Michele G Sullivan

STOCKHOLM – The artificial beta cell is moving from the lab bench to the bedside table.

These experimental closed-loop insulin systems, which deliver constantly adjusted pulses of insulin, continue to rack up research success. Tightly controlled studies have given way to more free-ranging trials conducted in diabetes camps and, now, even at home. The endpoints continue to align, providing a growing certainty that the systems regulate glucose much more efficiently than does a traditional insulin pump.

“We now have a large number of studies in patients of various types – adults, children, adolescents, and even pregnant women – and in various situations – at home, at camp, in clinics, and even in acute illness,” Dr. Lalantha Leelarathna said at the annual meeting of the European Association for the Study of Diabetes. “Compared with our current best therapy, these studies consistently show more time in target, lower mean glucose, less burden of hypoglycemia, less glucose variability, and an improvement in hemoglobin A_1c.”

Not all the studies of the artificial beta-cell insulin system have been completely successful, he admitted. “We’ve had problems with sense accuracy, with device connectivity, and there is an urgent need to miniaturize these devices and integrate them so patients can use them easily. But there is no hiding the fact that there has been tremendous progress over the past 5-10 years in this field, and it’s becoming a realistic option for our patients to have these in the not-too-distant future.”

Dr. Leelarathna of the University of Manchester, England, discussed some of the newest data on the closed-loop systems, including two 12-week home-use trials, which were simultaneously published in the New England Journal of Medicine. They were conducted by the APCam Consortium and the AP@home Consortium. One examined the system’s 24-hour use in a population of adults; the other was an overnight study in children and teens. Both were randomized crossover trials that compared a closed-loop system with sensor-augmented pump therapy.

Both studies used the FlorenceD2A closed-loop system. The Florence system uses a smartphone or tablet to wirelessly communicate a model predictive algorithm to the pump. Every 12 minutes, the system calculates a new insulin infusion rate. The treat-to-target control algorithm aims to achieve glucose levels between 5.8 and 7.3 mmol/L and adjusts the actual level depending on fasting vs. postprandial status and the accuracy of model-based glucose predictions.

AP@home04

The study was conducted in the United Kingdom, Austria, and Germany; it comprised 33 adults with type 1 diabetes.

After a 4-week optimization period, the patients used either their control system or the closed-loop system day and night for 3 months. There was then a 4-week washout period, followed by 12 weeks’ use of the comparator system. The Florence system ran wirelessly off the patients’ smartphone, which was with them at all times.

The results consistently favored the closed-loop system, Dr. Leelarathna said. It significantly improved time spent in the target glucose range of 70-180 mg/dL (76% vs. 56% per 24 hours). It also reduced the time spent with glucose above 180 mg/dL (29% vs. 39%), as well as the time spent in the hypoglycemic range of less than 50 m/dL (0.3% vs. 0.4%). The mean glucose level was significantly lower (157 vs. 168 mg/dL). These improvements were achieved despite no increase in insulin (48.8 vs. 48.1 U/day).

HbA_1cwas significantly improved from baseline on the closed-loop system, dropping from 7.6%-7.3%. While on the insulin pump, HbA_1cwas unchanged (7.6% at both time points).

APCam08

The children’s study was conducted in three U.K. centers, and comprised 25 children and teens with type 1 diabetes. The mean HbA_1c at baseline was 8.1%. The study protocol was the same, except that the children used the pumps only from midnight-8 a.m. The algorithm was transmitted to the unit via USB cable from a tablet on the bedside table.

The results were also quite similar. The closed-loop system significantly increased the time spent in the target range of 70-145 mg/dL (60% vs. 34% per 24 hours). Likewise, the time in hyperglycemia (above 145 mg/dL) was significantly reduced (37% vs. 61%). However, there was no difference in time spent in hypoglycemia.

Mean glucose level was significantly improved (146 vs. 176 mg/dL), and overnight insulin use slightly, but not significantly, reduced (7.6 vs. 7.7 U).

After the initial optimization period, the subjects’ mean HbA_1c was 7.8%. This improved significantly on the closed loop system (7.6%), but rose slightly on the insulin pump (7.9%).

Although these two trials represent the longest free-living studies with the closed-loop system, they’re not the only ones, Dr. Leelarathna mentioned. A third was also presented at the meeting

Dr. Hans DeVries of the University of Amsterdam examined the closed-loop device for 2 months in 32 adults with type 1 diabetes. They used it overnight; the comparator was their own sensor-augmented pump, which they used during the day while at home.

Again, the closed-loop system improved time spent in target (66.7% vs. 58%); reduced time in hyperglycemia (31.6% vs. 38.5%); reduced time in hypoglycemia (1.6% vs. 3%)); and improved mean glucose (161.6 vs. 167.6 mg/dL). This study also showed a significant reduction in daily insulin (16.2 vs. 18.4 U/kg per day).

The devices are also being tested in a cohort of pregnant women who are enrolled at 8-24 weeks’ gestation. The planned sample size is 18, Dr. Leelarathna said. This is a randomized, crossover study that will use the closed-loop and insulin pump systems for 28 nights with a 2-4 week washout in between. At the end, the women will choose which system to continue with. Some have completed the study, and used the closed-loop system in labor and delivery. Preliminary results look good, Dr. Leelarathna said, although he didn’t release any data.

He had no financial disclosures.

msullivan@frontlinemedcom.com

STOCKHOLM – The artificial beta cell is moving from the lab bench to the bedside table.

These experimental closed-loop insulin systems, which deliver constantly adjusted pulses of insulin, continue to rack up research success. Tightly controlled studies have given way to more free-ranging trials conducted in diabetes camps and, now, even at home. The endpoints continue to align, providing a growing certainty that the systems regulate glucose much more efficiently than does a traditional insulin pump.

“We now have a large number of studies in patients of various types – adults, children, adolescents, and even pregnant women – and in various situations – at home, at camp, in clinics, and even in acute illness,” Dr. Lalantha Leelarathna said at the annual meeting of the European Association for the Study of Diabetes. “Compared with our current best therapy, these studies consistently show more time in target, lower mean glucose, less burden of hypoglycemia, less glucose variability, and an improvement in hemoglobin A_1c.”

Not all the studies of the artificial beta-cell insulin system have been completely successful, he admitted. “We’ve had problems with sense accuracy, with device connectivity, and there is an urgent need to miniaturize these devices and integrate them so patients can use them easily. But there is no hiding the fact that there has been tremendous progress over the past 5-10 years in this field, and it’s becoming a realistic option for our patients to have these in the not-too-distant future.”

Dr. Leelarathna of the University of Manchester, England, discussed some of the newest data on the closed-loop systems, including two 12-week home-use trials, which were simultaneously published in the New England Journal of Medicine. They were conducted by the APCam Consortium and the AP@home Consortium. One examined the system’s 24-hour use in a population of adults; the other was an overnight study in children and teens. Both were randomized crossover trials that compared a closed-loop system with sensor-augmented pump therapy.

Both studies used the FlorenceD2A closed-loop system. The Florence system uses a smartphone or tablet to wirelessly communicate a model predictive algorithm to the pump. Every 12 minutes, the system calculates a new insulin infusion rate. The treat-to-target control algorithm aims to achieve glucose levels between 5.8 and 7.3 mmol/L and adjusts the actual level depending on fasting vs. postprandial status and the accuracy of model-based glucose predictions.

AP@home04

The study was conducted in the United Kingdom, Austria, and Germany; it comprised 33 adults with type 1 diabetes.

After a 4-week optimization period, the patients used either their control system or the closed-loop system day and night for 3 months. There was then a 4-week washout period, followed by 12 weeks’ use of the comparator system. The Florence system ran wirelessly off the patients’ smartphone, which was with them at all times.

The results consistently favored the closed-loop system, Dr. Leelarathna said. It significantly improved time spent in the target glucose range of 70-180 mg/dL (76% vs. 56% per 24 hours). It also reduced the time spent with glucose above 180 mg/dL (29% vs. 39%), as well as the time spent in the hypoglycemic range of less than 50 m/dL (0.3% vs. 0.4%). The mean glucose level was significantly lower (157 vs. 168 mg/dL). These improvements were achieved despite no increase in insulin (48.8 vs. 48.1 U/day).

HbA_1cwas significantly improved from baseline on the closed-loop system, dropping from 7.6%-7.3%. While on the insulin pump, HbA_1cwas unchanged (7.6% at both time points).

APCam08

The children’s study was conducted in three U.K. centers, and comprised 25 children and teens with type 1 diabetes. The mean HbA_1c at baseline was 8.1%. The study protocol was the same, except that the children used the pumps only from midnight-8 a.m. The algorithm was transmitted to the unit via USB cable from a tablet on the bedside table.

The results were also quite similar. The closed-loop system significantly increased the time spent in the target range of 70-145 mg/dL (60% vs. 34% per 24 hours). Likewise, the time in hyperglycemia (above 145 mg/dL) was significantly reduced (37% vs. 61%). However, there was no difference in time spent in hypoglycemia.

Mean glucose level was significantly improved (146 vs. 176 mg/dL), and overnight insulin use slightly, but not significantly, reduced (7.6 vs. 7.7 U).

