Michele G. Sullivan

WASHINGTON – Gastric bypass surgery resulted in significantly more weight loss and also improved measures of glycemic control significantly more than did other forms of bariatric surgery, Dr. John Morton reported at the annual clinical congress of the American College of Surgeons.

However, he noted, while remission did correlate with weight loss in patients who had gastric banding or sleeving, it appeared to be independent of weight loss in those who had the bypass surgery. While he didn’t speculate on the reasons for this finding, he did affirm his belief that gastric bypass is the best option for most obese patients with comorbid diabetes.

"I feel very comfortable recommending it" for these patients, said Dr. Morton of the Stanford (Calif.) University. "There are, of course, other clinical conditions to consider when deciding [among] bypass, banding, and sleeve, but if the only consideration is around diabetes, I’m 100% comfortable in recommending it for obese diabetics."

Michele G. Sullivan/IMNG Medical Media

He presented the 1-year follow-up data on 1,792 obese patients who underwent bariatric surgery. Of these, 1,364 had a Roux-en-Y bypass; 264 had a sleeve gastrectomy; and 164 had adjustable gastric banding.

The patients were a mean of about 46 years old. Body mass index was statistically, but not clinically, different between the groups (bypass 47 kg/m2; band 44 kg/m2; sleeve 44 kg/m2). Waist circumference ranged from 51 to 53 inches. About 75% of the group was female and more than half, white.

Overall, about one-third of each group had type 2 diabetes. Most were taking only oral medications. About 5% took only insulin, and about a quarter took both oral agents and insulin. At baseline, the mean HbA_1c was more than 7% in each group. The mean fasting insulin was 36 microU/mL in the bypass group, 28 microU/mL in the band group, and 32 microU/mL in the sleeve group.

By 12 months after surgery, patients with diabetes who had bypass had lost the most weight – a mean of 71% of their excess body weight, compared with 38% in the banding group and 50% in the sleeve group.

Those who had the bypass surgery also experienced the biggest change in their HbA_1c – dropping almost 16% to a mean of 5.8%. Patients in the other two groups experienced a mean drop of 10%, resulting in HbA_1c levels of right around 6%.

Fasting insulin levels also improved significantly more in the bypass group, falling from a baseline mean of 56 microU/mL to 7.8 microU/mL – a decrease of 68%. In the band group, the level fell from 28 microU/mL to 12 microU/mL – a 52% decrease. In the sleeve group, levels fell from 32 microU/mL to 10 microU/mL – a 61% decrease.

"Fasting insulin is also considered an independent marker of cardiac risk," Dr. Morton added, indicating that the risk of cardiovascular problems would fall along with insulin levels.

Blood glucose improved significantly more in the bypass group, falling from a baseline mean of 149 mg/dL to 101 mg/dL – a 22% change. In the band group, the level fell from 140 mg/dL to 125 mg/dL (8%) and in the sleeve group, from 130 mg/dL to 118 mg/dL (5.6%).

A multivariate analysis controlled for surgery type, sex, body mass index, race, age, and insurance status. Of these factors, surgery type was the strongest predictor, with bypass patients three times more likely to achieve that goal than those undergoing banding or sleeve placement.

Dr. Morton did not present his complication data. However, during the discussion period, he said the three procedures were similarly safe. The gastric sleeve group had a higher leak rate than did the other groups, but that remained less than 1%. Readmission rates were comparable, he said, but he did not provide that number.

"Any time you consider this, it has to be a risk/benefit analysis," he said. "It’s our philosophy that for obese patients with severe diabetes, we approach them first with the bypass because it has the most proven track record over time."

Dr. Morton has up to 7 years of data on some of the patients, and said he is now analyzing that. But when questioned about durability, he agreed that diabetes can recur in the rather common scenario of a patient regaining weight. "At the end of the day, though, what’s important is that the obese patient with diabetes gets treatment. All three surgeries demonstrated some improvement, and I believe that any surgery is better than no surgery at all."

Dr. Morton has received research support from Covidien.

[email protected]

WASHINGTON – Gastric bypass surgery resulted in significantly more weight loss and also improved measures of glycemic control significantly more than did other forms of bariatric surgery, Dr. John Morton reported at the annual clinical congress of the American College of Surgeons.

However, he noted, while remission did correlate with weight loss in patients who had gastric banding or sleeving, it appeared to be independent of weight loss in those who had the bypass surgery. While he didn’t speculate on the reasons for this finding, he did affirm his belief that gastric bypass is the best option for most obese patients with comorbid diabetes.

"I feel very comfortable recommending it" for these patients, said Dr. Morton of the Stanford (Calif.) University. "There are, of course, other clinical conditions to consider when deciding [among] bypass, banding, and sleeve, but if the only consideration is around diabetes, I’m 100% comfortable in recommending it for obese diabetics."

Michele G. Sullivan/IMNG Medical Media

He presented the 1-year follow-up data on 1,792 obese patients who underwent bariatric surgery. Of these, 1,364 had a Roux-en-Y bypass; 264 had a sleeve gastrectomy; and 164 had adjustable gastric banding.

The patients were a mean of about 46 years old. Body mass index was statistically, but not clinically, different between the groups (bypass 47 kg/m2; band 44 kg/m2; sleeve 44 kg/m2). Waist circumference ranged from 51 to 53 inches. About 75% of the group was female and more than half, white.

Overall, about one-third of each group had type 2 diabetes. Most were taking only oral medications. About 5% took only insulin, and about a quarter took both oral agents and insulin. At baseline, the mean HbA_1c was more than 7% in each group. The mean fasting insulin was 36 microU/mL in the bypass group, 28 microU/mL in the band group, and 32 microU/mL in the sleeve group.

By 12 months after surgery, patients with diabetes who had bypass had lost the most weight – a mean of 71% of their excess body weight, compared with 38% in the banding group and 50% in the sleeve group.

Those who had the bypass surgery also experienced the biggest change in their HbA_1c – dropping almost 16% to a mean of 5.8%. Patients in the other two groups experienced a mean drop of 10%, resulting in HbA_1c levels of right around 6%.

Fasting insulin levels also improved significantly more in the bypass group, falling from a baseline mean of 56 microU/mL to 7.8 microU/mL – a decrease of 68%. In the band group, the level fell from 28 microU/mL to 12 microU/mL – a 52% decrease. In the sleeve group, levels fell from 32 microU/mL to 10 microU/mL – a 61% decrease.

"Fasting insulin is also considered an independent marker of cardiac risk," Dr. Morton added, indicating that the risk of cardiovascular problems would fall along with insulin levels.

Blood glucose improved significantly more in the bypass group, falling from a baseline mean of 149 mg/dL to 101 mg/dL – a 22% change. In the band group, the level fell from 140 mg/dL to 125 mg/dL (8%) and in the sleeve group, from 130 mg/dL to 118 mg/dL (5.6%).

A multivariate analysis controlled for surgery type, sex, body mass index, race, age, and insurance status. Of these factors, surgery type was the strongest predictor, with bypass patients three times more likely to achieve that goal than those undergoing banding or sleeve placement.

Dr. Morton did not present his complication data. However, during the discussion period, he said the three procedures were similarly safe. The gastric sleeve group had a higher leak rate than did the other groups, but that remained less than 1%. Readmission rates were comparable, he said, but he did not provide that number.

"Any time you consider this, it has to be a risk/benefit analysis," he said. "It’s our philosophy that for obese patients with severe diabetes, we approach them first with the bypass because it has the most proven track record over time."

Dr. Morton has up to 7 years of data on some of the patients, and said he is now analyzing that. But when questioned about durability, he agreed that diabetes can recur in the rather common scenario of a patient regaining weight. "At the end of the day, though, what’s important is that the obese patient with diabetes gets treatment. All three surgeries demonstrated some improvement, and I believe that any surgery is better than no surgery at all."

Dr. Morton has received research support from Covidien.

[email protected]

WASHINGTON – Gastric bypass surgery resulted in significantly more weight loss and also improved measures of glycemic control significantly more than did other forms of bariatric surgery, Dr. John Morton reported at the annual clinical congress of the American College of Surgeons.

However, he noted, while remission did correlate with weight loss in patients who had gastric banding or sleeving, it appeared to be independent of weight loss in those who had the bypass surgery. While he didn’t speculate on the reasons for this finding, he did affirm his belief that gastric bypass is the best option for most obese patients with comorbid diabetes.

"I feel very comfortable recommending it" for these patients, said Dr. Morton of the Stanford (Calif.) University. "There are, of course, other clinical conditions to consider when deciding [among] bypass, banding, and sleeve, but if the only consideration is around diabetes, I’m 100% comfortable in recommending it for obese diabetics."

Michele G. Sullivan/IMNG Medical Media

He presented the 1-year follow-up data on 1,792 obese patients who underwent bariatric surgery. Of these, 1,364 had a Roux-en-Y bypass; 264 had a sleeve gastrectomy; and 164 had adjustable gastric banding.

The patients were a mean of about 46 years old. Body mass index was statistically, but not clinically, different between the groups (bypass 47 kg/m2; band 44 kg/m2; sleeve 44 kg/m2). Waist circumference ranged from 51 to 53 inches. About 75% of the group was female and more than half, white.

Overall, about one-third of each group had type 2 diabetes. Most were taking only oral medications. About 5% took only insulin, and about a quarter took both oral agents and insulin. At baseline, the mean HbA_1c was more than 7% in each group. The mean fasting insulin was 36 microU/mL in the bypass group, 28 microU/mL in the band group, and 32 microU/mL in the sleeve group.

By 12 months after surgery, patients with diabetes who had bypass had lost the most weight – a mean of 71% of their excess body weight, compared with 38% in the banding group and 50% in the sleeve group.

Those who had the bypass surgery also experienced the biggest change in their HbA_1c – dropping almost 16% to a mean of 5.8%. Patients in the other two groups experienced a mean drop of 10%, resulting in HbA_1c levels of right around 6%.

Fasting insulin levels also improved significantly more in the bypass group, falling from a baseline mean of 56 microU/mL to 7.8 microU/mL – a decrease of 68%. In the band group, the level fell from 28 microU/mL to 12 microU/mL – a 52% decrease. In the sleeve group, levels fell from 32 microU/mL to 10 microU/mL – a 61% decrease.

"Fasting insulin is also considered an independent marker of cardiac risk," Dr. Morton added, indicating that the risk of cardiovascular problems would fall along with insulin levels.

Blood glucose improved significantly more in the bypass group, falling from a baseline mean of 149 mg/dL to 101 mg/dL – a 22% change. In the band group, the level fell from 140 mg/dL to 125 mg/dL (8%) and in the sleeve group, from 130 mg/dL to 118 mg/dL (5.6%).

A multivariate analysis controlled for surgery type, sex, body mass index, race, age, and insurance status. Of these factors, surgery type was the strongest predictor, with bypass patients three times more likely to achieve that goal than those undergoing banding or sleeve placement.

Dr. Morton did not present his complication data. However, during the discussion period, he said the three procedures were similarly safe. The gastric sleeve group had a higher leak rate than did the other groups, but that remained less than 1%. Readmission rates were comparable, he said, but he did not provide that number.

"Any time you consider this, it has to be a risk/benefit analysis," he said. "It’s our philosophy that for obese patients with severe diabetes, we approach them first with the bypass because it has the most proven track record over time."

Dr. Morton has up to 7 years of data on some of the patients, and said he is now analyzing that. But when questioned about durability, he agreed that diabetes can recur in the rather common scenario of a patient regaining weight. "At the end of the day, though, what’s important is that the obese patient with diabetes gets treatment. All three surgeries demonstrated some improvement, and I believe that any surgery is better than no surgery at all."

Dr. Morton has received research support from Covidien.

[email protected]

Earn 0.25 hours AMA PRA Category 1 credit: Read this article, and click the link at the end to take the post-test.

BARCELONA – Starting a triple-drug regimen of metformin, exenatide, and pioglitazone at the onset of type 2 diabetes decreased 2-year treatment failure rates by 84%, compared with a conventional, stepwise treatment program.

After 2 years, patients taking the combination treatment showed significantly lower hemoglobin A_1c levels than those who had graduated treatment – a mean of 5.9% vs. 6.6%, Dr. Ralph A. DeFronzo said at the annual meeting of the European Association for the Study of Diabetes.

If those interim results hold for the length of the 3-year study, they have the potential to dramatically alter the long-term consequences of poorly controlled type 2 diabetes, said Dr. DeFronzo, deputy director of the Texas Diabetes Institute, San Antonio.

"If we could maintain an HbA_1c of 5.9% after 3 years, I don’t think we will see many patients going on to develop blindness or kidney failure," he noted. "We may pay more up front for these more-expensive drugs, but we need to think of what will happen in 10 years if we really can control the HbA_1c and prevent microvascular complications."

The open-label study – partially funded by the American Diabetes Association – compared the two treatment strategies among patients with newly diagnosed type 2 diabetes.

Conventional therapy consisted of stepwise treatment beginning with 1 g metformin daily. Over the first 3 months, that could be augmented by increasing metformin to 2 g/day and, if necessary, adding up to 20 mg/day of glipizide. If HbA_1c still didn’t meet the 6.5% target, up to 60 units of insulin glargine could be added on as needed. Patients were removed from the study and censored if their blood sugar remained elevated despite being on all three drugs, including the maximum insulin dose.

The triple-drug therapy used three drugs from the very beginning: metformin 1 g/day; pioglitazone 30 mg/day; and exenatide 10 mcg/day.

The drugs were chosen to combat diabetes on three pathophysiologic fronts, Dr. DeFronzo said. "Metformin is a good insulin sensitizer in the liver, but has no effect on muscle and does nothing for beta cells. Pioglitazone is a powerful insulin sensitizer that works in both muscle and liver. And exenatide exerts beneficial effects on both alpha- and beta-cells, and promotes weight loss."

The regimen’s aim is to stem the decline of beta-cell function, which Dr. DeFronzo said is virtually inevitable in most type 2 patients.

"As long as the beta-cells are healthy, people destined to develop type 2 diabetes can secrete enough insulin to overcome their [genetic predilection for] insulin resistance," he explained. "But their beta-cells are preprogrammed to die, and as they fail, we see the onset of impaired glucose tolerance and eventually, the development of overt diabetes.

"Our hypothesis was that we could initiate early therapy with agents that can correct these known pathophysiologic abnormalities and achieve a greater, more durable reduction in HbA_1c, while avoiding hypoglycemia."

The open-label study randomized 169 patients with newly diagnosed type 2 diabetes who were also drug-naive to either the conventional therapy (90 patients) or triple therapy (79 patients). The patients had mean disease duration of 5 months, and all had been diagnosed less than 2 years earlier. All medications could be adjusted as necessary to avoid hypoglycemia.

All patients were seen every 12 weeks, at which time they had measures of fasting plasma glucose, postprandial glucose, HbA_1c, and weight. Their daily home blood glucose monitoring data were also reviewed. The primary endpoint was treatment failure, defined as an HbA_1c of more than 6.5% on two consecutive visits 3 months apart, despite being on maximum therapy. Secondary endpoints were changes in fasting and postprandial glucose, rates of hypoglycemia, and other adverse events.

The cohort’s mean age was 47 years, and their mean body mass index was 36 kg/m². They had a mean HbA_1c of 8.6%, but the range was wide, from 6.6% to 14%. It was more than 10% in about a quarter of the group. The mean fasting plasma glucose was 190 mg/dL.

In the first 6 months of treatment, HbA_1c in both groups fell rapidly and significantly, to a mean of 6.6%, Dr. DeFronzo said. After that, patients in the conventional therapy group began to experience a slow increase in their blood sugar levels – a phenomenon consistently observed in studies and in clinical practice. By the end of 24 months, the mean HbA_1c in the group was 6.6%.

Those in the triple-therapy group, however, experienced a continued, slow decline in blood sugar levels. By 24 months, the mean HbA_1c in the triple-therapy group was 5.9% – significantly lower than that in the conventional group. Significantly more of the triple-therapy group achieved a median HbA_1c of less than 6% (60% vs. 27%), and of less than 7% (92% vs. 72%).

Patients taking the triple therapy also did significantly better on 24-hour measures of fasting plasma and postprandial glucose. They showed "markedly attenuated" increases in postprandial glucose, Dr. DeFronzo said – up to 30 mg/dL lower than the conventional treatment group 2 hours after each meal.

By 24 months, treatment failure occurred in 17% of the triple-therapy group and 42% of the conventional therapy group – also a significant difference. A survival analysis showed that most patients who failed triple therapy did so in the first year, with a leveling off after that.

"With all drugs, there are a certain number of patients who don’t respond," Dr. DeFronzo said. "We saw the initial nonresponders, but those who did respond maintained their HbA_1c improvement to the end of the 2 years."

Patients randomized to the triple therapy were 84% more likely to achieve sustained treatment response (hazard ratio, 0.16), a difference that was significant. They also lost a mean of 1.2 kg during the study, compared with a mean 4 kg weight gain in the conventional treatment group.

There were no episodes of severe hypoglycemia in either group. The rate of mild hypoglycemia was significantly lower in the triple-therapy group – 15% vs. 46%; a rate of 0.27 vs. 2 events/person per year. "Despite the fact that the HbA_1c was 5.9%, [triple-therapy patients] had a seven- to eightfold lower risk of hypoglycemia," Dr. DeFronzo said.

Patients taking the triple therapy had significantly more edema (5% vs. 1%), which Dr. DeFronzo said was related pioglitazone. However, that was lower than what typically is seen in pioglitazone treatment, probably because of the natriuretic action of concomitant exenatide. The triple-therapy group also experienced significantly more gastrointestinal events (33% vs. 21%). There were no fractures in either treatment group.

A regimen containing pioglitazone could be a tough sell for some clinicians, Dr. DeFronzo acknowledged. The drug has been associated with a 40% increased risk of bladder cancer in patients who took it for more than 2 years, according to the Food and Drug Administration.

In addition, a French registry study that included 1.5 million people with diabetes also found a dose- and time-dependent signal for increased risk of the cancer. Based on the results of that study, France suspended the use of pioglitazone, and Germany has recommended not starting pioglitazone in new patients.

But in its data review, the FDA said clinicians "should have greater confidence in prescribing all FDA-approved antihyperglycemic medications according to current clinical practice recommendations."

