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European Association for the Study of Diabetes (EASD): Annual Meeting
Large U.K. database shows sulfonylurea mortality link
BARCELONA – Treatment of type 2 diabetes with a sulfonylurea drug was tied to a significantly increased risk of death in two large U.K. epidemiology studies with a total of more than 100,000 patients.
These and other recent findings that raised questions about the safety and efficacy of sulfonylurea drugs for type 2 diabetes highlight the need for regulatory reassessment of the sulfonylurea drug class, Craig J. Currie, Ph.D., said at the annual meeting of the European Association for the Study of Diabetes.
"The safety of sulfonylureas needs urgent evaluation," said Dr. Currie, professor of applied pharmacoepidemiology at Cardiff (Wales) University. "Regulatory agencies have to take this seriously." He noted that current U.K. recommendations from the U.K. National Institute for Health and Care Excellence (NICE) cite sulfonylurea drugs as the top second-line drug treatment for patients with type 2 diabetes if monotherapy with metformin fails. Last year, management guidelines from the American Diabetes Association and the EASD listed sulfonylurea drugs as candidate second-line agents after metformin along with several other drug classes (Diabetes Care 2012;35:1364-79).
But others cautioned of the risk for unrecognized confounding when using observational data to gauge drug safety. "I’m not sure they can get rid of all the confounders; the patients [treated with a sulfonylurea] may just be fundamentally different. In most clinical trials we did not see harm" from sulfonylureas, commented Dean T. Eurich, Ph.D., a pharmacoepidemiologist at the University of Alberta in Edmonton.
Both studies reported by Dr. Currie and his associates used data collected by the Clinical Practice Research Datalink , an observational database of the U.K. National Health Service that routinely collects data from a representative sample of British patients. In one study, they focused on patients who began initial therapy for type 2 diabetes during 2000-2012 with metformin monotherapy, 76,811 patients, or sulfonylurea monotherapy, 15.687 patients. During an average 3-year follow-up, the all-cause mortality rate was roughly 14 deaths/1,000 patient-years for those on metformin, and about 45/1,000 patient-years for those on a sulfonylurea. After adjustment for many potential confounders, including age, sex, body mass index, duration of diabetes, serum creatinine, and hemoglobin A1c level, the analysis found a relative 58% increased risk for death in the sulfonylurea patients compared with those taking metformin, a statistically significant difference, reported Christopher L. Morgan, a researcher at Cardiff University.
The second study compared patients who began a two-drug combination regimen during 2007-2013, comprising 33,983 patients who began metformin plus a sulfonylurea and 7,864 who began metformin plus a dipeptidyl peptidase-4 inhibitor. The adjusted rate of all-cause mortality was a relative 36% higher among patients treated with a sulfonylurea, compared with those treated with a DPP-4 inhibitor, Dr. Currie reported.
Metformin plus a sulfonylurea is the most commonly used drug combination for treating type 2 diabetes worldwide, Dr. Currie noted.
He speculated that sulfonylureas may boost mortality by increasing insulin levels and thereby causing more episodes of severe hypoglycemia than other oral diabetes drugs.
The study was funded by Astra Zeneca and Bristol-Myers Squibb. Dr. Currie said he owns a drug-assessment company that has done work for several drug companies. Mr. Morgan and Dr. Eurich said they had no relevant financial disclosures.
On Twitter @mitchelzoler
Results from clinical trials that included patients treated with sulfonylurea drugs have not shown evidence of harm from these drugs. Major trials such as ACCORD, ADVANCE, and UKPDS ran subgroup analyses to try to look at whether certain drugs seemed to drive poor outcomes, and nothing has been reported for sulfonylureas.
In contrast, observational studies like the ones reported by Dr. Currie and Mr. Morgan have shown links between sulfonylurea treatment and worse outcomes, but these analyses face the problem that physicians prescribe various diabetes drugs to very different groups of patients. We can use fancy statistical models to try to adjust for this, but it’s not clear that they adjust for all possible confounding factors.
For example, one of the big differences between sulfonylureas and other possible second-line drugs that patients might get is cost. So socioeconomic differences might exist between the patients who received a sulfonylurea and those who received a DPP-4 inhibitor that were not included in the adjustments. Many factors enter into the decision for a physician to prescribe one drug or another.
A major limitation of the sulfonylurea drugs is that they have never been the subject of a large, well-designed study to test their cardiovascular safety, such as the studies begun a few years ago for several newer drugs following suggestions of a problem with rosiglitazone. One problem we know for certain about sulfonylureas is that they pose more of a risk for causing hypoglycemic events than do other oral drugs, and there is increasing evidence that severe hypoglycemic events can affect the rates of cardiovascular outcomes. There is also good evidence that the glycemic control exerted by sulfonylureas is not as durable as that of other drugs, and they also cause weight gain, so for several reasons, the sulfonylurea class is gradually being bypassed in favor of other options.
However, many of the alternative agents have their own limitations, especially higher cost. Clinicians need to weigh the suggestions of harm caused by sulfonylurea drugs against their better affordability. If patients can’t afford their diabetes medications, they won’t take them, and undertreated diabetes may pose an even greater risk.
Much more definitive data on the efficacy and safety of sulfonylurea drugs should come from the Cardiovascular Outcome Study of Linagliptin versus Glimeprimide in Patients With Type 2 Diabetes (CAROLINA). These results should be the make or break for sulfonylureas, but data from this study are not expected until 2018.
Dean T. Eurich, Ph.D., is a pharmacoepidemiologist at the University of Alberta in Edmonton. He made these comments in an interview. He said he had no relevant financial disclosures.
Results from clinical trials that included patients treated with sulfonylurea drugs have not shown evidence of harm from these drugs. Major trials such as ACCORD, ADVANCE, and UKPDS ran subgroup analyses to try to look at whether certain drugs seemed to drive poor outcomes, and nothing has been reported for sulfonylureas.
In contrast, observational studies like the ones reported by Dr. Currie and Mr. Morgan have shown links between sulfonylurea treatment and worse outcomes, but these analyses face the problem that physicians prescribe various diabetes drugs to very different groups of patients. We can use fancy statistical models to try to adjust for this, but it’s not clear that they adjust for all possible confounding factors.
For example, one of the big differences between sulfonylureas and other possible second-line drugs that patients might get is cost. So socioeconomic differences might exist between the patients who received a sulfonylurea and those who received a DPP-4 inhibitor that were not included in the adjustments. Many factors enter into the decision for a physician to prescribe one drug or another.
A major limitation of the sulfonylurea drugs is that they have never been the subject of a large, well-designed study to test their cardiovascular safety, such as the studies begun a few years ago for several newer drugs following suggestions of a problem with rosiglitazone. One problem we know for certain about sulfonylureas is that they pose more of a risk for causing hypoglycemic events than do other oral drugs, and there is increasing evidence that severe hypoglycemic events can affect the rates of cardiovascular outcomes. There is also good evidence that the glycemic control exerted by sulfonylureas is not as durable as that of other drugs, and they also cause weight gain, so for several reasons, the sulfonylurea class is gradually being bypassed in favor of other options.
However, many of the alternative agents have their own limitations, especially higher cost. Clinicians need to weigh the suggestions of harm caused by sulfonylurea drugs against their better affordability. If patients can’t afford their diabetes medications, they won’t take them, and undertreated diabetes may pose an even greater risk.
Much more definitive data on the efficacy and safety of sulfonylurea drugs should come from the Cardiovascular Outcome Study of Linagliptin versus Glimeprimide in Patients With Type 2 Diabetes (CAROLINA). These results should be the make or break for sulfonylureas, but data from this study are not expected until 2018.
Dean T. Eurich, Ph.D., is a pharmacoepidemiologist at the University of Alberta in Edmonton. He made these comments in an interview. He said he had no relevant financial disclosures.
Results from clinical trials that included patients treated with sulfonylurea drugs have not shown evidence of harm from these drugs. Major trials such as ACCORD, ADVANCE, and UKPDS ran subgroup analyses to try to look at whether certain drugs seemed to drive poor outcomes, and nothing has been reported for sulfonylureas.
In contrast, observational studies like the ones reported by Dr. Currie and Mr. Morgan have shown links between sulfonylurea treatment and worse outcomes, but these analyses face the problem that physicians prescribe various diabetes drugs to very different groups of patients. We can use fancy statistical models to try to adjust for this, but it’s not clear that they adjust for all possible confounding factors.
For example, one of the big differences between sulfonylureas and other possible second-line drugs that patients might get is cost. So socioeconomic differences might exist between the patients who received a sulfonylurea and those who received a DPP-4 inhibitor that were not included in the adjustments. Many factors enter into the decision for a physician to prescribe one drug or another.
