patients who received placebo.

In addition to efficacy, the safety of BG-12 in the study is reassuring, Dr. Paul O’Connor, director of the MS Clinic at St. Michael’s Hospital in Toronto, said in an interview. He noted that data from a second ongoing phase III trial, called CONFIRM, would be needed before any firm conclusions could be drawn. CONFIRM is comparing BG-12 with an active comparator, glatiramer acetate (Copaxone).

"The safety data are very encouraging because there have been various new treatments over the past 4 or 5 years that looked to have a more powerful effect than our conventional treatments, but all of them have come with significant safety problems," Dr. Neil Scolding of the University of Bristol (United Kingdom), said in an interview.

Dr. Daniel Kantor, president of the Florida Society of Neurology and director of the Neurologique Foundation in Ponte Vedra Beach, Fla., said after the study’s presentation that "I think I speak for many people when I say, ‘wow.’ "

"Right now, as it stands, the data from the phase III trial are better than the phase II trial, which is not normally the case," Dr. Kantor said. He hoped that the CONFIRM trial can replicate the results of DEFINE and noted that no previous trial has compared an active drug against glatiramer acetate.

The study was supported by Biogen Idec. Dr. Gold disclosed receiving honoraria and research support from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience. Dr. Arnold has received consulting fees from Bayer HealthCare, Biogen Idec, Genentech, Merck Serono, NeuroRx Research, Roche, Schering-Plough, and Teva Neuroscience. Dr. O’Connor has received consulting fees and honoraria from Bayer, Biogen Idec, EMD Serono, Genentech, Novartis, Roche, Sanofi-Aventis, and Teva. Dr. Scolding had nothing to disclose. Dr. Kantor disclosed acting as an investigator or having commercial relationships with Acorda, Avanir, Biogen Idec (although not in relation to BG-12), Genzyme, Novartis, and Teva Neuroscience.

LISBON – Conventional liver function tests may miss a diagnosis of nonalcoholic fatty liver disease in patients with type 2 diabetes, according to prospective study findings.

Data from the NAFLD substudy of the ongoing Edinburgh Type 2 Diabetes Study (ET2DS) found that although hyaluronic acid (HA) may be a reasonably good indicator of whether liver fibrosis was absent, standard enzyme tests missed a significant proportion of fibrosis cases.

"The literature that we have is biased by the fact that when researchers have looked at more advanced liver disease, it’s been in patients who have already earned themselves a liver biopsy for whatever reason," Dr. Rachel Williamson said in an interview at the annual meeting of the European Association for the Study of Diabetes (EASD).

"So what we add by this study is that this is an unselected population of patients who are essentially otherwise potentially well, from a liver point of view," said Dr. Williamson of the Western General Hospital in Edinburgh.

The primary aim of the ET2DS is to identify risk factors for memory problems in people with type 2 diabetes. The 5-year study is also providing the opportunity to study the natural history and risk factors for comorbid disease and complications associated with diabetes.

Liver assessment was performed in 939 of 1,000 individuals aged 60-75 years who were randomly selected from the Lothian Diabetes Register. The mean age of the cohort was 69 years, 52% were women, and 98% were white. Mean body mass index was 31.3 kg/m², mean HbA_1c was 7.2%, and the duration of diabetes was 9 years.

All patients in the liver cohort underwent abdominal ultrasound, standard liver function tests (LFTs), detailed screening of secondary causes of liver disease, HA level, platelet count, and alpha-fetoprotein measurements. Because HA is found in high concentrations in the synovial joints, patients’ history of joint disease was obtained.

"Liver disease is common in type 2 diabetes and this is mainly due to nonalcoholic fatty liver disease," Dr. Williamson said. "The prevalence of NAFLD in our population was 42%," she added, which is lower than the 70%-80% seen in some studies.

Despite the high prevalence of NAFLD in patients with diabetes, its detection is fraught with difficulty. Patients are often asymptomatic; conventional LFTs do not reflect changes in personal history; and liver biopsy, which remains the clinical standard for diagnosis, is invasive, expensive, and prone to sampling bias.

The quest to find reliable, noninvasive markers for advanced liver disease led Dr. Williamson and colleagues to examine the relationship between HA and the prevalence of hepatic fibrosis, portal hypertension, and hepatocellular carcinoma (HCC). Another noninvasive marker, the ratio of the platelet count to spleen size, was also used, and the usefulness of LFTs, alanine aminotransferase, aspartate aminotransferase, bilirubin, and gamma-glutamyltransferase were assessed.

An HA level greater than 50 ng/mL has previously been linked to liver fibrosis, with a higher cut-off of 100 ng/mL deemed to be more predictive of advanced liver disease. Using the lower threshold, 45% of the cohort had high HA levels, which could have been due to liver fibrosis in 24%. In all, 6% of the study population had HA in excess of 100 ng/mL. "We concluded that this 6% almost certainly had liver fibrosis," Dr. Williamson said.

The prevalence of portal hypertension, cirrhosis and HCC in the entire cohort was 1.1%, 0.4%, and 0.2%, respectively. Figures were slightly lower in patients who had a no secondary cause of liver disease (0.6%, 0.2%, and 0.3%).

Although mean levels of ALT, AST and GGT were highest in patients with liver cirrhosis, compared with those with raised HA (more than 50 ng/mL or more than 100 ng/mL) and no arthritis, steatosis, or normal liver scan, these levels remained within normal limits.

The positive predictive values of ALT and GGT above normal for predicting fibrosis were low (26% and 29%, respectively). The respective negative predictive values were 75% and 75%.

"The use of conventional liver function tests to screen for liver disease missed a significant proportion of cases of fibrosis predicted by raised HA levels, Dr. Williams concluded.

"A normal hyaluronic acid level can be quite reassuring," Dr. Williamson observed in the interview. She noted that although HA may only be measured in patients with known steatosis or abnormal LFTs, it could help to decide if referral to a gastroenterologist was needed, or if follow-up in the diabetes clinic was sufficient.

"I would routinely refer somebody with a significantly high hyaluronic acid onto the gastroenterologist, and we might then be considering doing liver biopsy or more invasive monitoring or further tests."

The ET2DS study is funded by Pfizer. Dr. Williamson reported having no financial conflicts of interest.

LISBON – Conventional liver function tests may miss a diagnosis of nonalcoholic fatty liver disease in patients with type 2 diabetes, according to prospective study findings.

Data from the NAFLD substudy of the ongoing Edinburgh Type 2 Diabetes Study (ET2DS) found that although hyaluronic acid (HA) may be a reasonably good indicator of whether liver fibrosis was absent, standard enzyme tests missed a significant proportion of fibrosis cases.

"The literature that we have is biased by the fact that when researchers have looked at more advanced liver disease, it’s been in patients who have already earned themselves a liver biopsy for whatever reason," Dr. Rachel Williamson said in an interview at the annual meeting of the European Association for the Study of Diabetes (EASD).

"So what we add by this study is that this is an unselected population of patients who are essentially otherwise potentially well, from a liver point of view," said Dr. Williamson of the Western General Hospital in Edinburgh.

The primary aim of the ET2DS is to identify risk factors for memory problems in people with type 2 diabetes. The 5-year study is also providing the opportunity to study the natural history and risk factors for comorbid disease and complications associated with diabetes.

Liver assessment was performed in 939 of 1,000 individuals aged 60-75 years who were randomly selected from the Lothian Diabetes Register. The mean age of the cohort was 69 years, 52% were women, and 98% were white. Mean body mass index was 31.3 kg/m², mean HbA_1c was 7.2%, and the duration of diabetes was 9 years.

All patients in the liver cohort underwent abdominal ultrasound, standard liver function tests (LFTs), detailed screening of secondary causes of liver disease, HA level, platelet count, and alpha-fetoprotein measurements. Because HA is found in high concentrations in the synovial joints, patients’ history of joint disease was obtained.

"Liver disease is common in type 2 diabetes and this is mainly due to nonalcoholic fatty liver disease," Dr. Williamson said. "The prevalence of NAFLD in our population was 42%," she added, which is lower than the 70%-80% seen in some studies.

Despite the high prevalence of NAFLD in patients with diabetes, its detection is fraught with difficulty. Patients are often asymptomatic; conventional LFTs do not reflect changes in personal history; and liver biopsy, which remains the clinical standard for diagnosis, is invasive, expensive, and prone to sampling bias.

The quest to find reliable, noninvasive markers for advanced liver disease led Dr. Williamson and colleagues to examine the relationship between HA and the prevalence of hepatic fibrosis, portal hypertension, and hepatocellular carcinoma (HCC). Another noninvasive marker, the ratio of the platelet count to spleen size, was also used, and the usefulness of LFTs, alanine aminotransferase, aspartate aminotransferase, bilirubin, and gamma-glutamyltransferase were assessed.

An HA level greater than 50 ng/mL has previously been linked to liver fibrosis, with a higher cut-off of 100 ng/mL deemed to be more predictive of advanced liver disease. Using the lower threshold, 45% of the cohort had high HA levels, which could have been due to liver fibrosis in 24%. In all, 6% of the study population had HA in excess of 100 ng/mL. "We concluded that this 6% almost certainly had liver fibrosis," Dr. Williamson said.

The prevalence of portal hypertension, cirrhosis and HCC in the entire cohort was 1.1%, 0.4%, and 0.2%, respectively. Figures were slightly lower in patients who had a no secondary cause of liver disease (0.6%, 0.2%, and 0.3%).

Although mean levels of ALT, AST and GGT were highest in patients with liver cirrhosis, compared with those with raised HA (more than 50 ng/mL or more than 100 ng/mL) and no arthritis, steatosis, or normal liver scan, these levels remained within normal limits.