After the initial optimization period, the subjects’ mean HbA_1c was 7.8%. This improved significantly on the closed loop system (7.6%), but rose slightly on the insulin pump (7.9%).

Although these two trials represent the longest free-living studies with the closed-loop system, they’re not the only ones, Dr. Leelarathna mentioned. A third was also presented at the meeting

Dr. Hans DeVries of the University of Amsterdam examined the closed-loop device for 2 months in 32 adults with type 1 diabetes. They used it overnight; the comparator was their own sensor-augmented pump, which they used during the day while at home.

Again, the closed-loop system improved time spent in target (66.7% vs. 58%); reduced time in hyperglycemia (31.6% vs. 38.5%); reduced time in hypoglycemia (1.6% vs. 3%)); and improved mean glucose (161.6 vs. 167.6 mg/dL). This study also showed a significant reduction in daily insulin (16.2 vs. 18.4 U/kg per day).

The devices are also being tested in a cohort of pregnant women who are enrolled at 8-24 weeks’ gestation. The planned sample size is 18, Dr. Leelarathna said. This is a randomized, crossover study that will use the closed-loop and insulin pump systems for 28 nights with a 2-4 week washout in between. At the end, the women will choose which system to continue with. Some have completed the study, and used the closed-loop system in labor and delivery. Preliminary results look good, Dr. Leelarathna said, although he didn’t release any data.

He had no financial disclosures.

msullivan@frontlinemedcom.com

STOCKHOLM – The artificial beta cell is moving from the lab bench to the bedside table.

These experimental closed-loop insulin systems, which deliver constantly adjusted pulses of insulin, continue to rack up research success. Tightly controlled studies have given way to more free-ranging trials conducted in diabetes camps and, now, even at home. The endpoints continue to align, providing a growing certainty that the systems regulate glucose much more efficiently than does a traditional insulin pump.

“We now have a large number of studies in patients of various types – adults, children, adolescents, and even pregnant women – and in various situations – at home, at camp, in clinics, and even in acute illness,” Dr. Lalantha Leelarathna said at the annual meeting of the European Association for the Study of Diabetes. “Compared with our current best therapy, these studies consistently show more time in target, lower mean glucose, less burden of hypoglycemia, less glucose variability, and an improvement in hemoglobin A_1c.”

Not all the studies of the artificial beta-cell insulin system have been completely successful, he admitted. “We’ve had problems with sense accuracy, with device connectivity, and there is an urgent need to miniaturize these devices and integrate them so patients can use them easily. But there is no hiding the fact that there has been tremendous progress over the past 5-10 years in this field, and it’s becoming a realistic option for our patients to have these in the not-too-distant future.”

Dr. Leelarathna of the University of Manchester, England, discussed some of the newest data on the closed-loop systems, including two 12-week home-use trials, which were simultaneously published in the New England Journal of Medicine. They were conducted by the APCam Consortium and the AP@home Consortium. One examined the system’s 24-hour use in a population of adults; the other was an overnight study in children and teens. Both were randomized crossover trials that compared a closed-loop system with sensor-augmented pump therapy.

Both studies used the FlorenceD2A closed-loop system. The Florence system uses a smartphone or tablet to wirelessly communicate a model predictive algorithm to the pump. Every 12 minutes, the system calculates a new insulin infusion rate. The treat-to-target control algorithm aims to achieve glucose levels between 5.8 and 7.3 mmol/L and adjusts the actual level depending on fasting vs. postprandial status and the accuracy of model-based glucose predictions.

AP@home04

The study was conducted in the United Kingdom, Austria, and Germany; it comprised 33 adults with type 1 diabetes.

After a 4-week optimization period, the patients used either their control system or the closed-loop system day and night for 3 months. There was then a 4-week washout period, followed by 12 weeks’ use of the comparator system. The Florence system ran wirelessly off the patients’ smartphone, which was with them at all times.

The results consistently favored the closed-loop system, Dr. Leelarathna said. It significantly improved time spent in the target glucose range of 70-180 mg/dL (76% vs. 56% per 24 hours). It also reduced the time spent with glucose above 180 mg/dL (29% vs. 39%), as well as the time spent in the hypoglycemic range of less than 50 m/dL (0.3% vs. 0.4%). The mean glucose level was significantly lower (157 vs. 168 mg/dL). These improvements were achieved despite no increase in insulin (48.8 vs. 48.1 U/day).

HbA_1cwas significantly improved from baseline on the closed-loop system, dropping from 7.6%-7.3%. While on the insulin pump, HbA_1cwas unchanged (7.6% at both time points).

APCam08

The children’s study was conducted in three U.K. centers, and comprised 25 children and teens with type 1 diabetes. The mean HbA_1c at baseline was 8.1%. The study protocol was the same, except that the children used the pumps only from midnight-8 a.m. The algorithm was transmitted to the unit via USB cable from a tablet on the bedside table.

The results were also quite similar. The closed-loop system significantly increased the time spent in the target range of 70-145 mg/dL (60% vs. 34% per 24 hours). Likewise, the time in hyperglycemia (above 145 mg/dL) was significantly reduced (37% vs. 61%). However, there was no difference in time spent in hypoglycemia.

Mean glucose level was significantly improved (146 vs. 176 mg/dL), and overnight insulin use slightly, but not significantly, reduced (7.6 vs. 7.7 U).

After the initial optimization period, the subjects’ mean HbA_1c was 7.8%. This improved significantly on the closed loop system (7.6%), but rose slightly on the insulin pump (7.9%).

Although these two trials represent the longest free-living studies with the closed-loop system, they’re not the only ones, Dr. Leelarathna mentioned. A third was also presented at the meeting

Dr. Hans DeVries of the University of Amsterdam examined the closed-loop device for 2 months in 32 adults with type 1 diabetes. They used it overnight; the comparator was their own sensor-augmented pump, which they used during the day while at home.

Again, the closed-loop system improved time spent in target (66.7% vs. 58%); reduced time in hyperglycemia (31.6% vs. 38.5%); reduced time in hypoglycemia (1.6% vs. 3%)); and improved mean glucose (161.6 vs. 167.6 mg/dL). This study also showed a significant reduction in daily insulin (16.2 vs. 18.4 U/kg per day).

The devices are also being tested in a cohort of pregnant women who are enrolled at 8-24 weeks’ gestation. The planned sample size is 18, Dr. Leelarathna said. This is a randomized, crossover study that will use the closed-loop and insulin pump systems for 28 nights with a 2-4 week washout in between. At the end, the women will choose which system to continue with. Some have completed the study, and used the closed-loop system in labor and delivery. Preliminary results look good, Dr. Leelarathna said, although he didn’t release any data.

He had no financial disclosures.

msullivan@frontlinemedcom.com

STOCKHOLM – Patients with poorly controlled type 2 diabetes who take the combination of liraglutide and metformin are about four times more likely to hit their glycemic target than those who take lixisenatide and metformin.

After 26 weeks of treatment, hemoglobin A_1cdropped a mean of 1.8% among those on the liraglutide regimen, compared with 1.2% among those taking lixisenatide. The change brought 74% of the liraglutide group into a treatment target of HbA_1c less than 7%; 45% of the lixisenatide group reached that goal (odds ratio, 4.16).

Those taking liraglutide also were almost four times as likely to reach a target of 6.5% or less (55% vs. 26%; OR, 3.6), Dr. Michael A. Nauck said at the annual meeting of the European Association for the Study of Diabetes.

Both of the drugs are glucagon-like peptide-1 receptor agonists, and both are formulated for once-daily injection, but liraglutide’s 13-hour half-life gives it a strong clinical edge.

“Lixisenatide has a 3-hour half-life, so it’s only going to be around for 6 to a maximum of 10 hours after injection,” said Dr. Nauck, head of the Diabeteszentrum in Bad Lauterberg, Germany. “For the most part of the night there’s no exposure to lixisenatide at all, while liraglutide is present 24 hours.”

The study randomized 404 patients with poorly controlled type 2 diabetes to metformin plus either liraglutide 1.8 mg/day or lixisenatide 20 mcg/day, he reported. Patients were a mean of 56 years old, with a mean body mass index of 35 kg/m². Their mean HbA_1c was 8.4%.

At the end of the 26-week study, fasting plasma glucose measurements mirrored the HbA_1c improvements. Both drugs significantly reduced glucose within the first 6 weeks, but liraglutide did so to a significantly greater extent (–2.85 mmol/L vs. –1.7 mmol/L). Each reduction held steady through the end of the trial.

Both drugs effected a similar weight loss by the study’s end – about 4 kg. Both also reduced systolic blood pressure similarly, with a mean drop of about 5 mm Hg for liraglutide and 4 mm Hg for lixisenatide. Liraglutide increased the mean pulse rate from 75 beats per minute (bpm) at baseline to 80 bpm by week 6. The mean decreased to 78 by the end of the study. Pulse declined by 1 bpm from baseline among patients taking lixisenatide.

Liraglutide seemed to exert a beneficial effect on beta cells, as measured by the homeostatic model assessment (HOMA-B). At baseline, mean HOMA-B was 60%. By 26 weeks, it had increased to near 100% among those taking the drug; among those taking lixisenatide, HOMA-B had increased to about 77% – a significant difference.