Data on the thiazolidinedione-cancer link are "limited and conflicting," the FDA said, although "clinicians should monitor patients on pioglitazone and avoid prescribing it to patients with a high risk or history of bladder cancer."

Dr. DeFronzo said he believes the drug is safe and can be a very valuable therapeutic option. But news of the cancer association has clearly affected its use.

"In the U.S., sales of pioglitazone are really down because of this," he said. "When I prescribe it, I explain the issues, what the controversy is, and tell patients I feel it’s safe. And they trust me."

The American Diabetes Association and Amylin Pharmaceuticals funded the study. Dr. DeFronzo has acted as a consultant for Amylin, Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, Johnson and Johnson, Merck, Novartis, and Takeda. He has received research grants from Amylin, Bristol-Myers Squibb, Eli Lilly, and Takeda.

To earn 0.25 hours AMA PRA Category 1 credit after reading this article, take the post-test here.

[email protected]

Earn 0.25 hours AMA PRA Category 1 credit: Read this article, and click the link at the end to take the post-test.

BARCELONA – Starting a triple-drug regimen of metformin, exenatide, and pioglitazone at the onset of type 2 diabetes decreased 2-year treatment failure rates by 84%, compared with a conventional, stepwise treatment program.

After 2 years, patients taking the combination treatment showed significantly lower hemoglobin A_1c levels than those who had graduated treatment – a mean of 5.9% vs. 6.6%, Dr. Ralph A. DeFronzo said at the annual meeting of the European Association for the Study of Diabetes.

If those interim results hold for the length of the 3-year study, they have the potential to dramatically alter the long-term consequences of poorly controlled type 2 diabetes, said Dr. DeFronzo, deputy director of the Texas Diabetes Institute, San Antonio.

"If we could maintain an HbA_1c of 5.9% after 3 years, I don’t think we will see many patients going on to develop blindness or kidney failure," he noted. "We may pay more up front for these more-expensive drugs, but we need to think of what will happen in 10 years if we really can control the HbA_1c and prevent microvascular complications."

The open-label study – partially funded by the American Diabetes Association – compared the two treatment strategies among patients with newly diagnosed type 2 diabetes.

Conventional therapy consisted of stepwise treatment beginning with 1 g metformin daily. Over the first 3 months, that could be augmented by increasing metformin to 2 g/day and, if necessary, adding up to 20 mg/day of glipizide. If HbA_1c still didn’t meet the 6.5% target, up to 60 units of insulin glargine could be added on as needed. Patients were removed from the study and censored if their blood sugar remained elevated despite being on all three drugs, including the maximum insulin dose.

The triple-drug therapy used three drugs from the very beginning: metformin 1 g/day; pioglitazone 30 mg/day; and exenatide 10 mcg/day.

The drugs were chosen to combat diabetes on three pathophysiologic fronts, Dr. DeFronzo said. "Metformin is a good insulin sensitizer in the liver, but has no effect on muscle and does nothing for beta cells. Pioglitazone is a powerful insulin sensitizer that works in both muscle and liver. And exenatide exerts beneficial effects on both alpha- and beta-cells, and promotes weight loss."

The regimen’s aim is to stem the decline of beta-cell function, which Dr. DeFronzo said is virtually inevitable in most type 2 patients.

"As long as the beta-cells are healthy, people destined to develop type 2 diabetes can secrete enough insulin to overcome their [genetic predilection for] insulin resistance," he explained. "But their beta-cells are preprogrammed to die, and as they fail, we see the onset of impaired glucose tolerance and eventually, the development of overt diabetes.

"Our hypothesis was that we could initiate early therapy with agents that can correct these known pathophysiologic abnormalities and achieve a greater, more durable reduction in HbA_1c, while avoiding hypoglycemia."

The open-label study randomized 169 patients with newly diagnosed type 2 diabetes who were also drug-naive to either the conventional therapy (90 patients) or triple therapy (79 patients). The patients had mean disease duration of 5 months, and all had been diagnosed less than 2 years earlier. All medications could be adjusted as necessary to avoid hypoglycemia.

All patients were seen every 12 weeks, at which time they had measures of fasting plasma glucose, postprandial glucose, HbA_1c, and weight. Their daily home blood glucose monitoring data were also reviewed. The primary endpoint was treatment failure, defined as an HbA_1c of more than 6.5% on two consecutive visits 3 months apart, despite being on maximum therapy. Secondary endpoints were changes in fasting and postprandial glucose, rates of hypoglycemia, and other adverse events.

The cohort’s mean age was 47 years, and their mean body mass index was 36 kg/m². They had a mean HbA_1c of 8.6%, but the range was wide, from 6.6% to 14%. It was more than 10% in about a quarter of the group. The mean fasting plasma glucose was 190 mg/dL.

In the first 6 months of treatment, HbA_1c in both groups fell rapidly and significantly, to a mean of 6.6%, Dr. DeFronzo said. After that, patients in the conventional therapy group began to experience a slow increase in their blood sugar levels – a phenomenon consistently observed in studies and in clinical practice. By the end of 24 months, the mean HbA_1c in the group was 6.6%.

Those in the triple-therapy group, however, experienced a continued, slow decline in blood sugar levels. By 24 months, the mean HbA_1c in the triple-therapy group was 5.9% – significantly lower than that in the conventional group. Significantly more of the triple-therapy group achieved a median HbA_1c of less than 6% (60% vs. 27%), and of less than 7% (92% vs. 72%).

Patients taking the triple therapy also did significantly better on 24-hour measures of fasting plasma and postprandial glucose. They showed "markedly attenuated" increases in postprandial glucose, Dr. DeFronzo said – up to 30 mg/dL lower than the conventional treatment group 2 hours after each meal.

By 24 months, treatment failure occurred in 17% of the triple-therapy group and 42% of the conventional therapy group – also a significant difference. A survival analysis showed that most patients who failed triple therapy did so in the first year, with a leveling off after that.

"With all drugs, there are a certain number of patients who don’t respond," Dr. DeFronzo said. "We saw the initial nonresponders, but those who did respond maintained their HbA_1c improvement to the end of the 2 years."

Patients randomized to the triple therapy were 84% more likely to achieve sustained treatment response (hazard ratio, 0.16), a difference that was significant. They also lost a mean of 1.2 kg during the study, compared with a mean 4 kg weight gain in the conventional treatment group.

There were no episodes of severe hypoglycemia in either group. The rate of mild hypoglycemia was significantly lower in the triple-therapy group – 15% vs. 46%; a rate of 0.27 vs. 2 events/person per year. "Despite the fact that the HbA_1c was 5.9%, [triple-therapy patients] had a seven- to eightfold lower risk of hypoglycemia," Dr. DeFronzo said.

Patients taking the triple therapy had significantly more edema (5% vs. 1%), which Dr. DeFronzo said was related pioglitazone. However, that was lower than what typically is seen in pioglitazone treatment, probably because of the natriuretic action of concomitant exenatide. The triple-therapy group also experienced significantly more gastrointestinal events (33% vs. 21%). There were no fractures in either treatment group.

A regimen containing pioglitazone could be a tough sell for some clinicians, Dr. DeFronzo acknowledged. The drug has been associated with a 40% increased risk of bladder cancer in patients who took it for more than 2 years, according to the Food and Drug Administration.

In addition, a French registry study that included 1.5 million people with diabetes also found a dose- and time-dependent signal for increased risk of the cancer. Based on the results of that study, France suspended the use of pioglitazone, and Germany has recommended not starting pioglitazone in new patients.

But in its data review, the FDA said clinicians "should have greater confidence in prescribing all FDA-approved antihyperglycemic medications according to current clinical practice recommendations."

Data on the thiazolidinedione-cancer link are "limited and conflicting," the FDA said, although "clinicians should monitor patients on pioglitazone and avoid prescribing it to patients with a high risk or history of bladder cancer."

Dr. DeFronzo said he believes the drug is safe and can be a very valuable therapeutic option. But news of the cancer association has clearly affected its use.

"In the U.S., sales of pioglitazone are really down because of this," he said. "When I prescribe it, I explain the issues, what the controversy is, and tell patients I feel it’s safe. And they trust me."

The American Diabetes Association and Amylin Pharmaceuticals funded the study. Dr. DeFronzo has acted as a consultant for Amylin, Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, Johnson and Johnson, Merck, Novartis, and Takeda. He has received research grants from Amylin, Bristol-Myers Squibb, Eli Lilly, and Takeda.

To earn 0.25 hours AMA PRA Category 1 credit after reading this article, take the post-test here.

[email protected]

Earn 0.25 hours AMA PRA Category 1 credit: Read this article, and click the link at the end to take the post-test.

BARCELONA – Starting a triple-drug regimen of metformin, exenatide, and pioglitazone at the onset of type 2 diabetes decreased 2-year treatment failure rates by 84%, compared with a conventional, stepwise treatment program.

After 2 years, patients taking the combination treatment showed significantly lower hemoglobin A_1c levels than those who had graduated treatment – a mean of 5.9% vs. 6.6%, Dr. Ralph A. DeFronzo said at the annual meeting of the European Association for the Study of Diabetes.

If those interim results hold for the length of the 3-year study, they have the potential to dramatically alter the long-term consequences of poorly controlled type 2 diabetes, said Dr. DeFronzo, deputy director of the Texas Diabetes Institute, San Antonio.

"If we could maintain an HbA_1c of 5.9% after 3 years, I don’t think we will see many patients going on to develop blindness or kidney failure," he noted. "We may pay more up front for these more-expensive drugs, but we need to think of what will happen in 10 years if we really can control the HbA_1c and prevent microvascular complications."

The open-label study – partially funded by the American Diabetes Association – compared the two treatment strategies among patients with newly diagnosed type 2 diabetes.

Conventional therapy consisted of stepwise treatment beginning with 1 g metformin daily. Over the first 3 months, that could be augmented by increasing metformin to 2 g/day and, if necessary, adding up to 20 mg/day of glipizide. If HbA_1c still didn’t meet the 6.5% target, up to 60 units of insulin glargine could be added on as needed. Patients were removed from the study and censored if their blood sugar remained elevated despite being on all three drugs, including the maximum insulin dose.

The triple-drug therapy used three drugs from the very beginning: metformin 1 g/day; pioglitazone 30 mg/day; and exenatide 10 mcg/day.

The drugs were chosen to combat diabetes on three pathophysiologic fronts, Dr. DeFronzo said. "Metformin is a good insulin sensitizer in the liver, but has no effect on muscle and does nothing for beta cells. Pioglitazone is a powerful insulin sensitizer that works in both muscle and liver. And exenatide exerts beneficial effects on both alpha- and beta-cells, and promotes weight loss."

The regimen’s aim is to stem the decline of beta-cell function, which Dr. DeFronzo said is virtually inevitable in most type 2 patients.

"As long as the beta-cells are healthy, people destined to develop type 2 diabetes can secrete enough insulin to overcome their [genetic predilection for] insulin resistance," he explained. "But their beta-cells are preprogrammed to die, and as they fail, we see the onset of impaired glucose tolerance and eventually, the development of overt diabetes.

"Our hypothesis was that we could initiate early therapy with agents that can correct these known pathophysiologic abnormalities and achieve a greater, more durable reduction in HbA_1c, while avoiding hypoglycemia."

The open-label study randomized 169 patients with newly diagnosed type 2 diabetes who were also drug-naive to either the conventional therapy (90 patients) or triple therapy (79 patients). The patients had mean disease duration of 5 months, and all had been diagnosed less than 2 years earlier. All medications could be adjusted as necessary to avoid hypoglycemia.

All patients were seen every 12 weeks, at which time they had measures of fasting plasma glucose, postprandial glucose, HbA_1c, and weight. Their daily home blood glucose monitoring data were also reviewed. The primary endpoint was treatment failure, defined as an HbA_1c of more than 6.5% on two consecutive visits 3 months apart, despite being on maximum therapy. Secondary endpoints were changes in fasting and postprandial glucose, rates of hypoglycemia, and other adverse events.

The cohort’s mean age was 47 years, and their mean body mass index was 36 kg/m². They had a mean HbA_1c of 8.6%, but the range was wide, from 6.6% to 14%. It was more than 10% in about a quarter of the group. The mean fasting plasma glucose was 190 mg/dL.

In the first 6 months of treatment, HbA_1c in both groups fell rapidly and significantly, to a mean of 6.6%, Dr. DeFronzo said. After that, patients in the conventional therapy group began to experience a slow increase in their blood sugar levels – a phenomenon consistently observed in studies and in clinical practice. By the end of 24 months, the mean HbA_1c in the group was 6.6%.

Those in the triple-therapy group, however, experienced a continued, slow decline in blood sugar levels. By 24 months, the mean HbA_1c in the triple-therapy group was 5.9% – significantly lower than that in the conventional group. Significantly more of the triple-therapy group achieved a median HbA_1c of less than 6% (60% vs. 27%), and of less than 7% (92% vs. 72%).

Patients taking the triple therapy also did significantly better on 24-hour measures of fasting plasma and postprandial glucose. They showed "markedly attenuated" increases in postprandial glucose, Dr. DeFronzo said – up to 30 mg/dL lower than the conventional treatment group 2 hours after each meal.

By 24 months, treatment failure occurred in 17% of the triple-therapy group and 42% of the conventional therapy group – also a significant difference. A survival analysis showed that most patients who failed triple therapy did so in the first year, with a leveling off after that.

"With all drugs, there are a certain number of patients who don’t respond," Dr. DeFronzo said. "We saw the initial nonresponders, but those who did respond maintained their HbA_1c improvement to the end of the 2 years."

Patients randomized to the triple therapy were 84% more likely to achieve sustained treatment response (hazard ratio, 0.16), a difference that was significant. They also lost a mean of 1.2 kg during the study, compared with a mean 4 kg weight gain in the conventional treatment group.

There were no episodes of severe hypoglycemia in either group. The rate of mild hypoglycemia was significantly lower in the triple-therapy group – 15% vs. 46%; a rate of 0.27 vs. 2 events/person per year. "Despite the fact that the HbA_1c was 5.9%, [triple-therapy patients] had a seven- to eightfold lower risk of hypoglycemia," Dr. DeFronzo said.

Patients taking the triple therapy had significantly more edema (5% vs. 1%), which Dr. DeFronzo said was related pioglitazone. However, that was lower than what typically is seen in pioglitazone treatment, probably because of the natriuretic action of concomitant exenatide. The triple-therapy group also experienced significantly more gastrointestinal events (33% vs. 21%). There were no fractures in either treatment group.

A regimen containing pioglitazone could be a tough sell for some clinicians, Dr. DeFronzo acknowledged. The drug has been associated with a 40% increased risk of bladder cancer in patients who took it for more than 2 years, according to the Food and Drug Administration.

In addition, a French registry study that included 1.5 million people with diabetes also found a dose- and time-dependent signal for increased risk of the cancer. Based on the results of that study, France suspended the use of pioglitazone, and Germany has recommended not starting pioglitazone in new patients.

But in its data review, the FDA said clinicians "should have greater confidence in prescribing all FDA-approved antihyperglycemic medications according to current clinical practice recommendations."

Data on the thiazolidinedione-cancer link are "limited and conflicting," the FDA said, although "clinicians should monitor patients on pioglitazone and avoid prescribing it to patients with a high risk or history of bladder cancer."

Dr. DeFronzo said he believes the drug is safe and can be a very valuable therapeutic option. But news of the cancer association has clearly affected its use.

"In the U.S., sales of pioglitazone are really down because of this," he said. "When I prescribe it, I explain the issues, what the controversy is, and tell patients I feel it’s safe. And they trust me."

The American Diabetes Association and Amylin Pharmaceuticals funded the study. Dr. DeFronzo has acted as a consultant for Amylin, Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, Johnson and Johnson, Merck, Novartis, and Takeda. He has received research grants from Amylin, Bristol-Myers Squibb, Eli Lilly, and Takeda.

To earn 0.25 hours AMA PRA Category 1 credit after reading this article, take the post-test here.

[email protected]

BARCELONA – Starting a triple-drug regimen of metformin, exenatide, and pioglitazone at the onset of type 2 diabetes decreased 2-year treatment failure rates by 84%, compared with a conventional, stepwise treatment program.

After 2 years, patients taking the combination treatment showed significantly lower hemoglobin A_1c levels than those who had graduated treatment – a mean of 5.9% vs. 6.6%, Dr. Ralph A. DeFronzo said at the annual meeting of the European Association for the Study of Diabetes.

If those interim results hold for the length of the 3-year study, they have the potential to dramatically alter the long-term consequences of poorly controlled type 2 diabetes, said Dr. DeFronzo, deputy director of the Texas Diabetes Institute, San Antonio.

Michele G. Sullivan/IMNG Medical Media

"If we could maintain an HbA_1c of 5.9% after 3 years, I don’t think we will see many patients going on to develop blindness or kidney failure," he noted. "We may pay more up front for these more-expensive drugs, but we need to think of what will happen in 10 years if we really can control the HbA_1c and prevent microvascular complications."

The open-label study – partially funded by the American Diabetes Association – compared the two treatment strategies among patients with newly diagnosed type 2 diabetes.

Conventional therapy consisted of stepwise treatment beginning with 1 g metformin daily. Over the first 3 months, that could be augmented by increasing metformin to 2 g/day and, if necessary, adding up to 20 mg/day of glipizide. If HbA_1c still didn’t meet the 6.5% target, up to 60 units of insulin glargine could be added on as needed. Patients were removed from the study and censored if their blood sugar remained elevated despite being on all three drugs, including the maximum insulin dose.

The triple-drug therapy used three drugs from the very beginning: metformin 1 g/day; pioglitazone 30 mg/day; and exenatide 10 mcg/day.

The drugs were chosen to combat diabetes on three pathophysiologic fronts, Dr. DeFronzo said. "Metformin is a good insulin sensitizer in the liver, but has no effect on muscle and does nothing for beta cells. Pioglitazone is a powerful insulin sensitizer that works in both muscle and liver. And exenatide exerts beneficial effects on both alpha- and beta-cells, and promotes weight loss."

The regimen’s aim is to stem the decline of beta-cell function, which Dr. DeFronzo said is virtually inevitable in most type 2 patients.