The positive predictive values of ALT and GGT above normal for predicting fibrosis were low (26% and 29%, respectively). The respective negative predictive values were 75% and 75%.

"The use of conventional liver function tests to screen for liver disease missed a significant proportion of cases of fibrosis predicted by raised HA levels, Dr. Williams concluded.

"A normal hyaluronic acid level can be quite reassuring," Dr. Williamson observed in the interview. She noted that although HA may only be measured in patients with known steatosis or abnormal LFTs, it could help to decide if referral to a gastroenterologist was needed, or if follow-up in the diabetes clinic was sufficient.

"I would routinely refer somebody with a significantly high hyaluronic acid onto the gastroenterologist, and we might then be considering doing liver biopsy or more invasive monitoring or further tests."

The ET2DS study is funded by Pfizer. Dr. Williamson reported having no financial conflicts of interest.

LISBON – Conventional liver function tests may miss a diagnosis of nonalcoholic fatty liver disease in patients with type 2 diabetes, according to prospective study findings.

Data from the NAFLD substudy of the ongoing Edinburgh Type 2 Diabetes Study (ET2DS) found that although hyaluronic acid (HA) may be a reasonably good indicator of whether liver fibrosis was absent, standard enzyme tests missed a significant proportion of fibrosis cases.

"The literature that we have is biased by the fact that when researchers have looked at more advanced liver disease, it’s been in patients who have already earned themselves a liver biopsy for whatever reason," Dr. Rachel Williamson said in an interview at the annual meeting of the European Association for the Study of Diabetes (EASD).

"So what we add by this study is that this is an unselected population of patients who are essentially otherwise potentially well, from a liver point of view," said Dr. Williamson of the Western General Hospital in Edinburgh.

The primary aim of the ET2DS is to identify risk factors for memory problems in people with type 2 diabetes. The 5-year study is also providing the opportunity to study the natural history and risk factors for comorbid disease and complications associated with diabetes.

Liver assessment was performed in 939 of 1,000 individuals aged 60-75 years who were randomly selected from the Lothian Diabetes Register. The mean age of the cohort was 69 years, 52% were women, and 98% were white. Mean body mass index was 31.3 kg/m², mean HbA_1c was 7.2%, and the duration of diabetes was 9 years.

All patients in the liver cohort underwent abdominal ultrasound, standard liver function tests (LFTs), detailed screening of secondary causes of liver disease, HA level, platelet count, and alpha-fetoprotein measurements. Because HA is found in high concentrations in the synovial joints, patients’ history of joint disease was obtained.

"Liver disease is common in type 2 diabetes and this is mainly due to nonalcoholic fatty liver disease," Dr. Williamson said. "The prevalence of NAFLD in our population was 42%," she added, which is lower than the 70%-80% seen in some studies.

Despite the high prevalence of NAFLD in patients with diabetes, its detection is fraught with difficulty. Patients are often asymptomatic; conventional LFTs do not reflect changes in personal history; and liver biopsy, which remains the clinical standard for diagnosis, is invasive, expensive, and prone to sampling bias.

The quest to find reliable, noninvasive markers for advanced liver disease led Dr. Williamson and colleagues to examine the relationship between HA and the prevalence of hepatic fibrosis, portal hypertension, and hepatocellular carcinoma (HCC). Another noninvasive marker, the ratio of the platelet count to spleen size, was also used, and the usefulness of LFTs, alanine aminotransferase, aspartate aminotransferase, bilirubin, and gamma-glutamyltransferase were assessed.

An HA level greater than 50 ng/mL has previously been linked to liver fibrosis, with a higher cut-off of 100 ng/mL deemed to be more predictive of advanced liver disease. Using the lower threshold, 45% of the cohort had high HA levels, which could have been due to liver fibrosis in 24%. In all, 6% of the study population had HA in excess of 100 ng/mL. "We concluded that this 6% almost certainly had liver fibrosis," Dr. Williamson said.

The prevalence of portal hypertension, cirrhosis and HCC in the entire cohort was 1.1%, 0.4%, and 0.2%, respectively. Figures were slightly lower in patients who had a no secondary cause of liver disease (0.6%, 0.2%, and 0.3%).

Although mean levels of ALT, AST and GGT were highest in patients with liver cirrhosis, compared with those with raised HA (more than 50 ng/mL or more than 100 ng/mL) and no arthritis, steatosis, or normal liver scan, these levels remained within normal limits.

The positive predictive values of ALT and GGT above normal for predicting fibrosis were low (26% and 29%, respectively). The respective negative predictive values were 75% and 75%.

"The use of conventional liver function tests to screen for liver disease missed a significant proportion of cases of fibrosis predicted by raised HA levels, Dr. Williams concluded.

"A normal hyaluronic acid level can be quite reassuring," Dr. Williamson observed in the interview. She noted that although HA may only be measured in patients with known steatosis or abnormal LFTs, it could help to decide if referral to a gastroenterologist was needed, or if follow-up in the diabetes clinic was sufficient.

"I would routinely refer somebody with a significantly high hyaluronic acid onto the gastroenterologist, and we might then be considering doing liver biopsy or more invasive monitoring or further tests."

The ET2DS study is funded by Pfizer. Dr. Williamson reported having no financial conflicts of interest.

Major Finding: Mean Kleiner scores were higher in patients with diabetes than in those who did not have diabetes (6.4 vs. 4.7; P less than .001).

Data Source: Retrospective study of 112 patients with biopsy-proven NAFLD linking severity of disease with the Framingham Risk Score and QRISK2; 32 had diabetes mellitus.

Disclosures: The study was funded by the National Institute for Health Research and Diabetes UK. Dr. Byrne and Ms. Hudson said they had no relevant financial disclosures. Dr. Byrne has given lectures on behalf of pharmaceutical companies in the past, including Pfizer.

LISBON – Increasing accumulation of fat, inflammation, and fibrosis of the liver appears tied to corresponding increases in the risk of cardiovascular disease, especially in patients with diabetes, according to the findings of a small retrospective study presented at the meeting.

“What we are realizing is that [nonalcoholic fatty liver disease] is adding extra cardiovascular risk to people with diabetes, and to those without, on top of that which is already existing,” Dr. Christopher Byrne, one of the lead study investigators, said in an interview.

Dr. Byrne, professor of endocrinology and metabolism at the University of Southampton (England), said that patients with documented liver disease may require more aggressive therapies to address the added risk. Such therapies need to target the liver as much as the heart.

In the study of 112 patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD), Kleiner scores – a histologic measure of NAFLD severity – were highly correlated with both Framingham Risk Score (FRS) and QRISK2, two cardiovascular risk calculators.

“Nonalcoholic fatty liver disease represents a spectrum of fat-mediated liver conditions causing progressive hepatocellular damage,” said Sarah Hudson, a 5th-year medical student at the University of Southampton.

“There is increasing evidence of an increased cardiovascular risk associated with progression of nonalcoholic fatty liver disease,” Ms. Hudson explained, noting that the preferred method of determining NAFLD severity was via histopathologic assessment.

The aim of the study was to see if a histopathologic marker – Kleiner score – correlated with cardiovascular risk, and if scores were higher in people already known to have a high cardiovascular risk, namely those with diabetes.

Kleiner scores assess the degree of steatosis, lobular inflammation, hepatocyte “ballooning,” and fibrosis, with higher scores indicating more severe liver disease (Hepatology 2005;41:1313-21).

The mean age of the study cohort was 48 years and the mean Kleiner score was 5.3. The median FRS was 13 and the median QRISK2 score was 8. The mean body mass index of participants was approximately 34 kg/m

Kleiner scores were not only found to be highly correlated with both cardiovascular risk models used, but they were also higher in a subgroup of 32 patients with diabetes when compared with those without diabetes (6.4 vs. 4.7, P less than .001).

The increased risk of cardiovascular disease in correlation with increasing NAFLD severity was found to be independent of both hyperglycemia and increasing body weight.

“We need more prospective studies to see what markers may be used to help stratify who requires biopsy and how best to manage people who have got NAFLD.” Nonalcoholic steatohepatitis was associated with the highest cardiovascular risk estimates in the study.

“Up until now we've been very poor in providing cardiovascular risk reduction treatments for patients with NAFLD,” Dr. Byrne said. Currently the only treatment strategy proven to work for NAFLD is lifestyle changes.

“We know that losing weight and increasing activity levels are very effective at decreasing liver fat,” Dr. Byrne explained. “But what we don't know is whether those lifestyle changes are good at decreasing liver inflammation, or decreasing liver fibrosis.”

Treatment to decrease liver fat and prevent progression to fibrosis is thus urgently needed, and Dr. Byrne is part of a team now looking at the use of a high concentration of highly purified omega-3 fatty acid ethyl esters to treat NAFLD.

The highly purified fish oil being used in the trial has been available commercially in Europe for at least a decade (Omacor) and in the United States since 2004 (Lovaza), and is currently licensed to treat hypertriglyceridemia.

NAFLD 'is adding extra cardiovascular risk to people with diabetes, and to those without.'

Source DR. BYRNE

Major Finding: Mean Kleiner scores were higher in patients with diabetes than in those who did not have diabetes (6.4 vs. 4.7; P less than .001).

Data Source: Retrospective study of 112 patients with biopsy-proven NAFLD linking severity of disease with the Framingham Risk Score and QRISK2; 32 had diabetes mellitus.

Disclosures: The study was funded by the National Institute for Health Research and Diabetes UK. Dr. Byrne and Ms. Hudson said they had no relevant financial disclosures. Dr. Byrne has given lectures on behalf of pharmaceutical companies in the past, including Pfizer.

LISBON – Increasing accumulation of fat, inflammation, and fibrosis of the liver appears tied to corresponding increases in the risk of cardiovascular disease, especially in patients with diabetes, according to the findings of a small retrospective study presented at the meeting.

