Drug Combo in New-onset Diabetes

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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.

msullivan@frontlinemedcom.com

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.

msullivan@frontlinemedcom.com

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.

msullivan@frontlinemedcom.com