A major limitation of the sulfonylurea drugs is that they have never been the subject of a large, well-designed study to test their cardiovascular safety, such as the studies begun a few years ago for several newer drugs following suggestions of a problem with rosiglitazone. One problem we know for certain about sulfonylureas is that they pose more of a risk for causing hypoglycemic events than do other oral drugs, and there is increasing evidence that severe hypoglycemic events can affect the rates of cardiovascular outcomes. There is also good evidence that the glycemic control exerted by sulfonylureas is not as durable as that of other drugs, and they also cause weight gain, so for several reasons, the sulfonylurea class is gradually being bypassed in favor of other options.
However, many of the alternative agents have their own limitations, especially higher cost. Clinicians need to weigh the suggestions of harm caused by sulfonylurea drugs against their better affordability. If patients can’t afford their diabetes medications, they won’t take them, and undertreated diabetes may pose an even greater risk.
Much more definitive data on the efficacy and safety of sulfonylurea drugs should come from the Cardiovascular Outcome Study of Linagliptin versus Glimeprimide in Patients With Type 2 Diabetes (CAROLINA). These results should be the make or break for sulfonylureas, but data from this study are not expected until 2018.
Dean T. Eurich, Ph.D., is a pharmacoepidemiologist at the University of Alberta in Edmonton. He made these comments in an interview. He said he had no relevant financial disclosures.
BARCELONA – Treatment of type 2 diabetes with a sulfonylurea drug was tied to a significantly increased risk of death in two large U.K. epidemiology studies with a total of more than 100,000 patients.
These and other recent findings that raised questions about the safety and efficacy of sulfonylurea drugs for type 2 diabetes highlight the need for regulatory reassessment of the sulfonylurea drug class, Craig J. Currie, Ph.D., said at the annual meeting of the European Association for the Study of Diabetes.
"The safety of sulfonylureas needs urgent evaluation," said Dr. Currie, professor of applied pharmacoepidemiology at Cardiff (Wales) University. "Regulatory agencies have to take this seriously." He noted that current U.K. recommendations from the U.K. National Institute for Health and Care Excellence (NICE) cite sulfonylurea drugs as the top second-line drug treatment for patients with type 2 diabetes if monotherapy with metformin fails. Last year, management guidelines from the American Diabetes Association and the EASD listed sulfonylurea drugs as candidate second-line agents after metformin along with several other drug classes (Diabetes Care 2012;35:1364-79).
But others cautioned of the risk for unrecognized confounding when using observational data to gauge drug safety. "I’m not sure they can get rid of all the confounders; the patients [treated with a sulfonylurea] may just be fundamentally different. In most clinical trials we did not see harm" from sulfonylureas, commented Dean T. Eurich, Ph.D., a pharmacoepidemiologist at the University of Alberta in Edmonton.
Both studies reported by Dr. Currie and his associates used data collected by the Clinical Practice Research Datalink , an observational database of the U.K. National Health Service that routinely collects data from a representative sample of British patients. In one study, they focused on patients who began initial therapy for type 2 diabetes during 2000-2012 with metformin monotherapy, 76,811 patients, or sulfonylurea monotherapy, 15.687 patients. During an average 3-year follow-up, the all-cause mortality rate was roughly 14 deaths/1,000 patient-years for those on metformin, and about 45/1,000 patient-years for those on a sulfonylurea. After adjustment for many potential confounders, including age, sex, body mass index, duration of diabetes, serum creatinine, and hemoglobin A1c level, the analysis found a relative 58% increased risk for death in the sulfonylurea patients compared with those taking metformin, a statistically significant difference, reported Christopher L. Morgan, a researcher at Cardiff University.
The second study compared patients who began a two-drug combination regimen during 2007-2013, comprising 33,983 patients who began metformin plus a sulfonylurea and 7,864 who began metformin plus a dipeptidyl peptidase-4 inhibitor. The adjusted rate of all-cause mortality was a relative 36% higher among patients treated with a sulfonylurea, compared with those treated with a DPP-4 inhibitor, Dr. Currie reported.
Metformin plus a sulfonylurea is the most commonly used drug combination for treating type 2 diabetes worldwide, Dr. Currie noted.
He speculated that sulfonylureas may boost mortality by increasing insulin levels and thereby causing more episodes of severe hypoglycemia than other oral diabetes drugs.
The study was funded by Astra Zeneca and Bristol-Myers Squibb. Dr. Currie said he owns a drug-assessment company that has done work for several drug companies. Mr. Morgan and Dr. Eurich said they had no relevant financial disclosures.
On Twitter @mitchelzoler
BARCELONA – Treatment of type 2 diabetes with a sulfonylurea drug was tied to a significantly increased risk of death in two large U.K. epidemiology studies with a total of more than 100,000 patients.
These and other recent findings that raised questions about the safety and efficacy of sulfonylurea drugs for type 2 diabetes highlight the need for regulatory reassessment of the sulfonylurea drug class, Craig J. Currie, Ph.D., said at the annual meeting of the European Association for the Study of Diabetes.
"The safety of sulfonylureas needs urgent evaluation," said Dr. Currie, professor of applied pharmacoepidemiology at Cardiff (Wales) University. "Regulatory agencies have to take this seriously." He noted that current U.K. recommendations from the U.K. National Institute for Health and Care Excellence (NICE) cite sulfonylurea drugs as the top second-line drug treatment for patients with type 2 diabetes if monotherapy with metformin fails. Last year, management guidelines from the American Diabetes Association and the EASD listed sulfonylurea drugs as candidate second-line agents after metformin along with several other drug classes (Diabetes Care 2012;35:1364-79).
But others cautioned of the risk for unrecognized confounding when using observational data to gauge drug safety. "I’m not sure they can get rid of all the confounders; the patients [treated with a sulfonylurea] may just be fundamentally different. In most clinical trials we did not see harm" from sulfonylureas, commented Dean T. Eurich, Ph.D., a pharmacoepidemiologist at the University of Alberta in Edmonton.
Both studies reported by Dr. Currie and his associates used data collected by the Clinical Practice Research Datalink , an observational database of the U.K. National Health Service that routinely collects data from a representative sample of British patients. In one study, they focused on patients who began initial therapy for type 2 diabetes during 2000-2012 with metformin monotherapy, 76,811 patients, or sulfonylurea monotherapy, 15.687 patients. During an average 3-year follow-up, the all-cause mortality rate was roughly 14 deaths/1,000 patient-years for those on metformin, and about 45/1,000 patient-years for those on a sulfonylurea. After adjustment for many potential confounders, including age, sex, body mass index, duration of diabetes, serum creatinine, and hemoglobin A1c level, the analysis found a relative 58% increased risk for death in the sulfonylurea patients compared with those taking metformin, a statistically significant difference, reported Christopher L. Morgan, a researcher at Cardiff University.
The second study compared patients who began a two-drug combination regimen during 2007-2013, comprising 33,983 patients who began metformin plus a sulfonylurea and 7,864 who began metformin plus a dipeptidyl peptidase-4 inhibitor. The adjusted rate of all-cause mortality was a relative 36% higher among patients treated with a sulfonylurea, compared with those treated with a DPP-4 inhibitor, Dr. Currie reported.
Metformin plus a sulfonylurea is the most commonly used drug combination for treating type 2 diabetes worldwide, Dr. Currie noted.
He speculated that sulfonylureas may boost mortality by increasing insulin levels and thereby causing more episodes of severe hypoglycemia than other oral diabetes drugs.
The study was funded by Astra Zeneca and Bristol-Myers Squibb. Dr. Currie said he owns a drug-assessment company that has done work for several drug companies. Mr. Morgan and Dr. Eurich said they had no relevant financial disclosures.
On Twitter @mitchelzoler
AT THE EASD ANNUAL MEETING
Major finding: Type 2 diabetes monotherapy with sulfonylurea was linked with 58% higher mortality, compared with metformin monotherapy, during a mean 3-year follow-up.
Data source: A review of 92,498 U.K. patients who started treatment for type 2 diabetes with either metformin or sulfonylurea monotherapy during 2000-2012.
Disclosures: The study was funded by Astra Zeneca and Bristol-Myers Squibb. Dr. Currie said he owns a drug-consultant company that has done work for several drug companies. Mr. Morgan and Dr. Eurich said they had no relevant financial disclosures.
Whither sulfonylureas?
For sulfonylureas, the hits keep coming, but so far they remain standing.