“What we are realizing is that [nonalcoholic fatty liver disease] is adding extra cardiovascular risk to people with diabetes, and to those without, on top of that which is already existing,” Dr. Christopher Byrne, one of the lead study investigators, said in an interview.

Dr. Byrne, professor of endocrinology and metabolism at the University of Southampton (England), said that patients with documented liver disease may require more aggressive therapies to address the added risk. Such therapies need to target the liver as much as the heart.

In the study of 112 patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD), Kleiner scores – a histologic measure of NAFLD severity – were highly correlated with both Framingham Risk Score (FRS) and QRISK2, two cardiovascular risk calculators.

“Nonalcoholic fatty liver disease represents a spectrum of fat-mediated liver conditions causing progressive hepatocellular damage,” said Sarah Hudson, a 5th-year medical student at the University of Southampton.

“There is increasing evidence of an increased cardiovascular risk associated with progression of nonalcoholic fatty liver disease,” Ms. Hudson explained, noting that the preferred method of determining NAFLD severity was via histopathologic assessment.

The aim of the study was to see if a histopathologic marker – Kleiner score – correlated with cardiovascular risk, and if scores were higher in people already known to have a high cardiovascular risk, namely those with diabetes.

Kleiner scores assess the degree of steatosis, lobular inflammation, hepatocyte “ballooning,” and fibrosis, with higher scores indicating more severe liver disease (Hepatology 2005;41:1313-21).

The mean age of the study cohort was 48 years and the mean Kleiner score was 5.3. The median FRS was 13 and the median QRISK2 score was 8. The mean body mass index of participants was approximately 34 kg/m

Kleiner scores were not only found to be highly correlated with both cardiovascular risk models used, but they were also higher in a subgroup of 32 patients with diabetes when compared with those without diabetes (6.4 vs. 4.7, P less than .001).

The increased risk of cardiovascular disease in correlation with increasing NAFLD severity was found to be independent of both hyperglycemia and increasing body weight.

“We need more prospective studies to see what markers may be used to help stratify who requires biopsy and how best to manage people who have got NAFLD.” Nonalcoholic steatohepatitis was associated with the highest cardiovascular risk estimates in the study.

“Up until now we've been very poor in providing cardiovascular risk reduction treatments for patients with NAFLD,” Dr. Byrne said. Currently the only treatment strategy proven to work for NAFLD is lifestyle changes.

“We know that losing weight and increasing activity levels are very effective at decreasing liver fat,” Dr. Byrne explained. “But what we don't know is whether those lifestyle changes are good at decreasing liver inflammation, or decreasing liver fibrosis.”

Treatment to decrease liver fat and prevent progression to fibrosis is thus urgently needed, and Dr. Byrne is part of a team now looking at the use of a high concentration of highly purified omega-3 fatty acid ethyl esters to treat NAFLD.

The highly purified fish oil being used in the trial has been available commercially in Europe for at least a decade (Omacor) and in the United States since 2004 (Lovaza), and is currently licensed to treat hypertriglyceridemia.

NAFLD 'is adding extra cardiovascular risk to people with diabetes, and to those without.'

Source DR. BYRNE

Major Finding: Mean Kleiner scores were higher in patients with diabetes than in those who did not have diabetes (6.4 vs. 4.7; P less than .001).

Data Source: Retrospective study of 112 patients with biopsy-proven NAFLD linking severity of disease with the Framingham Risk Score and QRISK2; 32 had diabetes mellitus.

Disclosures: The study was funded by the National Institute for Health Research and Diabetes UK. Dr. Byrne and Ms. Hudson said they had no relevant financial disclosures. Dr. Byrne has given lectures on behalf of pharmaceutical companies in the past, including Pfizer.

LISBON – Increasing accumulation of fat, inflammation, and fibrosis of the liver appears tied to corresponding increases in the risk of cardiovascular disease, especially in patients with diabetes, according to the findings of a small retrospective study presented at the meeting.

“What we are realizing is that [nonalcoholic fatty liver disease] is adding extra cardiovascular risk to people with diabetes, and to those without, on top of that which is already existing,” Dr. Christopher Byrne, one of the lead study investigators, said in an interview.

Dr. Byrne, professor of endocrinology and metabolism at the University of Southampton (England), said that patients with documented liver disease may require more aggressive therapies to address the added risk. Such therapies need to target the liver as much as the heart.

In the study of 112 patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD), Kleiner scores – a histologic measure of NAFLD severity – were highly correlated with both Framingham Risk Score (FRS) and QRISK2, two cardiovascular risk calculators.

“Nonalcoholic fatty liver disease represents a spectrum of fat-mediated liver conditions causing progressive hepatocellular damage,” said Sarah Hudson, a 5th-year medical student at the University of Southampton.

“There is increasing evidence of an increased cardiovascular risk associated with progression of nonalcoholic fatty liver disease,” Ms. Hudson explained, noting that the preferred method of determining NAFLD severity was via histopathologic assessment.

The aim of the study was to see if a histopathologic marker – Kleiner score – correlated with cardiovascular risk, and if scores were higher in people already known to have a high cardiovascular risk, namely those with diabetes.

Kleiner scores assess the degree of steatosis, lobular inflammation, hepatocyte “ballooning,” and fibrosis, with higher scores indicating more severe liver disease (Hepatology 2005;41:1313-21).

The mean age of the study cohort was 48 years and the mean Kleiner score was 5.3. The median FRS was 13 and the median QRISK2 score was 8. The mean body mass index of participants was approximately 34 kg/m

Kleiner scores were not only found to be highly correlated with both cardiovascular risk models used, but they were also higher in a subgroup of 32 patients with diabetes when compared with those without diabetes (6.4 vs. 4.7, P less than .001).

The increased risk of cardiovascular disease in correlation with increasing NAFLD severity was found to be independent of both hyperglycemia and increasing body weight.

“We need more prospective studies to see what markers may be used to help stratify who requires biopsy and how best to manage people who have got NAFLD.” Nonalcoholic steatohepatitis was associated with the highest cardiovascular risk estimates in the study.

“Up until now we've been very poor in providing cardiovascular risk reduction treatments for patients with NAFLD,” Dr. Byrne said. Currently the only treatment strategy proven to work for NAFLD is lifestyle changes.

“We know that losing weight and increasing activity levels are very effective at decreasing liver fat,” Dr. Byrne explained. “But what we don't know is whether those lifestyle changes are good at decreasing liver inflammation, or decreasing liver fibrosis.”

Treatment to decrease liver fat and prevent progression to fibrosis is thus urgently needed, and Dr. Byrne is part of a team now looking at the use of a high concentration of highly purified omega-3 fatty acid ethyl esters to treat NAFLD.

The highly purified fish oil being used in the trial has been available commercially in Europe for at least a decade (Omacor) and in the United States since 2004 (Lovaza), and is currently licensed to treat hypertriglyceridemia.

NAFLD 'is adding extra cardiovascular risk to people with diabetes, and to those without.'

Source DR. BYRNE

LISBON – Improved glucose parameters, substantial weight loss, and increased incretin hormone levels can be achieved by the insertion of a novel, minimally invasive, intestinal device in obese patients with type 2 diabetes.

The use of a duodenal-jejunal bypass liner (DJBL) not only improves hemoglobin A_1c and aids weight loss, but also appears to increase levels of glucagon-like peptide (GLP)-1 and peptide YY while in place, according to the findings of a small study presented at the meeting.

Although the effects may be temporary, they could offer patients a reversible alternative to bariatric surgery that helps to kick-start weight loss and self-management of diabetes, said study author Dr. Charlotte de Jonge of Maastricht University in the Netherlands. “Not all patients want [bariatric] surgery, as it is permanent.”

She added that the DJBL was perhaps “an easy first step” and that patients could perhaps still opt for weight-loss surgery later on or be retreated with the device to the point that medication was again sufficient to help manage their diabetes.

The DJBL (EndoBarrier) is a 60-cm impermeable sleeve that is inserted and removed endoscopically, and which effectively blocks the duodenum and proximal jejunum in a manner similar to the Roux-en-Y-gastric bypass procedure. It is thought to work by creating a physical barrier between ingested food and the intestinal wall, and perhaps alters the activation of incretin hormones in the gut. On average, the device can be inserted in 20 minutes and removed in 10 minutes, under conscious sedation, which allows the patient to go home the same day as the procedure.

The aim of the 17-patient study was to investigate the possible mechanisms for the improvement in diabetic parameters after insertion of the DJBL seen in previous studies. Fourteen men and three women participated, all of whom had type 2 diabetes and a body mass index in excess of 30 kg/m

Before implantation of the device, subjects underwent a meal tolerance test that involved a 12-hour fast, then ingestion of a 500-kcal liquid meal and blood sampling at baseline and at 10-, 20-, 30-, 60-, 90-, and 120-minute intervals. HbA_1c, glucose, insulin, GLP-1, and PYY concentrations were measured. Measurements were repeated before removal of the device, and again 1 week after removal of the device.

The DJBL was left in place for 24 weeks, although Dr. de Jonge noted that the device could be used for up to 2 years in some patients. About 500 patients have received the device in clinical studies, she said in an interview. It has received approval for use in a few European countries and Australia. It remains investigational in the United States.

Within 1 week after implantation, fasting and area under the curve (AUC) glucose concentrations were improved (11.4±0.5 mmol/L vs. 8.9±0.4 mmol/L and 1,999±88 vs. 1,535±53), respectively. In addition, AUC concentrations of GLP-1 increased from 2,584 at baseline to 4,112 at removal and PYY from 4,440 to 6,448. All differences were statistically significant.