Liraglutide was associated with a significant increase in lipase, Dr. Nauck said. Baseline lipase was 40 U/L. By 12 weeks, both drugs had increased lipase significantly – lixisenatide to about 50 U/L and liraglutide to about 60 U/L. These levels were constant through the study’s end. There were, however, no cases of pancreatitis or pancreatic cancer in either treatment arm, he noted.

Liraglutide use was associated with significantly more adverse events than lixisenatide (72% vs. 64%), but few of those were serious (6% vs. 3.5%). There were no cases of severe hypoglycemia and no deaths. Less than 5% of patients experienced a treatment-emergent or serious adverse event. The most common of these were nausea (22% in each group), diarrhea (12% liraglutide vs. 10% lixisenatide), vomiting (7% vs. 9%), increased lipase (8% vs. 2.5%), nasopharyngitis (6% vs. 10%), decreased appetite (6% vs. 2.5%), and dyspepsia (5.4% vs. 3%).

Although lixisenatide was outperformed in this analysis, it is still a valuable alternative for some patients, Dr. Bo Ahren said in an interview.

“Its primary action is to reduce postprandial glucose,” said Dr. Ahren, who is dean of the Faculty of Medicine at Lund (Sweden) University. “Therefore, there may be a use for this agent in patients who have controlled fasting glucose, for example, with insulin, but still have high postprandial glucose.”

Although the adverse event data were encouraging, more study is necessary, he added. The current data aren’t enough to hone any patient selection criteria.

“The lipase increases need to be examined in more detail, although it’s true there were no cases of pancreatitis. Also, the heart rate was measured only in the clinic, not as a 24-hour measurement. Therefore it’s too early to base any patient selection on this,” Dr. Ahren said.

Both Dr. Nauck and Dr. Ahren disclosed numerous financial relationships with pharmaceutical companies.

msullivan@frontlinemedcom.com

STOCKHOLM – Patients with poorly controlled type 2 diabetes who take the combination of liraglutide and metformin are about four times more likely to hit their glycemic target than those who take lixisenatide and metformin.

After 26 weeks of treatment, hemoglobin A_1cdropped a mean of 1.8% among those on the liraglutide regimen, compared with 1.2% among those taking lixisenatide. The change brought 74% of the liraglutide group into a treatment target of HbA_1c less than 7%; 45% of the lixisenatide group reached that goal (odds ratio, 4.16).

Those taking liraglutide also were almost four times as likely to reach a target of 6.5% or less (55% vs. 26%; OR, 3.6), Dr. Michael A. Nauck said at the annual meeting of the European Association for the Study of Diabetes.

Both of the drugs are glucagon-like peptide-1 receptor agonists, and both are formulated for once-daily injection, but liraglutide’s 13-hour half-life gives it a strong clinical edge.

“Lixisenatide has a 3-hour half-life, so it’s only going to be around for 6 to a maximum of 10 hours after injection,” said Dr. Nauck, head of the Diabeteszentrum in Bad Lauterberg, Germany. “For the most part of the night there’s no exposure to lixisenatide at all, while liraglutide is present 24 hours.”

The study randomized 404 patients with poorly controlled type 2 diabetes to metformin plus either liraglutide 1.8 mg/day or lixisenatide 20 mcg/day, he reported. Patients were a mean of 56 years old, with a mean body mass index of 35 kg/m². Their mean HbA_1c was 8.4%.

At the end of the 26-week study, fasting plasma glucose measurements mirrored the HbA_1c improvements. Both drugs significantly reduced glucose within the first 6 weeks, but liraglutide did so to a significantly greater extent (–2.85 mmol/L vs. –1.7 mmol/L). Each reduction held steady through the end of the trial.

Both drugs effected a similar weight loss by the study’s end – about 4 kg. Both also reduced systolic blood pressure similarly, with a mean drop of about 5 mm Hg for liraglutide and 4 mm Hg for lixisenatide. Liraglutide increased the mean pulse rate from 75 beats per minute (bpm) at baseline to 80 bpm by week 6. The mean decreased to 78 by the end of the study. Pulse declined by 1 bpm from baseline among patients taking lixisenatide.

Liraglutide seemed to exert a beneficial effect on beta cells, as measured by the homeostatic model assessment (HOMA-B). At baseline, mean HOMA-B was 60%. By 26 weeks, it had increased to near 100% among those taking the drug; among those taking lixisenatide, HOMA-B had increased to about 77% – a significant difference.

Liraglutide was associated with a significant increase in lipase, Dr. Nauck said. Baseline lipase was 40 U/L. By 12 weeks, both drugs had increased lipase significantly – lixisenatide to about 50 U/L and liraglutide to about 60 U/L. These levels were constant through the study’s end. There were, however, no cases of pancreatitis or pancreatic cancer in either treatment arm, he noted.

Liraglutide use was associated with significantly more adverse events than lixisenatide (72% vs. 64%), but few of those were serious (6% vs. 3.5%). There were no cases of severe hypoglycemia and no deaths. Less than 5% of patients experienced a treatment-emergent or serious adverse event. The most common of these were nausea (22% in each group), diarrhea (12% liraglutide vs. 10% lixisenatide), vomiting (7% vs. 9%), increased lipase (8% vs. 2.5%), nasopharyngitis (6% vs. 10%), decreased appetite (6% vs. 2.5%), and dyspepsia (5.4% vs. 3%).

Although lixisenatide was outperformed in this analysis, it is still a valuable alternative for some patients, Dr. Bo Ahren said in an interview.

“Its primary action is to reduce postprandial glucose,” said Dr. Ahren, who is dean of the Faculty of Medicine at Lund (Sweden) University. “Therefore, there may be a use for this agent in patients who have controlled fasting glucose, for example, with insulin, but still have high postprandial glucose.”

Although the adverse event data were encouraging, more study is necessary, he added. The current data aren’t enough to hone any patient selection criteria.

“The lipase increases need to be examined in more detail, although it’s true there were no cases of pancreatitis. Also, the heart rate was measured only in the clinic, not as a 24-hour measurement. Therefore it’s too early to base any patient selection on this,” Dr. Ahren said.

Both Dr. Nauck and Dr. Ahren disclosed numerous financial relationships with pharmaceutical companies.

msullivan@frontlinemedcom.com

STOCKHOLM – Patients with poorly controlled type 2 diabetes who take the combination of liraglutide and metformin are about four times more likely to hit their glycemic target than those who take lixisenatide and metformin.

After 26 weeks of treatment, hemoglobin A_1cdropped a mean of 1.8% among those on the liraglutide regimen, compared with 1.2% among those taking lixisenatide. The change brought 74% of the liraglutide group into a treatment target of HbA_1c less than 7%; 45% of the lixisenatide group reached that goal (odds ratio, 4.16).

Those taking liraglutide also were almost four times as likely to reach a target of 6.5% or less (55% vs. 26%; OR, 3.6), Dr. Michael A. Nauck said at the annual meeting of the European Association for the Study of Diabetes.

Both of the drugs are glucagon-like peptide-1 receptor agonists, and both are formulated for once-daily injection, but liraglutide’s 13-hour half-life gives it a strong clinical edge.

“Lixisenatide has a 3-hour half-life, so it’s only going to be around for 6 to a maximum of 10 hours after injection,” said Dr. Nauck, head of the Diabeteszentrum in Bad Lauterberg, Germany. “For the most part of the night there’s no exposure to lixisenatide at all, while liraglutide is present 24 hours.”

The study randomized 404 patients with poorly controlled type 2 diabetes to metformin plus either liraglutide 1.8 mg/day or lixisenatide 20 mcg/day, he reported. Patients were a mean of 56 years old, with a mean body mass index of 35 kg/m². Their mean HbA_1c was 8.4%.

At the end of the 26-week study, fasting plasma glucose measurements mirrored the HbA_1c improvements. Both drugs significantly reduced glucose within the first 6 weeks, but liraglutide did so to a significantly greater extent (–2.85 mmol/L vs. –1.7 mmol/L). Each reduction held steady through the end of the trial.

Both drugs effected a similar weight loss by the study’s end – about 4 kg. Both also reduced systolic blood pressure similarly, with a mean drop of about 5 mm Hg for liraglutide and 4 mm Hg for lixisenatide. Liraglutide increased the mean pulse rate from 75 beats per minute (bpm) at baseline to 80 bpm by week 6. The mean decreased to 78 by the end of the study. Pulse declined by 1 bpm from baseline among patients taking lixisenatide.

Liraglutide seemed to exert a beneficial effect on beta cells, as measured by the homeostatic model assessment (HOMA-B). At baseline, mean HOMA-B was 60%. By 26 weeks, it had increased to near 100% among those taking the drug; among those taking lixisenatide, HOMA-B had increased to about 77% – a significant difference.

Liraglutide was associated with a significant increase in lipase, Dr. Nauck said. Baseline lipase was 40 U/L. By 12 weeks, both drugs had increased lipase significantly – lixisenatide to about 50 U/L and liraglutide to about 60 U/L. These levels were constant through the study’s end. There were, however, no cases of pancreatitis or pancreatic cancer in either treatment arm, he noted.