I’ve run into several diabetes experts over the past few weeks who touted the apparent downside of using a sulfonylurea drug such as glipizide for treating patients with type 2 diabetes. For several years now, conventional wisdom has regarded sulfonylureas as the second-line oral agent – because of their efficacy, long track record, and availability as low-cost generics – to use after metformin for patients with type 2 diabetes who need drug treatment for hyperglycemia.
But in September, at the European Society of Cardiology Congress, Swedish cardiologist Dr. Lars Rydén and British diabetologist Dr. Peter Grant both spoke to me with concern about the clinical consequences of the hypoglycemia episodes triggered by sulfonylureas.
A few weeks later, at the Congress of the European Association for the Study of Diabetes, British pharmacoepidemiologist Craig Currie and his associates presented observational data from well over 100,000 British residents who received oral drug treatment for type 2 diabetes and showed a statistically significant, roughly 50% boost in all-cause mortality over the course of 3 years in those treated with a sulfonylurea, compared with other oral drugs.
In addition to calling for an "urgent" reassessment of the safety of sulfonylureas, Prof. Currie said that he considers pioglitazone, available as a U.S. generic since last year, the most attractive oral drug option following metformin on the basis of its safety record, efficacy, and affordability.
But others are not so quick to pull the plug on sulfonylureas. I posed the question at EASD to Dr. Michael Nauck, a German diabetes expert, who cited the good safety and efficacy performance of sulfonylureas in big trials such as the UKPDS, and said that a decision on the drug class will need to wait until data are available from the CAROLINA trial, which is comparing the sulfonylurea glimepiride and the DPP4 inhibitor linagliptin in about 6,000 patients at more than 600 worldwide centers. Unfortunately those data are not expected for another 5 years. The researchers who designed the CAROLINA trial have said that they see this study as a major test of the cardiovascular safety of sulfonylurea drugs.
In addition to no signals of harm in big trials, the observational data that have tarred the sulfonylurea class, like the findings Prof. Currie reported, are vulnerable to unidentified biases from confounding factors, Canadian pharmacoepidemiologist Dean Eurich told me at EASD. Despite that, Dr. Eurich agreed that sentiment today is running against the sulfonylureas, which also usually cause weight gain and show a decline in their glycemic benefit over time. Plus, he underscored the clear risk that sulfonylurea treatment poses for causing hypoglycemia. "I think the trend is not to use sulfonylureas as much," he told me.
On Twitter @mitchelzoler
For sulfonylureas, the hits keep coming, but so far they remain standing.
I’ve run into several diabetes experts over the past few weeks who touted the apparent downside of using a sulfonylurea drug such as glipizide for treating patients with type 2 diabetes. For several years now, conventional wisdom has regarded sulfonylureas as the second-line oral agent – because of their efficacy, long track record, and availability as low-cost generics – to use after metformin for patients with type 2 diabetes who need drug treatment for hyperglycemia.
But in September, at the European Society of Cardiology Congress, Swedish cardiologist Dr. Lars Rydén and British diabetologist Dr. Peter Grant both spoke to me with concern about the clinical consequences of the hypoglycemia episodes triggered by sulfonylureas.
A few weeks later, at the Congress of the European Association for the Study of Diabetes, British pharmacoepidemiologist Craig Currie and his associates presented observational data from well over 100,000 British residents who received oral drug treatment for type 2 diabetes and showed a statistically significant, roughly 50% boost in all-cause mortality over the course of 3 years in those treated with a sulfonylurea, compared with other oral drugs.
In addition to calling for an "urgent" reassessment of the safety of sulfonylureas, Prof. Currie said that he considers pioglitazone, available as a U.S. generic since last year, the most attractive oral drug option following metformin on the basis of its safety record, efficacy, and affordability.
But others are not so quick to pull the plug on sulfonylureas. I posed the question at EASD to Dr. Michael Nauck, a German diabetes expert, who cited the good safety and efficacy performance of sulfonylureas in big trials such as the UKPDS, and said that a decision on the drug class will need to wait until data are available from the CAROLINA trial, which is comparing the sulfonylurea glimepiride and the DPP4 inhibitor linagliptin in about 6,000 patients at more than 600 worldwide centers. Unfortunately those data are not expected for another 5 years. The researchers who designed the CAROLINA trial have said that they see this study as a major test of the cardiovascular safety of sulfonylurea drugs.
In addition to no signals of harm in big trials, the observational data that have tarred the sulfonylurea class, like the findings Prof. Currie reported, are vulnerable to unidentified biases from confounding factors, Canadian pharmacoepidemiologist Dean Eurich told me at EASD. Despite that, Dr. Eurich agreed that sentiment today is running against the sulfonylureas, which also usually cause weight gain and show a decline in their glycemic benefit over time. Plus, he underscored the clear risk that sulfonylurea treatment poses for causing hypoglycemia. "I think the trend is not to use sulfonylureas as much," he told me.
On Twitter @mitchelzoler
For sulfonylureas, the hits keep coming, but so far they remain standing.
I’ve run into several diabetes experts over the past few weeks who touted the apparent downside of using a sulfonylurea drug such as glipizide for treating patients with type 2 diabetes. For several years now, conventional wisdom has regarded sulfonylureas as the second-line oral agent – because of their efficacy, long track record, and availability as low-cost generics – to use after metformin for patients with type 2 diabetes who need drug treatment for hyperglycemia.
But in September, at the European Society of Cardiology Congress, Swedish cardiologist Dr. Lars Rydén and British diabetologist Dr. Peter Grant both spoke to me with concern about the clinical consequences of the hypoglycemia episodes triggered by sulfonylureas.
A few weeks later, at the Congress of the European Association for the Study of Diabetes, British pharmacoepidemiologist Craig Currie and his associates presented observational data from well over 100,000 British residents who received oral drug treatment for type 2 diabetes and showed a statistically significant, roughly 50% boost in all-cause mortality over the course of 3 years in those treated with a sulfonylurea, compared with other oral drugs.
In addition to calling for an "urgent" reassessment of the safety of sulfonylureas, Prof. Currie said that he considers pioglitazone, available as a U.S. generic since last year, the most attractive oral drug option following metformin on the basis of its safety record, efficacy, and affordability.
But others are not so quick to pull the plug on sulfonylureas. I posed the question at EASD to Dr. Michael Nauck, a German diabetes expert, who cited the good safety and efficacy performance of sulfonylureas in big trials such as the UKPDS, and said that a decision on the drug class will need to wait until data are available from the CAROLINA trial, which is comparing the sulfonylurea glimepiride and the DPP4 inhibitor linagliptin in about 6,000 patients at more than 600 worldwide centers. Unfortunately those data are not expected for another 5 years. The researchers who designed the CAROLINA trial have said that they see this study as a major test of the cardiovascular safety of sulfonylurea drugs.
In addition to no signals of harm in big trials, the observational data that have tarred the sulfonylurea class, like the findings Prof. Currie reported, are vulnerable to unidentified biases from confounding factors, Canadian pharmacoepidemiologist Dean Eurich told me at EASD. Despite that, Dr. Eurich agreed that sentiment today is running against the sulfonylureas, which also usually cause weight gain and show a decline in their glycemic benefit over time. Plus, he underscored the clear risk that sulfonylurea treatment poses for causing hypoglycemia. "I think the trend is not to use sulfonylureas as much," he told me.
On Twitter @mitchelzoler
Life Expectancy Grows for Young Adults With Type 1 Diabetes
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 – Young adults with type 1 diabetes are living substantially longer than they did a couple of generations ago, according to a study of nearly 25,000 people with type 1 diabetes living in Scotland during 2008-2010.
Researchers took observed mortality rates during this period and calculated that the life expectancy for patients aged 20-24 years with type 1 diabetes was about 45 years for men and 47 years for women, respectively 11 and 14 years less than the life expectancy of an average Scottish man or women aged 20-24 years without diabetes.
These rates at which the life expectancy of patients with diabetes lagged behind that of the general population showed a dramatic narrowing of the life-expectancy gap, compared with an average 27-year gap reported in 1975 for men and women with type 1 diabetes versus people without diabetes (J. Occup. Med. 1975;17:716-21), Dr. Helen M. Colhoun said at the annual meeting of the European Association for the Study of Diabetes.
"I’m confident that the much narrowed life-expectancy differences we see now reflect the enormous advances in management of type 1 diabetes in the last 20-30 years," said Dr. Colhoun, a professor of public health at the University of Dundee (Scotland).
Dr. Colhoun also noted that similar findings recently reported for U.S. patients (Diabetes 2012;61:2987-92) suggest that similar trends are occurring among type 1 diabetes patients elsewhere, although she cautioned that current data from other countries are not now available. "I don’t think that Scotland is that different from other populations," she said.