When the device was removed at 6 months, a significant mean weight loss of 13 kg had been recorded, with a mean loss of excess weight of 30%, said Dr. de Jonge. Importantly, mean HbA_1c decreased from 8.4% at baseline to 7.0% at removal and there was a reduction in the use of antidiabetic medication in all but one of the study participants. All these difference were highly significant.

“Interestingly, GLP-1 and GIP [glucose-dependent insulinotropic peptide] not only have an effect on insulin, but they also affect glucagon as well,” Dr. de Jonge reported during her presentation. There was a normalization of the glucagon response during treatment with the DJBL to a more physiological response.

Almost all patients reported increased satiety, she added.

Commenting on the presentation, Dr. Roy Taylor, professor of medicine and metabolism at the University of Newcastle (U.K.), noted that it would be useful to know what the effects of diet alone were and to see the relationship to the other changes in parameters shown.

In an interview, Dr. de Jonge noted that other data had suggested the weight loss achieved by diet alone was around 4–5 kg, so there did appear to be a greater weight loss effect when the DJBL was inserted.

With regard to side effects, the most common adverse events were abdominal discomfort, including epigastric pain and nausea. Such events were more common in the first 1–2 weeks, but tended to resolve with longer duration of use. There was no withdrawal of the device, and Dr. de Jonge noted that even when patients reported side effects, they were loath to have it removed.

“What we hope is that we can encourage lifestyle changes and we can motivate patients to remain at a lower weight,” Dr. de Jonge observed.

GI Dynamics funded the study. Dr. de Jonge and Dr. Taylor reported having no conflicts of interest.

The EndoBarrier is a 60-cm sleeve that blocks the duodenum and proximal jejunum.

Source Courtesy Pure Communications Inc

LISBON – Improved glucose parameters, substantial weight loss, and increased incretin hormone levels can be achieved by the insertion of a novel, minimally invasive, intestinal device in obese patients with type 2 diabetes.

The use of a duodenal-jejunal bypass liner (DJBL) not only improves hemoglobin A_1c and aids weight loss, but also appears to increase levels of glucagon-like peptide (GLP)-1 and peptide YY while in place, according to the findings of a small study presented at the meeting.

Although the effects may be temporary, they could offer patients a reversible alternative to bariatric surgery that helps to kick-start weight loss and self-management of diabetes, said study author Dr. Charlotte de Jonge of Maastricht University in the Netherlands. “Not all patients want [bariatric] surgery, as it is permanent.”

She added that the DJBL was perhaps “an easy first step” and that patients could perhaps still opt for weight-loss surgery later on or be retreated with the device to the point that medication was again sufficient to help manage their diabetes.

The DJBL (EndoBarrier) is a 60-cm impermeable sleeve that is inserted and removed endoscopically, and which effectively blocks the duodenum and proximal jejunum in a manner similar to the Roux-en-Y-gastric bypass procedure. It is thought to work by creating a physical barrier between ingested food and the intestinal wall, and perhaps alters the activation of incretin hormones in the gut. On average, the device can be inserted in 20 minutes and removed in 10 minutes, under conscious sedation, which allows the patient to go home the same day as the procedure.

The aim of the 17-patient study was to investigate the possible mechanisms for the improvement in diabetic parameters after insertion of the DJBL seen in previous studies. Fourteen men and three women participated, all of whom had type 2 diabetes and a body mass index in excess of 30 kg/m

Before implantation of the device, subjects underwent a meal tolerance test that involved a 12-hour fast, then ingestion of a 500-kcal liquid meal and blood sampling at baseline and at 10-, 20-, 30-, 60-, 90-, and 120-minute intervals. HbA_1c, glucose, insulin, GLP-1, and PYY concentrations were measured. Measurements were repeated before removal of the device, and again 1 week after removal of the device.

The DJBL was left in place for 24 weeks, although Dr. de Jonge noted that the device could be used for up to 2 years in some patients. About 500 patients have received the device in clinical studies, she said in an interview. It has received approval for use in a few European countries and Australia. It remains investigational in the United States.

Within 1 week after implantation, fasting and area under the curve (AUC) glucose concentrations were improved (11.4±0.5 mmol/L vs. 8.9±0.4 mmol/L and 1,999±88 vs. 1,535±53), respectively. In addition, AUC concentrations of GLP-1 increased from 2,584 at baseline to 4,112 at removal and PYY from 4,440 to 6,448. All differences were statistically significant.

When the device was removed at 6 months, a significant mean weight loss of 13 kg had been recorded, with a mean loss of excess weight of 30%, said Dr. de Jonge. Importantly, mean HbA_1c decreased from 8.4% at baseline to 7.0% at removal and there was a reduction in the use of antidiabetic medication in all but one of the study participants. All these difference were highly significant.

“Interestingly, GLP-1 and GIP [glucose-dependent insulinotropic peptide] not only have an effect on insulin, but they also affect glucagon as well,” Dr. de Jonge reported during her presentation. There was a normalization of the glucagon response during treatment with the DJBL to a more physiological response.

Almost all patients reported increased satiety, she added.

Commenting on the presentation, Dr. Roy Taylor, professor of medicine and metabolism at the University of Newcastle (U.K.), noted that it would be useful to know what the effects of diet alone were and to see the relationship to the other changes in parameters shown.

In an interview, Dr. de Jonge noted that other data had suggested the weight loss achieved by diet alone was around 4–5 kg, so there did appear to be a greater weight loss effect when the DJBL was inserted.

With regard to side effects, the most common adverse events were abdominal discomfort, including epigastric pain and nausea. Such events were more common in the first 1–2 weeks, but tended to resolve with longer duration of use. There was no withdrawal of the device, and Dr. de Jonge noted that even when patients reported side effects, they were loath to have it removed.

“What we hope is that we can encourage lifestyle changes and we can motivate patients to remain at a lower weight,” Dr. de Jonge observed.

GI Dynamics funded the study. Dr. de Jonge and Dr. Taylor reported having no conflicts of interest.

The EndoBarrier is a 60-cm sleeve that blocks the duodenum and proximal jejunum.

Source Courtesy Pure Communications Inc

LISBON – Improved glucose parameters, substantial weight loss, and increased incretin hormone levels can be achieved by the insertion of a novel, minimally invasive, intestinal device in obese patients with type 2 diabetes.

The use of a duodenal-jejunal bypass liner (DJBL) not only improves hemoglobin A_1c and aids weight loss, but also appears to increase levels of glucagon-like peptide (GLP)-1 and peptide YY while in place, according to the findings of a small study presented at the meeting.

Although the effects may be temporary, they could offer patients a reversible alternative to bariatric surgery that helps to kick-start weight loss and self-management of diabetes, said study author Dr. Charlotte de Jonge of Maastricht University in the Netherlands. “Not all patients want [bariatric] surgery, as it is permanent.”

She added that the DJBL was perhaps “an easy first step” and that patients could perhaps still opt for weight-loss surgery later on or be retreated with the device to the point that medication was again sufficient to help manage their diabetes.

The DJBL (EndoBarrier) is a 60-cm impermeable sleeve that is inserted and removed endoscopically, and which effectively blocks the duodenum and proximal jejunum in a manner similar to the Roux-en-Y-gastric bypass procedure. It is thought to work by creating a physical barrier between ingested food and the intestinal wall, and perhaps alters the activation of incretin hormones in the gut. On average, the device can be inserted in 20 minutes and removed in 10 minutes, under conscious sedation, which allows the patient to go home the same day as the procedure.

The aim of the 17-patient study was to investigate the possible mechanisms for the improvement in diabetic parameters after insertion of the DJBL seen in previous studies. Fourteen men and three women participated, all of whom had type 2 diabetes and a body mass index in excess of 30 kg/m

Before implantation of the device, subjects underwent a meal tolerance test that involved a 12-hour fast, then ingestion of a 500-kcal liquid meal and blood sampling at baseline and at 10-, 20-, 30-, 60-, 90-, and 120-minute intervals. HbA_1c, glucose, insulin, GLP-1, and PYY concentrations were measured. Measurements were repeated before removal of the device, and again 1 week after removal of the device.

The DJBL was left in place for 24 weeks, although Dr. de Jonge noted that the device could be used for up to 2 years in some patients. About 500 patients have received the device in clinical studies, she said in an interview. It has received approval for use in a few European countries and Australia. It remains investigational in the United States.

Within 1 week after implantation, fasting and area under the curve (AUC) glucose concentrations were improved (11.4±0.5 mmol/L vs. 8.9±0.4 mmol/L and 1,999±88 vs. 1,535±53), respectively. In addition, AUC concentrations of GLP-1 increased from 2,584 at baseline to 4,112 at removal and PYY from 4,440 to 6,448. All differences were statistically significant.

When the device was removed at 6 months, a significant mean weight loss of 13 kg had been recorded, with a mean loss of excess weight of 30%, said Dr. de Jonge. Importantly, mean HbA_1c decreased from 8.4% at baseline to 7.0% at removal and there was a reduction in the use of antidiabetic medication in all but one of the study participants. All these difference were highly significant.

“Interestingly, GLP-1 and GIP [glucose-dependent insulinotropic peptide] not only have an effect on insulin, but they also affect glucagon as well,” Dr. de Jonge reported during her presentation. There was a normalization of the glucagon response during treatment with the DJBL to a more physiological response.

Almost all patients reported increased satiety, she added.

Commenting on the presentation, Dr. Roy Taylor, professor of medicine and metabolism at the University of Newcastle (U.K.), noted that it would be useful to know what the effects of diet alone were and to see the relationship to the other changes in parameters shown.

In an interview, Dr. de Jonge noted that other data had suggested the weight loss achieved by diet alone was around 4–5 kg, so there did appear to be a greater weight loss effect when the DJBL was inserted.