Liraglutide use was associated with significantly more adverse events than lixisenatide (72% vs. 64%), but few of those were serious (6% vs. 3.5%). There were no cases of severe hypoglycemia and no deaths. Less than 5% of patients experienced a treatment-emergent or serious adverse event. The most common of these were nausea (22% in each group), diarrhea (12% liraglutide vs. 10% lixisenatide), vomiting (7% vs. 9%), increased lipase (8% vs. 2.5%), nasopharyngitis (6% vs. 10%), decreased appetite (6% vs. 2.5%), and dyspepsia (5.4% vs. 3%).

Although lixisenatide was outperformed in this analysis, it is still a valuable alternative for some patients, Dr. Bo Ahren said in an interview.

“Its primary action is to reduce postprandial glucose,” said Dr. Ahren, who is dean of the Faculty of Medicine at Lund (Sweden) University. “Therefore, there may be a use for this agent in patients who have controlled fasting glucose, for example, with insulin, but still have high postprandial glucose.”

Although the adverse event data were encouraging, more study is necessary, he added. The current data aren’t enough to hone any patient selection criteria.

“The lipase increases need to be examined in more detail, although it’s true there were no cases of pancreatitis. Also, the heart rate was measured only in the clinic, not as a 24-hour measurement. Therefore it’s too early to base any patient selection on this,” Dr. Ahren said.

Both Dr. Nauck and Dr. Ahren disclosed numerous financial relationships with pharmaceutical companies.

msullivan@frontlinemedcom.com

Screening asymptomatic adults for heart disease with an electrocardiogram provides little useful risk information but may cause substantial harm, according to a new recommendation by the United States Preventive Services Task Force.

A thorough history and physical exam are the best ways to ascertain risk, wrote task force chair Dr. Virginia A. Moyer and her fellow panel members.

Photo hepatus/iStockphoto.com

"The incremental information offered by resting or exercise ECG (beyond that obtained with conventional CHD risk factors) is highly unlikely to result in changes in risks stratification that would prompt interventions and ultimately reduce CHD-related events."

However, the harms may be very real, noted Dr. Moyer of the Baylor College of Medicine, Houston, and her coauthors.

"An ECG abnormality, as a result of a true- or false-positive test, can lead to invasive confirmatory testing and treatments that have the potential for serious harm, including unnecessary radiation exposure and the associated risk for cancer," the panel members noted (Ann. Intern. Med.; 2012 July 31 [online first]).

Invasive testing – angiography and revascularization – could confer an additional set of problems, including bleeding, contrast-induced nephropathy, and allergic reactions to contrast agents.

The new recommendation is an update of one made in 2004. At that time, the task force advised against resting or exercise ECG and electron-based computer tomography (EBCT), but said there was not enough evidence to weigh in on ECG screening. The new paper included more recent data on direct harm due to the ECG itself, physical adverse events related to any additional testing, and psychological issues related to screening, including anxiety.

The guide also discourages baseline ECGs. "Performing baseline ECG so that results may be compared with future ECG findings is considered screening ... and is not recommended for asymptomatic adults at low risk for CHD," the authors cautioned. "There is insufficient evidence about its usefulness in adults at increased risk."

The recommendation also addresses ECG screening in adults who are at intermediate or high risk of heart disease, because these people would potentially reap the greatest benefit from early detection and intervention.

"Reclassification into a higher risk category might lead to more intensive medical management that could lower the risk for CHD events, but it might also result in harms, including medication adverse events such as gastrointestinal bleeding and hepatic injury," the panel noted. "The risk-benefit tradeoff would be most favorable if persons can be accurately reclassified from intermediate to high risk."

Adults who are known to be at high risk should already be receiving intensive risk factor modification, so a resting or exercise ECG would probably not change that management.

"Irrespective of ECG findings, asymptomatic adults at increased risk for CHD are usually managed with a combination of aspirin, hypertension management, and tobacco cessation," the authors said.

The new recommendation differs slightly from that of the American College of Cardiology Foundation and the America Heart Association. Their guideline suggests that screening is "reasonable" in asymptomatic adults who have hypertension or diabetes.

Those groups support the concept of an exercise ECG for those at intermediate risk – including sedentary adults who are starting an exercise program.

The American Academy of Family Physicians does not recommend a routine ECG in the periodic health exams of asymptomatic adults.

As members of a federal group, none of the task force participants has any financial declarations. Dr. Golden said has no relevant financial disclosures.

Screening asymptomatic adults for heart disease with an electrocardiogram provides little useful risk information but may cause substantial harm, according to a new recommendation by the United States Preventive Services Task Force.

A thorough history and physical exam are the best ways to ascertain risk, wrote task force chair Dr. Virginia A. Moyer and her fellow panel members.

Photo hepatus/iStockphoto.com

"The incremental information offered by resting or exercise ECG (beyond that obtained with conventional CHD risk factors) is highly unlikely to result in changes in risks stratification that would prompt interventions and ultimately reduce CHD-related events."

However, the harms may be very real, noted Dr. Moyer of the Baylor College of Medicine, Houston, and her coauthors.

"An ECG abnormality, as a result of a true- or false-positive test, can lead to invasive confirmatory testing and treatments that have the potential for serious harm, including unnecessary radiation exposure and the associated risk for cancer," the panel members noted (Ann. Intern. Med.; 2012 July 31 [online first]).

Invasive testing – angiography and revascularization – could confer an additional set of problems, including bleeding, contrast-induced nephropathy, and allergic reactions to contrast agents.

The new recommendation is an update of one made in 2004. At that time, the task force advised against resting or exercise ECG and electron-based computer tomography (EBCT), but said there was not enough evidence to weigh in on ECG screening. The new paper included more recent data on direct harm due to the ECG itself, physical adverse events related to any additional testing, and psychological issues related to screening, including anxiety.

The guide also discourages baseline ECGs. "Performing baseline ECG so that results may be compared with future ECG findings is considered screening ... and is not recommended for asymptomatic adults at low risk for CHD," the authors cautioned. "There is insufficient evidence about its usefulness in adults at increased risk."

The recommendation also addresses ECG screening in adults who are at intermediate or high risk of heart disease, because these people would potentially reap the greatest benefit from early detection and intervention.

"Reclassification into a higher risk category might lead to more intensive medical management that could lower the risk for CHD events, but it might also result in harms, including medication adverse events such as gastrointestinal bleeding and hepatic injury," the panel noted. "The risk-benefit tradeoff would be most favorable if persons can be accurately reclassified from intermediate to high risk."

Adults who are known to be at high risk should already be receiving intensive risk factor modification, so a resting or exercise ECG would probably not change that management.

"Irrespective of ECG findings, asymptomatic adults at increased risk for CHD are usually managed with a combination of aspirin, hypertension management, and tobacco cessation," the authors said.

The new recommendation differs slightly from that of the American College of Cardiology Foundation and the America Heart Association. Their guideline suggests that screening is "reasonable" in asymptomatic adults who have hypertension or diabetes.

Those groups support the concept of an exercise ECG for those at intermediate risk – including sedentary adults who are starting an exercise program.

The American Academy of Family Physicians does not recommend a routine ECG in the periodic health exams of asymptomatic adults.

As members of a federal group, none of the task force participants has any financial declarations. Dr. Golden said has no relevant financial disclosures.

Screening asymptomatic adults for heart disease with an electrocardiogram provides little useful risk information but may cause substantial harm, according to a new recommendation by the United States Preventive Services Task Force.

A thorough history and physical exam are the best ways to ascertain risk, wrote task force chair Dr. Virginia A. Moyer and her fellow panel members.

Photo hepatus/iStockphoto.com

"The incremental information offered by resting or exercise ECG (beyond that obtained with conventional CHD risk factors) is highly unlikely to result in changes in risks stratification that would prompt interventions and ultimately reduce CHD-related events."

However, the harms may be very real, noted Dr. Moyer of the Baylor College of Medicine, Houston, and her coauthors.

"An ECG abnormality, as a result of a true- or false-positive test, can lead to invasive confirmatory testing and treatments that have the potential for serious harm, including unnecessary radiation exposure and the associated risk for cancer," the panel members noted (Ann. Intern. Med.; 2012 July 31 [online first]).

Invasive testing – angiography and revascularization – could confer an additional set of problems, including bleeding, contrast-induced nephropathy, and allergic reactions to contrast agents.

The new recommendation is an update of one made in 2004. At that time, the task force advised against resting or exercise ECG and electron-based computer tomography (EBCT), but said there was not enough evidence to weigh in on ECG screening. The new paper included more recent data on direct harm due to the ECG itself, physical adverse events related to any additional testing, and psychological issues related to screening, including anxiety.

The guide also discourages baseline ECGs. "Performing baseline ECG so that results may be compared with future ECG findings is considered screening ... and is not recommended for asymptomatic adults at low risk for CHD," the authors cautioned. "There is insufficient evidence about its usefulness in adults at increased risk."

The recommendation also addresses ECG screening in adults who are at intermediate or high risk of heart disease, because these people would potentially reap the greatest benefit from early detection and intervention.

"Reclassification into a higher risk category might lead to more intensive medical management that could lower the risk for CHD events, but it might also result in harms, including medication adverse events such as gastrointestinal bleeding and hepatic injury," the panel noted. "The risk-benefit tradeoff would be most favorable if persons can be accurately reclassified from intermediate to high risk."

Adults who are known to be at high risk should already be receiving intensive risk factor modification, so a resting or exercise ECG would probably not change that management.