Despite this positive development, which Dr. Colhoun hoped may eventually reduce life insurance costs for type 1 diabetes patients, a substantial life-expectancy gap remains and means that efforts to improve patient care, prevent morbidity, and increase survival must continue, she said.
"We need to get these [life-expectancy] differences down to zero," she said. "There is no doubt that glycemic control is important for long-term outcomes in patients with type 1 diabetes," and data collected by Dr. Colhoun and her associates in this study showed that in recent years, 37% of these patients in Scotland had poor glycemic control. Better glycemic control may be possible through increased education and empowerment of patients and wider availability of insulin pumps, she said. Their data also showed that other risk factors – such as smoking and hypertension – also need improved management.
But Dr. Colhoun cautioned that their research has not yet confirmed specific factors driving survival and mortality in the population studied. "The next stage of our analysis will look to see how life expectancy differs according to risk-factor profiles, which will give us greater insight into where the improvements have occurred. However, we already know that there have been substantial improvements in the last 20 years in cardiovascular risk factors such as lipid profiles and blood pressure. We have not seen improvements in smoking or glycemic control."
The study used data from 24,971 people aged 20 years or older with type 1 diabetes and living in Scotland during 2008-2010, and compared the calculated life-expectancy rates with those of average men and women without type 1 diabetes in the Scottish population of about 12 million people. The gap between life expectancy for type 1 patients and the general population was highest among those aged 20-24 years. The gap progressively narrowed as people aged: Among those 60-65 years old, the life expectancy gap was 5 years for men and 7 years for women.
Dr. Colhoun said that she had no disclosures.
To earn 0.25 hours AMA PRA Category 1 credit after reading this article, take the post-test here.
On Twitter @mitchelzoler
Dr. Helen M. Colhoun,
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 – Young adults with type 1 diabetes are living substantially longer than they did a couple of generations ago, according to a study of nearly 25,000 people with type 1 diabetes living in Scotland during 2008-2010.
Researchers took observed mortality rates during this period and calculated that the life expectancy for patients aged 20-24 years with type 1 diabetes was about 45 years for men and 47 years for women, respectively 11 and 14 years less than the life expectancy of an average Scottish man or women aged 20-24 years without diabetes.
These rates at which the life expectancy of patients with diabetes lagged behind that of the general population showed a dramatic narrowing of the life-expectancy gap, compared with an average 27-year gap reported in 1975 for men and women with type 1 diabetes versus people without diabetes (J. Occup. Med. 1975;17:716-21), Dr. Helen M. Colhoun said at the annual meeting of the European Association for the Study of Diabetes.
"I’m confident that the much narrowed life-expectancy differences we see now reflect the enormous advances in management of type 1 diabetes in the last 20-30 years," said Dr. Colhoun, a professor of public health at the University of Dundee (Scotland).
Dr. Colhoun also noted that similar findings recently reported for U.S. patients (Diabetes 2012;61:2987-92) suggest that similar trends are occurring among type 1 diabetes patients elsewhere, although she cautioned that current data from other countries are not now available. "I don’t think that Scotland is that different from other populations," she said.
Despite this positive development, which Dr. Colhoun hoped may eventually reduce life insurance costs for type 1 diabetes patients, a substantial life-expectancy gap remains and means that efforts to improve patient care, prevent morbidity, and increase survival must continue, she said.
"We need to get these [life-expectancy] differences down to zero," she said. "There is no doubt that glycemic control is important for long-term outcomes in patients with type 1 diabetes," and data collected by Dr. Colhoun and her associates in this study showed that in recent years, 37% of these patients in Scotland had poor glycemic control. Better glycemic control may be possible through increased education and empowerment of patients and wider availability of insulin pumps, she said. Their data also showed that other risk factors – such as smoking and hypertension – also need improved management.
But Dr. Colhoun cautioned that their research has not yet confirmed specific factors driving survival and mortality in the population studied. "The next stage of our analysis will look to see how life expectancy differs according to risk-factor profiles, which will give us greater insight into where the improvements have occurred. However, we already know that there have been substantial improvements in the last 20 years in cardiovascular risk factors such as lipid profiles and blood pressure. We have not seen improvements in smoking or glycemic control."
The study used data from 24,971 people aged 20 years or older with type 1 diabetes and living in Scotland during 2008-2010, and compared the calculated life-expectancy rates with those of average men and women without type 1 diabetes in the Scottish population of about 12 million people. The gap between life expectancy for type 1 patients and the general population was highest among those aged 20-24 years. The gap progressively narrowed as people aged: Among those 60-65 years old, the life expectancy gap was 5 years for men and 7 years for women.
Dr. Colhoun said that she had no disclosures.
To earn 0.25 hours AMA PRA Category 1 credit after reading this article, take the post-test here.
On Twitter @mitchelzoler
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 – Young adults with type 1 diabetes are living substantially longer than they did a couple of generations ago, according to a study of nearly 25,000 people with type 1 diabetes living in Scotland during 2008-2010.
Researchers took observed mortality rates during this period and calculated that the life expectancy for patients aged 20-24 years with type 1 diabetes was about 45 years for men and 47 years for women, respectively 11 and 14 years less than the life expectancy of an average Scottish man or women aged 20-24 years without diabetes.
These rates at which the life expectancy of patients with diabetes lagged behind that of the general population showed a dramatic narrowing of the life-expectancy gap, compared with an average 27-year gap reported in 1975 for men and women with type 1 diabetes versus people without diabetes (J. Occup. Med. 1975;17:716-21), Dr. Helen M. Colhoun said at the annual meeting of the European Association for the Study of Diabetes.
"I’m confident that the much narrowed life-expectancy differences we see now reflect the enormous advances in management of type 1 diabetes in the last 20-30 years," said Dr. Colhoun, a professor of public health at the University of Dundee (Scotland).
Dr. Colhoun also noted that similar findings recently reported for U.S. patients (Diabetes 2012;61:2987-92) suggest that similar trends are occurring among type 1 diabetes patients elsewhere, although she cautioned that current data from other countries are not now available. "I don’t think that Scotland is that different from other populations," she said.
Despite this positive development, which Dr. Colhoun hoped may eventually reduce life insurance costs for type 1 diabetes patients, a substantial life-expectancy gap remains and means that efforts to improve patient care, prevent morbidity, and increase survival must continue, she said.
"We need to get these [life-expectancy] differences down to zero," she said. "There is no doubt that glycemic control is important for long-term outcomes in patients with type 1 diabetes," and data collected by Dr. Colhoun and her associates in this study showed that in recent years, 37% of these patients in Scotland had poor glycemic control. Better glycemic control may be possible through increased education and empowerment of patients and wider availability of insulin pumps, she said. Their data also showed that other risk factors – such as smoking and hypertension – also need improved management.
But Dr. Colhoun cautioned that their research has not yet confirmed specific factors driving survival and mortality in the population studied. "The next stage of our analysis will look to see how life expectancy differs according to risk-factor profiles, which will give us greater insight into where the improvements have occurred. However, we already know that there have been substantial improvements in the last 20 years in cardiovascular risk factors such as lipid profiles and blood pressure. We have not seen improvements in smoking or glycemic control."
The study used data from 24,971 people aged 20 years or older with type 1 diabetes and living in Scotland during 2008-2010, and compared the calculated life-expectancy rates with those of average men and women without type 1 diabetes in the Scottish population of about 12 million people. The gap between life expectancy for type 1 patients and the general population was highest among those aged 20-24 years. The gap progressively narrowed as people aged: Among those 60-65 years old, the life expectancy gap was 5 years for men and 7 years for women.
Dr. Colhoun said that she had no disclosures.
To earn 0.25 hours AMA PRA Category 1 credit after reading this article, take the post-test here.
On Twitter @mitchelzoler
Dr. Helen M. Colhoun,
Dr. Helen M. Colhoun,
AT THE EASD ANNUAL MEETING
Life expectancy grows for young adults with type 1 diabetes
BARCELONA – Young adults with type 1 diabetes are living substantially longer than they did a couple of generations ago, according to a study of nearly 25,000 people with type 1 diabetes living in Scotland during 2008-2010.
Researchers took observed mortality rates during this period and calculated that the life expectancy for patients aged 20-24 years with type 1 diabetes was about 45 years for men and 47 years for women, respectively 11 and 14 years less than the life expectancy of an average Scottish man or women aged 20-24 years without diabetes.
These rates at which the life expectancy of patients with diabetes lagged behind that of the general population showed a dramatic narrowing of the life-expectancy gap, compared with an average 27-year gap reported in 1975 for men and women with type 1 diabetes versus people without diabetes (J. Occup. Med. 1975;17:716-21), Dr. Helen M. Colhoun said at the annual meeting of the European Association for the Study of Diabetes.