With regard to side effects, the most common adverse events were abdominal discomfort, including epigastric pain and nausea. Such events were more common in the first 1–2 weeks, but tended to resolve with longer duration of use. There was no withdrawal of the device, and Dr. de Jonge noted that even when patients reported side effects, they were loath to have it removed.

“What we hope is that we can encourage lifestyle changes and we can motivate patients to remain at a lower weight,” Dr. de Jonge observed.

GI Dynamics funded the study. Dr. de Jonge and Dr. Taylor reported having no conflicts of interest.

The EndoBarrier is a 60-cm sleeve that blocks the duodenum and proximal jejunum.

Source Courtesy Pure Communications Inc

LISBON – Increasing accumulation of fat, inflammation, and fibrosis of the liver appears tied to corresponding increases in the risk of cardiovascular disease, especially in patients with diabetes, according to the findings of a small retrospective study presented at the annual meeting of the European Society for the Study of Diabetes.

"What we are realizing is that [nonalcoholic fatty liver disease] is adding extra cardiovascular risk to people with diabetes, and to those without, on top of that which is already existing," Dr. Christopher Byrne, one of the lead study investigators, said in an interview.

Dr. Byrne, professor of endocrinology and metabolism at the University of Southampton (England), suggested that patients with documented liver disease perhaps require more aggressive therapies to address the additional risk. Such therapies need to target the liver as much as the heart.

In the study of 112 patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD), Kleiner scores – a histologic measure of NAFLD severity – were shown to be highly correlated with both Framingham Risk Score (FRS) and QRISK2, two cardiovascular risk calculators.

"Nonalcoholic fatty liver disease represents a spectrum of fat-mediated liver conditions causing progressive hepatocellular damage," said Sarah Hudson, a 5th-year medical student at the University of Southampton.

"There is increasing evidence of an increased cardiovascular risk associated with progression of nonalcoholic fatty liver disease," Ms. Hudson explained, noting that the preferred method of determining NAFLD severity was via histopathologic assessment.

The aim of the study was to see if a histopathologic marker – Kleiner score – correlated with cardiovascular risk, and if scores were higher in people already known to have a high cardiovascular risk, namely those with diabetes.

Kleiner scores assess the degree of steatosis, lobular inflammation, hepatocyte "ballooning," and fibrosis, with higher scores indicating more severe liver disease (Hepatology 2005;41:1313-21).

The mean age of the study cohort was 48 years and the mean Kleiner score was 5.3. The median FRS was 13 and the median QRISK2 score was 8. The mean body mass index of participants was approximately 34 kg/m².

Kleiner scores were not only found to be highly correlated with both cardiovascular risk models used, but they were also higher in a subgroup of 32 patients with diabetes when compared with those without diabetes (6.4 vs. 4.7, P less than .001).

The increased risk of cardiovascular disease in correlation with increasing NAFLD severity was found to be independent of both hyperglycemia and increasing body weight.

"We need more prospective studies to see what markers may be used to help stratify who requires biopsy and how best to manage people who have got NAFLD." Nonalcoholic steatohepatitis was associated with the highest cardiovascular risk estimates in the study.

"Up until now we’ve been very poor in providing cardiovascular risk reduction treatments for patients with NAFLD," Dr. Byrne said. Currently the only treatment strategy proven to work for NAFLD is lifestyle changes.

"We know that losing weight and increasing activity levels are very effective at decreasing liver fat," Dr. Byrne explained. "But what we don’t know is whether those lifestyle changes are good at decreasing liver inflammation, or decreasing liver fibrosis."

Treatment to decrease liver fat and prevent progression to fibrosis is thus urgently needed, and Dr. Byrne is part of a team now looking at the use of a high concentration of highly purified omega-3 fatty acid ethyl esters in the treatment of NAFLD.

The highly purified fish oil being used in the trial has been available commercially in Europe for at least a decade (Omacor) and in the United States since 2004 (Lovaza), and is currently licensed to treat hypertriglyceridemia.

The study is not due to be completed until December 2012. Until then, clinicians need to optimize the treatments they have at their disposal, including antihypertensive and lipid-lowering medicines commonly used to lower cardiovascular risk in conjunction with lifestyle modifications.

The study was funded by the National Institute for Health Research and Diabetes UK. Dr. Byrne and Ms. Hudson said they had no relevant financial disclosures. Dr. Byrne said he has given lectures on behalf of pharmaceutical companies in the past, including Pfizer.

LISBON – Increasing accumulation of fat, inflammation, and fibrosis of the liver appears tied to corresponding increases in the risk of cardiovascular disease, especially in patients with diabetes, according to the findings of a small retrospective study presented at the annual meeting of the European Society for the Study of Diabetes.

"What we are realizing is that [nonalcoholic fatty liver disease] is adding extra cardiovascular risk to people with diabetes, and to those without, on top of that which is already existing," Dr. Christopher Byrne, one of the lead study investigators, said in an interview.

Dr. Byrne, professor of endocrinology and metabolism at the University of Southampton (England), suggested that patients with documented liver disease perhaps require more aggressive therapies to address the additional risk. Such therapies need to target the liver as much as the heart.

In the study of 112 patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD), Kleiner scores – a histologic measure of NAFLD severity – were shown to be highly correlated with both Framingham Risk Score (FRS) and QRISK2, two cardiovascular risk calculators.

"Nonalcoholic fatty liver disease represents a spectrum of fat-mediated liver conditions causing progressive hepatocellular damage," said Sarah Hudson, a 5th-year medical student at the University of Southampton.

"There is increasing evidence of an increased cardiovascular risk associated with progression of nonalcoholic fatty liver disease," Ms. Hudson explained, noting that the preferred method of determining NAFLD severity was via histopathologic assessment.

The aim of the study was to see if a histopathologic marker – Kleiner score – correlated with cardiovascular risk, and if scores were higher in people already known to have a high cardiovascular risk, namely those with diabetes.

Kleiner scores assess the degree of steatosis, lobular inflammation, hepatocyte "ballooning," and fibrosis, with higher scores indicating more severe liver disease (Hepatology 2005;41:1313-21).

The mean age of the study cohort was 48 years and the mean Kleiner score was 5.3. The median FRS was 13 and the median QRISK2 score was 8. The mean body mass index of participants was approximately 34 kg/m².

Kleiner scores were not only found to be highly correlated with both cardiovascular risk models used, but they were also higher in a subgroup of 32 patients with diabetes when compared with those without diabetes (6.4 vs. 4.7, P less than .001).

The increased risk of cardiovascular disease in correlation with increasing NAFLD severity was found to be independent of both hyperglycemia and increasing body weight.

"We need more prospective studies to see what markers may be used to help stratify who requires biopsy and how best to manage people who have got NAFLD." Nonalcoholic steatohepatitis was associated with the highest cardiovascular risk estimates in the study.

"Up until now we’ve been very poor in providing cardiovascular risk reduction treatments for patients with NAFLD," Dr. Byrne said. Currently the only treatment strategy proven to work for NAFLD is lifestyle changes.

"We know that losing weight and increasing activity levels are very effective at decreasing liver fat," Dr. Byrne explained. "But what we don’t know is whether those lifestyle changes are good at decreasing liver inflammation, or decreasing liver fibrosis."

Treatment to decrease liver fat and prevent progression to fibrosis is thus urgently needed, and Dr. Byrne is part of a team now looking at the use of a high concentration of highly purified omega-3 fatty acid ethyl esters in the treatment of NAFLD.

The highly purified fish oil being used in the trial has been available commercially in Europe for at least a decade (Omacor) and in the United States since 2004 (Lovaza), and is currently licensed to treat hypertriglyceridemia.

The study is not due to be completed until December 2012. Until then, clinicians need to optimize the treatments they have at their disposal, including antihypertensive and lipid-lowering medicines commonly used to lower cardiovascular risk in conjunction with lifestyle modifications.

The study was funded by the National Institute for Health Research and Diabetes UK. Dr. Byrne and Ms. Hudson said they had no relevant financial disclosures. Dr. Byrne said he has given lectures on behalf of pharmaceutical companies in the past, including Pfizer.

LISBON – Increasing accumulation of fat, inflammation, and fibrosis of the liver appears tied to corresponding increases in the risk of cardiovascular disease, especially in patients with diabetes, according to the findings of a small retrospective study presented at the annual meeting of the European Society for the Study of Diabetes.

"What we are realizing is that [nonalcoholic fatty liver disease] is adding extra cardiovascular risk to people with diabetes, and to those without, on top of that which is already existing," Dr. Christopher Byrne, one of the lead study investigators, said in an interview.

Dr. Byrne, professor of endocrinology and metabolism at the University of Southampton (England), suggested that patients with documented liver disease perhaps require more aggressive therapies to address the additional risk. Such therapies need to target the liver as much as the heart.

In the study of 112 patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD), Kleiner scores – a histologic measure of NAFLD severity – were shown to be highly correlated with both Framingham Risk Score (FRS) and QRISK2, two cardiovascular risk calculators.

"Nonalcoholic fatty liver disease represents a spectrum of fat-mediated liver conditions causing progressive hepatocellular damage," said Sarah Hudson, a 5th-year medical student at the University of Southampton.

"There is increasing evidence of an increased cardiovascular risk associated with progression of nonalcoholic fatty liver disease," Ms. Hudson explained, noting that the preferred method of determining NAFLD severity was via histopathologic assessment.

The aim of the study was to see if a histopathologic marker – Kleiner score – correlated with cardiovascular risk, and if scores were higher in people already known to have a high cardiovascular risk, namely those with diabetes.