"As long as the beta-cells are healthy, people destined to develop type 2 diabetes can secrete enough insulin to overcome their [genetic predilection for] insulin resistance," he explained. "But their beta-cells are preprogrammed to die, and as they fail, we see the onset of impaired glucose tolerance and eventually, the development of overt diabetes.

"Our hypothesis was that we could initiate early therapy with agents that can correct these known pathophysiologic abnormalities and achieve a greater, more durable reduction in HbA_1c, while avoiding hypoglycemia."

The open-label study randomized 169 patients with newly diagnosed type 2 diabetes who were also drug-naive to either the conventional therapy (90 patients) or triple therapy (79 patients). The patients had mean disease duration of 5 months, and all had been diagnosed less than 2 years earlier. All medications could be adjusted as necessary to avoid hypoglycemia.

All patients were seen every 12 weeks, at which time they had measures of fasting plasma glucose, postprandial glucose, HbA_1c, and weight. Their daily home blood glucose monitoring data were also reviewed. The primary endpoint was treatment failure, defined as an HbA_1c of more than 6.5% on two consecutive visits 3 months apart, despite being on maximum therapy. Secondary endpoints were changes in fasting and postprandial glucose, rates of hypoglycemia, and other adverse events.

The cohort’s mean age was 47 years, and their mean body mass index was 36 kg/m². They had a mean HbA_1c of 8.6%, but the range was wide, from 6.6% to 14%. It was more than 10% in about a quarter of the group. The mean fasting plasma glucose was 190 mg/dL.

In the first 6 months of treatment, HbA_1c in both groups fell rapidly and significantly, to a mean of 6.6%, Dr. DeFronzo said. After that, patients in the conventional therapy group began to experience a slow increase in their blood sugar levels – a phenomenon consistently observed in studies and in clinical practice. By the end of 24 months, the mean HbA_1c in the group was 6.6%.

Those in the triple-therapy group, however, experienced a continued, slow decline in blood sugar levels. By 24 months, the mean HbA_1c in the triple-therapy group was 5.9% – significantly lower than that in the conventional group. Significantly more of the triple-therapy group achieved a median HbA_1c of less than 6% (60% vs. 27%), and of less than 7% (92% vs. 72%).

Patients taking the triple therapy also did significantly better on 24-hour measures of fasting plasma and postprandial glucose. They showed "markedly attenuated" increases in postprandial glucose, Dr. DeFronzo said – up to 30 mg/dL lower than the conventional treatment group 2 hours after each meal.

By 24 months, treatment failure occurred in 17% of the triple-therapy group and 42% of the conventional therapy group – also a significant difference. A survival analysis showed that most patients who failed triple therapy did so in the first year, with a leveling off after that.

"With all drugs, there are a certain number of patients who don’t respond," Dr. DeFronzo said. "We saw the initial nonresponders, but those who did respond maintained their HbA_1c improvement to the end of the 2 years."

Patients randomized to the triple therapy were 84% more likely to achieve sustained treatment response (hazard ratio, 0.16), a difference that was significant. They also lost a mean of 1.2 kg during the study, compared with a mean 4 kg weight gain in the conventional treatment group.

There were no episodes of severe hypoglycemia in either group. The rate of mild hypoglycemia was significantly lower in the triple-therapy group – 15% vs. 46%; a rate of 0.27 vs. 2 events/person per year. "Despite the fact that the HbA_1c was 5.9%, [triple-therapy patients] had a seven- to eightfold lower risk of hypoglycemia," Dr. DeFronzo said.

Patients taking the triple therapy had significantly more edema (5% vs. 1%), which Dr. DeFronzo said was related pioglitazone. However, that was lower than what typically is seen in pioglitazone treatment, probably because of the natriuretic action of concomitant exenatide. The triple-therapy group also experienced significantly more gastrointestinal events (33% vs. 21%). There were no fractures in either treatment group.

A regimen containing pioglitazone could be a tough sell for some clinicians, Dr. DeFronzo acknowledged. The drug has been associated with a 40% increased risk of bladder cancer in patients who took it for more than 2 years, according to the Food and Drug Administration.

In addition, a French registry study that included 1.5 million people with diabetes also found a dose- and time-dependent signal for increased risk of the cancer. Based on the results of that study, France suspended the use of pioglitazone, and Germany has recommended not starting pioglitazone in new patients.

But in its data review, the FDA said clinicians "should have greater confidence in prescribing all FDA-approved antihyperglycemic medications according to current clinical practice recommendations."

Data on the thiazolidinedione-cancer link are "limited and conflicting," the FDA said, although "clinicians should monitor patients on pioglitazone and avoid prescribing it to patients with a high risk or history of bladder cancer."

Dr. DeFronzo said he believes the drug is safe and can be a very valuable therapeutic option. But news of the cancer association has clearly affected its use.

"In the U.S., sales of pioglitazone are really down because of this," he said. "When I prescribe it, I explain the issues, what the controversy is, and tell patients I feel it’s safe. And they trust me."

The American Diabetes Association and Amylin Pharmaceuticals funded the study. Dr. DeFronzo has acted as a consultant for Amylin, Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, Johnson and Johnson, Merck, Novartis, and Takeda. He has received research grants from Amylin, Bristol-Myers Squibb, Eli Lilly, and Takeda.

[email protected]

BARCELONA – Starting a triple-drug regimen of metformin, exenatide, and pioglitazone at the onset of type 2 diabetes decreased 2-year treatment failure rates by 84%, compared with a conventional, stepwise treatment program.

After 2 years, patients taking the combination treatment showed significantly lower hemoglobin A_1c levels than those who had graduated treatment – a mean of 5.9% vs. 6.6%, Dr. Ralph A. DeFronzo said at the annual meeting of the European Association for the Study of Diabetes.

If those interim results hold for the length of the 3-year study, they have the potential to dramatically alter the long-term consequences of poorly controlled type 2 diabetes, said Dr. DeFronzo, deputy director of the Texas Diabetes Institute, San Antonio.

Michele G. Sullivan/IMNG Medical Media

"If we could maintain an HbA_1c of 5.9% after 3 years, I don’t think we will see many patients going on to develop blindness or kidney failure," he noted. "We may pay more up front for these more-expensive drugs, but we need to think of what will happen in 10 years if we really can control the HbA_1c and prevent microvascular complications."

The open-label study – partially funded by the American Diabetes Association – compared the two treatment strategies among patients with newly diagnosed type 2 diabetes.

Conventional therapy consisted of stepwise treatment beginning with 1 g metformin daily. Over the first 3 months, that could be augmented by increasing metformin to 2 g/day and, if necessary, adding up to 20 mg/day of glipizide. If HbA_1c still didn’t meet the 6.5% target, up to 60 units of insulin glargine could be added on as needed. Patients were removed from the study and censored if their blood sugar remained elevated despite being on all three drugs, including the maximum insulin dose.

The triple-drug therapy used three drugs from the very beginning: metformin 1 g/day; pioglitazone 30 mg/day; and exenatide 10 mcg/day.

The drugs were chosen to combat diabetes on three pathophysiologic fronts, Dr. DeFronzo said. "Metformin is a good insulin sensitizer in the liver, but has no effect on muscle and does nothing for beta cells. Pioglitazone is a powerful insulin sensitizer that works in both muscle and liver. And exenatide exerts beneficial effects on both alpha- and beta-cells, and promotes weight loss."

The regimen’s aim is to stem the decline of beta-cell function, which Dr. DeFronzo said is virtually inevitable in most type 2 patients.

"As long as the beta-cells are healthy, people destined to develop type 2 diabetes can secrete enough insulin to overcome their [genetic predilection for] insulin resistance," he explained. "But their beta-cells are preprogrammed to die, and as they fail, we see the onset of impaired glucose tolerance and eventually, the development of overt diabetes.

"Our hypothesis was that we could initiate early therapy with agents that can correct these known pathophysiologic abnormalities and achieve a greater, more durable reduction in HbA_1c, while avoiding hypoglycemia."

The open-label study randomized 169 patients with newly diagnosed type 2 diabetes who were also drug-naive to either the conventional therapy (90 patients) or triple therapy (79 patients). The patients had mean disease duration of 5 months, and all had been diagnosed less than 2 years earlier. All medications could be adjusted as necessary to avoid hypoglycemia.

All patients were seen every 12 weeks, at which time they had measures of fasting plasma glucose, postprandial glucose, HbA_1c, and weight. Their daily home blood glucose monitoring data were also reviewed. The primary endpoint was treatment failure, defined as an HbA_1c of more than 6.5% on two consecutive visits 3 months apart, despite being on maximum therapy. Secondary endpoints were changes in fasting and postprandial glucose, rates of hypoglycemia, and other adverse events.

The cohort’s mean age was 47 years, and their mean body mass index was 36 kg/m². They had a mean HbA_1c of 8.6%, but the range was wide, from 6.6% to 14%. It was more than 10% in about a quarter of the group. The mean fasting plasma glucose was 190 mg/dL.

In the first 6 months of treatment, HbA_1c in both groups fell rapidly and significantly, to a mean of 6.6%, Dr. DeFronzo said. After that, patients in the conventional therapy group began to experience a slow increase in their blood sugar levels – a phenomenon consistently observed in studies and in clinical practice. By the end of 24 months, the mean HbA_1c in the group was 6.6%.

Those in the triple-therapy group, however, experienced a continued, slow decline in blood sugar levels. By 24 months, the mean HbA_1c in the triple-therapy group was 5.9% – significantly lower than that in the conventional group. Significantly more of the triple-therapy group achieved a median HbA_1c of less than 6% (60% vs. 27%), and of less than 7% (92% vs. 72%).

Patients taking the triple therapy also did significantly better on 24-hour measures of fasting plasma and postprandial glucose. They showed "markedly attenuated" increases in postprandial glucose, Dr. DeFronzo said – up to 30 mg/dL lower than the conventional treatment group 2 hours after each meal.

By 24 months, treatment failure occurred in 17% of the triple-therapy group and 42% of the conventional therapy group – also a significant difference. A survival analysis showed that most patients who failed triple therapy did so in the first year, with a leveling off after that.

"With all drugs, there are a certain number of patients who don’t respond," Dr. DeFronzo said. "We saw the initial nonresponders, but those who did respond maintained their HbA_1c improvement to the end of the 2 years."

Patients randomized to the triple therapy were 84% more likely to achieve sustained treatment response (hazard ratio, 0.16), a difference that was significant. They also lost a mean of 1.2 kg during the study, compared with a mean 4 kg weight gain in the conventional treatment group.

There were no episodes of severe hypoglycemia in either group. The rate of mild hypoglycemia was significantly lower in the triple-therapy group – 15% vs. 46%; a rate of 0.27 vs. 2 events/person per year. "Despite the fact that the HbA_1c was 5.9%, [triple-therapy patients] had a seven- to eightfold lower risk of hypoglycemia," Dr. DeFronzo said.

Patients taking the triple therapy had significantly more edema (5% vs. 1%), which Dr. DeFronzo said was related pioglitazone. However, that was lower than what typically is seen in pioglitazone treatment, probably because of the natriuretic action of concomitant exenatide. The triple-therapy group also experienced significantly more gastrointestinal events (33% vs. 21%). There were no fractures in either treatment group.

A regimen containing pioglitazone could be a tough sell for some clinicians, Dr. DeFronzo acknowledged. The drug has been associated with a 40% increased risk of bladder cancer in patients who took it for more than 2 years, according to the Food and Drug Administration.

In addition, a French registry study that included 1.5 million people with diabetes also found a dose- and time-dependent signal for increased risk of the cancer. Based on the results of that study, France suspended the use of pioglitazone, and Germany has recommended not starting pioglitazone in new patients.

But in its data review, the FDA said clinicians "should have greater confidence in prescribing all FDA-approved antihyperglycemic medications according to current clinical practice recommendations."

Data on the thiazolidinedione-cancer link are "limited and conflicting," the FDA said, although "clinicians should monitor patients on pioglitazone and avoid prescribing it to patients with a high risk or history of bladder cancer."

Dr. DeFronzo said he believes the drug is safe and can be a very valuable therapeutic option. But news of the cancer association has clearly affected its use.

"In the U.S., sales of pioglitazone are really down because of this," he said. "When I prescribe it, I explain the issues, what the controversy is, and tell patients I feel it’s safe. And they trust me."

The American Diabetes Association and Amylin Pharmaceuticals funded the study. Dr. DeFronzo has acted as a consultant for Amylin, Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, Johnson and Johnson, Merck, Novartis, and Takeda. He has received research grants from Amylin, Bristol-Myers Squibb, Eli Lilly, and Takeda.

[email protected]

BARCELONA – Starting a triple-drug regimen of metformin, exenatide, and pioglitazone at the onset of type 2 diabetes decreased 2-year treatment failure rates by 84%, compared with a conventional, stepwise treatment program.

After 2 years, patients taking the combination treatment showed significantly lower hemoglobin A_1c levels than those who had graduated treatment – a mean of 5.9% vs. 6.6%, Dr. Ralph A. DeFronzo said at the annual meeting of the European Association for the Study of Diabetes.

If those interim results hold for the length of the 3-year study, they have the potential to dramatically alter the long-term consequences of poorly controlled type 2 diabetes, said Dr. DeFronzo, deputy director of the Texas Diabetes Institute, San Antonio.

Michele G. Sullivan/IMNG Medical Media

"If we could maintain an HbA_1c of 5.9% after 3 years, I don’t think we will see many patients going on to develop blindness or kidney failure," he noted. "We may pay more up front for these more-expensive drugs, but we need to think of what will happen in 10 years if we really can control the HbA_1c and prevent microvascular complications."

The open-label study – partially funded by the American Diabetes Association – compared the two treatment strategies among patients with newly diagnosed type 2 diabetes.

Conventional therapy consisted of stepwise treatment beginning with 1 g metformin daily. Over the first 3 months, that could be augmented by increasing metformin to 2 g/day and, if necessary, adding up to 20 mg/day of glipizide. If HbA_1c still didn’t meet the 6.5% target, up to 60 units of insulin glargine could be added on as needed. Patients were removed from the study and censored if their blood sugar remained elevated despite being on all three drugs, including the maximum insulin dose.

The triple-drug therapy used three drugs from the very beginning: metformin 1 g/day; pioglitazone 30 mg/day; and exenatide 10 mcg/day.

The drugs were chosen to combat diabetes on three pathophysiologic fronts, Dr. DeFronzo said. "Metformin is a good insulin sensitizer in the liver, but has no effect on muscle and does nothing for beta cells. Pioglitazone is a powerful insulin sensitizer that works in both muscle and liver. And exenatide exerts beneficial effects on both alpha- and beta-cells, and promotes weight loss."

The regimen’s aim is to stem the decline of beta-cell function, which Dr. DeFronzo said is virtually inevitable in most type 2 patients.

"As long as the beta-cells are healthy, people destined to develop type 2 diabetes can secrete enough insulin to overcome their [genetic predilection for] insulin resistance," he explained. "But their beta-cells are preprogrammed to die, and as they fail, we see the onset of impaired glucose tolerance and eventually, the development of overt diabetes.

"Our hypothesis was that we could initiate early therapy with agents that can correct these known pathophysiologic abnormalities and achieve a greater, more durable reduction in HbA_1c, while avoiding hypoglycemia."

The open-label study randomized 169 patients with newly diagnosed type 2 diabetes who were also drug-naive to either the conventional therapy (90 patients) or triple therapy (79 patients). The patients had mean disease duration of 5 months, and all had been diagnosed less than 2 years earlier. All medications could be adjusted as necessary to avoid hypoglycemia.

All patients were seen every 12 weeks, at which time they had measures of fasting plasma glucose, postprandial glucose, HbA_1c, and weight. Their daily home blood glucose monitoring data were also reviewed. The primary endpoint was treatment failure, defined as an HbA_1c of more than 6.5% on two consecutive visits 3 months apart, despite being on maximum therapy. Secondary endpoints were changes in fasting and postprandial glucose, rates of hypoglycemia, and other adverse events.

The cohort’s mean age was 47 years, and their mean body mass index was 36 kg/m². They had a mean HbA_1c of 8.6%, but the range was wide, from 6.6% to 14%. It was more than 10% in about a quarter of the group. The mean fasting plasma glucose was 190 mg/dL.

In the first 6 months of treatment, HbA_1c in both groups fell rapidly and significantly, to a mean of 6.6%, Dr. DeFronzo said. After that, patients in the conventional therapy group began to experience a slow increase in their blood sugar levels – a phenomenon consistently observed in studies and in clinical practice. By the end of 24 months, the mean HbA_1c in the group was 6.6%.

Those in the triple-therapy group, however, experienced a continued, slow decline in blood sugar levels. By 24 months, the mean HbA_1c in the triple-therapy group was 5.9% – significantly lower than that in the conventional group. Significantly more of the triple-therapy group achieved a median HbA_1c of less than 6% (60% vs. 27%), and of less than 7% (92% vs. 72%).

Patients taking the triple therapy also did significantly better on 24-hour measures of fasting plasma and postprandial glucose. They showed "markedly attenuated" increases in postprandial glucose, Dr. DeFronzo said – up to 30 mg/dL lower than the conventional treatment group 2 hours after each meal.

By 24 months, treatment failure occurred in 17% of the triple-therapy group and 42% of the conventional therapy group – also a significant difference. A survival analysis showed that most patients who failed triple therapy did so in the first year, with a leveling off after that.

"With all drugs, there are a certain number of patients who don’t respond," Dr. DeFronzo said. "We saw the initial nonresponders, but those who did respond maintained their HbA_1c improvement to the end of the 2 years."

Patients randomized to the triple therapy were 84% more likely to achieve sustained treatment response (hazard ratio, 0.16), a difference that was significant. They also lost a mean of 1.2 kg during the study, compared with a mean 4 kg weight gain in the conventional treatment group.

There were no episodes of severe hypoglycemia in either group. The rate of mild hypoglycemia was significantly lower in the triple-therapy group – 15% vs. 46%; a rate of 0.27 vs. 2 events/person per year. "Despite the fact that the HbA_1c was 5.9%, [triple-therapy patients] had a seven- to eightfold lower risk of hypoglycemia," Dr. DeFronzo said.

Patients taking the triple therapy had significantly more edema (5% vs. 1%), which Dr. DeFronzo said was related pioglitazone. However, that was lower than what typically is seen in pioglitazone treatment, probably because of the natriuretic action of concomitant exenatide. The triple-therapy group also experienced significantly more gastrointestinal events (33% vs. 21%). There were no fractures in either treatment group.