"I’m confident that the much narrowed life-expectancy differences we see now reflect the enormous advances in management of type 1 diabetes in the last 20-30 years," said Dr. Colhoun, a professor of public health at the University of Dundee (Scotland).
Dr. Colhoun also noted that similar findings recently reported for U.S. patients (Diabetes 2012;61:2987-92) suggest that similar trends are occurring among type 1 diabetes patients elsewhere, although she cautioned that current data from other countries are not now available. "I don’t think that Scotland is that different from other populations," she said.
Despite this positive development, which Dr. Colhoun hoped may eventually reduce life insurance costs for type 1 diabetes patients, a substantial life-expectancy gap remains and means that efforts to improve patient care, prevent morbidity, and increase survival must continue, she said.
"We need to get these [life-expectancy] differences down to zero," she said. "There is no doubt that glycemic control is important for long-term outcomes in patients with type 1 diabetes," and data collected by Dr. Colhoun and her associates in this study showed that in recent years, 37% of these patients in Scotland had poor glycemic control. Better glycemic control may be possible through increased education and empowerment of patients and wider availability of insulin pumps, she said. Their data also showed that other risk factors – such as smoking and hypertension – also need improved management.
But Dr. Colhoun cautioned that their research has not yet confirmed specific factors driving survival and mortality in the population studied. "The next stage of our analysis will look to see how life expectancy differs according to risk-factor profiles, which will give us greater insight into where the improvements have occurred. However, we already know that there have been substantial improvements in the last 20 years in cardiovascular risk factors such as lipid profiles and blood pressure. We have not seen improvements in smoking or glycemic control."
The study used data from 24,971 people aged 20 years or older with type 1 diabetes and living in Scotland during 2008-2010, and compared the calculated life-expectancy rates with those of average men and women without type 1 diabetes in the Scottish population of about 12 million people. The gap between life expectancy for type 1 patients and the general population was highest among those aged 20-24 years. The gap progressively narrowed as people aged: Among those 60-65 years old, the life expectancy gap was 5 years for men and 7 years for women.
Dr. Colhoun said that she had no disclosures.
On Twitter @mitchelzoler
Dr. Helen M. Colhoun,
BARCELONA – Young adults with type 1 diabetes are living substantially longer than they did a couple of generations ago, according to a study of nearly 25,000 people with type 1 diabetes living in Scotland during 2008-2010.
Researchers took observed mortality rates during this period and calculated that the life expectancy for patients aged 20-24 years with type 1 diabetes was about 45 years for men and 47 years for women, respectively 11 and 14 years less than the life expectancy of an average Scottish man or women aged 20-24 years without diabetes.
These rates at which the life expectancy of patients with diabetes lagged behind that of the general population showed a dramatic narrowing of the life-expectancy gap, compared with an average 27-year gap reported in 1975 for men and women with type 1 diabetes versus people without diabetes (J. Occup. Med. 1975;17:716-21), Dr. Helen M. Colhoun said at the annual meeting of the European Association for the Study of Diabetes.
"I’m confident that the much narrowed life-expectancy differences we see now reflect the enormous advances in management of type 1 diabetes in the last 20-30 years," said Dr. Colhoun, a professor of public health at the University of Dundee (Scotland).
Dr. Colhoun also noted that similar findings recently reported for U.S. patients (Diabetes 2012;61:2987-92) suggest that similar trends are occurring among type 1 diabetes patients elsewhere, although she cautioned that current data from other countries are not now available. "I don’t think that Scotland is that different from other populations," she said.
Despite this positive development, which Dr. Colhoun hoped may eventually reduce life insurance costs for type 1 diabetes patients, a substantial life-expectancy gap remains and means that efforts to improve patient care, prevent morbidity, and increase survival must continue, she said.
"We need to get these [life-expectancy] differences down to zero," she said. "There is no doubt that glycemic control is important for long-term outcomes in patients with type 1 diabetes," and data collected by Dr. Colhoun and her associates in this study showed that in recent years, 37% of these patients in Scotland had poor glycemic control. Better glycemic control may be possible through increased education and empowerment of patients and wider availability of insulin pumps, she said. Their data also showed that other risk factors – such as smoking and hypertension – also need improved management.
But Dr. Colhoun cautioned that their research has not yet confirmed specific factors driving survival and mortality in the population studied. "The next stage of our analysis will look to see how life expectancy differs according to risk-factor profiles, which will give us greater insight into where the improvements have occurred. However, we already know that there have been substantial improvements in the last 20 years in cardiovascular risk factors such as lipid profiles and blood pressure. We have not seen improvements in smoking or glycemic control."
The study used data from 24,971 people aged 20 years or older with type 1 diabetes and living in Scotland during 2008-2010, and compared the calculated life-expectancy rates with those of average men and women without type 1 diabetes in the Scottish population of about 12 million people. The gap between life expectancy for type 1 patients and the general population was highest among those aged 20-24 years. The gap progressively narrowed as people aged: Among those 60-65 years old, the life expectancy gap was 5 years for men and 7 years for women.
Dr. Colhoun said that she had no disclosures.
On Twitter @mitchelzoler
BARCELONA – Young adults with type 1 diabetes are living substantially longer than they did a couple of generations ago, according to a study of nearly 25,000 people with type 1 diabetes living in Scotland during 2008-2010.
Researchers took observed mortality rates during this period and calculated that the life expectancy for patients aged 20-24 years with type 1 diabetes was about 45 years for men and 47 years for women, respectively 11 and 14 years less than the life expectancy of an average Scottish man or women aged 20-24 years without diabetes.
These rates at which the life expectancy of patients with diabetes lagged behind that of the general population showed a dramatic narrowing of the life-expectancy gap, compared with an average 27-year gap reported in 1975 for men and women with type 1 diabetes versus people without diabetes (J. Occup. Med. 1975;17:716-21), Dr. Helen M. Colhoun said at the annual meeting of the European Association for the Study of Diabetes.
"I’m confident that the much narrowed life-expectancy differences we see now reflect the enormous advances in management of type 1 diabetes in the last 20-30 years," said Dr. Colhoun, a professor of public health at the University of Dundee (Scotland).
Dr. Colhoun also noted that similar findings recently reported for U.S. patients (Diabetes 2012;61:2987-92) suggest that similar trends are occurring among type 1 diabetes patients elsewhere, although she cautioned that current data from other countries are not now available. "I don’t think that Scotland is that different from other populations," she said.
Despite this positive development, which Dr. Colhoun hoped may eventually reduce life insurance costs for type 1 diabetes patients, a substantial life-expectancy gap remains and means that efforts to improve patient care, prevent morbidity, and increase survival must continue, she said.
"We need to get these [life-expectancy] differences down to zero," she said. "There is no doubt that glycemic control is important for long-term outcomes in patients with type 1 diabetes," and data collected by Dr. Colhoun and her associates in this study showed that in recent years, 37% of these patients in Scotland had poor glycemic control. Better glycemic control may be possible through increased education and empowerment of patients and wider availability of insulin pumps, she said. Their data also showed that other risk factors – such as smoking and hypertension – also need improved management.
But Dr. Colhoun cautioned that their research has not yet confirmed specific factors driving survival and mortality in the population studied. "The next stage of our analysis will look to see how life expectancy differs according to risk-factor profiles, which will give us greater insight into where the improvements have occurred. However, we already know that there have been substantial improvements in the last 20 years in cardiovascular risk factors such as lipid profiles and blood pressure. We have not seen improvements in smoking or glycemic control."
The study used data from 24,971 people aged 20 years or older with type 1 diabetes and living in Scotland during 2008-2010, and compared the calculated life-expectancy rates with those of average men and women without type 1 diabetes in the Scottish population of about 12 million people. The gap between life expectancy for type 1 patients and the general population was highest among those aged 20-24 years. The gap progressively narrowed as people aged: Among those 60-65 years old, the life expectancy gap was 5 years for men and 7 years for women.
Dr. Colhoun said that she had no disclosures.
On Twitter @mitchelzoler
Dr. Helen M. Colhoun,
Dr. Helen M. Colhoun,
AT THE EASD ANNUAL MEETING
Major finding: Patients aged 20-24 years with type 1 diabetes had life expectancy deficits of 11-14 years, compared with nondiabetics.
Data source: An analysis of the 1,079 deaths among 24,971 patients with type 1 diabetes collected in Scottish national databases for diabetes and mortality during 2008-2010.
Disclosures: Dr. Colhoun said that she had no disclosures.