"Irrespective of ECG findings, asymptomatic adults at increased risk for CHD are usually managed with a combination of aspirin, hypertension management, and tobacco cessation," the authors said.

The new recommendation differs slightly from that of the American College of Cardiology Foundation and the America Heart Association. Their guideline suggests that screening is "reasonable" in asymptomatic adults who have hypertension or diabetes.

Those groups support the concept of an exercise ECG for those at intermediate risk – including sedentary adults who are starting an exercise program.

The American Academy of Family Physicians does not recommend a routine ECG in the periodic health exams of asymptomatic adults.

As members of a federal group, none of the task force participants has any financial declarations. Dr. Golden said has no relevant financial disclosures.

Screening asymptomatic adults for heart disease with an electrocardiogram provides little useful risk information but may cause substantial harm, according to a new recommendation by the United States Preventive Services Task Force.

A thorough history and physical exam are the best ways to ascertain risk, wrote task force chair Dr. Virginia A. Moyer and her fellow panel members.

"The incremental information offered by resting or exercise ECG (beyond that obtained with conventional CHD risk factors) is highly unlikely to result in changes in risks stratification that would prompt interventions and ultimately reduce CHD-related events."

However, the harms may be very real, noted Dr. Moyer of the Baylor College of Medicine, Houston, and her coauthors.

"An ECG abnormality, as a result of a true- or false-positive test, can lead to invasive confirmatory testing and treatments that have the potential for serious harm, including unnecessary radiation exposure and the associated risk for cancer," the panel members noted (Ann. Intern. Med.; 2012 July 31 [online first]).

Invasive testing – angiography and revascularization – could confer an additional set of problems, including bleeding, contrast-induced nephropathy, and allergic reactions to contrast agents.

The new recommendation is an update of one made in 2004. At that time, the task force advised against resting or exercise ECG and electron-based computer tomography (EBCT), but said there was not enough evidence to weigh in on ECG screening. The new paper included more recent data on direct harm due to the ECG itself, physical adverse events related to any additional testing, and psychological issues related to screening, including anxiety.

The guide also discourages baseline ECGs. "Performing baseline ECG so that results may be compared with future ECG findings is considered screening ... and is not recommended for asymptomatic adults at low risk for CHD," the authors cautioned. "There is insufficient evidence about its usefulness in adults at increased risk."

The recommendation also addresses ECG screening in adults who are at intermediate or high risk of heart disease, because these people would potentially reap the greatest benefit from early detection and intervention.

"Reclassification into a higher risk category might lead to more intensive medical management that could lower the risk for CHD events, but it might also result in harms, including medication adverse events such as gastrointestinal bleeding and hepatic injury," the panel noted. "The risk-benefit tradeoff would be most favorable if persons can be accurately reclassified from intermediate to high risk."

Adults who are known to be at high risk should already be receiving intensive risk factor modification, so a resting or exercise ECG would probably not change that management.

"Irrespective of ECG findings, asymptomatic adults at increased risk for CHD are usually managed with a combination of aspirin, hypertension management, and tobacco cessation," the authors said.

The new recommendation differs slightly from that of the American College of Cardiology Foundation and the America Heart Association. Their guideline suggests that screening is "reasonable" in asymptomatic adults who have hypertension or diabetes.

Those groups support the concept of an exercise ECG for those at intermediate risk – including sedentary adults who are starting an exercise program.

The American Academy of Family Physicians does not recommend a routine ECG in the periodic health exams of asymptomatic adults.

As members of a federal group, none of the task force participants has any financial declarations. Dr. Golden said has no relevant financial disclosures.

Screening asymptomatic adults for heart disease with an electrocardiogram provides little useful risk information but may cause substantial harm, according to a new recommendation by the United States Preventive Services Task Force.

A thorough history and physical exam are the best ways to ascertain risk, wrote task force chair Dr. Virginia A. Moyer and her fellow panel members.

"The incremental information offered by resting or exercise ECG (beyond that obtained with conventional CHD risk factors) is highly unlikely to result in changes in risks stratification that would prompt interventions and ultimately reduce CHD-related events."

However, the harms may be very real, noted Dr. Moyer of the Baylor College of Medicine, Houston, and her coauthors.

"An ECG abnormality, as a result of a true- or false-positive test, can lead to invasive confirmatory testing and treatments that have the potential for serious harm, including unnecessary radiation exposure and the associated risk for cancer," the panel members noted (Ann. Intern. Med.; 2012 July 31 [online first]).

Invasive testing – angiography and revascularization – could confer an additional set of problems, including bleeding, contrast-induced nephropathy, and allergic reactions to contrast agents.

The new recommendation is an update of one made in 2004. At that time, the task force advised against resting or exercise ECG and electron-based computer tomography (EBCT), but said there was not enough evidence to weigh in on ECG screening. The new paper included more recent data on direct harm due to the ECG itself, physical adverse events related to any additional testing, and psychological issues related to screening, including anxiety.

The guide also discourages baseline ECGs. "Performing baseline ECG so that results may be compared with future ECG findings is considered screening ... and is not recommended for asymptomatic adults at low risk for CHD," the authors cautioned. "There is insufficient evidence about its usefulness in adults at increased risk."

The recommendation also addresses ECG screening in adults who are at intermediate or high risk of heart disease, because these people would potentially reap the greatest benefit from early detection and intervention.

"Reclassification into a higher risk category might lead to more intensive medical management that could lower the risk for CHD events, but it might also result in harms, including medication adverse events such as gastrointestinal bleeding and hepatic injury," the panel noted. "The risk-benefit tradeoff would be most favorable if persons can be accurately reclassified from intermediate to high risk."

Adults who are known to be at high risk should already be receiving intensive risk factor modification, so a resting or exercise ECG would probably not change that management.

"Irrespective of ECG findings, asymptomatic adults at increased risk for CHD are usually managed with a combination of aspirin, hypertension management, and tobacco cessation," the authors said.

The new recommendation differs slightly from that of the American College of Cardiology Foundation and the America Heart Association. Their guideline suggests that screening is "reasonable" in asymptomatic adults who have hypertension or diabetes.

Those groups support the concept of an exercise ECG for those at intermediate risk – including sedentary adults who are starting an exercise program.

The American Academy of Family Physicians does not recommend a routine ECG in the periodic health exams of asymptomatic adults.

As members of a federal group, none of the task force participants has any financial declarations. Dr. Golden said has no relevant financial disclosures.

Screening asymptomatic adults for heart disease with an electrocardiogram provides little useful risk information but may cause substantial harm, according to a new recommendation by the United States Preventive Services Task Force.

A thorough history and physical exam are the best ways to ascertain risk, wrote task force chair Dr. Virginia A. Moyer and her fellow panel members.

"The incremental information offered by resting or exercise ECG (beyond that obtained with conventional CHD risk factors) is highly unlikely to result in changes in risks stratification that would prompt interventions and ultimately reduce CHD-related events."

However, the harms may be very real, noted Dr. Moyer of the Baylor College of Medicine, Houston, and her coauthors.

"An ECG abnormality, as a result of a true- or false-positive test, can lead to invasive confirmatory testing and treatments that have the potential for serious harm, including unnecessary radiation exposure and the associated risk for cancer," the panel members noted (Ann. Intern. Med.; 2012 July 31 [online first]).

Invasive testing – angiography and revascularization – could confer an additional set of problems, including bleeding, contrast-induced nephropathy, and allergic reactions to contrast agents.

The new recommendation is an update of one made in 2004. At that time, the task force advised against resting or exercise ECG and electron-based computer tomography (EBCT), but said there was not enough evidence to weigh in on ECG screening. The new paper included more recent data on direct harm due to the ECG itself, physical adverse events related to any additional testing, and psychological issues related to screening, including anxiety.

The guide also discourages baseline ECGs. "Performing baseline ECG so that results may be compared with future ECG findings is considered screening ... and is not recommended for asymptomatic adults at low risk for CHD," the authors cautioned. "There is insufficient evidence about its usefulness in adults at increased risk."

The recommendation also addresses ECG screening in adults who are at intermediate or high risk of heart disease, because these people would potentially reap the greatest benefit from early detection and intervention.

"Reclassification into a higher risk category might lead to more intensive medical management that could lower the risk for CHD events, but it might also result in harms, including medication adverse events such as gastrointestinal bleeding and hepatic injury," the panel noted. "The risk-benefit tradeoff would be most favorable if persons can be accurately reclassified from intermediate to high risk."

Adults who are known to be at high risk should already be receiving intensive risk factor modification, so a resting or exercise ECG would probably not change that management.

"Irrespective of ECG findings, asymptomatic adults at increased risk for CHD are usually managed with a combination of aspirin, hypertension management, and tobacco cessation," the authors said.

The new recommendation differs slightly from that of the American College of Cardiology Foundation and the America Heart Association. Their guideline suggests that screening is "reasonable" in asymptomatic adults who have hypertension or diabetes.

Those groups support the concept of an exercise ECG for those at intermediate risk – including sedentary adults who are starting an exercise program.

The American Academy of Family Physicians does not recommend a routine ECG in the periodic health exams of asymptomatic adults.

As members of a federal group, none of the task force participants has any financial declarations. Dr. Golden said has no relevant financial disclosures.