A regimen containing pioglitazone could be a tough sell for some clinicians, Dr. DeFronzo acknowledged. The drug has been associated with a 40% increased risk of bladder cancer in patients who took it for more than 2 years, according to the Food and Drug Administration.

In addition, a French registry study that included 1.5 million people with diabetes also found a dose- and time-dependent signal for increased risk of the cancer. Based on the results of that study, France suspended the use of pioglitazone, and Germany has recommended not starting pioglitazone in new patients.

But in its data review, the FDA said clinicians "should have greater confidence in prescribing all FDA-approved antihyperglycemic medications according to current clinical practice recommendations."

Data on the thiazolidinedione-cancer link are "limited and conflicting," the FDA said, although "clinicians should monitor patients on pioglitazone and avoid prescribing it to patients with a high risk or history of bladder cancer."

Dr. DeFronzo said he believes the drug is safe and can be a very valuable therapeutic option. But news of the cancer association has clearly affected its use.

"In the U.S., sales of pioglitazone are really down because of this," he said. "When I prescribe it, I explain the issues, what the controversy is, and tell patients I feel it’s safe. And they trust me."

The American Diabetes Association and Amylin Pharmaceuticals funded the study. Dr. DeFronzo has acted as a consultant for Amylin, Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, Johnson and Johnson, Merck, Novartis, and Takeda. He has received research grants from Amylin, Bristol-Myers Squibb, Eli Lilly, and Takeda.

[email protected]

Medicare will pay for one amyloid PET imaging brain scan per patient, but only if the patient is participating in a federally approved clinical study with an objective of developing better treatments or prevention strategies for Alzheimer’s disease, identifying subpopulations at risk for developing the condition, or ruling out Alzheimer’s disease in difficult differential diagnoses when the use of PET amyloid imaging appears to improve health outcomes.

The announcement Sept. 27 of the agency's final rule on payment for the procedure is in line with a proposal drafted last summer by the Centers for Medicare and Medicaid Services. The recommendation was based on the CMS’s findings of "insufficient evidence" that PET scanning with an amyloid ligand is necessary for diagnosing Alzheimer’s, or that it could be helpful in preventing or treating the disease.

The agency did, however, determine that amyloid imaging could be useful in excluding Alzheimer’s in "narrowly defined and clinically difficult differential diagnoses," such as Alzheimer’s versus frontotemporal dementia. The agents would also be useful in selecting populations enrolled in clinical trials, the CMS said.

Because of these limited applications, the agency will cover the procedure under its Coverage With Evidence Development (CED) program, which provides coverage while collecting additional outcomes data. Coverage under CED contributes to a new technology’s developmental pathway by encouraging more studies that employ it, according to the CMS.

For now, PET amyloid imaging will be covered only in CMS-approved, prospective randomized trials that include subjects from appropriate populations, and, when appropriate, employ the gold standard of postmortem Alzheimer’s diagnosis.

This decision on public coverage will almost certainly affect patients with private insurance as well, according to Dr. Richard J. Caselli, professor of neurology at the Mayo Clinic in Scottsdale, Ariz. and clinical core director of Mayo’s Alzheimer’s disease center.

"Their decision may be reasonable in older patients, which of course is their target patient population, but if other payers follow the CMS model, we will have overlooked the potential utility of this test in young patients, forcing such individuals to either go without or pay out of pocket," he said in an interview. "That is a clinically important issue that does not seem to have been aired in this deliberation."

The decision comes as a blow to Eli Lilly, the company developing florbetapir (Amyvid), one of the amyloid imaging agents. "Coverage With Evidence Development as proposed by CMS does not provide patients appropriate access to these amyloid imaging brain scans," Eric Dozier, the company’s senior director of business, said in a press statement. "Instead, it creates additional complexity for the broader community in determining the best path forward for patients. As we continue to review the final decision memo, we will be evaluating all available options to ensure patients and physicians can gain access to this innovative diagnostic tool as soon as possible."

Lilly said the decision contradicts the CMS’s own support of the National Alzheimer's Project Act, in whose creation it participated. "Yet the same agency is challenging the value of the only technology approved by the Food and Drug Administration for estimating beta-amyloid neuritic plaque density in the living brain, which can aid in helping doctors make a more informed diagnosis."

The decision also goes against the clinical recommendations of several groups, Lilly maintained – including the Alzheimer’s Association, which issued a statement citing its own concern.

"The Alzheimer’s Association is disappointed by the ... decision to only allow Coverage With Evidence Development (CED) for an Alzheimer’s imaging test that would improve diagnostic accuracy and certainty in challenging cases," the statement said. "When used in specific populations ... this tool has the potential to ... resolve distressing medical uncertainty."

Early this year, a task force convened by the Alzheimer’s Association and the Society of Nuclear Medicine and Molecular Imaging developed a set of criteria that would guide the appropriate clinical use of amyloid imaging agents (Alzheimers Dement. 2013;9:E1-16).

The document advised limiting scans to patients with persistent or progressive unexplained memory loss along with cognitive impairments, and those who test as possibly having Alzheimer’s but have an unusual clinical presentation. Imaging would also be appropriate in patients younger than 65 years who present with unexplained memory deficits.

"The Alzheimer’s Association appreciates that the evaluation of the impact of brain amyloid imaging on health outcomes can be complex in the absence of a treatment to stop or even slow the progression of the disease," the association noted. "However, as the scientific community races toward the National Alzheimer's Plan goal of prevention and effective treatment by 2025, many people facing confusion and frustration would benefit from the accurate and accelerated diagnosis this tool could offer."

Dr. Caselli said he had no relevant financial disclosures.

[email protected]

On Twitter @Alz_Gal

Medicare will pay for one amyloid PET imaging brain scan per patient, but only if the patient is participating in a federally approved clinical study with an objective of developing better treatments or prevention strategies for Alzheimer’s disease, identifying subpopulations at risk for developing the condition, or ruling out Alzheimer’s disease in difficult differential diagnoses when the use of PET amyloid imaging appears to improve health outcomes.

The announcement Sept. 27 of the agency's final rule on payment for the procedure is in line with a proposal drafted last summer by the Centers for Medicare and Medicaid Services. The recommendation was based on the CMS’s findings of "insufficient evidence" that PET scanning with an amyloid ligand is necessary for diagnosing Alzheimer’s, or that it could be helpful in preventing or treating the disease.

The agency did, however, determine that amyloid imaging could be useful in excluding Alzheimer’s in "narrowly defined and clinically difficult differential diagnoses," such as Alzheimer’s versus frontotemporal dementia. The agents would also be useful in selecting populations enrolled in clinical trials, the CMS said.

Because of these limited applications, the agency will cover the procedure under its Coverage With Evidence Development (CED) program, which provides coverage while collecting additional outcomes data. Coverage under CED contributes to a new technology’s developmental pathway by encouraging more studies that employ it, according to the CMS.

For now, PET amyloid imaging will be covered only in CMS-approved, prospective randomized trials that include subjects from appropriate populations, and, when appropriate, employ the gold standard of postmortem Alzheimer’s diagnosis.

This decision on public coverage will almost certainly affect patients with private insurance as well, according to Dr. Richard J. Caselli, professor of neurology at the Mayo Clinic in Scottsdale, Ariz. and clinical core director of Mayo’s Alzheimer’s disease center.

"Their decision may be reasonable in older patients, which of course is their target patient population, but if other payers follow the CMS model, we will have overlooked the potential utility of this test in young patients, forcing such individuals to either go without or pay out of pocket," he said in an interview. "That is a clinically important issue that does not seem to have been aired in this deliberation."

The decision comes as a blow to Eli Lilly, the company developing florbetapir (Amyvid), one of the amyloid imaging agents. "Coverage With Evidence Development as proposed by CMS does not provide patients appropriate access to these amyloid imaging brain scans," Eric Dozier, the company’s senior director of business, said in a press statement. "Instead, it creates additional complexity for the broader community in determining the best path forward for patients. As we continue to review the final decision memo, we will be evaluating all available options to ensure patients and physicians can gain access to this innovative diagnostic tool as soon as possible."

Lilly said the decision contradicts the CMS’s own support of the National Alzheimer's Project Act, in whose creation it participated. "Yet the same agency is challenging the value of the only technology approved by the Food and Drug Administration for estimating beta-amyloid neuritic plaque density in the living brain, which can aid in helping doctors make a more informed diagnosis."

The decision also goes against the clinical recommendations of several groups, Lilly maintained – including the Alzheimer’s Association, which issued a statement citing its own concern.

"The Alzheimer’s Association is disappointed by the ... decision to only allow Coverage With Evidence Development (CED) for an Alzheimer’s imaging test that would improve diagnostic accuracy and certainty in challenging cases," the statement said. "When used in specific populations ... this tool has the potential to ... resolve distressing medical uncertainty."

Early this year, a task force convened by the Alzheimer’s Association and the Society of Nuclear Medicine and Molecular Imaging developed a set of criteria that would guide the appropriate clinical use of amyloid imaging agents (Alzheimers Dement. 2013;9:E1-16).

The document advised limiting scans to patients with persistent or progressive unexplained memory loss along with cognitive impairments, and those who test as possibly having Alzheimer’s but have an unusual clinical presentation. Imaging would also be appropriate in patients younger than 65 years who present with unexplained memory deficits.

"The Alzheimer’s Association appreciates that the evaluation of the impact of brain amyloid imaging on health outcomes can be complex in the absence of a treatment to stop or even slow the progression of the disease," the association noted. "However, as the scientific community races toward the National Alzheimer's Plan goal of prevention and effective treatment by 2025, many people facing confusion and frustration would benefit from the accurate and accelerated diagnosis this tool could offer."

Dr. Caselli said he had no relevant financial disclosures.

[email protected]

On Twitter @Alz_Gal

Medicare will pay for one amyloid PET imaging brain scan per patient, but only if the patient is participating in a federally approved clinical study with an objective of developing better treatments or prevention strategies for Alzheimer’s disease, identifying subpopulations at risk for developing the condition, or ruling out Alzheimer’s disease in difficult differential diagnoses when the use of PET amyloid imaging appears to improve health outcomes.

The announcement Sept. 27 of the agency's final rule on payment for the procedure is in line with a proposal drafted last summer by the Centers for Medicare and Medicaid Services. The recommendation was based on the CMS’s findings of "insufficient evidence" that PET scanning with an amyloid ligand is necessary for diagnosing Alzheimer’s, or that it could be helpful in preventing or treating the disease.

The agency did, however, determine that amyloid imaging could be useful in excluding Alzheimer’s in "narrowly defined and clinically difficult differential diagnoses," such as Alzheimer’s versus frontotemporal dementia. The agents would also be useful in selecting populations enrolled in clinical trials, the CMS said.

Because of these limited applications, the agency will cover the procedure under its Coverage With Evidence Development (CED) program, which provides coverage while collecting additional outcomes data. Coverage under CED contributes to a new technology’s developmental pathway by encouraging more studies that employ it, according to the CMS.

For now, PET amyloid imaging will be covered only in CMS-approved, prospective randomized trials that include subjects from appropriate populations, and, when appropriate, employ the gold standard of postmortem Alzheimer’s diagnosis.

This decision on public coverage will almost certainly affect patients with private insurance as well, according to Dr. Richard J. Caselli, professor of neurology at the Mayo Clinic in Scottsdale, Ariz. and clinical core director of Mayo’s Alzheimer’s disease center.

"Their decision may be reasonable in older patients, which of course is their target patient population, but if other payers follow the CMS model, we will have overlooked the potential utility of this test in young patients, forcing such individuals to either go without or pay out of pocket," he said in an interview. "That is a clinically important issue that does not seem to have been aired in this deliberation."

The decision comes as a blow to Eli Lilly, the company developing florbetapir (Amyvid), one of the amyloid imaging agents. "Coverage With Evidence Development as proposed by CMS does not provide patients appropriate access to these amyloid imaging brain scans," Eric Dozier, the company’s senior director of business, said in a press statement. "Instead, it creates additional complexity for the broader community in determining the best path forward for patients. As we continue to review the final decision memo, we will be evaluating all available options to ensure patients and physicians can gain access to this innovative diagnostic tool as soon as possible."

Lilly said the decision contradicts the CMS’s own support of the National Alzheimer's Project Act, in whose creation it participated. "Yet the same agency is challenging the value of the only technology approved by the Food and Drug Administration for estimating beta-amyloid neuritic plaque density in the living brain, which can aid in helping doctors make a more informed diagnosis."

The decision also goes against the clinical recommendations of several groups, Lilly maintained – including the Alzheimer’s Association, which issued a statement citing its own concern.

"The Alzheimer’s Association is disappointed by the ... decision to only allow Coverage With Evidence Development (CED) for an Alzheimer’s imaging test that would improve diagnostic accuracy and certainty in challenging cases," the statement said. "When used in specific populations ... this tool has the potential to ... resolve distressing medical uncertainty."

Early this year, a task force convened by the Alzheimer’s Association and the Society of Nuclear Medicine and Molecular Imaging developed a set of criteria that would guide the appropriate clinical use of amyloid imaging agents (Alzheimers Dement. 2013;9:E1-16).

The document advised limiting scans to patients with persistent or progressive unexplained memory loss along with cognitive impairments, and those who test as possibly having Alzheimer’s but have an unusual clinical presentation. Imaging would also be appropriate in patients younger than 65 years who present with unexplained memory deficits.

"The Alzheimer’s Association appreciates that the evaluation of the impact of brain amyloid imaging on health outcomes can be complex in the absence of a treatment to stop or even slow the progression of the disease," the association noted. "However, as the scientific community races toward the National Alzheimer's Plan goal of prevention and effective treatment by 2025, many people facing confusion and frustration would benefit from the accurate and accelerated diagnosis this tool could offer."

Dr. Caselli said he had no relevant financial disclosures.

[email protected]

On Twitter @Alz_Gal

BARCELONA – It’s taken 15 years, but newly released data are finally clearing the last shadow of doubt over metformin’s safety in type 2 diabetes.

Patients in the groundbreaking U.K. Prospective Diabetes Study (UKPDS) who took the drug along with a sulfonylurea don’t appear to have any long-term increases in the risk of diabetes-related death, all-cause mortality, or cardiovascular events, Dr. Rury R. Holman said at the annual meeting of the European Association for the Study of Diabetes.

Michele G. Sullivan/IMNG Medical Media

However, although they are strongly reassuring, these data can’t yet be considered ironclad, said Dr. Holman, a primary UKPDS investigator and director of the University of Oxford Diabetes Trials Unit. "What we have here is comforting, but it is not proof positive. It’s not a second trial, but it does suggest that [the apparent early risk] may have evened out over time."

The Sulfonylurea and Metformin Substudy was designed to investigate the combination’s effect on patients in UKPDS who had not achieved the target glucose goal of 6 mmol/L (108 mg/dL), despite being on sulfonylurea monotherapy for the entire 7-year study. This group of 537 patients was secondarily randomized to either staying with the sulfonylurea monotherapy or adding metformin. "The impact of this was actually to add glycemic rescue therapy at 6 mmol/L rather than 15 mmol/L [270 mg/dL]," the level built into UKPDS, Dr. Holman said.

The substudy patients were a fairly representative mix of those in the larger study. They were a mean of 64 years old, with a mean body mass index of about 28 kg/m². They did differ significantly in two major categories, however, Dr. Holman pointed out. Patients in the combination therapy group had lower fasting plasma glucose (9 vs. 10 mmol/L; 162 vs. 180 mg/dL), hemoglobin A_1c (8.3% vs. 7.9%) and lower LDL cholesterol (3.4 vs. 3.2 mmol/L; 61.2 mg/dL vs. 57.6 mg/dL). These baseline differences could have helped set the stage for the differences in mortality outcomes, he suggested.

After the secondary randomization, those who got the addition of metformin showed an immediate, significant, decrease in fasting plasma glucose. This was a very encouraging finding, he said, because it broke the disappointing pattern of improvement followed eventually by beta-cell deterioration, which UKPDS characterized in all of its treatment arms. But, Dr. Holman said, after reaching a nadir at about 18 months, glucose levels in the dual-therapy patients did begin to creep back up, taking a parallel – although less pronounced – track to the monotherapy group.

The glucose response was encouraging, but clouded by an unexpected finding. By 6 years, those taking the drug combination were almost twice as likely to have died from a diabetes-related complication as were those in the monotherapy group (risk ratio, 1.96). The overall risk of death from any cause was also significantly increased in those taking the combination (RR, 0.60). However, there were no differences in fatal or nonfatal stroke or myocardial infarction.

"There was a separation of the mortality curves at around 3 years" that continued to separate through the entire study period, Dr. Holman said. "This was contrary to everything else UKPDS had shown, and raised considerable concern and alarm. It looked horrific and it could potentially have been horrific."

The investigators tried to make sense of the results, without much luck. Matching the cohorts with similar groups in other studies shed no light on the matter. The disconnect between the increase in all-cause mortality and stable cardiovascular events remained a puzzle. Because only 40 patients had died at that point – a reflection of the relative good baseline health of the UKPDS group – there was limited power to fully explore the finding.

Nonetheless, "when we found this, we said that these results could be real and that the addition of metformin to patients on sulfonylureas required more study, which is what we now have done."

At the meeting, Dr. Holman reported the most recent, yet-unpublished, data on these patients, who were followed for up to 15 years. In 1997, the hazard ratio for diabetes-related deaths was 1.96, with a high level of statistical significance (P = .039). It hovered near that point until 2001, when it began to decline. By 2003, it dropped to about 1.50, and was no longer statistically significant. Since then, the risk has declined close to null; it has never regained a significant value.

"Over time, the combination of sulfonylurea and metformin does not appear to have any continued adverse effect," Dr. Holman said. "We saw a diminishing risk ratio and at this point, close to 15 years after we started UKPDS, there appears to be no evidence of harm."

All-cause mortality showed a similar pattern, with a 60% increased risk in 1997 and a gradual improvement. "Although it’s still on the wrong side of 1.0, it’s not close to being statistically significant."