Kleiner scores assess the degree of steatosis, lobular inflammation, hepatocyte "ballooning," and fibrosis, with higher scores indicating more severe liver disease (Hepatology 2005;41:1313-21).

The mean age of the study cohort was 48 years and the mean Kleiner score was 5.3. The median FRS was 13 and the median QRISK2 score was 8. The mean body mass index of participants was approximately 34 kg/m².

Kleiner scores were not only found to be highly correlated with both cardiovascular risk models used, but they were also higher in a subgroup of 32 patients with diabetes when compared with those without diabetes (6.4 vs. 4.7, P less than .001).

The increased risk of cardiovascular disease in correlation with increasing NAFLD severity was found to be independent of both hyperglycemia and increasing body weight.

"We need more prospective studies to see what markers may be used to help stratify who requires biopsy and how best to manage people who have got NAFLD." Nonalcoholic steatohepatitis was associated with the highest cardiovascular risk estimates in the study.

"Up until now we’ve been very poor in providing cardiovascular risk reduction treatments for patients with NAFLD," Dr. Byrne said. Currently the only treatment strategy proven to work for NAFLD is lifestyle changes.

"We know that losing weight and increasing activity levels are very effective at decreasing liver fat," Dr. Byrne explained. "But what we don’t know is whether those lifestyle changes are good at decreasing liver inflammation, or decreasing liver fibrosis."

Treatment to decrease liver fat and prevent progression to fibrosis is thus urgently needed, and Dr. Byrne is part of a team now looking at the use of a high concentration of highly purified omega-3 fatty acid ethyl esters in the treatment of NAFLD.

The highly purified fish oil being used in the trial has been available commercially in Europe for at least a decade (Omacor) and in the United States since 2004 (Lovaza), and is currently licensed to treat hypertriglyceridemia.

The study is not due to be completed until December 2012. Until then, clinicians need to optimize the treatments they have at their disposal, including antihypertensive and lipid-lowering medicines commonly used to lower cardiovascular risk in conjunction with lifestyle modifications.

The study was funded by the National Institute for Health Research and Diabetes UK. Dr. Byrne and Ms. Hudson said they had no relevant financial disclosures. Dr. Byrne said he has given lectures on behalf of pharmaceutical companies in the past, including Pfizer.

LISBON – Improved glucose parameters, substantial weight loss, and increased incretin hormone levels can be achieved by the insertion of a novel, minimally invasive, intestinal device in obese patients with type 2 diabetes.

The use of a duodenal-jejunal bypass liner (DJBL) not only improves hemoglobin A_1c and aids weight loss, but also appears to increase levels of glucagon-like peptide (GLP)-1 and peptide YY while in place, according to the findings of a small study presented at the annual meeting of the European Society for the Study of Diabetes.

Although the effects may be temporary, they could offer patients a reversible alternative to bariatric surgery that helps to kick-start weight loss and self-management of diabetes, said study author Dr. Charlotte de Jonge of Maastricht University Medical Centre in the Netherlands. "Not all patients want [bariatric] surgery, as it is permanent."

She added that the DJBL was perhaps "an easy first step" and that patients could perhaps still opt for weight-loss surgery later on or be retreated with the device to the point that medication was again sufficient to help manage their diabetes.

The DJBL (EndoBarrier) is a 60-cm impermeable sleeve that is inserted and removed endoscopically, and which effectively blocks the duodenum and proximal jejunum in a manner similar to the Roux-en-Y-gastric bypass procedure. It is thought to work by creating a physical barrier between ingested food and the intestinal wall, and perhaps alters the activation of incretin hormones in the gut. On average, the device can be inserted in 20 minutes and removed in 10 minutes, under conscious sedation, which allows the patient to go home the same day as the procedure.

The aim of the 17-patient study was to investigate the possible mechanisms for the improvement in diabetic parameters after insertion of the DJBL seen in previous studies. Fourteen men and three women participated, all of whom had type 2 diabetes and a body mass index in excess of 30 kg/m². All ate a low-calorie diet during the study, which restricted their intake to around 1,200-1,500 kcal per day. Participants consulted a nutritionist every month, but the diet was not prescriptive.

Before implantation of the device, subjects underwent a meal tolerance test that involved a 12-hour fast, then ingestion of a 500-kcal liquid meal and blood sampling at baseline and at 10-, 20-, 30-, 60-, 90-, and 120-minute intervals. HbA_1c, glucose, insulin, GLP-1, and PYY concentrations were measured. Measurements were repeated before removal of the device, and again 1 week after removal of the device.

The DJBL was left in place for 24 weeks, although Dr. de Jonge noted that the device could be used for up to 2 years in some patients. Around 500 patients have received the device in clinical studies, she said in an interview. It has received approval for use in a few European countries and Australia. It remains investigational in the United States.

Within 1 week after implantation, fasting and area under the curve (AUC) glucose concentrations were improved (11.4±0.5 mmol/L vs. 8.9±0.4 mmol/L and 1,999±88 vs. 1,535±53), respectively. In addition, AUC concentrations of GLP-1 increased from 2,584 at baseline to 4,112 at removal and PYY from 4,440 to 6,448 (P less than .01 for all comparisons with baseline).

When the device was removed at 6 months, a significant mean weight loss of 13 kg (P less than .001) had been recorded, with a mean loss of excess weight of 30% (P less than .001), said Dr. de Jonge. Importantly, mean HbA_1c decreased from 8.4% at baseline to 7.0% at removal (P less than .001) and there was a reduction in the use of antidiabetic medication in all but one of the study participants.

"Interestingly, GLP-1 and GIP [glucose-dependent insulinotropic peptide] not only have an effect on insulin, but they also affect glucagon as well," Dr. de Jonge reported during her presentation. There was a normalization of the glucagon response during treatment with the DJBL to a more physiological response.

Almost all patients reported increased satiety, she added.

Commenting on the presentation, Dr. Roy Taylor, professor of medicine and metabolism at the University of Newcastle in England, noted that it would be useful to know what the effects of diet alone were and to see the relationship to the other changes in parameters shown.

In an interview, Dr. de Jonge noted that other data had suggested the weight loss achieved by diet alone was around 4-5 kg, so there did appear to be a greater weight loss effect when the DJBL was inserted.

With regard to side effects, the most common adverse events were abdominal discomfort, including epigastric pain and nausea. Such events were more common in the first 1-2 weeks, but tended to resolve with longer duration of use. There was no withdrawal of the device, and Dr. de Jonge noted that even when patients reported side effects, they were loath to have it removed.

"What we hope is that we can encourage lifestyle changes and we can motivate patients to remain at a lower weight," Dr. de Jonge observed. "Maybe people still need a little bit of medication, but at least their diabetes is better [controlled] than before they had the procedure."

GI Dynamics funded the study. Dr. de Jonge and Dr. Taylor reported having no conflicts of interest.

LISBON – Improved glucose parameters, substantial weight loss, and increased incretin hormone levels can be achieved by the insertion of a novel, minimally invasive, intestinal device in obese patients with type 2 diabetes.

The use of a duodenal-jejunal bypass liner (DJBL) not only improves hemoglobin A_1c and aids weight loss, but also appears to increase levels of glucagon-like peptide (GLP)-1 and peptide YY while in place, according to the findings of a small study presented at the annual meeting of the European Society for the Study of Diabetes.

Although the effects may be temporary, they could offer patients a reversible alternative to bariatric surgery that helps to kick-start weight loss and self-management of diabetes, said study author Dr. Charlotte de Jonge of Maastricht University Medical Centre in the Netherlands. "Not all patients want [bariatric] surgery, as it is permanent."

She added that the DJBL was perhaps "an easy first step" and that patients could perhaps still opt for weight-loss surgery later on or be retreated with the device to the point that medication was again sufficient to help manage their diabetes.

The DJBL (EndoBarrier) is a 60-cm impermeable sleeve that is inserted and removed endoscopically, and which effectively blocks the duodenum and proximal jejunum in a manner similar to the Roux-en-Y-gastric bypass procedure. It is thought to work by creating a physical barrier between ingested food and the intestinal wall, and perhaps alters the activation of incretin hormones in the gut. On average, the device can be inserted in 20 minutes and removed in 10 minutes, under conscious sedation, which allows the patient to go home the same day as the procedure.

The aim of the 17-patient study was to investigate the possible mechanisms for the improvement in diabetic parameters after insertion of the DJBL seen in previous studies. Fourteen men and three women participated, all of whom had type 2 diabetes and a body mass index in excess of 30 kg/m². All ate a low-calorie diet during the study, which restricted their intake to around 1,200-1,500 kcal per day. Participants consulted a nutritionist every month, but the diet was not prescriptive.

Before implantation of the device, subjects underwent a meal tolerance test that involved a 12-hour fast, then ingestion of a 500-kcal liquid meal and blood sampling at baseline and at 10-, 20-, 30-, 60-, 90-, and 120-minute intervals. HbA_1c, glucose, insulin, GLP-1, and PYY concentrations were measured. Measurements were repeated before removal of the device, and again 1 week after removal of the device.

The DJBL was left in place for 24 weeks, although Dr. de Jonge noted that the device could be used for up to 2 years in some patients. Around 500 patients have received the device in clinical studies, she said in an interview. It has received approval for use in a few European countries and Australia. It remains investigational in the United States.

Within 1 week after implantation, fasting and area under the curve (AUC) glucose concentrations were improved (11.4±0.5 mmol/L vs. 8.9±0.4 mmol/L and 1,999±88 vs. 1,535±53), respectively. In addition, AUC concentrations of GLP-1 increased from 2,584 at baseline to 4,112 at removal and PYY from 4,440 to 6,448 (P less than .01 for all comparisons with baseline).