Hunting for cardiovascular signals from diabetes drugs
Diabetes drug development entered a new era in 2007 when a meta-analysis of 42 studies that had compared rosiglitazone with other drugs in a total of nearly 28,000 patients suggested that rosiglitazone treatment led to significantly increased rates of cardiovascular death and myocardial infarction.
Based largely on that, the Food and Drug Administration in 2008 issued recommendations to companies developing new diabetes drugs to run large-scale trials aimed at assessing their cardiovascular effects.
In 2011, the FDA placed restrictions on prescribing rosiglitazone, and U.S. use of the drug plummeted. (An FDA panel voted in June to relax some of the restrictions the agency had imposed.)
Some consequences of the long shadow cast by the rosiglitazone experience played out in talks at the annual congress of the European Society for the Study of Diabetes in September, as well as at the annual congress of the European Society of Cardiology a few weeks before that. The new data show just how painstaking investigators have become in trying to parse out hints of cardiovascular danger lurking in masses of megatrial data.
Heart failure haunts DPP-4 inhibitors
At ESC, as well as in a pair of simultaneously published articles, researchers reported results from two large trials designed to follow the FDA recommendations and assess cardiovascular safety for two new selective dipeptidyl peptidase-4 (DPP-4) inhibitors, saxagliptin (Onglyza) and alogliptin, in patients with type 2 diabetes.
Saxagliptin was the drug with the red-flag signal, while alogliptin faced guilt by association. The saxagliptin study, SAVOR-TIMI 53, used patients with either an established history of cardiovascular disease (CVD) or multiple CVD risk factors. The study’s primary safety endpoint, the combined rate of CVD death, nonfatal myocardial infarction, or nonfatal stroke during 2 years of follow-up, was virtually identical in the two groups, 7.3% in the saxagliptin patients and 7.2% in the controls.
The study’s secondary safety endpoint, which included the primary combined plus other endpoints such as need for revascularization and hospitalization for heart failure, was also similar in the two study arms, with this expanded combined endpoint occurring in 12.8% of the saxagliptin patients and 12.4% of the controls (N. Engl. J. Med. 2013;369:1317-26).
The whisper of a saxagliptin problem was in just one secondary, individual safety endpoint, hospitalizations for heart failure. These occurred in 3.5% of the saxagliptin patients and in 2.8% of controls, a statistically significant difference. Further data presented at EASD showed that this difference clustered predominantly in the subgroup of patients who entered the study with presumed heart failure, based on having a blood level of NT-pro brain natriuretic peptide of at least 333, about 25% of patients in both treatment arms (although the investigators identified heart failure in only 13% of enrolled patients). Within this subgroup, heart failure–associated hospitalizations occurred in 10.9% of the saxagliptin patients and 8.9% of the controls, a statistically significant difference, reported Dr. Deepak L. Bhatt, one of the investigators for the SAVOR-TIMI 53 study, which randomized more than 16,000 patients.
In contrast, the alogliptin study, EXAMINE, which randomized more than 5,000 patients with type 2 diabetes and a recent acute coronary syndrome event to treatment with alogliptin or placebo, found no real confirmation of this problem (N. Engl. J. Med. 2013;369:1327-35).
After the early-September report of this saxagliptin and heart failure hospitalization signal, the EXAMINE researchers went back to their data to specifically look at this issue, Dr. William B. White, the lead investigator, said when he presented the new findings at EASD. During a median of 18 months of follow-up, the rate of hospitalizations for heart failure was 3.1% in the alogliptin group and 2.9% in the placebo group, a difference that was not statistically significant, although it trended just slightly toward an alogliptin problem. Among the subgroup of patients who entered EXAMINE with a history of heart failure, the rate of the combined cardiovascular safety endpoint of CV death, nonfatal MI, or nonfatal stroke was 18% in the alogliptin group and 22% in the placebo group, a difference that was not statistically significant.
Despite the absence of any apparent heart failure–hospitalization effect in EXAMINE, Dr. Naveed Sattar, the invited discussant for the two reports at EASD, meta-analyzed the heart failure–hospitalization results from both studies, and found a combined, 24% relative increase in this outcome for the two DPP-4 inhibitors combined, a statistically significant effect largely driven toward significance by the underlying statistical significance in the saxagliptin study; the alogliptin results couldn’t resolve this difference since they trended in the same direction. Dr. Sattar concluded that it raised enough doubt about the safety of this entire drug class in patients with pre-existing heart failure to recommend not using drugs from this class in patients with any indication of heart failure – regardless of severity – until the apparent link received further scrutiny. Dr. Bhatt promised a report with further information on the heart failure issue at the American Heart Association Scientific Sessions in November.
Signals for canagliflozin, too?
SAVOR-TIMI 53 and EXAMINE provide the first results from what are more than a dozen large studies – involving more than 100,000 patients – launched recently to look for adverse cardiovascular effects from drugs in six different diabetes drug classes, according to Dr. Sanjay Kaul, who also spoke at EASD. He presented results from a meta-analysis he performed on results from nine phase III and phase II trials of canagliflozin (Invokana), an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class and approved by the FDA last March for treatment of type 2 diabetes, the first drug in that class to get U.S. marketing approval.
In the largest of these trials, CANVAS – the cardiovascular-assessment study for canagliflozin set up by the drug’s developer, Janssen – treatment with canagliflozin linked with a statistically significant, sixfold increase in cardiovascular events during the first 30 days of treatment, a link that then disappeared with longer-term treatment in patients with high CV risk. (Complete results from CANVAS have not yet been reported.) But Dr. Kaul did not see a similar excess in the other eight studies.
The canagliflozin meta-analysis also showed a nonsignificant, 46% increased risk of stroke in patients on the drug, a signal not seen in any other individual cardiovascular endpoint. Dr. Kaul analyzed data from 14 phase II and III trials for a second SGLT2 inhibitor drug, dapagliflozin, which showed no suggestion of causing any cardiovascular risk.
The canagliflozin risk signals are not reasons to stop using the drug or to withdraw it from the market, said Dr. Kaul, a member of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee. The early signal of risk in CANVAS was not seen in any other study, and it may have been a statistical artifact, he said.
He said that signals of risk must be considered relative to a drug’s benefit. Applying the same standard of cardiovascular harm to drugs that are highly effective and to drugs that are not very effective "doesn’t make sense," he said. "A risk-benefit trade-off depends on the benefit. If you have a diabetes drug that lowers hemoglobin A1c by 1.5%-2% I’m willing to accept greater harm than I would from a drug that produced a 0.5% drop in hemoglobin A1c."
A final rosiglitazone thought
Dr. Kaul also made this observation about the rosiglitazone experience, which in retrospect produced "insufficient evidence to either incriminate or exonerate rosiglitazone," he said.
"That a diabetes drug [rosiglitazone] could have become a blockbuster without any established outcome benefits does not reflect well on the drug development and approval process. Equally lamentable is that this drug was virtually killed based on insufficient evidence and entrenched opinions."
Dr. Bhatt has received research grants from several companies, including AstraZeneca and Bristol-Myers Squibb (BMS), which market saxagliptin, and Takeda, maker of alogliptin. Dr. White is a safety consultant for several companies, including AstraZeneca and Takeda. Dr. Sattar is a consultant to several pharmaceutical firms, including AstraZeneca and BMS. Dr. Kaul is a consultant to Novo Nordisk, Sanofi, and Boehringer Ingelheim, and owns stock in Johnson & Johnson.
On Twitter @mitchelzoler
Diabetes drug development entered a new era in 2007 when a meta-analysis of 42 studies that had compared rosiglitazone with other drugs in a total of nearly 28,000 patients suggested that rosiglitazone treatment led to significantly increased rates of cardiovascular death and myocardial infarction.
Based largely on that, the Food and Drug Administration in 2008 issued recommendations to companies developing new diabetes drugs to run large-scale trials aimed at assessing their cardiovascular effects.
In 2011, the FDA placed restrictions on prescribing rosiglitazone, and U.S. use of the drug plummeted. (An FDA panel voted in June to relax some of the restrictions the agency had imposed.)
Some consequences of the long shadow cast by the rosiglitazone experience played out in talks at the annual congress of the European Society for the Study of Diabetes in September, as well as at the annual congress of the European Society of Cardiology a few weeks before that. The new data show just how painstaking investigators have become in trying to parse out hints of cardiovascular danger lurking in masses of megatrial data.
Heart failure haunts DPP-4 inhibitors
At ESC, as well as in a pair of simultaneously published articles, researchers reported results from two large trials designed to follow the FDA recommendations and assess cardiovascular safety for two new selective dipeptidyl peptidase-4 (DPP-4) inhibitors, saxagliptin (Onglyza) and alogliptin, in patients with type 2 diabetes.