Overall, 226 patients have now died: 107 in the monotherapy group (40%) and 119 in the combination group (44%). Death from a diabetes-related cause has occurred in 57 of the monotherapy group (21%) and 60 of the combination therapy group (22%), for a nonsignificant risk ratio of 1.18.

There is no significant increase in the risk of myocardial infarction (1.09) or stroke (0.86), whether fatal or nonfatal.

Two more studies are in the works to try and sort out the sulfonylurea-metformin mash-up, Dr. Holman said: GRADE and GLINT. GRADE (Glycemic Reduction Approaches in Diabetes) is a four-arm comparative effectiveness study sponsored by the National Institutes of Health. It will randomize 6,000 patients with type 2 diabetes to metformin and either a sulfonylurea (glimepiride), a DPP-4 inhibitor (sitagliptin), a GLP-1 agonist (liraglutide), or insulin glargine. The groups will be followed for 5 years, Dr. Holman said. "Certainly, if there is a doubling in the risk of death in the sulfonylurea/metformin group, we will see it."

The second study, called GLINT (Glucose Lowering in Non-diabetic Hyperglycemia Trial), is just getting ramped up in the United Kingdom. It’s aimed at patients whose HbA_1c is elevated, but not yet in the diabetic range of 6.5%.

The 5-year GLINT aims to recruit nearly 12,000 people aged 40 years and older, who have a 10-year calculated cardiovascular disease risk of at least 20%. Subjects will be randomized to metformin or placebo. The primary endpoint is a composite cardiovascular outcome of death or nonfatal MI or stroke. The first patients are being seen this month, Dr. Holman noted.

The study is also well powered to look at the increased risk of bowel and breast cancers among diabetes patients, he added

"Perhaps this will be the pivotal second study that will help confirm the preeminence of metformin as first-line therapy."

Becton Dickinson, Boehringer Mannheim, Bristol Myers Squibb, Hoechst, Lilly, Lipha, and Novo Nordisk contributed to the funding for the UKPDS study. Dr. Holman had no financial disclosures.

[email protected]

On Twitter @Alz_gal

BARCELONA – It’s taken 15 years, but newly released data are finally clearing the last shadow of doubt over metformin’s safety in type 2 diabetes.

Patients in the groundbreaking U.K. Prospective Diabetes Study (UKPDS) who took the drug along with a sulfonylurea don’t appear to have any long-term increases in the risk of diabetes-related death, all-cause mortality, or cardiovascular events, Dr. Rury R. Holman said at the annual meeting of the European Association for the Study of Diabetes.

Michele G. Sullivan/IMNG Medical Media

However, although they are strongly reassuring, these data can’t yet be considered ironclad, said Dr. Holman, a primary UKPDS investigator and director of the University of Oxford Diabetes Trials Unit. "What we have here is comforting, but it is not proof positive. It’s not a second trial, but it does suggest that [the apparent early risk] may have evened out over time."

The Sulfonylurea and Metformin Substudy was designed to investigate the combination’s effect on patients in UKPDS who had not achieved the target glucose goal of 6 mmol/L (108 mg/dL), despite being on sulfonylurea monotherapy for the entire 7-year study. This group of 537 patients was secondarily randomized to either staying with the sulfonylurea monotherapy or adding metformin. "The impact of this was actually to add glycemic rescue therapy at 6 mmol/L rather than 15 mmol/L [270 mg/dL]," the level built into UKPDS, Dr. Holman said.

The substudy patients were a fairly representative mix of those in the larger study. They were a mean of 64 years old, with a mean body mass index of about 28 kg/m². They did differ significantly in two major categories, however, Dr. Holman pointed out. Patients in the combination therapy group had lower fasting plasma glucose (9 vs. 10 mmol/L; 162 vs. 180 mg/dL), hemoglobin A_1c (8.3% vs. 7.9%) and lower LDL cholesterol (3.4 vs. 3.2 mmol/L; 61.2 mg/dL vs. 57.6 mg/dL). These baseline differences could have helped set the stage for the differences in mortality outcomes, he suggested.

After the secondary randomization, those who got the addition of metformin showed an immediate, significant, decrease in fasting plasma glucose. This was a very encouraging finding, he said, because it broke the disappointing pattern of improvement followed eventually by beta-cell deterioration, which UKPDS characterized in all of its treatment arms. But, Dr. Holman said, after reaching a nadir at about 18 months, glucose levels in the dual-therapy patients did begin to creep back up, taking a parallel – although less pronounced – track to the monotherapy group.

The glucose response was encouraging, but clouded by an unexpected finding. By 6 years, those taking the drug combination were almost twice as likely to have died from a diabetes-related complication as were those in the monotherapy group (risk ratio, 1.96). The overall risk of death from any cause was also significantly increased in those taking the combination (RR, 0.60). However, there were no differences in fatal or nonfatal stroke or myocardial infarction.

"There was a separation of the mortality curves at around 3 years" that continued to separate through the entire study period, Dr. Holman said. "This was contrary to everything else UKPDS had shown, and raised considerable concern and alarm. It looked horrific and it could potentially have been horrific."

The investigators tried to make sense of the results, without much luck. Matching the cohorts with similar groups in other studies shed no light on the matter. The disconnect between the increase in all-cause mortality and stable cardiovascular events remained a puzzle. Because only 40 patients had died at that point – a reflection of the relative good baseline health of the UKPDS group – there was limited power to fully explore the finding.

Nonetheless, "when we found this, we said that these results could be real and that the addition of metformin to patients on sulfonylureas required more study, which is what we now have done."

At the meeting, Dr. Holman reported the most recent, yet-unpublished, data on these patients, who were followed for up to 15 years. In 1997, the hazard ratio for diabetes-related deaths was 1.96, with a high level of statistical significance (P = .039). It hovered near that point until 2001, when it began to decline. By 2003, it dropped to about 1.50, and was no longer statistically significant. Since then, the risk has declined close to null; it has never regained a significant value.

"Over time, the combination of sulfonylurea and metformin does not appear to have any continued adverse effect," Dr. Holman said. "We saw a diminishing risk ratio and at this point, close to 15 years after we started UKPDS, there appears to be no evidence of harm."

All-cause mortality showed a similar pattern, with a 60% increased risk in 1997 and a gradual improvement. "Although it’s still on the wrong side of 1.0, it’s not close to being statistically significant."

Overall, 226 patients have now died: 107 in the monotherapy group (40%) and 119 in the combination group (44%). Death from a diabetes-related cause has occurred in 57 of the monotherapy group (21%) and 60 of the combination therapy group (22%), for a nonsignificant risk ratio of 1.18.

There is no significant increase in the risk of myocardial infarction (1.09) or stroke (0.86), whether fatal or nonfatal.

Two more studies are in the works to try and sort out the sulfonylurea-metformin mash-up, Dr. Holman said: GRADE and GLINT. GRADE (Glycemic Reduction Approaches in Diabetes) is a four-arm comparative effectiveness study sponsored by the National Institutes of Health. It will randomize 6,000 patients with type 2 diabetes to metformin and either a sulfonylurea (glimepiride), a DPP-4 inhibitor (sitagliptin), a GLP-1 agonist (liraglutide), or insulin glargine. The groups will be followed for 5 years, Dr. Holman said. "Certainly, if there is a doubling in the risk of death in the sulfonylurea/metformin group, we will see it."

The second study, called GLINT (Glucose Lowering in Non-diabetic Hyperglycemia Trial), is just getting ramped up in the United Kingdom. It’s aimed at patients whose HbA_1c is elevated, but not yet in the diabetic range of 6.5%.

The 5-year GLINT aims to recruit nearly 12,000 people aged 40 years and older, who have a 10-year calculated cardiovascular disease risk of at least 20%. Subjects will be randomized to metformin or placebo. The primary endpoint is a composite cardiovascular outcome of death or nonfatal MI or stroke. The first patients are being seen this month, Dr. Holman noted.

The study is also well powered to look at the increased risk of bowel and breast cancers among diabetes patients, he added

"Perhaps this will be the pivotal second study that will help confirm the preeminence of metformin as first-line therapy."

Becton Dickinson, Boehringer Mannheim, Bristol Myers Squibb, Hoechst, Lilly, Lipha, and Novo Nordisk contributed to the funding for the UKPDS study. Dr. Holman had no financial disclosures.

[email protected]

On Twitter @Alz_gal

BARCELONA – It’s taken 15 years, but newly released data are finally clearing the last shadow of doubt over metformin’s safety in type 2 diabetes.

Patients in the groundbreaking U.K. Prospective Diabetes Study (UKPDS) who took the drug along with a sulfonylurea don’t appear to have any long-term increases in the risk of diabetes-related death, all-cause mortality, or cardiovascular events, Dr. Rury R. Holman said at the annual meeting of the European Association for the Study of Diabetes.

Michele G. Sullivan/IMNG Medical Media

However, although they are strongly reassuring, these data can’t yet be considered ironclad, said Dr. Holman, a primary UKPDS investigator and director of the University of Oxford Diabetes Trials Unit. "What we have here is comforting, but it is not proof positive. It’s not a second trial, but it does suggest that [the apparent early risk] may have evened out over time."

The Sulfonylurea and Metformin Substudy was designed to investigate the combination’s effect on patients in UKPDS who had not achieved the target glucose goal of 6 mmol/L (108 mg/dL), despite being on sulfonylurea monotherapy for the entire 7-year study. This group of 537 patients was secondarily randomized to either staying with the sulfonylurea monotherapy or adding metformin. "The impact of this was actually to add glycemic rescue therapy at 6 mmol/L rather than 15 mmol/L [270 mg/dL]," the level built into UKPDS, Dr. Holman said.

The substudy patients were a fairly representative mix of those in the larger study. They were a mean of 64 years old, with a mean body mass index of about 28 kg/m². They did differ significantly in two major categories, however, Dr. Holman pointed out. Patients in the combination therapy group had lower fasting plasma glucose (9 vs. 10 mmol/L; 162 vs. 180 mg/dL), hemoglobin A_1c (8.3% vs. 7.9%) and lower LDL cholesterol (3.4 vs. 3.2 mmol/L; 61.2 mg/dL vs. 57.6 mg/dL). These baseline differences could have helped set the stage for the differences in mortality outcomes, he suggested.

After the secondary randomization, those who got the addition of metformin showed an immediate, significant, decrease in fasting plasma glucose. This was a very encouraging finding, he said, because it broke the disappointing pattern of improvement followed eventually by beta-cell deterioration, which UKPDS characterized in all of its treatment arms. But, Dr. Holman said, after reaching a nadir at about 18 months, glucose levels in the dual-therapy patients did begin to creep back up, taking a parallel – although less pronounced – track to the monotherapy group.

The glucose response was encouraging, but clouded by an unexpected finding. By 6 years, those taking the drug combination were almost twice as likely to have died from a diabetes-related complication as were those in the monotherapy group (risk ratio, 1.96). The overall risk of death from any cause was also significantly increased in those taking the combination (RR, 0.60). However, there were no differences in fatal or nonfatal stroke or myocardial infarction.

"There was a separation of the mortality curves at around 3 years" that continued to separate through the entire study period, Dr. Holman said. "This was contrary to everything else UKPDS had shown, and raised considerable concern and alarm. It looked horrific and it could potentially have been horrific."

The investigators tried to make sense of the results, without much luck. Matching the cohorts with similar groups in other studies shed no light on the matter. The disconnect between the increase in all-cause mortality and stable cardiovascular events remained a puzzle. Because only 40 patients had died at that point – a reflection of the relative good baseline health of the UKPDS group – there was limited power to fully explore the finding.

Nonetheless, "when we found this, we said that these results could be real and that the addition of metformin to patients on sulfonylureas required more study, which is what we now have done."

At the meeting, Dr. Holman reported the most recent, yet-unpublished, data on these patients, who were followed for up to 15 years. In 1997, the hazard ratio for diabetes-related deaths was 1.96, with a high level of statistical significance (P = .039). It hovered near that point until 2001, when it began to decline. By 2003, it dropped to about 1.50, and was no longer statistically significant. Since then, the risk has declined close to null; it has never regained a significant value.

"Over time, the combination of sulfonylurea and metformin does not appear to have any continued adverse effect," Dr. Holman said. "We saw a diminishing risk ratio and at this point, close to 15 years after we started UKPDS, there appears to be no evidence of harm."

All-cause mortality showed a similar pattern, with a 60% increased risk in 1997 and a gradual improvement. "Although it’s still on the wrong side of 1.0, it’s not close to being statistically significant."

Overall, 226 patients have now died: 107 in the monotherapy group (40%) and 119 in the combination group (44%). Death from a diabetes-related cause has occurred in 57 of the monotherapy group (21%) and 60 of the combination therapy group (22%), for a nonsignificant risk ratio of 1.18.

There is no significant increase in the risk of myocardial infarction (1.09) or stroke (0.86), whether fatal or nonfatal.

Two more studies are in the works to try and sort out the sulfonylurea-metformin mash-up, Dr. Holman said: GRADE and GLINT. GRADE (Glycemic Reduction Approaches in Diabetes) is a four-arm comparative effectiveness study sponsored by the National Institutes of Health. It will randomize 6,000 patients with type 2 diabetes to metformin and either a sulfonylurea (glimepiride), a DPP-4 inhibitor (sitagliptin), a GLP-1 agonist (liraglutide), or insulin glargine. The groups will be followed for 5 years, Dr. Holman said. "Certainly, if there is a doubling in the risk of death in the sulfonylurea/metformin group, we will see it."

The second study, called GLINT (Glucose Lowering in Non-diabetic Hyperglycemia Trial), is just getting ramped up in the United Kingdom. It’s aimed at patients whose HbA_1c is elevated, but not yet in the diabetic range of 6.5%.

The 5-year GLINT aims to recruit nearly 12,000 people aged 40 years and older, who have a 10-year calculated cardiovascular disease risk of at least 20%. Subjects will be randomized to metformin or placebo. The primary endpoint is a composite cardiovascular outcome of death or nonfatal MI or stroke. The first patients are being seen this month, Dr. Holman noted.

The study is also well powered to look at the increased risk of bowel and breast cancers among diabetes patients, he added

"Perhaps this will be the pivotal second study that will help confirm the preeminence of metformin as first-line therapy."

Becton Dickinson, Boehringer Mannheim, Bristol Myers Squibb, Hoechst, Lilly, Lipha, and Novo Nordisk contributed to the funding for the UKPDS study. Dr. Holman had no financial disclosures.

[email protected]

On Twitter @Alz_gal

BARCELONA – Use of a subcutaneous continuous glucose monitoring system translated into better glycemic control for critically ill patients in intensive care, a study has shown.

Compared with those monitored by point-of-care testing, patients with continuous monitoring spent significantly more time in their target blood glucose range, Daphne Boom reported at the annual meeting of the European Association for the Study of Diabetes.

The implantable device also markedly reduced the need for blood samples, said Ms. Boom, a medical student at the Onze Lieve Vrouwe Gasthuis, Amsterdam. Nurses obtained a mean of just two samples over a 24-hour period for these patients, compared with 12 over the same time for point-of-care patients.

Ms. Boom and her colleagues compared the two monitoring regimens in a group of 177 patients who were admitted to intensive care with an expected stay of at least 24 hours; 87 were randomized to continuous subcutaneous glucose monitoring and 90 to point-of-care monitoring. The target glucose range for each group was 5-9 mmol/L. The continuous monitoring system measured glucose every 10 minutes, and sounded an alarm whenever it registered outside this parameter. Blood samples were drawn every 2 hours for the point-of-care patients. A computer algorithm made insulin dosing recommendations for patients in both groups, based on the monitoring system level or the results of finger-stick samples.

In both groups, an arterial blood sample provided a reference glucose range every 6 hours; however, the samples were blinded to clinicians and used only for calibrating medications.

The primary endpoints were the incidence of severe hypoglycemia (below 2.2 mmol/L) and severe hyperglycemia (above 25 mmol/L). The measure of efficacy was the total time spent within the blood glucose target range. Nursing workload was assessed by the number of blood samples drawn every 24 hours.

Most patients were from the medical service; 13% were complicated cardiac surgery patients. The majority (92%) were mechanically ventilated. The investigators looked at 1,358 paired measurements.

There were five incidents of severe hypoglycemia in the intervention group and two in the control group, but the difference was not statistically significant. There were no cases of severe hyperglycemia in either group.

There was one case of mild hypoglycemia in each group. There was one case of mild hyperglycemia in the intervention group and two in the control group.

The mean study duration was 73 hours for the intervention group, of which 58 (79%) were spent within the target glucose range. The mean study duration for the control group was 59 hours, of which 43 (73%) were spent in the target range. This difference was statistically significant.

Significantly fewer blood samples were drawn from the intervention group (2 vs. 12 every 24 hours), showing that the continuous monitoring system was a more efficient use of nursing time, Ms. Boom added.

She said she had no relevant financial disclosures.

[email protected]

BARCELONA – Use of a subcutaneous continuous glucose monitoring system translated into better glycemic control for critically ill patients in intensive care, a study has shown.

Compared with those monitored by point-of-care testing, patients with continuous monitoring spent significantly more time in their target blood glucose range, Daphne Boom reported at the annual meeting of the European Association for the Study of Diabetes.

The implantable device also markedly reduced the need for blood samples, said Ms. Boom, a medical student at the Onze Lieve Vrouwe Gasthuis, Amsterdam. Nurses obtained a mean of just two samples over a 24-hour period for these patients, compared with 12 over the same time for point-of-care patients.

Ms. Boom and her colleagues compared the two monitoring regimens in a group of 177 patients who were admitted to intensive care with an expected stay of at least 24 hours; 87 were randomized to continuous subcutaneous glucose monitoring and 90 to point-of-care monitoring. The target glucose range for each group was 5-9 mmol/L. The continuous monitoring system measured glucose every 10 minutes, and sounded an alarm whenever it registered outside this parameter. Blood samples were drawn every 2 hours for the point-of-care patients. A computer algorithm made insulin dosing recommendations for patients in both groups, based on the monitoring system level or the results of finger-stick samples.

In both groups, an arterial blood sample provided a reference glucose range every 6 hours; however, the samples were blinded to clinicians and used only for calibrating medications.

The primary endpoints were the incidence of severe hypoglycemia (below 2.2 mmol/L) and severe hyperglycemia (above 25 mmol/L). The measure of efficacy was the total time spent within the blood glucose target range. Nursing workload was assessed by the number of blood samples drawn every 24 hours.