When the device was removed at 6 months, a significant mean weight loss of 13 kg (P less than .001) had been recorded, with a mean loss of excess weight of 30% (P less than .001), said Dr. de Jonge. Importantly, mean HbA_1c decreased from 8.4% at baseline to 7.0% at removal (P less than .001) and there was a reduction in the use of antidiabetic medication in all but one of the study participants.

"Interestingly, GLP-1 and GIP [glucose-dependent insulinotropic peptide] not only have an effect on insulin, but they also affect glucagon as well," Dr. de Jonge reported during her presentation. There was a normalization of the glucagon response during treatment with the DJBL to a more physiological response.

Almost all patients reported increased satiety, she added.

Commenting on the presentation, Dr. Roy Taylor, professor of medicine and metabolism at the University of Newcastle in England, noted that it would be useful to know what the effects of diet alone were and to see the relationship to the other changes in parameters shown.

In an interview, Dr. de Jonge noted that other data had suggested the weight loss achieved by diet alone was around 4-5 kg, so there did appear to be a greater weight loss effect when the DJBL was inserted.

With regard to side effects, the most common adverse events were abdominal discomfort, including epigastric pain and nausea. Such events were more common in the first 1-2 weeks, but tended to resolve with longer duration of use. There was no withdrawal of the device, and Dr. de Jonge noted that even when patients reported side effects, they were loath to have it removed.

"What we hope is that we can encourage lifestyle changes and we can motivate patients to remain at a lower weight," Dr. de Jonge observed. "Maybe people still need a little bit of medication, but at least their diabetes is better [controlled] than before they had the procedure."

GI Dynamics funded the study. Dr. de Jonge and Dr. Taylor reported having no conflicts of interest.

LISBON – Improved glucose parameters, substantial weight loss, and increased incretin hormone levels can be achieved by the insertion of a novel, minimally invasive, intestinal device in obese patients with type 2 diabetes.

The use of a duodenal-jejunal bypass liner (DJBL) not only improves hemoglobin A_1c and aids weight loss, but also appears to increase levels of glucagon-like peptide (GLP)-1 and peptide YY while in place, according to the findings of a small study presented at the annual meeting of the European Society for the Study of Diabetes.

Although the effects may be temporary, they could offer patients a reversible alternative to bariatric surgery that helps to kick-start weight loss and self-management of diabetes, said study author Dr. Charlotte de Jonge of Maastricht University Medical Centre in the Netherlands. "Not all patients want [bariatric] surgery, as it is permanent."

She added that the DJBL was perhaps "an easy first step" and that patients could perhaps still opt for weight-loss surgery later on or be retreated with the device to the point that medication was again sufficient to help manage their diabetes.

The DJBL (EndoBarrier) is a 60-cm impermeable sleeve that is inserted and removed endoscopically, and which effectively blocks the duodenum and proximal jejunum in a manner similar to the Roux-en-Y-gastric bypass procedure. It is thought to work by creating a physical barrier between ingested food and the intestinal wall, and perhaps alters the activation of incretin hormones in the gut. On average, the device can be inserted in 20 minutes and removed in 10 minutes, under conscious sedation, which allows the patient to go home the same day as the procedure.

The aim of the 17-patient study was to investigate the possible mechanisms for the improvement in diabetic parameters after insertion of the DJBL seen in previous studies. Fourteen men and three women participated, all of whom had type 2 diabetes and a body mass index in excess of 30 kg/m². All ate a low-calorie diet during the study, which restricted their intake to around 1,200-1,500 kcal per day. Participants consulted a nutritionist every month, but the diet was not prescriptive.

Before implantation of the device, subjects underwent a meal tolerance test that involved a 12-hour fast, then ingestion of a 500-kcal liquid meal and blood sampling at baseline and at 10-, 20-, 30-, 60-, 90-, and 120-minute intervals. HbA_1c, glucose, insulin, GLP-1, and PYY concentrations were measured. Measurements were repeated before removal of the device, and again 1 week after removal of the device.

The DJBL was left in place for 24 weeks, although Dr. de Jonge noted that the device could be used for up to 2 years in some patients. Around 500 patients have received the device in clinical studies, she said in an interview. It has received approval for use in a few European countries and Australia. It remains investigational in the United States.

Within 1 week after implantation, fasting and area under the curve (AUC) glucose concentrations were improved (11.4±0.5 mmol/L vs. 8.9±0.4 mmol/L and 1,999±88 vs. 1,535±53), respectively. In addition, AUC concentrations of GLP-1 increased from 2,584 at baseline to 4,112 at removal and PYY from 4,440 to 6,448 (P less than .01 for all comparisons with baseline).

When the device was removed at 6 months, a significant mean weight loss of 13 kg (P less than .001) had been recorded, with a mean loss of excess weight of 30% (P less than .001), said Dr. de Jonge. Importantly, mean HbA_1c decreased from 8.4% at baseline to 7.0% at removal (P less than .001) and there was a reduction in the use of antidiabetic medication in all but one of the study participants.

"Interestingly, GLP-1 and GIP [glucose-dependent insulinotropic peptide] not only have an effect on insulin, but they also affect glucagon as well," Dr. de Jonge reported during her presentation. There was a normalization of the glucagon response during treatment with the DJBL to a more physiological response.

Almost all patients reported increased satiety, she added.

Commenting on the presentation, Dr. Roy Taylor, professor of medicine and metabolism at the University of Newcastle in England, noted that it would be useful to know what the effects of diet alone were and to see the relationship to the other changes in parameters shown.

In an interview, Dr. de Jonge noted that other data had suggested the weight loss achieved by diet alone was around 4-5 kg, so there did appear to be a greater weight loss effect when the DJBL was inserted.

With regard to side effects, the most common adverse events were abdominal discomfort, including epigastric pain and nausea. Such events were more common in the first 1-2 weeks, but tended to resolve with longer duration of use. There was no withdrawal of the device, and Dr. de Jonge noted that even when patients reported side effects, they were loath to have it removed.

"What we hope is that we can encourage lifestyle changes and we can motivate patients to remain at a lower weight," Dr. de Jonge observed. "Maybe people still need a little bit of medication, but at least their diabetes is better [controlled] than before they had the procedure."

GI Dynamics funded the study. Dr. de Jonge and Dr. Taylor reported having no conflicts of interest.

LISBON – Reasonably similar glucose-lowering effects and modest weight loss can be achieved in patients with type 2 diabetes who are treated with a once-weekly, extended-release formulation of exenatide or once-daily liraglutide, the DURATION-6 study results show.

Liraglutide resulted in a mean change in hemoglobin A_1c of –1.48%, compared with baseline. This was slightly (but not significantly) lower than the result for exenatide, which produced a mean drop in HbA_1c of –1.28%. Change in HbA_1c was the primary end point of the trial, but once-weekly exenatide did not demonstrate noninferiority to once-daily liraglutide.

In addition, significantly more patients who took liraglutide rather than exenatide achieved an HbA_1c lower than 7% (60% and 52% of patients, respectively).

These results, from the first head-to-head study comparing the two injected regimens, were discussed in full Sept. 14 at the annual meeting of the European Society for the Study of Diabetes, although they had been previously mentioned in a brief press release from Eli Lilly, which manufactures the once-weekly exenatide formulation (Bydureon) in collaboration with Amylin Pharmaceuticals and Alkermes.

"Both exenatide once-weekly and liraglutide once-daily provided effective glucose control with substantial lowering of HbA_1c," commented study investigator Dr. John Buse of the University of North Carolina at Chapel Hill, as he presented these data.

DURATION-6 was a 26-week, multicenter, open-label, trial in which 911 patients with suboptimal control of type 2 diabetes were randomized to treatment with 2 mg once-weekly exenatide, or 1.8 mg once-daily liraglutide. The mean age of participants was 57 years and the mean duration of diabetes was 8-9 years.

Dr. Buse noted that "modest weight loss" could be achieved with both agents, although results reached statistical significance with liraglutide. The mean change in weight from baseline to posttreatment assessment was –2.68 kg for exenatide and –3.58 kg for liraglutide, with a mean difference of 0.9 kg overall.

However, liraglutide was associated with more gastrointestinal side effects than was exenatide, which may be an influencing factor when clinicians and patients decide which of the glucagonlike peptide–1 (GLP-1) receptor agonist regimens to use.

When liraglutide and exenatide were compared, the incidence of GI adverse events was 20.4% vs. 9.4% for nausea, 13.1% vs. 6.1% for diarrhea, and 10.7% vs. 3.7% for vomiting.

Patients taking liraglutide were more likely than those taking exenatide to discontinue treatment as a result of non-GI treatment-emergent adverse effects (5.3% vs. 2.6%).

No major hypoglycemic episodes were reported during the trial, and Dr. Buse reported no significant difference in minor hypoglycemia between the groups (10.8% of patients treated with liraglutide vs. 8.9% for exenatide). Hypoglycemia was more likely if patients were also receiving sulfonylurea therapy.

Bydureon has been approved for use in Europe since June, and is available in the United Kingdom. In the United States, however, the Food and Drug Administration bounced the application back to Amylin and Alkermes last October because of concerns of potential QT prolongation with high circulating levels of the drug. The two companies have since submitted new tQT studies, the results of DURATION-5 (comparing Bydureon with Byetta), and updated safety data from previous studies. The agency is expected to respond in January 2012.

In an interview, Dr. Michaela Diamant, who chaired the session in which the DURATION-6 results were revealed, commented that although there appear to be subtle differences between the regimens studied, the findings could still help clinical decision making, particularly if they are considered alongside the other DURATION trial findings.

"If you have two or three studies, then you can say, ‘As a physician, I’ve seen this evidence and, well, I’m going to discuss [this] with my patients,’ " said Dr. Diamant, professor of diabetology and director of the diabetes center at the Free University Medical Center in Amsterdam.