Saxagliptin was the drug with the red-flag signal, while alogliptin faced guilt by association. The saxagliptin study, SAVOR-TIMI 53, used patients with either an established history of cardiovascular disease (CVD) or multiple CVD risk factors. The study’s primary safety endpoint, the combined rate of CVD death, nonfatal myocardial infarction, or nonfatal stroke during 2 years of follow-up, was virtually identical in the two groups, 7.3% in the saxagliptin patients and 7.2% in the controls.
The study’s secondary safety endpoint, which included the primary combined plus other endpoints such as need for revascularization and hospitalization for heart failure, was also similar in the two study arms, with this expanded combined endpoint occurring in 12.8% of the saxagliptin patients and 12.4% of the controls (N. Engl. J. Med. 2013;369:1317-26).
The whisper of a saxagliptin problem was in just one secondary, individual safety endpoint, hospitalizations for heart failure. These occurred in 3.5% of the saxagliptin patients and in 2.8% of controls, a statistically significant difference. Further data presented at EASD showed that this difference clustered predominantly in the subgroup of patients who entered the study with presumed heart failure, based on having a blood level of NT-pro brain natriuretic peptide of at least 333, about 25% of patients in both treatment arms (although the investigators identified heart failure in only 13% of enrolled patients). Within this subgroup, heart failure–associated hospitalizations occurred in 10.9% of the saxagliptin patients and 8.9% of the controls, a statistically significant difference, reported Dr. Deepak L. Bhatt, one of the investigators for the SAVOR-TIMI 53 study, which randomized more than 16,000 patients.
In contrast, the alogliptin study, EXAMINE, which randomized more than 5,000 patients with type 2 diabetes and a recent acute coronary syndrome event to treatment with alogliptin or placebo, found no real confirmation of this problem (N. Engl. J. Med. 2013;369:1327-35).
After the early-September report of this saxagliptin and heart failure hospitalization signal, the EXAMINE researchers went back to their data to specifically look at this issue, Dr. William B. White, the lead investigator, said when he presented the new findings at EASD. During a median of 18 months of follow-up, the rate of hospitalizations for heart failure was 3.1% in the alogliptin group and 2.9% in the placebo group, a difference that was not statistically significant, although it trended just slightly toward an alogliptin problem. Among the subgroup of patients who entered EXAMINE with a history of heart failure, the rate of the combined cardiovascular safety endpoint of CV death, nonfatal MI, or nonfatal stroke was 18% in the alogliptin group and 22% in the placebo group, a difference that was not statistically significant.
Despite the absence of any apparent heart failure–hospitalization effect in EXAMINE, Dr. Naveed Sattar, the invited discussant for the two reports at EASD, meta-analyzed the heart failure–hospitalization results from both studies, and found a combined, 24% relative increase in this outcome for the two DPP-4 inhibitors combined, a statistically significant effect largely driven toward significance by the underlying statistical significance in the saxagliptin study; the alogliptin results couldn’t resolve this difference since they trended in the same direction. Dr. Sattar concluded that it raised enough doubt about the safety of this entire drug class in patients with pre-existing heart failure to recommend not using drugs from this class in patients with any indication of heart failure – regardless of severity – until the apparent link received further scrutiny. Dr. Bhatt promised a report with further information on the heart failure issue at the American Heart Association Scientific Sessions in November.
Signals for canagliflozin, too?
SAVOR-TIMI 53 and EXAMINE provide the first results from what are more than a dozen large studies – involving more than 100,000 patients – launched recently to look for adverse cardiovascular effects from drugs in six different diabetes drug classes, according to Dr. Sanjay Kaul, who also spoke at EASD. He presented results from a meta-analysis he performed on results from nine phase III and phase II trials of canagliflozin (Invokana), an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class and approved by the FDA last March for treatment of type 2 diabetes, the first drug in that class to get U.S. marketing approval.
In the largest of these trials, CANVAS – the cardiovascular-assessment study for canagliflozin set up by the drug’s developer, Janssen – treatment with canagliflozin linked with a statistically significant, sixfold increase in cardiovascular events during the first 30 days of treatment, a link that then disappeared with longer-term treatment in patients with high CV risk. (Complete results from CANVAS have not yet been reported.) But Dr. Kaul did not see a similar excess in the other eight studies.
The canagliflozin meta-analysis also showed a nonsignificant, 46% increased risk of stroke in patients on the drug, a signal not seen in any other individual cardiovascular endpoint. Dr. Kaul analyzed data from 14 phase II and III trials for a second SGLT2 inhibitor drug, dapagliflozin, which showed no suggestion of causing any cardiovascular risk.
The canagliflozin risk signals are not reasons to stop using the drug or to withdraw it from the market, said Dr. Kaul, a member of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee. The early signal of risk in CANVAS was not seen in any other study, and it may have been a statistical artifact, he said.
He said that signals of risk must be considered relative to a drug’s benefit. Applying the same standard of cardiovascular harm to drugs that are highly effective and to drugs that are not very effective "doesn’t make sense," he said. "A risk-benefit trade-off depends on the benefit. If you have a diabetes drug that lowers hemoglobin A1c by 1.5%-2% I’m willing to accept greater harm than I would from a drug that produced a 0.5% drop in hemoglobin A1c."
A final rosiglitazone thought
Dr. Kaul also made this observation about the rosiglitazone experience, which in retrospect produced "insufficient evidence to either incriminate or exonerate rosiglitazone," he said.
"That a diabetes drug [rosiglitazone] could have become a blockbuster without any established outcome benefits does not reflect well on the drug development and approval process. Equally lamentable is that this drug was virtually killed based on insufficient evidence and entrenched opinions."
Dr. Bhatt has received research grants from several companies, including AstraZeneca and Bristol-Myers Squibb (BMS), which market saxagliptin, and Takeda, maker of alogliptin. Dr. White is a safety consultant for several companies, including AstraZeneca and Takeda. Dr. Sattar is a consultant to several pharmaceutical firms, including AstraZeneca and BMS. Dr. Kaul is a consultant to Novo Nordisk, Sanofi, and Boehringer Ingelheim, and owns stock in Johnson & Johnson.
On Twitter @mitchelzoler
Diabetes drug development entered a new era in 2007 when a meta-analysis of 42 studies that had compared rosiglitazone with other drugs in a total of nearly 28,000 patients suggested that rosiglitazone treatment led to significantly increased rates of cardiovascular death and myocardial infarction.
Based largely on that, the Food and Drug Administration in 2008 issued recommendations to companies developing new diabetes drugs to run large-scale trials aimed at assessing their cardiovascular effects.
In 2011, the FDA placed restrictions on prescribing rosiglitazone, and U.S. use of the drug plummeted. (An FDA panel voted in June to relax some of the restrictions the agency had imposed.)
Some consequences of the long shadow cast by the rosiglitazone experience played out in talks at the annual congress of the European Society for the Study of Diabetes in September, as well as at the annual congress of the European Society of Cardiology a few weeks before that. The new data show just how painstaking investigators have become in trying to parse out hints of cardiovascular danger lurking in masses of megatrial data.
Heart failure haunts DPP-4 inhibitors
At ESC, as well as in a pair of simultaneously published articles, researchers reported results from two large trials designed to follow the FDA recommendations and assess cardiovascular safety for two new selective dipeptidyl peptidase-4 (DPP-4) inhibitors, saxagliptin (Onglyza) and alogliptin, in patients with type 2 diabetes.
Saxagliptin was the drug with the red-flag signal, while alogliptin faced guilt by association. The saxagliptin study, SAVOR-TIMI 53, used patients with either an established history of cardiovascular disease (CVD) or multiple CVD risk factors. The study’s primary safety endpoint, the combined rate of CVD death, nonfatal myocardial infarction, or nonfatal stroke during 2 years of follow-up, was virtually identical in the two groups, 7.3% in the saxagliptin patients and 7.2% in the controls.
The study’s secondary safety endpoint, which included the primary combined plus other endpoints such as need for revascularization and hospitalization for heart failure, was also similar in the two study arms, with this expanded combined endpoint occurring in 12.8% of the saxagliptin patients and 12.4% of the controls (N. Engl. J. Med. 2013;369:1317-26).