Most patients were from the medical service; 13% were complicated cardiac surgery patients. The majority (92%) were mechanically ventilated. The investigators looked at 1,358 paired measurements.

There were five incidents of severe hypoglycemia in the intervention group and two in the control group, but the difference was not statistically significant. There were no cases of severe hyperglycemia in either group.

There was one case of mild hypoglycemia in each group. There was one case of mild hyperglycemia in the intervention group and two in the control group.

The mean study duration was 73 hours for the intervention group, of which 58 (79%) were spent within the target glucose range. The mean study duration for the control group was 59 hours, of which 43 (73%) were spent in the target range. This difference was statistically significant.

Significantly fewer blood samples were drawn from the intervention group (2 vs. 12 every 24 hours), showing that the continuous monitoring system was a more efficient use of nursing time, Ms. Boom added.

She said she had no relevant financial disclosures.

[email protected]

BARCELONA – Use of a subcutaneous continuous glucose monitoring system translated into better glycemic control for critically ill patients in intensive care, a study has shown.

Compared with those monitored by point-of-care testing, patients with continuous monitoring spent significantly more time in their target blood glucose range, Daphne Boom reported at the annual meeting of the European Association for the Study of Diabetes.

The implantable device also markedly reduced the need for blood samples, said Ms. Boom, a medical student at the Onze Lieve Vrouwe Gasthuis, Amsterdam. Nurses obtained a mean of just two samples over a 24-hour period for these patients, compared with 12 over the same time for point-of-care patients.

Ms. Boom and her colleagues compared the two monitoring regimens in a group of 177 patients who were admitted to intensive care with an expected stay of at least 24 hours; 87 were randomized to continuous subcutaneous glucose monitoring and 90 to point-of-care monitoring. The target glucose range for each group was 5-9 mmol/L. The continuous monitoring system measured glucose every 10 minutes, and sounded an alarm whenever it registered outside this parameter. Blood samples were drawn every 2 hours for the point-of-care patients. A computer algorithm made insulin dosing recommendations for patients in both groups, based on the monitoring system level or the results of finger-stick samples.

In both groups, an arterial blood sample provided a reference glucose range every 6 hours; however, the samples were blinded to clinicians and used only for calibrating medications.

The primary endpoints were the incidence of severe hypoglycemia (below 2.2 mmol/L) and severe hyperglycemia (above 25 mmol/L). The measure of efficacy was the total time spent within the blood glucose target range. Nursing workload was assessed by the number of blood samples drawn every 24 hours.

Most patients were from the medical service; 13% were complicated cardiac surgery patients. The majority (92%) were mechanically ventilated. The investigators looked at 1,358 paired measurements.

There were five incidents of severe hypoglycemia in the intervention group and two in the control group, but the difference was not statistically significant. There were no cases of severe hyperglycemia in either group.

There was one case of mild hypoglycemia in each group. There was one case of mild hyperglycemia in the intervention group and two in the control group.

The mean study duration was 73 hours for the intervention group, of which 58 (79%) were spent within the target glucose range. The mean study duration for the control group was 59 hours, of which 43 (73%) were spent in the target range. This difference was statistically significant.

Significantly fewer blood samples were drawn from the intervention group (2 vs. 12 every 24 hours), showing that the continuous monitoring system was a more efficient use of nursing time, Ms. Boom added.

She said she had no relevant financial disclosures.

[email protected]

Earn 0.25 hours AMA PRA Category 1 credit: Read this article, and click the link at the end to take the post-test.

BARCELONA – High levels of pro-B-type natriuretic peptide significantly predicted cardiovascular events in patients with type 2 diabetes, a prospective study has found.

Over 6 years, patients with diabetes and high levels of the cardiac protein were more than 50% as likely to have an acute cardiovascular event than were patients without diabetes who had low pro-BNP levels, Dr. Christoph H. Saely said at the annual meeting of the European Association for the Study of Diabetes.

The finding could be useful in risk stratification of patients with diabetes, said Dr. Saely of the Academic Teaching Hospital Feldkirch, Austria.

He and his colleagues followed 750 patients who underwent coronary angiography for the evaluation of established or suspected stable coronary artery disease for a mean of 6 years.

At baseline, the patients’ mean age was 66 years. Most (64%) were men. About 60% were current or past smokers, and 24% had type 2 diabetes.

Generally, those with diabetes had worse markers of cardiac health, including a higher incidence of hypertension (91% vs. 79%); a higher body mass index (29 vs. 27 kg/m²); and worse lipid measurements. At baseline, 65% of those with diabetes had marked coronary artery disease, compared with 50% of those without diabetes – a significant difference.

The baseline pro-BNP level was also significantly higher in the patients with diabetes (mean of 750 pg/mL vs. 500 pg/mL).

Over the follow-up period, there were 119 coronary events (16%), including cardiovascular death (24), nonfatal heart attack (18), and nonfatal stroke (12). There were also 10 coronary artery bypass grafts, 27 percutaneous coronary interventions, and 28 noncoronary revascularizations.

To evaluate the impact of pro-BNP levels on cardiovascular risk, Dr. Saely divided the cohort into four groups according to diabetes and either high or low pro-BNP levels; a low level was less than 314 pg/mL, while a high level was 314 pg/mL or more. Patients were classified into nondiabetes with low pro-BNP (391); nondiabetes with high pro-BNP (182); diabetes with low pro-BNP (109); and diabetes with high pro-BNP (68).

By the end of the study, there had been significantly fewer cardiovascular events among patients with low pro-BNP; 95% of those without diabetes and 90% of those with diabetes were free of such events.

Among those patients who had no diabetes but had a high pro-BNP, 80% were event free by 6 years. But the picture was much worse for patients who had diabetes coupled with a high pro-BNP level, Dr. Saely said. By 6 years, about half had experienced some kind of major cardiovascular event; the excess risk associated with high levels was more than 50%, he said, even after adjustment for age, gender, hypertension, body mass index, and smoking status.

The protein is generally thought of as a marker for heart failure, he added. In patients with long-standing diabetes, he said, it may be associated with metabolically induced cardiac fibrosis.

Dr. Saely had no financial disclosures.

To earn 0.25 hours AMA PRA Category 1 credit after reading this article, take the post-test here.

[email protected]

Earn 0.25 hours AMA PRA Category 1 credit: Read this article, and click the link at the end to take the post-test.

BARCELONA – High levels of pro-B-type natriuretic peptide significantly predicted cardiovascular events in patients with type 2 diabetes, a prospective study has found.

Over 6 years, patients with diabetes and high levels of the cardiac protein were more than 50% as likely to have an acute cardiovascular event than were patients without diabetes who had low pro-BNP levels, Dr. Christoph H. Saely said at the annual meeting of the European Association for the Study of Diabetes.

The finding could be useful in risk stratification of patients with diabetes, said Dr. Saely of the Academic Teaching Hospital Feldkirch, Austria.

He and his colleagues followed 750 patients who underwent coronary angiography for the evaluation of established or suspected stable coronary artery disease for a mean of 6 years.

At baseline, the patients’ mean age was 66 years. Most (64%) were men. About 60% were current or past smokers, and 24% had type 2 diabetes.

Generally, those with diabetes had worse markers of cardiac health, including a higher incidence of hypertension (91% vs. 79%); a higher body mass index (29 vs. 27 kg/m²); and worse lipid measurements. At baseline, 65% of those with diabetes had marked coronary artery disease, compared with 50% of those without diabetes – a significant difference.

The baseline pro-BNP level was also significantly higher in the patients with diabetes (mean of 750 pg/mL vs. 500 pg/mL).

Over the follow-up period, there were 119 coronary events (16%), including cardiovascular death (24), nonfatal heart attack (18), and nonfatal stroke (12). There were also 10 coronary artery bypass grafts, 27 percutaneous coronary interventions, and 28 noncoronary revascularizations.

To evaluate the impact of pro-BNP levels on cardiovascular risk, Dr. Saely divided the cohort into four groups according to diabetes and either high or low pro-BNP levels; a low level was less than 314 pg/mL, while a high level was 314 pg/mL or more. Patients were classified into nondiabetes with low pro-BNP (391); nondiabetes with high pro-BNP (182); diabetes with low pro-BNP (109); and diabetes with high pro-BNP (68).

By the end of the study, there had been significantly fewer cardiovascular events among patients with low pro-BNP; 95% of those without diabetes and 90% of those with diabetes were free of such events.

Among those patients who had no diabetes but had a high pro-BNP, 80% were event free by 6 years. But the picture was much worse for patients who had diabetes coupled with a high pro-BNP level, Dr. Saely said. By 6 years, about half had experienced some kind of major cardiovascular event; the excess risk associated with high levels was more than 50%, he said, even after adjustment for age, gender, hypertension, body mass index, and smoking status.

The protein is generally thought of as a marker for heart failure, he added. In patients with long-standing diabetes, he said, it may be associated with metabolically induced cardiac fibrosis.

Dr. Saely had no financial disclosures.

To earn 0.25 hours AMA PRA Category 1 credit after reading this article, take the post-test here.

[email protected]

Earn 0.25 hours AMA PRA Category 1 credit: Read this article, and click the link at the end to take the post-test.

BARCELONA – High levels of pro-B-type natriuretic peptide significantly predicted cardiovascular events in patients with type 2 diabetes, a prospective study has found.

Over 6 years, patients with diabetes and high levels of the cardiac protein were more than 50% as likely to have an acute cardiovascular event than were patients without diabetes who had low pro-BNP levels, Dr. Christoph H. Saely said at the annual meeting of the European Association for the Study of Diabetes.

The finding could be useful in risk stratification of patients with diabetes, said Dr. Saely of the Academic Teaching Hospital Feldkirch, Austria.

He and his colleagues followed 750 patients who underwent coronary angiography for the evaluation of established or suspected stable coronary artery disease for a mean of 6 years.

At baseline, the patients’ mean age was 66 years. Most (64%) were men. About 60% were current or past smokers, and 24% had type 2 diabetes.

Generally, those with diabetes had worse markers of cardiac health, including a higher incidence of hypertension (91% vs. 79%); a higher body mass index (29 vs. 27 kg/m²); and worse lipid measurements. At baseline, 65% of those with diabetes had marked coronary artery disease, compared with 50% of those without diabetes – a significant difference.

The baseline pro-BNP level was also significantly higher in the patients with diabetes (mean of 750 pg/mL vs. 500 pg/mL).

Over the follow-up period, there were 119 coronary events (16%), including cardiovascular death (24), nonfatal heart attack (18), and nonfatal stroke (12). There were also 10 coronary artery bypass grafts, 27 percutaneous coronary interventions, and 28 noncoronary revascularizations.

To evaluate the impact of pro-BNP levels on cardiovascular risk, Dr. Saely divided the cohort into four groups according to diabetes and either high or low pro-BNP levels; a low level was less than 314 pg/mL, while a high level was 314 pg/mL or more. Patients were classified into nondiabetes with low pro-BNP (391); nondiabetes with high pro-BNP (182); diabetes with low pro-BNP (109); and diabetes with high pro-BNP (68).

By the end of the study, there had been significantly fewer cardiovascular events among patients with low pro-BNP; 95% of those without diabetes and 90% of those with diabetes were free of such events.

Among those patients who had no diabetes but had a high pro-BNP, 80% were event free by 6 years. But the picture was much worse for patients who had diabetes coupled with a high pro-BNP level, Dr. Saely said. By 6 years, about half had experienced some kind of major cardiovascular event; the excess risk associated with high levels was more than 50%, he said, even after adjustment for age, gender, hypertension, body mass index, and smoking status.

The protein is generally thought of as a marker for heart failure, he added. In patients with long-standing diabetes, he said, it may be associated with metabolically induced cardiac fibrosis.

Dr. Saely had no financial disclosures.

To earn 0.25 hours AMA PRA Category 1 credit after reading this article, take the post-test here.

[email protected]

BARCELONA – High levels of pro-B-type natriuretic peptide significantly predicted cardiovascular events in patients with type 2 diabetes, a prospective study has found.

Over 6 years, patients with diabetes and high levels of the cardiac protein were more than 50% as likely to have an acute cardiovascular event than were patients without diabetes who had low pro-BNP levels, Dr. Christoph H. Saely said at the annual meeting of the European Association for the Study of Diabetes.

The finding could be useful in risk stratification of patients with diabetes, said Dr. Saely of the Academic Teaching Hospital Feldkirch, Austria.

He and his colleagues followed 750 patients who underwent coronary angiography for the evaluation of established or suspected stable coronary artery disease for a mean of 6 years.

At baseline, the patients’ mean age was 66 years. Most (64%) were men. About 60% were current or past smokers, and 24% had type 2 diabetes.

Generally, those with diabetes had worse markers of cardiac health, including a higher incidence of hypertension (91% vs. 79%); a higher body mass index (29 vs. 27 kg/m²); and worse lipid measurements. At baseline, 65% of those with diabetes had marked coronary artery disease, compared with 50% of those without diabetes – a significant difference.

The baseline pro-BNP level was also significantly higher in the patients with diabetes (mean of 750 pg/mL vs. 500 pg/mL).

Over the follow-up period, there were 119 coronary events (16%), including cardiovascular death (24), nonfatal heart attack (18), and nonfatal stroke (12). There were also 10 coronary artery bypass grafts, 27 percutaneous coronary interventions, and 28 noncoronary revascularizations.

To evaluate the impact of pro-BNP levels on cardiovascular risk, Dr. Saely divided the cohort into four groups according to diabetes and either high or low pro-BNP levels; a low level was less than 314 pg/mL, while a high level was 314 pg/mL or more. Patients were classified into nondiabetes with low pro-BNP (391); nondiabetes with high pro-BNP (182); diabetes with low pro-BNP (109); and diabetes with high pro-BNP (68).

By the end of the study, there had been significantly fewer cardiovascular events among patients with low pro-BNP; 95% of those without diabetes and 90% of those with diabetes were free of such events.

Among those patients who had no diabetes but had a high pro-BNP, 80% were event free by 6 years. But the picture was much worse for patients who had diabetes coupled with a high pro-BNP level, Dr. Saely said. By 6 years, about half had experienced some kind of major cardiovascular event; the excess risk associated with high levels was more than 50%, he said, even after adjustment for age, gender, hypertension, body mass index, and smoking status.

The protein is generally thought of as a marker for heart failure, he added. In patients with long-standing diabetes, he said, it may be associated with metabolically induced cardiac fibrosis.

Dr. Saely had no financial disclosures.

[email protected]

BARCELONA – High levels of pro-B-type natriuretic peptide significantly predicted cardiovascular events in patients with type 2 diabetes, a prospective study has found.

Over 6 years, patients with diabetes and high levels of the cardiac protein were more than 50% as likely to have an acute cardiovascular event than were patients without diabetes who had low pro-BNP levels, Dr. Christoph H. Saely said at the annual meeting of the European Association for the Study of Diabetes.

The finding could be useful in risk stratification of patients with diabetes, said Dr. Saely of the Academic Teaching Hospital Feldkirch, Austria.

He and his colleagues followed 750 patients who underwent coronary angiography for the evaluation of established or suspected stable coronary artery disease for a mean of 6 years.

At baseline, the patients’ mean age was 66 years. Most (64%) were men. About 60% were current or past smokers, and 24% had type 2 diabetes.

Generally, those with diabetes had worse markers of cardiac health, including a higher incidence of hypertension (91% vs. 79%); a higher body mass index (29 vs. 27 kg/m²); and worse lipid measurements. At baseline, 65% of those with diabetes had marked coronary artery disease, compared with 50% of those without diabetes – a significant difference.

The baseline pro-BNP level was also significantly higher in the patients with diabetes (mean of 750 pg/mL vs. 500 pg/mL).

Over the follow-up period, there were 119 coronary events (16%), including cardiovascular death (24), nonfatal heart attack (18), and nonfatal stroke (12). There were also 10 coronary artery bypass grafts, 27 percutaneous coronary interventions, and 28 noncoronary revascularizations.

To evaluate the impact of pro-BNP levels on cardiovascular risk, Dr. Saely divided the cohort into four groups according to diabetes and either high or low pro-BNP levels; a low level was less than 314 pg/mL, while a high level was 314 pg/mL or more. Patients were classified into nondiabetes with low pro-BNP (391); nondiabetes with high pro-BNP (182); diabetes with low pro-BNP (109); and diabetes with high pro-BNP (68).

By the end of the study, there had been significantly fewer cardiovascular events among patients with low pro-BNP; 95% of those without diabetes and 90% of those with diabetes were free of such events.

Among those patients who had no diabetes but had a high pro-BNP, 80% were event free by 6 years. But the picture was much worse for patients who had diabetes coupled with a high pro-BNP level, Dr. Saely said. By 6 years, about half had experienced some kind of major cardiovascular event; the excess risk associated with high levels was more than 50%, he said, even after adjustment for age, gender, hypertension, body mass index, and smoking status.

The protein is generally thought of as a marker for heart failure, he added. In patients with long-standing diabetes, he said, it may be associated with metabolically induced cardiac fibrosis.

Dr. Saely had no financial disclosures.

[email protected]

BARCELONA – High levels of pro-B-type natriuretic peptide significantly predicted cardiovascular events in patients with type 2 diabetes, a prospective study has found.

Over 6 years, patients with diabetes and high levels of the cardiac protein were more than 50% as likely to have an acute cardiovascular event than were patients without diabetes who had low pro-BNP levels, Dr. Christoph H. Saely said at the annual meeting of the European Association for the Study of Diabetes.

The finding could be useful in risk stratification of patients with diabetes, said Dr. Saely of the Academic Teaching Hospital Feldkirch, Austria.

He and his colleagues followed 750 patients who underwent coronary angiography for the evaluation of established or suspected stable coronary artery disease for a mean of 6 years.

At baseline, the patients’ mean age was 66 years. Most (64%) were men. About 60% were current or past smokers, and 24% had type 2 diabetes.

Generally, those with diabetes had worse markers of cardiac health, including a higher incidence of hypertension (91% vs. 79%); a higher body mass index (29 vs. 27 kg/m²); and worse lipid measurements. At baseline, 65% of those with diabetes had marked coronary artery disease, compared with 50% of those without diabetes – a significant difference.