Some patients may prefer the once-daily injections with liraglutide, she suggested, as they then can "see a more direct coupling" with what they are eating and their treatment, whereas others may prefer the less-frequent dosing regimen offered by once-weekly exenatide.

Dr. Diamant noted that even marginally different treatments in terms of efficacy and safety could help tailor diabetes therapy more specifically to the individual. "It’s like with insulin," she said. "We have different insulins for [different] patients."

The study was funded by Amylin and Lilly. Dr. Buse disclosed acting as a consultant or investigator for multiple pharmaceutical companies via his contract with the University of North Carolina at Chapel Hill. Dr. Diamant has acted as a consultant, speaker, or both, for Lilly, Merck, Novo Nordisk, and Sanofi-Aventis. She has also received research support from Amylin, Lilly, Merck, Novartis, Novo Nordisk, and Takeda.

LISBON – Reasonably similar glucose-lowering effects and modest weight loss can be achieved in patients with type 2 diabetes who are treated with a once-weekly, extended-release formulation of exenatide or once-daily liraglutide, the DURATION-6 study results show.

Liraglutide resulted in a mean change in hemoglobin A_1c of –1.48%, compared with baseline. This was slightly (but not significantly) lower than the result for exenatide, which produced a mean drop in HbA_1c of –1.28%. Change in HbA_1c was the primary end point of the trial, but once-weekly exenatide did not demonstrate noninferiority to once-daily liraglutide.

In addition, significantly more patients who took liraglutide rather than exenatide achieved an HbA_1c lower than 7% (60% and 52% of patients, respectively).

These results, from the first head-to-head study comparing the two injected regimens, were discussed in full Sept. 14 at the annual meeting of the European Society for the Study of Diabetes, although they had been previously mentioned in a brief press release from Eli Lilly, which manufactures the once-weekly exenatide formulation (Bydureon) in collaboration with Amylin Pharmaceuticals and Alkermes.

"Both exenatide once-weekly and liraglutide once-daily provided effective glucose control with substantial lowering of HbA_1c," commented study investigator Dr. John Buse of the University of North Carolina at Chapel Hill, as he presented these data.

DURATION-6 was a 26-week, multicenter, open-label, trial in which 911 patients with suboptimal control of type 2 diabetes were randomized to treatment with 2 mg once-weekly exenatide, or 1.8 mg once-daily liraglutide. The mean age of participants was 57 years and the mean duration of diabetes was 8-9 years.

Dr. Buse noted that "modest weight loss" could be achieved with both agents, although results reached statistical significance with liraglutide. The mean change in weight from baseline to posttreatment assessment was –2.68 kg for exenatide and –3.58 kg for liraglutide, with a mean difference of 0.9 kg overall.

However, liraglutide was associated with more gastrointestinal side effects than was exenatide, which may be an influencing factor when clinicians and patients decide which of the glucagonlike peptide–1 (GLP-1) receptor agonist regimens to use.

When liraglutide and exenatide were compared, the incidence of GI adverse events was 20.4% vs. 9.4% for nausea, 13.1% vs. 6.1% for diarrhea, and 10.7% vs. 3.7% for vomiting.

Patients taking liraglutide were more likely than those taking exenatide to discontinue treatment as a result of non-GI treatment-emergent adverse effects (5.3% vs. 2.6%).

No major hypoglycemic episodes were reported during the trial, and Dr. Buse reported no significant difference in minor hypoglycemia between the groups (10.8% of patients treated with liraglutide vs. 8.9% for exenatide). Hypoglycemia was more likely if patients were also receiving sulfonylurea therapy.

Bydureon has been approved for use in Europe since June, and is available in the United Kingdom. In the United States, however, the Food and Drug Administration bounced the application back to Amylin and Alkermes last October because of concerns of potential QT prolongation with high circulating levels of the drug. The two companies have since submitted new tQT studies, the results of DURATION-5 (comparing Bydureon with Byetta), and updated safety data from previous studies. The agency is expected to respond in January 2012.

In an interview, Dr. Michaela Diamant, who chaired the session in which the DURATION-6 results were revealed, commented that although there appear to be subtle differences between the regimens studied, the findings could still help clinical decision making, particularly if they are considered alongside the other DURATION trial findings.

"If you have two or three studies, then you can say, ‘As a physician, I’ve seen this evidence and, well, I’m going to discuss [this] with my patients,’ " said Dr. Diamant, professor of diabetology and director of the diabetes center at the Free University Medical Center in Amsterdam.

Some patients may prefer the once-daily injections with liraglutide, she suggested, as they then can "see a more direct coupling" with what they are eating and their treatment, whereas others may prefer the less-frequent dosing regimen offered by once-weekly exenatide.

Dr. Diamant noted that even marginally different treatments in terms of efficacy and safety could help tailor diabetes therapy more specifically to the individual. "It’s like with insulin," she said. "We have different insulins for [different] patients."

The study was funded by Amylin and Lilly. Dr. Buse disclosed acting as a consultant or investigator for multiple pharmaceutical companies via his contract with the University of North Carolina at Chapel Hill. Dr. Diamant has acted as a consultant, speaker, or both, for Lilly, Merck, Novo Nordisk, and Sanofi-Aventis. She has also received research support from Amylin, Lilly, Merck, Novartis, Novo Nordisk, and Takeda.

LISBON – Reasonably similar glucose-lowering effects and modest weight loss can be achieved in patients with type 2 diabetes who are treated with a once-weekly, extended-release formulation of exenatide or once-daily liraglutide, the DURATION-6 study results show.

Liraglutide resulted in a mean change in hemoglobin A_1c of –1.48%, compared with baseline. This was slightly (but not significantly) lower than the result for exenatide, which produced a mean drop in HbA_1c of –1.28%. Change in HbA_1c was the primary end point of the trial, but once-weekly exenatide did not demonstrate noninferiority to once-daily liraglutide.

In addition, significantly more patients who took liraglutide rather than exenatide achieved an HbA_1c lower than 7% (60% and 52% of patients, respectively).

These results, from the first head-to-head study comparing the two injected regimens, were discussed in full Sept. 14 at the annual meeting of the European Society for the Study of Diabetes, although they had been previously mentioned in a brief press release from Eli Lilly, which manufactures the once-weekly exenatide formulation (Bydureon) in collaboration with Amylin Pharmaceuticals and Alkermes.

"Both exenatide once-weekly and liraglutide once-daily provided effective glucose control with substantial lowering of HbA_1c," commented study investigator Dr. John Buse of the University of North Carolina at Chapel Hill, as he presented these data.

DURATION-6 was a 26-week, multicenter, open-label, trial in which 911 patients with suboptimal control of type 2 diabetes were randomized to treatment with 2 mg once-weekly exenatide, or 1.8 mg once-daily liraglutide. The mean age of participants was 57 years and the mean duration of diabetes was 8-9 years.

Dr. Buse noted that "modest weight loss" could be achieved with both agents, although results reached statistical significance with liraglutide. The mean change in weight from baseline to posttreatment assessment was –2.68 kg for exenatide and –3.58 kg for liraglutide, with a mean difference of 0.9 kg overall.

However, liraglutide was associated with more gastrointestinal side effects than was exenatide, which may be an influencing factor when clinicians and patients decide which of the glucagonlike peptide–1 (GLP-1) receptor agonist regimens to use.

When liraglutide and exenatide were compared, the incidence of GI adverse events was 20.4% vs. 9.4% for nausea, 13.1% vs. 6.1% for diarrhea, and 10.7% vs. 3.7% for vomiting.

Patients taking liraglutide were more likely than those taking exenatide to discontinue treatment as a result of non-GI treatment-emergent adverse effects (5.3% vs. 2.6%).

No major hypoglycemic episodes were reported during the trial, and Dr. Buse reported no significant difference in minor hypoglycemia between the groups (10.8% of patients treated with liraglutide vs. 8.9% for exenatide). Hypoglycemia was more likely if patients were also receiving sulfonylurea therapy.

Bydureon has been approved for use in Europe since June, and is available in the United Kingdom. In the United States, however, the Food and Drug Administration bounced the application back to Amylin and Alkermes last October because of concerns of potential QT prolongation with high circulating levels of the drug. The two companies have since submitted new tQT studies, the results of DURATION-5 (comparing Bydureon with Byetta), and updated safety data from previous studies. The agency is expected to respond in January 2012.

In an interview, Dr. Michaela Diamant, who chaired the session in which the DURATION-6 results were revealed, commented that although there appear to be subtle differences between the regimens studied, the findings could still help clinical decision making, particularly if they are considered alongside the other DURATION trial findings.

"If you have two or three studies, then you can say, ‘As a physician, I’ve seen this evidence and, well, I’m going to discuss [this] with my patients,’ " said Dr. Diamant, professor of diabetology and director of the diabetes center at the Free University Medical Center in Amsterdam.

Some patients may prefer the once-daily injections with liraglutide, she suggested, as they then can "see a more direct coupling" with what they are eating and their treatment, whereas others may prefer the less-frequent dosing regimen offered by once-weekly exenatide.

Dr. Diamant noted that even marginally different treatments in terms of efficacy and safety could help tailor diabetes therapy more specifically to the individual. "It’s like with insulin," she said. "We have different insulins for [different] patients."

The study was funded by Amylin and Lilly. Dr. Buse disclosed acting as a consultant or investigator for multiple pharmaceutical companies via his contract with the University of North Carolina at Chapel Hill. Dr. Diamant has acted as a consultant, speaker, or both, for Lilly, Merck, Novo Nordisk, and Sanofi-Aventis. She has also received research support from Amylin, Lilly, Merck, Novartis, Novo Nordisk, and Takeda.