Although the Food and Drug Administration’s decision to keep rosiglitazone on the market with a risk management program in place that preserves some access to the controversial diabetes drug, the plan is expected to squelch most prescribing and therefore, could have an effect that approaches that in Europe, where it will no longer be marketed.

Under a risk evaluation and mitigation strategy (REMS), rosiglitazone will be available only to new patients with type 2 diabetes who are unable to adequately manage their blood glucose on pioglitazone or are unable to take pioglitazone, the only other approved thiazolidinedione (TZD). However, patients who are already taking rosiglitazone may continue if, through the REMS program, they acknowledge their understanding of the drug’s potential cardiac risks, Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, said during a press briefing this week. About 600,000 U.S. patients are taking the drug; Dr. Woodcock said the REMS program will “significantly reduce” that number, while ensuring that those who continue will fully understand its potential risk.

Additionally, the FDA instructed the drug’s manufacturer, GlaxoSmithKline, to commission an independent readjudication of the RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes) trial, which was submitted to the FDA in August 2009 and was undertaken to further explore cardiovascular safety signals seen in earlier trials.

At the same time, the European Medicines Agency announced it was pulling it off the shelves in the European Union, based on the same evidence reviewed by the FDA.

The FDA’s decision reflects the majority opinion of an FDA advisory panel, which in July met to review the cardiovascular safety data of the drug. The majority of the panel members voted to keep the drug on the market but with more warnings and restrictions on its use, but a significant proportion advocated that it should be taken off the market.

Rosiglitazone has been dogged for years by conflicting data on its cardiovascular safety profile and the decision to restrict access came on the heels of an ever-increasing debate about rosiglitazone’s cardiovascular safety. The RECORD trial, sponsored by GlaxoSmithKline, found no increased risk in myocardial infarction, overall death, or cardiovascular death. But several trials came to conflicting conclusions about whether the drug increased the risk of MI; a highly touted 2007 meta-analysis of 42 studies concluded that it increased that risk by up to 43%, and the risk of cardiovascular death by up to 64% (N. Engl. J. Med. 2007;356:2457-71).

The lead author of the meta-analysis, Dr. Steven E. Nissen, a vocal advocate for the withdrawal of rosiglitazone from the market, said in an interview that both the FDA and EMA decisions will result in almost the same outcomes and that rosiglitazone will soon be rarely used.

Even though the FDA did not opt for market withdrawal, the drug in the United States “is essentially off the market,” as long as the REMS is well executed, which he expects it will be. “What you have to actually do in order to prescribe the drug now is you have to say you’ve tried every other diabetes drug, including pioglitazone, and the patient couldn’t tolerate them. There’s nobody that meets that description,” said Dr. Nissen, chairman of the department of cardiovascular medicine, Cleveland Clinic Foundation.

At the July panel meeting, Dr. Nissen told the panel and the FDA that, with another thiazolidinedione available as an alternative (pioglitazone), continued marketing of rosiglitazone could not be medically or ethically justified. But, in the interview, he was positive about the agency’s decision. His message to clinicians is to “stop using the drug, get people on something else, and move on.”

Endocrinologist Clifford Rosen agreed. “This effectively puts an end to rosiglitazone in the United States ... it will be very, very rare to have a patient on rosiglitazone,” said Dr. Rosen, professor of medicine at Tufts University, Boston, and senior scientist at Maine Medical Center, Scarborough. He was among the 10 panel members at the July meeting who voted in favor of allowing continued marketing but with more warnings in the label and restrictions in its use.

The FDA decision “basically puts an end to rosiglitazone prescriptions in the United States,” he said in an interview. “It’s almost impossible for an individual practitioner to write a prescription after spending 20 minutes talking about risk, having the patient sign an informed consent and then filling out forms to send to the FDA. It’s just not going to happen.”

Dr. Rosen added that he expects that most patients who are on the drug now will probably be switched to other drugs. “Maybe a few people who have been on it for a long time, feel great, and have good glucose control might stay on it, but those individuals still need to have full informed consent and have the risks explained to them.”

Keeping a patient on rosiglitazone under the REMS “will be an onerous task” and the use of the drug will be “minimal,” said Dr. Paul Jellinger, professor of clinical medicine, University of Miami, and past president of the American College of Endocrinology and the American Association of Clinical Endocrinologists. Patients can easily be switched form rosiglitazone to pioglitazone, or a non-TZD drug, such as an incretin-based treatment, he said in an interview.

Dr. Jellinger said that he thought the FDA decision was appropriate and that the FDA acted on behalf of patient safety, based on substantial amount of data. Although there was “considerable uncertainty, there remains a potential risk and there is a signal that suggests there may be a relationship.”

One of the cardiologists on the panel in July, Dr. Sanjay Kaul of the Cedars-Sinai Heart Institute in Los Angeles, said in an interview that the FDA’s decision is “the right call to keep the drug accessible but with significant restrictions that have teeth.” The decision, though, “reflects the uncertainty in the evidence – it is insufficient to either implicate the drug or exonerate it.”

During the press briefing, Dr. Woodcock said, “We still believe there is considerable uncertainty about the magnitude of the cardiovascular risk.” RECORD was an open-label trial, “and it was determined that we can’t rely on those results, even though they did not show a significantly increased risk of cardiac harm. Therefore, the questions raised by the meta-analysis have not really been answered,” she said.

The FDA also decided to terminate the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) study, also sponsored by GlaxoSmithKline, which was designed to determine any difference in cardiovascular safety between rosiglitazone and pioglitazone. In July, the FDA put TIDE on a partial hold, allowing patient enrollment but not treatment. The panel had voted 19-11 to continue the TIDE trial, if rosiglitazone remained on the U.S. market.

Dr. Rosen, who was among those strongly opposed to continuing the study, lauded the decision to halt the TIDE study because it would be unethical to continue the study and subject people to a randomized trial that involved a drug ”where we know the risk and benefit is not established beyond pioglitazone.”

Dr. Kaul was among the panelists who supported continuing TIDE. ”If you stop the study, how else are you going to resolve this uncertainty,” he said. But he agrees with the FDA decision. “The FDA had to do what they did,” but pointed out that considerable controversy over the drug remains.

Dr. Jellinger also would have liked the TIDE study to continue, and found it “unusual” that the gold standard of clinical trials, the prospective randomized, controlled study, was trumped by studies like meta-analyses.

During the press briefing, Dr. Woodcock said that the signal of increased risk “has not been completely refuted by any evidence, so we think it is prudent to restrict access and make sure that those using and prescribing the medication are aware of the facts and make the choice in an informed manner.”

It will take several months to fully implement the REMS program, Dr. Joshua Sharfstein said during the briefing. Until then, “Patients who are taking rosiglitazone should continue to do so, and consult their physician to discuss the possibility of selecting another medication without this concern of cardiac ischemia,” said Dr. Sharfstein, FDA’s principal deputy commissioner. “Once the REMS is in place, physicians will need to enroll patients before they can continue to receive the drug.”

When the REMS is active, Dr. Sharfstein reiterated, rosiglitazone will be available only to patients who cannot control their blood sugar on any other medication and who are unable to take pioglitazone for medical reasons. “Doctors will have to document this, and also that they have discussed the risks of rosiglitazone in order for the patient to receive the drug.”

Researchers had hoped the RECORD study would set the rosiglitazone risk story straight. But in July, the FDA panel tasked with reviewing the drug’s safety questioned RECORD and its adjudication of cardiovascular events. The independent review of RECORD’s adjudication at a patient record level will be done, Dr. Sharfstein said, “to catch events that occurred but which might have not been properly referred to the adjudication committee.”

In a press statement, Dr. Ellen Strahlman, GlaxoSmithKline’s chief medical officer, said, “Our primary concern continues to be patients with type 2 diabetes, and we are making every effort to ensure that physicians in Europe and the U.S. have all the information they need to help them understand how these regulatory decisions affect them and their patients.”

The statement noted that “the company continues to believe that [rosiglitazone] is an important treatment for patients with type 2 diabetes and is now working with the FDA and EMA to implement the required actions ... GSK will voluntarily cease promotion of [rosiglitazone] in all the countries in which it operates and will continue to respond to requests for information and support from healthcare professionals and patients.”

But other REMS programs – including the one that will be established for rosiglitazone – are much more restrictive, such as the one for the antiepileptic vigabatrin. That REMS requires not only a medication guide, but also a communication plan to ensure reporting of adverse events, elements to assure safe use, and a system to ensure that physicians, pharmacies, and patients who do not comply with the rules lose access to the drug.

Dr. Nissen has received research support from Takeda Pharmaceutical Co., AstraZeneca, Daiichi Sankyo Co., and several other pharmaceutical companies and has consulted for a many such companies without financial compensation. All payments from any for-profit entity are paid directly to charity. Dr. Rosen reports receiving a lecture fee from GlaxoSmithKline and grant support from Eli Lilly & Co., Merck & Co., and Novartis. Dr. Kaul has received research support from Hoffmann-La Roche and has been a consultant for that company as well as from Novo-Nordisk. Dr. Jellinger is on the speakers bureaus of Amylin Pharmaceuticals, Eli Lilly, Merck, Novo-Nordisk, Sanofi-Aventis, and Takeda.