The baseline pro-BNP level was also significantly higher in the patients with diabetes (mean of 750 pg/mL vs. 500 pg/mL).

Over the follow-up period, there were 119 coronary events (16%), including cardiovascular death (24), nonfatal heart attack (18), and nonfatal stroke (12). There were also 10 coronary artery bypass grafts, 27 percutaneous coronary interventions, and 28 noncoronary revascularizations.

To evaluate the impact of pro-BNP levels on cardiovascular risk, Dr. Saely divided the cohort into four groups according to diabetes and either high or low pro-BNP levels; a low level was less than 314 pg/mL, while a high level was 314 pg/mL or more. Patients were classified into nondiabetes with low pro-BNP (391); nondiabetes with high pro-BNP (182); diabetes with low pro-BNP (109); and diabetes with high pro-BNP (68).

By the end of the study, there had been significantly fewer cardiovascular events among patients with low pro-BNP; 95% of those without diabetes and 90% of those with diabetes were free of such events.

Among those patients who had no diabetes but had a high pro-BNP, 80% were event free by 6 years. But the picture was much worse for patients who had diabetes coupled with a high pro-BNP level, Dr. Saely said. By 6 years, about half had experienced some kind of major cardiovascular event; the excess risk associated with high levels was more than 50%, he said, even after adjustment for age, gender, hypertension, body mass index, and smoking status.

The protein is generally thought of as a marker for heart failure, he added. In patients with long-standing diabetes, he said, it may be associated with metabolically induced cardiac fibrosis.

Dr. Saely had no financial disclosures.

[email protected]

A residency program that stresses minimally invasive hysterectomy as the preferred procedure for benign disease is a feasible undertaking, providing valuable surgeon experience and excellent patient outcomes, according to Dr. Joshua Kesterson.

Of 537 hysterectomies for benign disease performed in a single year at one such program, 526 (98%) were begun with a minimally invasive approach, and 517 were completed that way with a resident as the lead surgeon or the first assist, Dr. Kesterson reported at the minimally invasive surgery week annual meeting and endo expo. There were nine conversions to open surgery in the entire group, for a 96% completion rate, said Dr. Kesterson, a gynecologic oncologist at Penn State Milton S. Hershey Medical Center, Hershey Pa.

Surgical training that embraces minimally invasive techniques is a pressing need, he said in an interview. Despite the ever-growing evidence that the technique is associated with decreased pain, fewer infections, fewer gastrointestinal complications, and a quicker return to normal activities, about 60% of hysterectomies are still open procedures.

"Residency training programs around the United States are consistent with that 60% abdominal hysterectomy rate," he said. Recent residency data indicate that the average surgical resident will complete 64 abdominal hysterectomies, 18 vaginal hysterectomies, and 23 laparoscopic hysterectomies during training.

In 2009, the division of minimally invasive surgery at the Hershey facility decided to place more emphasis on a minimally invasive approach to gynecologic surgery. At the meeting in Reston, Va., Dr. Kesterson reported the first full year of safety and surgical outcomes data for minimally invasive hysterectomy in the residency training program.

During 2010, residents acted as the lead surgeon or first assist on 537 hysterectomies for benign disease. Indications included abnormal bleeding, pelvic pain, fibroids, endometriosis, and prolapse/incontinence.

The patients were a mean of 45 years old, with a mean body mass index of 30 kg/m². The mean uterine size was 11 cm, and the mean uterine weight, 199 g. About a fourth (22%) of the patients had a prior cesarean section.

The majority of the surgeries (526, or 98%) were started with a minimally invasive approach; 18% of these were vaginal hysterectomies and the balance involved laparoscopic surgeries. Of these, 517 were completed as minimally invasive procedures, for a total minimally invasive completion rate of 96%.

There were nine conversions to open procedures. Conversions were due to a lack of visualization (1 case), abdominal adhesions (1), homeostasis (1), and repair of bowel (3) or urinary tract injury (3). There were 12 reoperations for cuff abscess or dehiscence.

The mean operative time was 86 minutes, with a range of 30-390 minutes. The mean blood loss was 95 cc, and the mean hospital stay, 1 day.

All of these surgical outcomes are comparable to those achieved by experienced gynecologic surgeons, which were reported in a 2010 Cochrane review. The review included 34 studies comprising 4,500 women who underwent minimally invasive hysterectomy for benign disease.

"Our operative time of 86 minutes compares favorably to the mean review time of 121 minutes. Our reported blood loss was 95 cc vs. 311 cc, and our hospital stay was 1 day vs. 3 days."

The urinary tract injury rate in Dr. Kesterson’s study was 1% compared with 3% in the Cochrane review, and the vaginal cuff infection rate was 2% vs. 4%.

Despite the results, which show that a residency training program can achieve outcomes similar to – or better than – those of experienced surgeons, the Hershey program remains "an outlier," Dr. Kesterson said at the meeting presented by the Society of Laparoendoscopic .Surgeons and affiliated societies.

"Even though a majority of surgeons would likely agree that minimally invasive surgery is associated with the least morbidity and mortality, it seems like it’s not being offered as often as it could be. I really don’t understand the hesitation at academic centers," especially when operative data are so compelling.

Surgeons who know how to perform these procedures will have a marketable skill and one that is likely to become even more in demand, Dr. Kesterson added.

"I counsel medical students to look for centers that have programs like this. Consumers have become much more educated and are taking a more active role in making decisions about their treatment. They would rather have a surgery with fewer complications and less scarring. I hope the tide is shifting on how we educate our surgeons."

Dr. Kesterson said he had no relevant financial disclosures.

[email protected]

A residency program that stresses minimally invasive hysterectomy as the preferred procedure for benign disease is a feasible undertaking, providing valuable surgeon experience and excellent patient outcomes, according to Dr. Joshua Kesterson.

Of 537 hysterectomies for benign disease performed in a single year at one such program, 526 (98%) were begun with a minimally invasive approach, and 517 were completed that way with a resident as the lead surgeon or the first assist, Dr. Kesterson reported at the minimally invasive surgery week annual meeting and endo expo. There were nine conversions to open surgery in the entire group, for a 96% completion rate, said Dr. Kesterson, a gynecologic oncologist at Penn State Milton S. Hershey Medical Center, Hershey Pa.

Surgical training that embraces minimally invasive techniques is a pressing need, he said in an interview. Despite the ever-growing evidence that the technique is associated with decreased pain, fewer infections, fewer gastrointestinal complications, and a quicker return to normal activities, about 60% of hysterectomies are still open procedures.

"Residency training programs around the United States are consistent with that 60% abdominal hysterectomy rate," he said. Recent residency data indicate that the average surgical resident will complete 64 abdominal hysterectomies, 18 vaginal hysterectomies, and 23 laparoscopic hysterectomies during training.

In 2009, the division of minimally invasive surgery at the Hershey facility decided to place more emphasis on a minimally invasive approach to gynecologic surgery. At the meeting in Reston, Va., Dr. Kesterson reported the first full year of safety and surgical outcomes data for minimally invasive hysterectomy in the residency training program.

During 2010, residents acted as the lead surgeon or first assist on 537 hysterectomies for benign disease. Indications included abnormal bleeding, pelvic pain, fibroids, endometriosis, and prolapse/incontinence.

The patients were a mean of 45 years old, with a mean body mass index of 30 kg/m². The mean uterine size was 11 cm, and the mean uterine weight, 199 g. About a fourth (22%) of the patients had a prior cesarean section.

The majority of the surgeries (526, or 98%) were started with a minimally invasive approach; 18% of these were vaginal hysterectomies and the balance involved laparoscopic surgeries. Of these, 517 were completed as minimally invasive procedures, for a total minimally invasive completion rate of 96%.

There were nine conversions to open procedures. Conversions were due to a lack of visualization (1 case), abdominal adhesions (1), homeostasis (1), and repair of bowel (3) or urinary tract injury (3). There were 12 reoperations for cuff abscess or dehiscence.

The mean operative time was 86 minutes, with a range of 30-390 minutes. The mean blood loss was 95 cc, and the mean hospital stay, 1 day.

All of these surgical outcomes are comparable to those achieved by experienced gynecologic surgeons, which were reported in a 2010 Cochrane review. The review included 34 studies comprising 4,500 women who underwent minimally invasive hysterectomy for benign disease.

"Our operative time of 86 minutes compares favorably to the mean review time of 121 minutes. Our reported blood loss was 95 cc vs. 311 cc, and our hospital stay was 1 day vs. 3 days."

The urinary tract injury rate in Dr. Kesterson’s study was 1% compared with 3% in the Cochrane review, and the vaginal cuff infection rate was 2% vs. 4%.

Despite the results, which show that a residency training program can achieve outcomes similar to – or better than – those of experienced surgeons, the Hershey program remains "an outlier," Dr. Kesterson said at the meeting presented by the Society of Laparoendoscopic .Surgeons and affiliated societies.

"Even though a majority of surgeons would likely agree that minimally invasive surgery is associated with the least morbidity and mortality, it seems like it’s not being offered as often as it could be. I really don’t understand the hesitation at academic centers," especially when operative data are so compelling.

Surgeons who know how to perform these procedures will have a marketable skill and one that is likely to become even more in demand, Dr. Kesterson added.

"I counsel medical students to look for centers that have programs like this. Consumers have become much more educated and are taking a more active role in making decisions about their treatment. They would rather have a surgery with fewer complications and less scarring. I hope the tide is shifting on how we educate our surgeons."

Dr. Kesterson said he had no relevant financial disclosures.

[email protected]

A residency program that stresses minimally invasive hysterectomy as the preferred procedure for benign disease is a feasible undertaking, providing valuable surgeon experience and excellent patient outcomes, according to Dr. Joshua Kesterson.

Of 537 hysterectomies for benign disease performed in a single year at one such program, 526 (98%) were begun with a minimally invasive approach, and 517 were completed that way with a resident as the lead surgeon or the first assist, Dr. Kesterson reported at the minimally invasive surgery week annual meeting and endo expo. There were nine conversions to open surgery in the entire group, for a 96% completion rate, said Dr. Kesterson, a gynecologic oncologist at Penn State Milton S. Hershey Medical Center, Hershey Pa.

Surgical training that embraces minimally invasive techniques is a pressing need, he said in an interview. Despite the ever-growing evidence that the technique is associated with decreased pain, fewer infections, fewer gastrointestinal complications, and a quicker return to normal activities, about 60% of hysterectomies are still open procedures.

"Residency training programs around the United States are consistent with that 60% abdominal hysterectomy rate," he said. Recent residency data indicate that the average surgical resident will complete 64 abdominal hysterectomies, 18 vaginal hysterectomies, and 23 laparoscopic hysterectomies during training.

In 2009, the division of minimally invasive surgery at the Hershey facility decided to place more emphasis on a minimally invasive approach to gynecologic surgery. At the meeting in Reston, Va., Dr. Kesterson reported the first full year of safety and surgical outcomes data for minimally invasive hysterectomy in the residency training program.

During 2010, residents acted as the lead surgeon or first assist on 537 hysterectomies for benign disease. Indications included abnormal bleeding, pelvic pain, fibroids, endometriosis, and prolapse/incontinence.

The patients were a mean of 45 years old, with a mean body mass index of 30 kg/m². The mean uterine size was 11 cm, and the mean uterine weight, 199 g. About a fourth (22%) of the patients had a prior cesarean section.

The majority of the surgeries (526, or 98%) were started with a minimally invasive approach; 18% of these were vaginal hysterectomies and the balance involved laparoscopic surgeries. Of these, 517 were completed as minimally invasive procedures, for a total minimally invasive completion rate of 96%.

There were nine conversions to open procedures. Conversions were due to a lack of visualization (1 case), abdominal adhesions (1), homeostasis (1), and repair of bowel (3) or urinary tract injury (3). There were 12 reoperations for cuff abscess or dehiscence.

The mean operative time was 86 minutes, with a range of 30-390 minutes. The mean blood loss was 95 cc, and the mean hospital stay, 1 day.

All of these surgical outcomes are comparable to those achieved by experienced gynecologic surgeons, which were reported in a 2010 Cochrane review. The review included 34 studies comprising 4,500 women who underwent minimally invasive hysterectomy for benign disease.

"Our operative time of 86 minutes compares favorably to the mean review time of 121 minutes. Our reported blood loss was 95 cc vs. 311 cc, and our hospital stay was 1 day vs. 3 days."

The urinary tract injury rate in Dr. Kesterson’s study was 1% compared with 3% in the Cochrane review, and the vaginal cuff infection rate was 2% vs. 4%.

Despite the results, which show that a residency training program can achieve outcomes similar to – or better than – those of experienced surgeons, the Hershey program remains "an outlier," Dr. Kesterson said at the meeting presented by the Society of Laparoendoscopic .Surgeons and affiliated societies.

"Even though a majority of surgeons would likely agree that minimally invasive surgery is associated with the least morbidity and mortality, it seems like it’s not being offered as often as it could be. I really don’t understand the hesitation at academic centers," especially when operative data are so compelling.

Surgeons who know how to perform these procedures will have a marketable skill and one that is likely to become even more in demand, Dr. Kesterson added.

"I counsel medical students to look for centers that have programs like this. Consumers have become much more educated and are taking a more active role in making decisions about their treatment. They would rather have a surgery with fewer complications and less scarring. I hope the tide is shifting on how we educate our surgeons."

Dr. Kesterson said he had no relevant financial disclosures.

[email protected]

Another acronym is working its way into the rheumatology office, but instead of representing just one more thing to which patients passively submit, PROMIS intends to make them active partners in both clinical assessment and treatment.

The Patient-Reported Outcomes Measurement Information System (PROMIS) was created by the National Institutes of Health in 2004 as way of integrating direct patient input into both clinical care and research. Now rheumatologists are validating PROMIS measures for use in rheumatic diseases for adults and children, and envision a time when the computerized health assessments will become a routine part of their care.

Cincinnati Children's Hospital Medical Center

"The insights we gain from PROMIS answers are often things that our standard patient interviews don’t elicit," said Dr. Morgan DeWitt, a pediatric rheumatologist at the Cincinnati Children’s Hospital Medical Center who’s validating some of the tool’s pediatric question banks. "It’s complementary to our history and physical – another way to get the information we need to better serve our patients."

PROMIS is a publicly available Web-based system that uses questions driven by computer adaptive technology to qualify patient descriptions of health status in a number of very specific physical and psychological domains, including several applicable to the rheumatologic illnesses: gastrointestinal health including symptoms, pain, fatigue, depression and anxiety, and physical function.

The banks are not disease-specific, but domain specific – a design that increases their clinical flexibility and carves out for them a space in research and clinical trials. In a paper published just last month describing PROMIS progress, Dr. DeWitt and her coauthors explained how important this is: "The domain-specific approach is based on the perspective that health attributes are not unique to a specific disease, although disorders may have characteristic profiles within domains. The creation of item banks that are not disease-specific permits the comparison of measurements across diseases. Such an approach allows an investigator to determine, for example, the impact of a new medication on fatigue for patients with chronic fatigue syndrome, multiple sclerosis, and cancer. Moreover, it allows for pragmatic research with patients with several diseases, measuring outcomes for domains regardless of specific disease contribution."

PROMIS leads patients through an adaptive response pattern, in which each question presented relies on the answer to the prior question. At the end of each series, the instrument provides a score, compared against normative U.S. population data.

PROMIS and similar outcome measures add an invaluable patient viewpoint to the usual history and physical exam that focuses on specific clinical characteristics, said Dr. Dinesh Khanna, director of the University of Michigan Scleroderma Program, Ann Arbor.

"Physicians tend to believe – whether rightly or wrongly – that our objective measurements are more appropriate and superior ways to measure patients’ disease severity response than the patient’s own subjective complaints. We may be interested in seeing changes in specific things, like joint swelling or tenderness, or an acute phase reactant. But the patient may be much more interested in getting pain and fatigue under control."

Tools like PROMIS encourage physicians to lock onto the problems that are really interfering with patients’ health-related quality of life at the time of each visit, Dr. Khanna said in an interview. "When the patient walks in, I can glance through the questions and their responses – especially the GI topics – and say ‘Okay, today your problem seems to be bloating and reflux, so let’s focus on that.’ I can get right to what is bothering the patient," rather than run through an entire exam or health assessment that might cover irrelevant items.

Unlike some other patient-reported assessments, which are static and need to be completed in their totality, such as the Health Assessment Questionnaire, PROMIS assessments can be tailored to hone in on issues that are specifically meaningful to a unique group of patients. Other assessments "ask a lot of general questions that might not be valid or pertain to that patient, or don’t provide you much insight into physical function, especially in a healthy individual," Dr. Khanna said. As an example, patients with scleroderma took just over a minute to complete each item bank providing information about their physical, mental, and social well-being.

Courtesy Dr. Dinesh Khanna

Unlike paper-and-pencil forms, PROMIS has the ability to be fully integrated into existing electronic health record systems. Computer technology teams at Dr. DeWitt’s institution created their own hybrid platform. But a leading EHR developer, Epic, has incorporated PRO libraries – including some of the PROMIS question banks – into its newest EHR software, she said. Physicians can also include their own patient-related outcomes measures if they desire.

Epic’s new system allows patients to access a patient portal section of the EHR in which they can complete their health surveys before an appointment; they can also access "events," which are upcoming surgeries, appointments, or time-bound clinical goals. The system sends patients e-mail reminders to complete their tasks.

The more targeted approach of PROMIS and other patient reported outcome measures translates into a more efficient visit, Dr. DeWitt said in an interview. "You are really limited in your time with each patient. There are only so many things you can ask. Patient report tools can pick up on things that a typical exam, even lab reports, might not reveal. Sometimes labs can come back normal, for instance, when a patient feels really ill."

PROMIS is just one of these types of tools. In fact, Dr. Khanna is the creator of another, the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument (GIT).

The GIT assesses how a patient’s gastrointestinal health affects functional, psychological, and social well-being. But unlike the GIT and other disease-specific outcome measures, PROMIS offers a large menu of question banks that interrogate a wealth of health issues. Each bank is separately and freely available, allowing clinicians to pick and choose the topics most relevant to their patients. Each bank can be used in its entirety, or in a short form. The pediatric banks are designed for children to self-assess, but there are also a number designed for adult proxies to complete. Most are also available as PDFs that can be used for paper/pencil data collection.

In addition to PROMIS, Dr. DeWitt uses a variety of health assessments, including the Childhood Health Assessment Questionnaire. But in general, those are most useful when patients have serious disabilities. "They pick those problems up well, but as function improves, it becomes harder to differentiate and to track subtle change."

PROMIS offers an improvement in that area, she believes. "I always use the review of systems with patients to identify health concerns. But patients also have problems and limitations that don’t routinely get asked about, and they can be surprising. Without a survey with meaningful items they can report on, you might not get all the information."

Also, she added, "Patient-reported outcomes are a quantifiable way of assessing health outcomes and tracing a patient’s progress over time."

Pain interference is a good example, she said. "You can get the patient to give you a pain intensity score of 0-10, but you don’t see what the impact of that is on their day-to-day functioning."

Ongoing validation studies continue to support and refine the PROMIS measures, Dr. Khanna said. Although PROMIS can be integrated into clinical practice, clinicians need to be able to translate the results into real life decision making. Just how that can be done isn’t yet completely clear.

"The question really is how do you interpret the results and then what do you do about it? This is a problem with any patient-reported outcome measure early in its development," he said. "If I take your blood pressure and it’s 150/90, I see this as an abnormal sign, and I know how to interpret it and what to do. But if you complete a patient report and your score is 40, compared with the normative score of 50 for the U.S. population norm, what does that mean? I know it’s bad, but how bad is it? When do I take action? I have no metric in my mind that corresponds to it."

Validation studies continue to address this, he said. He and his team will soon present their initial interpretation schema for four rheumatology-related question banks at the upcoming annual meeting of the American College of Rheumatology.

Rheumatologist focus groups at the University of Michigan reviewed a series of PROMIS reports completed by rheumatology patients, assessing physical function, pain intensity, fatigue, and depression. Based on the groups’ input, Dr. Khanna and his team adapted the PROMIS heat map, which has a unique, color-coded pictorial representation of how the scores could interact with clinical decision making.

Instead of just looking at raw scores, the group endorsed a "thermal map" in which the population norm is in the center, colored light green. As percentiles decrease, indicating better scores, the colors fade down through blue to dark purple. Increasing percentiles, indicating worsening scores, corresponded to ever-warmer colors, from yellow to orange to red.

A key point of the map is the baseline comparison, which doesn’t use the U.S. norm as the comparator, Dr. Khanna said. "We already know our patients are doing worse than the average person, so why do we want to compare them that way? We want to know how the patient compares with other patients with the same issues for clinical decision making and provide a reference point for discussion with the patient."

"These kinds of things are growing pains," he said. "It just takes some time to work them out. But the rheumatology community is making great strides to in incorporating these into clinical practice."

Both Dr. DeWitt and Dr. Khanna are investigators in studies developing PROMIS question banks for rheumatic diseases.

[email protected]

On Twitter @Alz_Gal

Another acronym is working its way into the rheumatology office, but instead of representing just one more thing to which patients passively submit, PROMIS intends to make them active partners in both clinical assessment and treatment.

The Patient-Reported Outcomes Measurement Information System (PROMIS) was created by the National Institutes of Health in 2004 as way of integrating direct patient input into both clinical care and research. Now rheumatologists are validating PROMIS measures for use in rheumatic diseases for adults and children, and envision a time when the computerized health assessments will become a routine part of their care.

Cincinnati Children's Hospital Medical Center

"The insights we gain from PROMIS answers are often things that our standard patient interviews don’t elicit," said Dr. Morgan DeWitt, a pediatric rheumatologist at the Cincinnati Children’s Hospital Medical Center who’s validating some of the tool’s pediatric question banks. "It’s complementary to our history and physical – another way to get the information we need to better serve our patients."

PROMIS is a publicly available Web-based system that uses questions driven by computer adaptive technology to qualify patient descriptions of health status in a number of very specific physical and psychological domains, including several applicable to the rheumatologic illnesses: gastrointestinal health including symptoms, pain, fatigue, depression and anxiety, and physical function.

The banks are not disease-specific, but domain specific – a design that increases their clinical flexibility and carves out for them a space in research and clinical trials. In a paper published just last month describing PROMIS progress, Dr. DeWitt and her coauthors explained how important this is: "The domain-specific approach is based on the perspective that health attributes are not unique to a specific disease, although disorders may have characteristic profiles within domains. The creation of item banks that are not disease-specific permits the comparison of measurements across diseases. Such an approach allows an investigator to determine, for example, the impact of a new medication on fatigue for patients with chronic fatigue syndrome, multiple sclerosis, and cancer. Moreover, it allows for pragmatic research with patients with several diseases, measuring outcomes for domains regardless of specific disease contribution."

PROMIS leads patients through an adaptive response pattern, in which each question presented relies on the answer to the prior question. At the end of each series, the instrument provides a score, compared against normative U.S. population data.

PROMIS and similar outcome measures add an invaluable patient viewpoint to the usual history and physical exam that focuses on specific clinical characteristics, said Dr. Dinesh Khanna, director of the University of Michigan Scleroderma Program, Ann Arbor.

"Physicians tend to believe – whether rightly or wrongly – that our objective measurements are more appropriate and superior ways to measure patients’ disease severity response than the patient’s own subjective complaints. We may be interested in seeing changes in specific things, like joint swelling or tenderness, or an acute phase reactant. But the patient may be much more interested in getting pain and fatigue under control."

Tools like PROMIS encourage physicians to lock onto the problems that are really interfering with patients’ health-related quality of life at the time of each visit, Dr. Khanna said in an interview. "When the patient walks in, I can glance through the questions and their responses – especially the GI topics – and say ‘Okay, today your problem seems to be bloating and reflux, so let’s focus on that.’ I can get right to what is bothering the patient," rather than run through an entire exam or health assessment that might cover irrelevant items.

Unlike some other patient-reported assessments, which are static and need to be completed in their totality, such as the Health Assessment Questionnaire, PROMIS assessments can be tailored to hone in on issues that are specifically meaningful to a unique group of patients. Other assessments "ask a lot of general questions that might not be valid or pertain to that patient, or don’t provide you much insight into physical function, especially in a healthy individual," Dr. Khanna said. As an example, patients with scleroderma took just over a minute to complete each item bank providing information about their physical, mental, and social well-being.

Courtesy Dr. Dinesh Khanna

Unlike paper-and-pencil forms, PROMIS has the ability to be fully integrated into existing electronic health record systems. Computer technology teams at Dr. DeWitt’s institution created their own hybrid platform. But a leading EHR developer, Epic, has incorporated PRO libraries – including some of the PROMIS question banks – into its newest EHR software, she said. Physicians can also include their own patient-related outcomes measures if they desire.

Epic’s new system allows patients to access a patient portal section of the EHR in which they can complete their health surveys before an appointment; they can also access "events," which are upcoming surgeries, appointments, or time-bound clinical goals. The system sends patients e-mail reminders to complete their tasks.

The more targeted approach of PROMIS and other patient reported outcome measures translates into a more efficient visit, Dr. DeWitt said in an interview. "You are really limited in your time with each patient. There are only so many things you can ask. Patient report tools can pick up on things that a typical exam, even lab reports, might not reveal. Sometimes labs can come back normal, for instance, when a patient feels really ill."

PROMIS is just one of these types of tools. In fact, Dr. Khanna is the creator of another, the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument (GIT).

The GIT assesses how a patient’s gastrointestinal health affects functional, psychological, and social well-being. But unlike the GIT and other disease-specific outcome measures, PROMIS offers a large menu of question banks that interrogate a wealth of health issues. Each bank is separately and freely available, allowing clinicians to pick and choose the topics most relevant to their patients. Each bank can be used in its entirety, or in a short form. The pediatric banks are designed for children to self-assess, but there are also a number designed for adult proxies to complete. Most are also available as PDFs that can be used for paper/pencil data collection.

In addition to PROMIS, Dr. DeWitt uses a variety of health assessments, including the Childhood Health Assessment Questionnaire. But in general, those are most useful when patients have serious disabilities. "They pick those problems up well, but as function improves, it becomes harder to differentiate and to track subtle change."

PROMIS offers an improvement in that area, she believes. "I always use the review of systems with patients to identify health concerns. But patients also have problems and limitations that don’t routinely get asked about, and they can be surprising. Without a survey with meaningful items they can report on, you might not get all the information."

Also, she added, "Patient-reported outcomes are a quantifiable way of assessing health outcomes and tracing a patient’s progress over time."

Pain interference is a good example, she said. "You can get the patient to give you a pain intensity score of 0-10, but you don’t see what the impact of that is on their day-to-day functioning."

Ongoing validation studies continue to support and refine the PROMIS measures, Dr. Khanna said. Although PROMIS can be integrated into clinical practice, clinicians need to be able to translate the results into real life decision making. Just how that can be done isn’t yet completely clear.

"The question really is how do you interpret the results and then what do you do about it? This is a problem with any patient-reported outcome measure early in its development," he said. "If I take your blood pressure and it’s 150/90, I see this as an abnormal sign, and I know how to interpret it and what to do. But if you complete a patient report and your score is 40, compared with the normative score of 50 for the U.S. population norm, what does that mean? I know it’s bad, but how bad is it? When do I take action? I have no metric in my mind that corresponds to it."

Validation studies continue to address this, he said. He and his team will soon present their initial interpretation schema for four rheumatology-related question banks at the upcoming annual meeting of the American College of Rheumatology.

Rheumatologist focus groups at the University of Michigan reviewed a series of PROMIS reports completed by rheumatology patients, assessing physical function, pain intensity, fatigue, and depression. Based on the groups’ input, Dr. Khanna and his team adapted the PROMIS heat map, which has a unique, color-coded pictorial representation of how the scores could interact with clinical decision making.

Instead of just looking at raw scores, the group endorsed a "thermal map" in which the population norm is in the center, colored light green. As percentiles decrease, indicating better scores, the colors fade down through blue to dark purple. Increasing percentiles, indicating worsening scores, corresponded to ever-warmer colors, from yellow to orange to red.

A key point of the map is the baseline comparison, which doesn’t use the U.S. norm as the comparator, Dr. Khanna said. "We already know our patients are doing worse than the average person, so why do we want to compare them that way? We want to know how the patient compares with other patients with the same issues for clinical decision making and provide a reference point for discussion with the patient."

"These kinds of things are growing pains," he said. "It just takes some time to work them out. But the rheumatology community is making great strides to in incorporating these into clinical practice."

Both Dr. DeWitt and Dr. Khanna are investigators in studies developing PROMIS question banks for rheumatic diseases.

[email protected]

On Twitter @Alz_Gal

Another acronym is working its way into the rheumatology office, but instead of representing just one more thing to which patients passively submit, PROMIS intends to make them active partners in both clinical assessment and treatment.

The Patient-Reported Outcomes Measurement Information System (PROMIS) was created by the National Institutes of Health in 2004 as way of integrating direct patient input into both clinical care and research. Now rheumatologists are validating PROMIS measures for use in rheumatic diseases for adults and children, and envision a time when the computerized health assessments will become a routine part of their care.

Cincinnati Children's Hospital Medical Center

"The insights we gain from PROMIS answers are often things that our standard patient interviews don’t elicit," said Dr. Morgan DeWitt, a pediatric rheumatologist at the Cincinnati Children’s Hospital Medical Center who’s validating some of the tool’s pediatric question banks. "It’s complementary to our history and physical – another way to get the information we need to better serve our patients."

PROMIS is a publicly available Web-based system that uses questions driven by computer adaptive technology to qualify patient descriptions of health status in a number of very specific physical and psychological domains, including several applicable to the rheumatologic illnesses: gastrointestinal health including symptoms, pain, fatigue, depression and anxiety, and physical function.

The banks are not disease-specific, but domain specific – a design that increases their clinical flexibility and carves out for them a space in research and clinical trials. In a paper published just last month describing PROMIS progress, Dr. DeWitt and her coauthors explained how important this is: "The domain-specific approach is based on the perspective that health attributes are not unique to a specific disease, although disorders may have characteristic profiles within domains. The creation of item banks that are not disease-specific permits the comparison of measurements across diseases. Such an approach allows an investigator to determine, for example, the impact of a new medication on fatigue for patients with chronic fatigue syndrome, multiple sclerosis, and cancer. Moreover, it allows for pragmatic research with patients with several diseases, measuring outcomes for domains regardless of specific disease contribution."

PROMIS leads patients through an adaptive response pattern, in which each question presented relies on the answer to the prior question. At the end of each series, the instrument provides a score, compared against normative U.S. population data.

PROMIS and similar outcome measures add an invaluable patient viewpoint to the usual history and physical exam that focuses on specific clinical characteristics, said Dr. Dinesh Khanna, director of the University of Michigan Scleroderma Program, Ann Arbor.

"Physicians tend to believe – whether rightly or wrongly – that our objective measurements are more appropriate and superior ways to measure patients’ disease severity response than the patient’s own subjective complaints. We may be interested in seeing changes in specific things, like joint swelling or tenderness, or an acute phase reactant. But the patient may be much more interested in getting pain and fatigue under control."

Tools like PROMIS encourage physicians to lock onto the problems that are really interfering with patients’ health-related quality of life at the time of each visit, Dr. Khanna said in an interview. "When the patient walks in, I can glance through the questions and their responses – especially the GI topics – and say ‘Okay, today your problem seems to be bloating and reflux, so let’s focus on that.’ I can get right to what is bothering the patient," rather than run through an entire exam or health assessment that might cover irrelevant items.

Unlike some other patient-reported assessments, which are static and need to be completed in their totality, such as the Health Assessment Questionnaire, PROMIS assessments can be tailored to hone in on issues that are specifically meaningful to a unique group of patients. Other assessments "ask a lot of general questions that might not be valid or pertain to that patient, or don’t provide you much insight into physical function, especially in a healthy individual," Dr. Khanna said. As an example, patients with scleroderma took just over a minute to complete each item bank providing information about their physical, mental, and social well-being.

Courtesy Dr. Dinesh Khanna

Unlike paper-and-pencil forms, PROMIS has the ability to be fully integrated into existing electronic health record systems. Computer technology teams at Dr. DeWitt’s institution created their own hybrid platform. But a leading EHR developer, Epic, has incorporated PRO libraries – including some of the PROMIS question banks – into its newest EHR software, she said. Physicians can also include their own patient-related outcomes measures if they desire.

Epic’s new system allows patients to access a patient portal section of the EHR in which they can complete their health surveys before an appointment; they can also access "events," which are upcoming surgeries, appointments, or time-bound clinical goals. The system sends patients e-mail reminders to complete their tasks.

The more targeted approach of PROMIS and other patient reported outcome measures translates into a more efficient visit, Dr. DeWitt said in an interview. "You are really limited in your time with each patient. There are only so many things you can ask. Patient report tools can pick up on things that a typical exam, even lab reports, might not reveal. Sometimes labs can come back normal, for instance, when a patient feels really ill."

PROMIS is just one of these types of tools. In fact, Dr. Khanna is the creator of another, the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument (GIT).

The GIT assesses how a patient’s gastrointestinal health affects functional, psychological, and social well-being. But unlike the GIT and other disease-specific outcome measures, PROMIS offers a large menu of question banks that interrogate a wealth of health issues. Each bank is separately and freely available, allowing clinicians to pick and choose the topics most relevant to their patients. Each bank can be used in its entirety, or in a short form. The pediatric banks are designed for children to self-assess, but there are also a number designed for adult proxies to complete. Most are also available as PDFs that can be used for paper/pencil data collection.

In addition to PROMIS, Dr. DeWitt uses a variety of health assessments, including the Childhood Health Assessment Questionnaire. But in general, those are most useful when patients have serious disabilities. "They pick those problems up well, but as function improves, it becomes harder to differentiate and to track subtle change."

PROMIS offers an improvement in that area, she believes. "I always use the review of systems with patients to identify health concerns. But patients also have problems and limitations that don’t routinely get asked about, and they can be surprising. Without a survey with meaningful items they can report on, you might not get all the information."

Also, she added, "Patient-reported outcomes are a quantifiable way of assessing health outcomes and tracing a patient’s progress over time."

Pain interference is a good example, she said. "You can get the patient to give you a pain intensity score of 0-10, but you don’t see what the impact of that is on their day-to-day functioning."

Ongoing validation studies continue to support and refine the PROMIS measures, Dr. Khanna said. Although PROMIS can be integrated into clinical practice, clinicians need to be able to translate the results into real life decision making. Just how that can be done isn’t yet completely clear.

"The question really is how do you interpret the results and then what do you do about it? This is a problem with any patient-reported outcome measure early in its development," he said. "If I take your blood pressure and it’s 150/90, I see this as an abnormal sign, and I know how to interpret it and what to do. But if you complete a patient report and your score is 40, compared with the normative score of 50 for the U.S. population norm, what does that mean? I know it’s bad, but how bad is it? When do I take action? I have no metric in my mind that corresponds to it."

Validation studies continue to address this, he said. He and his team will soon present their initial interpretation schema for four rheumatology-related question banks at the upcoming annual meeting of the American College of Rheumatology.

Rheumatologist focus groups at the University of Michigan reviewed a series of PROMIS reports completed by rheumatology patients, assessing physical function, pain intensity, fatigue, and depression. Based on the groups’ input, Dr. Khanna and his team adapted the PROMIS heat map, which has a unique, color-coded pictorial representation of how the scores could interact with clinical decision making.

Instead of just looking at raw scores, the group endorsed a "thermal map" in which the population norm is in the center, colored light green. As percentiles decrease, indicating better scores, the colors fade down through blue to dark purple. Increasing percentiles, indicating worsening scores, corresponded to ever-warmer colors, from yellow to orange to red.

A key point of the map is the baseline comparison, which doesn’t use the U.S. norm as the comparator, Dr. Khanna said. "We already know our patients are doing worse than the average person, so why do we want to compare them that way? We want to know how the patient compares with other patients with the same issues for clinical decision making and provide a reference point for discussion with the patient."

"These kinds of things are growing pains," he said. "It just takes some time to work them out. But the rheumatology community is making great strides to in incorporating these into clinical practice."

Both Dr. DeWitt and Dr. Khanna are investigators in studies developing PROMIS question banks for rheumatic diseases.

[email protected]

On Twitter @Alz_Gal