Although the Food and Drug Administration’s decision to keep rosiglitazone on the market with a risk management program in place that preserves some access to the controversial diabetes drug, the plan is expected to squelch most prescribing and therefore, could have an effect that approaches that in Europe, where it will no longer be marketed.

Under a risk evaluation and mitigation strategy (REMS), rosiglitazone will be available only to new patients with type 2 diabetes who are unable to adequately manage their blood glucose on pioglitazone or are unable to take pioglitazone, the only other approved thiazolidinedione (TZD). However, patients who are already taking rosiglitazone may continue if, through the REMS program, they acknowledge their understanding of the drug’s potential cardiac risks, Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, said during a press briefing this week. About 600,000 U.S. patients are taking the drug; Dr. Woodcock said the REMS program will “significantly reduce” that number, while ensuring that those who continue will fully understand its potential risk.

Additionally, the FDA instructed the drug’s manufacturer, GlaxoSmithKline, to commission an independent readjudication of the RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes) trial, which was submitted to the FDA in August 2009 and was undertaken to further explore cardiovascular safety signals seen in earlier trials.

At the same time, the European Medicines Agency announced it was pulling it off the shelves in the European Union, based on the same evidence reviewed by the FDA.

The FDA’s decision reflects the majority opinion of an FDA advisory panel, which in July met to review the cardiovascular safety data of the drug. The majority of the panel members voted to keep the drug on the market but with more warnings and restrictions on its use, but a significant proportion advocated that it should be taken off the market.

Rosiglitazone has been dogged for years by conflicting data on its cardiovascular safety profile and the decision to restrict access came on the heels of an ever-increasing debate about rosiglitazone’s cardiovascular safety. The RECORD trial, sponsored by GlaxoSmithKline, found no increased risk in myocardial infarction, overall death, or cardiovascular death. But several trials came to conflicting conclusions about whether the drug increased the risk of MI; a highly touted 2007 meta-analysis of 42 studies concluded that it increased that risk by up to 43%, and the risk of cardiovascular death by up to 64% (N. Engl. J. Med. 2007;356:2457-71).

The lead author of the meta-analysis, Dr. Steven E. Nissen, a vocal advocate for the withdrawal of rosiglitazone from the market, said in an interview that both the FDA and EMA decisions will result in almost the same outcomes and that rosiglitazone will soon be rarely used.

Even though the FDA did not opt for market withdrawal, the drug in the United States “is essentially off the market,” as long as the REMS is well executed, which he expects it will be. “What you have to actually do in order to prescribe the drug now is you have to say you’ve tried every other diabetes drug, including pioglitazone, and the patient couldn’t tolerate them. There’s nobody that meets that description,” said Dr. Nissen, chairman of the department of cardiovascular medicine, Cleveland Clinic Foundation.

At the July panel meeting, Dr. Nissen told the panel and the FDA that, with another thiazolidinedione available as an alternative (pioglitazone), continued marketing of rosiglitazone could not be medically or ethically justified. But, in the interview, he was positive about the agency’s decision. His message to clinicians is to “stop using the drug, get people on something else, and move on.”

Endocrinologist Clifford Rosen agreed. “This effectively puts an end to rosiglitazone in the United States ... it will be very, very rare to have a patient on rosiglitazone,” said Dr. Rosen, professor of medicine at Tufts University, Boston, and senior scientist at Maine Medical Center, Scarborough. He was among the 10 panel members at the July meeting who voted in favor of allowing continued marketing but with more warnings in the label and restrictions in its use.

The FDA decision “basically puts an end to rosiglitazone prescriptions in the United States,” he said in an interview. “It’s almost impossible for an individual practitioner to write a prescription after spending 20 minutes talking about risk, having the patient sign an informed consent and then filling out forms to send to the FDA. It’s just not going to happen.”

Dr. Rosen added that he expects that most patients who are on the drug now will probably be switched to other drugs. “Maybe a few people who have been on it for a long time, feel great, and have good glucose control might stay on it, but those individuals still need to have full informed consent and have the risks explained to them.”

Keeping a patient on rosiglitazone under the REMS “will be an onerous task” and the use of the drug will be “minimal,” said Dr. Paul Jellinger, professor of clinical medicine, University of Miami, and past president of the American College of Endocrinology and the American Association of Clinical Endocrinologists. Patients can easily be switched form rosiglitazone to pioglitazone, or a non-TZD drug, such as an incretin-based treatment, he said in an interview.

Dr. Jellinger said that he thought the FDA decision was appropriate and that the FDA acted on behalf of patient safety, based on substantial amount of data. Although there was “considerable uncertainty, there remains a potential risk and there is a signal that suggests there may be a relationship.”

One of the cardiologists on the panel in July, Dr. Sanjay Kaul of the Cedars-Sinai Heart Institute in Los Angeles, said in an interview that the FDA’s decision is “the right call to keep the drug accessible but with significant restrictions that have teeth.” The decision, though, “reflects the uncertainty in the evidence – it is insufficient to either implicate the drug or exonerate it.”

During the press briefing, Dr. Woodcock said, “We still believe there is considerable uncertainty about the magnitude of the cardiovascular risk.” RECORD was an open-label trial, “and it was determined that we can’t rely on those results, even though they did not show a significantly increased risk of cardiac harm. Therefore, the questions raised by the meta-analysis have not really been answered,” she said.

The FDA also decided to terminate the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) study, also sponsored by GlaxoSmithKline, which was designed to determine any difference in cardiovascular safety between rosiglitazone and pioglitazone. In July, the FDA put TIDE on a partial hold, allowing patient enrollment but not treatment. The panel had voted 19-11 to continue the TIDE trial, if rosiglitazone remained on the U.S. market.

Dr. Rosen, who was among those strongly opposed to continuing the study, lauded the decision to halt the TIDE study because it would be unethical to continue the study and subject people to a randomized trial that involved a drug ”where we know the risk and benefit is not established beyond pioglitazone.”

Dr. Kaul was among the panelists who supported continuing TIDE. ”If you stop the study, how else are you going to resolve this uncertainty,” he said. But he agrees with the FDA decision. “The FDA had to do what they did,” but pointed out that considerable controversy over the drug remains.

Dr. Jellinger also would have liked the TIDE study to continue, and found it “unusual” that the gold standard of clinical trials, the prospective randomized, controlled study, was trumped by studies like meta-analyses.

During the press briefing, Dr. Woodcock said that the signal of increased risk “has not been completely refuted by any evidence, so we think it is prudent to restrict access and make sure that those using and prescribing the medication are aware of the facts and make the choice in an informed manner.”

It will take several months to fully implement the REMS program, Dr. Joshua Sharfstein said during the briefing. Until then, “Patients who are taking rosiglitazone should continue to do so, and consult their physician to discuss the possibility of selecting another medication without this concern of cardiac ischemia,” said Dr. Sharfstein, FDA’s principal deputy commissioner. “Once the REMS is in place, physicians will need to enroll patients before they can continue to receive the drug.”

When the REMS is active, Dr. Sharfstein reiterated, rosiglitazone will be available only to patients who cannot control their blood sugar on any other medication and who are unable to take pioglitazone for medical reasons. “Doctors will have to document this, and also that they have discussed the risks of rosiglitazone in order for the patient to receive the drug.”

Researchers had hoped the RECORD study would set the rosiglitazone risk story straight. But in July, the FDA panel tasked with reviewing the drug’s safety questioned RECORD and its adjudication of cardiovascular events. The independent review of RECORD’s adjudication at a patient record level will be done, Dr. Sharfstein said, “to catch events that occurred but which might have not been properly referred to the adjudication committee.”

In a press statement, Dr. Ellen Strahlman, GlaxoSmithKline’s chief medical officer, said, “Our primary concern continues to be patients with type 2 diabetes, and we are making every effort to ensure that physicians in Europe and the U.S. have all the information they need to help them understand how these regulatory decisions affect them and their patients.”

The statement noted that “the company continues to believe that [rosiglitazone] is an important treatment for patients with type 2 diabetes and is now working with the FDA and EMA to implement the required actions ... GSK will voluntarily cease promotion of [rosiglitazone] in all the countries in which it operates and will continue to respond to requests for information and support from healthcare professionals and patients.”

But other REMS programs – including the one that will be established for rosiglitazone – are much more restrictive, such as the one for the antiepileptic vigabatrin. That REMS requires not only a medication guide, but also a communication plan to ensure reporting of adverse events, elements to assure safe use, and a system to ensure that physicians, pharmacies, and patients who do not comply with the rules lose access to the drug.

Dr. Nissen has received research support from Takeda Pharmaceutical Co., AstraZeneca, Daiichi Sankyo Co., and several other pharmaceutical companies and has consulted for a many such companies without financial compensation. All payments from any for-profit entity are paid directly to charity. Dr. Rosen reports receiving a lecture fee from GlaxoSmithKline and grant support from Eli Lilly & Co., Merck & Co., and Novartis. Dr. Kaul has received research support from Hoffmann-La Roche and has been a consultant for that company as well as from Novo-Nordisk. Dr. Jellinger is on the speakers bureaus of Amylin Pharmaceuticals, Eli Lilly, Merck, Novo-Nordisk, Sanofi-Aventis, and Takeda.

Although the Food and Drug Administration’s decision to keep rosiglitazone on the market with a risk management program in place that preserves some access to the controversial diabetes drug, the plan is expected to squelch most prescribing and therefore, could have an effect that approaches that in Europe, where it will no longer be marketed.

Under a risk evaluation and mitigation strategy (REMS), rosiglitazone will be available only to new patients with type 2 diabetes who are unable to adequately manage their blood glucose on pioglitazone or are unable to take pioglitazone, the only other approved thiazolidinedione (TZD). However, patients who are already taking rosiglitazone may continue if, through the REMS program, they acknowledge their understanding of the drug’s potential cardiac risks, Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, said during a press briefing this week. About 600,000 U.S. patients are taking the drug; Dr. Woodcock said the REMS program will “significantly reduce” that number, while ensuring that those who continue will fully understand its potential risk.

Additionally, the FDA instructed the drug’s manufacturer, GlaxoSmithKline, to commission an independent readjudication of the RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes) trial, which was submitted to the FDA in August 2009 and was undertaken to further explore cardiovascular safety signals seen in earlier trials.

At the same time, the European Medicines Agency announced it was pulling it off the shelves in the European Union, based on the same evidence reviewed by the FDA.

The FDA’s decision reflects the majority opinion of an FDA advisory panel, which in July met to review the cardiovascular safety data of the drug. The majority of the panel members voted to keep the drug on the market but with more warnings and restrictions on its use, but a significant proportion advocated that it should be taken off the market.

Rosiglitazone has been dogged for years by conflicting data on its cardiovascular safety profile and the decision to restrict access came on the heels of an ever-increasing debate about rosiglitazone’s cardiovascular safety. The RECORD trial, sponsored by GlaxoSmithKline, found no increased risk in myocardial infarction, overall death, or cardiovascular death. But several trials came to conflicting conclusions about whether the drug increased the risk of MI; a highly touted 2007 meta-analysis of 42 studies concluded that it increased that risk by up to 43%, and the risk of cardiovascular death by up to 64% (N. Engl. J. Med. 2007;356:2457-71).

The lead author of the meta-analysis, Dr. Steven E. Nissen, a vocal advocate for the withdrawal of rosiglitazone from the market, said in an interview that both the FDA and EMA decisions will result in almost the same outcomes and that rosiglitazone will soon be rarely used.

Even though the FDA did not opt for market withdrawal, the drug in the United States “is essentially off the market,” as long as the REMS is well executed, which he expects it will be. “What you have to actually do in order to prescribe the drug now is you have to say you’ve tried every other diabetes drug, including pioglitazone, and the patient couldn’t tolerate them. There’s nobody that meets that description,” said Dr. Nissen, chairman of the department of cardiovascular medicine, Cleveland Clinic Foundation.

At the July panel meeting, Dr. Nissen told the panel and the FDA that, with another thiazolidinedione available as an alternative (pioglitazone), continued marketing of rosiglitazone could not be medically or ethically justified. But, in the interview, he was positive about the agency’s decision. His message to clinicians is to “stop using the drug, get people on something else, and move on.”

Endocrinologist Clifford Rosen agreed. “This effectively puts an end to rosiglitazone in the United States ... it will be very, very rare to have a patient on rosiglitazone,” said Dr. Rosen, professor of medicine at Tufts University, Boston, and senior scientist at Maine Medical Center, Scarborough. He was among the 10 panel members at the July meeting who voted in favor of allowing continued marketing but with more warnings in the label and restrictions in its use.

The FDA decision “basically puts an end to rosiglitazone prescriptions in the United States,” he said in an interview. “It’s almost impossible for an individual practitioner to write a prescription after spending 20 minutes talking about risk, having the patient sign an informed consent and then filling out forms to send to the FDA. It’s just not going to happen.”

Dr. Rosen added that he expects that most patients who are on the drug now will probably be switched to other drugs. “Maybe a few people who have been on it for a long time, feel great, and have good glucose control might stay on it, but those individuals still need to have full informed consent and have the risks explained to them.”

Keeping a patient on rosiglitazone under the REMS “will be an onerous task” and the use of the drug will be “minimal,” said Dr. Paul Jellinger, professor of clinical medicine, University of Miami, and past president of the American College of Endocrinology and the American Association of Clinical Endocrinologists. Patients can easily be switched form rosiglitazone to pioglitazone, or a non-TZD drug, such as an incretin-based treatment, he said in an interview.

Dr. Jellinger said that he thought the FDA decision was appropriate and that the FDA acted on behalf of patient safety, based on substantial amount of data. Although there was “considerable uncertainty, there remains a potential risk and there is a signal that suggests there may be a relationship.”

One of the cardiologists on the panel in July, Dr. Sanjay Kaul of the Cedars-Sinai Heart Institute in Los Angeles, said in an interview that the FDA’s decision is “the right call to keep the drug accessible but with significant restrictions that have teeth.” The decision, though, “reflects the uncertainty in the evidence – it is insufficient to either implicate the drug or exonerate it.”

During the press briefing, Dr. Woodcock said, “We still believe there is considerable uncertainty about the magnitude of the cardiovascular risk.” RECORD was an open-label trial, “and it was determined that we can’t rely on those results, even though they did not show a significantly increased risk of cardiac harm. Therefore, the questions raised by the meta-analysis have not really been answered,” she said.

The FDA also decided to terminate the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) study, also sponsored by GlaxoSmithKline, which was designed to determine any difference in cardiovascular safety between rosiglitazone and pioglitazone. In July, the FDA put TIDE on a partial hold, allowing patient enrollment but not treatment. The panel had voted 19-11 to continue the TIDE trial, if rosiglitazone remained on the U.S. market.

Dr. Rosen, who was among those strongly opposed to continuing the study, lauded the decision to halt the TIDE study because it would be unethical to continue the study and subject people to a randomized trial that involved a drug ”where we know the risk and benefit is not established beyond pioglitazone.”

Dr. Kaul was among the panelists who supported continuing TIDE. ”If you stop the study, how else are you going to resolve this uncertainty,” he said. But he agrees with the FDA decision. “The FDA had to do what they did,” but pointed out that considerable controversy over the drug remains.

Dr. Jellinger also would have liked the TIDE study to continue, and found it “unusual” that the gold standard of clinical trials, the prospective randomized, controlled study, was trumped by studies like meta-analyses.

During the press briefing, Dr. Woodcock said that the signal of increased risk “has not been completely refuted by any evidence, so we think it is prudent to restrict access and make sure that those using and prescribing the medication are aware of the facts and make the choice in an informed manner.”

It will take several months to fully implement the REMS program, Dr. Joshua Sharfstein said during the briefing. Until then, “Patients who are taking rosiglitazone should continue to do so, and consult their physician to discuss the possibility of selecting another medication without this concern of cardiac ischemia,” said Dr. Sharfstein, FDA’s principal deputy commissioner. “Once the REMS is in place, physicians will need to enroll patients before they can continue to receive the drug.”

When the REMS is active, Dr. Sharfstein reiterated, rosiglitazone will be available only to patients who cannot control their blood sugar on any other medication and who are unable to take pioglitazone for medical reasons. “Doctors will have to document this, and also that they have discussed the risks of rosiglitazone in order for the patient to receive the drug.”

Researchers had hoped the RECORD study would set the rosiglitazone risk story straight. But in July, the FDA panel tasked with reviewing the drug’s safety questioned RECORD and its adjudication of cardiovascular events. The independent review of RECORD’s adjudication at a patient record level will be done, Dr. Sharfstein said, “to catch events that occurred but which might have not been properly referred to the adjudication committee.”

In a press statement, Dr. Ellen Strahlman, GlaxoSmithKline’s chief medical officer, said, “Our primary concern continues to be patients with type 2 diabetes, and we are making every effort to ensure that physicians in Europe and the U.S. have all the information they need to help them understand how these regulatory decisions affect them and their patients.”

The statement noted that “the company continues to believe that [rosiglitazone] is an important treatment for patients with type 2 diabetes and is now working with the FDA and EMA to implement the required actions ... GSK will voluntarily cease promotion of [rosiglitazone] in all the countries in which it operates and will continue to respond to requests for information and support from healthcare professionals and patients.”

But other REMS programs – including the one that will be established for rosiglitazone – are much more restrictive, such as the one for the antiepileptic vigabatrin. That REMS requires not only a medication guide, but also a communication plan to ensure reporting of adverse events, elements to assure safe use, and a system to ensure that physicians, pharmacies, and patients who do not comply with the rules lose access to the drug.

Dr. Nissen has received research support from Takeda Pharmaceutical Co., AstraZeneca, Daiichi Sankyo Co., and several other pharmaceutical companies and has consulted for a many such companies without financial compensation. All payments from any for-profit entity are paid directly to charity. Dr. Rosen reports receiving a lecture fee from GlaxoSmithKline and grant support from Eli Lilly & Co., Merck & Co., and Novartis. Dr. Kaul has received research support from Hoffmann-La Roche and has been a consultant for that company as well as from Novo-Nordisk. Dr. Jellinger is on the speakers bureaus of Amylin Pharmaceuticals, Eli Lilly, Merck, Novo-Nordisk, Sanofi-Aventis, and Takeda.