The whisper of a saxagliptin problem was in just one secondary, individual safety endpoint, hospitalizations for heart failure. These occurred in 3.5% of the saxagliptin patients and in 2.8% of controls, a statistically significant difference. Further data presented at EASD showed that this difference clustered predominantly in the subgroup of patients who entered the study with presumed heart failure, based on having a blood level of NT-pro brain natriuretic peptide of at least 333, about 25% of patients in both treatment arms (although the investigators identified heart failure in only 13% of enrolled patients). Within this subgroup, heart failure–associated hospitalizations occurred in 10.9% of the saxagliptin patients and 8.9% of the controls, a statistically significant difference, reported Dr. Deepak L. Bhatt, one of the investigators for the SAVOR-TIMI 53 study, which randomized more than 16,000 patients.
In contrast, the alogliptin study, EXAMINE, which randomized more than 5,000 patients with type 2 diabetes and a recent acute coronary syndrome event to treatment with alogliptin or placebo, found no real confirmation of this problem (N. Engl. J. Med. 2013;369:1327-35).
After the early-September report of this saxagliptin and heart failure hospitalization signal, the EXAMINE researchers went back to their data to specifically look at this issue, Dr. William B. White, the lead investigator, said when he presented the new findings at EASD. During a median of 18 months of follow-up, the rate of hospitalizations for heart failure was 3.1% in the alogliptin group and 2.9% in the placebo group, a difference that was not statistically significant, although it trended just slightly toward an alogliptin problem. Among the subgroup of patients who entered EXAMINE with a history of heart failure, the rate of the combined cardiovascular safety endpoint of CV death, nonfatal MI, or nonfatal stroke was 18% in the alogliptin group and 22% in the placebo group, a difference that was not statistically significant.
Despite the absence of any apparent heart failure–hospitalization effect in EXAMINE, Dr. Naveed Sattar, the invited discussant for the two reports at EASD, meta-analyzed the heart failure–hospitalization results from both studies, and found a combined, 24% relative increase in this outcome for the two DPP-4 inhibitors combined, a statistically significant effect largely driven toward significance by the underlying statistical significance in the saxagliptin study; the alogliptin results couldn’t resolve this difference since they trended in the same direction. Dr. Sattar concluded that it raised enough doubt about the safety of this entire drug class in patients with pre-existing heart failure to recommend not using drugs from this class in patients with any indication of heart failure – regardless of severity – until the apparent link received further scrutiny. Dr. Bhatt promised a report with further information on the heart failure issue at the American Heart Association Scientific Sessions in November.
Signals for canagliflozin, too?
SAVOR-TIMI 53 and EXAMINE provide the first results from what are more than a dozen large studies – involving more than 100,000 patients – launched recently to look for adverse cardiovascular effects from drugs in six different diabetes drug classes, according to Dr. Sanjay Kaul, who also spoke at EASD. He presented results from a meta-analysis he performed on results from nine phase III and phase II trials of canagliflozin (Invokana), an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class and approved by the FDA last March for treatment of type 2 diabetes, the first drug in that class to get U.S. marketing approval.
In the largest of these trials, CANVAS – the cardiovascular-assessment study for canagliflozin set up by the drug’s developer, Janssen – treatment with canagliflozin linked with a statistically significant, sixfold increase in cardiovascular events during the first 30 days of treatment, a link that then disappeared with longer-term treatment in patients with high CV risk. (Complete results from CANVAS have not yet been reported.) But Dr. Kaul did not see a similar excess in the other eight studies.
The canagliflozin meta-analysis also showed a nonsignificant, 46% increased risk of stroke in patients on the drug, a signal not seen in any other individual cardiovascular endpoint. Dr. Kaul analyzed data from 14 phase II and III trials for a second SGLT2 inhibitor drug, dapagliflozin, which showed no suggestion of causing any cardiovascular risk.
The canagliflozin risk signals are not reasons to stop using the drug or to withdraw it from the market, said Dr. Kaul, a member of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee. The early signal of risk in CANVAS was not seen in any other study, and it may have been a statistical artifact, he said.
He said that signals of risk must be considered relative to a drug’s benefit. Applying the same standard of cardiovascular harm to drugs that are highly effective and to drugs that are not very effective "doesn’t make sense," he said. "A risk-benefit trade-off depends on the benefit. If you have a diabetes drug that lowers hemoglobin A1c by 1.5%-2% I’m willing to accept greater harm than I would from a drug that produced a 0.5% drop in hemoglobin A1c."
A final rosiglitazone thought
Dr. Kaul also made this observation about the rosiglitazone experience, which in retrospect produced "insufficient evidence to either incriminate or exonerate rosiglitazone," he said.
"That a diabetes drug [rosiglitazone] could have become a blockbuster without any established outcome benefits does not reflect well on the drug development and approval process. Equally lamentable is that this drug was virtually killed based on insufficient evidence and entrenched opinions."
Dr. Bhatt has received research grants from several companies, including AstraZeneca and Bristol-Myers Squibb (BMS), which market saxagliptin, and Takeda, maker of alogliptin. Dr. White is a safety consultant for several companies, including AstraZeneca and Takeda. Dr. Sattar is a consultant to several pharmaceutical firms, including AstraZeneca and BMS. Dr. Kaul is a consultant to Novo Nordisk, Sanofi, and Boehringer Ingelheim, and owns stock in Johnson & Johnson.
On Twitter @mitchelzoler
Bariatric surgery cuts long-term diabetes complications
BARCELONA – Patients with type 2 diabetes who undergo bariatric surgery benefit from an increasingly reduced incidence of macro- and microvascular complications over the ensuing 20 years compared with matched controls, based on 20-year follow-up of more than 600 patients treated in Sweden.
The rate of complications that were prevented accelerated during 20 years of follow-up even though the prevalence of patients in remission from type 2 diabetes following bariatric surgery fell over time, with a nadir in remission reached at 20 years, Dr. Lars Sjötröm reported at the annual meeting of the European Association for the Study of Diabetes.
Dr. Sjötröm and his associates previously reported results from the Swedish Obese Subjects (SOS) study showing that among the subgroup of patients who entered the study with diabetes, 72% were in remission from diabetes 2 years after bariatric surgery, and 36% were still in remission 10 years after surgery (N. Engl. J. Med. 2004;351:2683-93). Longer follow-up data he reported at the meeting show that after 15 years the remission rate dropped further to 30%, and after 20 years just 18% of the starting population remained in remission of their diabetes. After 20 years, roughly three-quarters of the patients who initially went into remission of their diabetes had relapsed back into active diabetes.
Despite this, the incidence of macro- and microvascular complications continued to fall compared with the control patients, reported Dr. Sjötröm, professor of medicine at the University of Gothenburg, Sweden, and lead investigator of SOS. The rate of complications of the eyes, kidneys, peripheral nerves, or peripheral circulation that required hospitalization was about 8% in the surgery patients and 12% in the controls after 10 years, and after 20 years the rates were about 20% in the surgery patients and 45% in the controls, a 54% relative risk reduction in favor of surgery that appeared greater than after 10 years. His group previously reported a similar finding for the incidence of myocardial infarctions (Diabetes Care 2012;35:2613-7).
"I think you should operate on patients with diabetes; we saw a drop in their complications," he said. "Even when patients relapse, their cardiovascular risk factors are still improved. This may be why we see an effect on complications despite the patients relapsing. Even with all the relapses, the effect of surgery on diabetic complications remains strong after 20 years." Gastric bypass surgery appeared to offer a feasible operation that also resulted in good diabetes control, he added.
The SOS enrolled 607 patients with diabetes out of the 4,047 total patients in the study. The diabetes subgroup comprised 345 who underwent some form of bariatric surgery, and 262 matched controls who did not receive surgery. Their average age was 50 years, their average body mass index was 40 kg/m2, and they had diabetes for an average of 3 years.
In addition to producing diabetes remission and preventing complications, surgery also blunted the incidence of new-onset diabetes. A prior report from SOS showed prevention of new-onset diabetes in the surgery group through the first 15 years of follow-up, (N. Engl. J. Med. 2012;367:695-704), and after 20 years this effect "remained quite strong," with a 77% relative risk reduction in incident diabetes during 20 years of follow-up compared with the controls, Dr. Sjötröm reported.
He also called for scaling back body mass index criteria for performing bariatric surgery because the benefits following surgery appeared similar in patients with relatively low BMIs. He cited a recent analysis his group ran on the 233 patients from SOS who did not meet current criteria for bariatric surgery because their BMI was too low. The average BMI in this subgroup was 36 kg/m2, and 104 of these patients underwent bariatric surgery (Diabetes Care 2013;36:1335-40). This exploratory analysis of SOS results showed that the benefits from bariatric surgery were similar in patients with lower BMIs and in patients with higher BMIs who meet the standard surgical criteria.
"Current BMI-based eligibility criteria [for bariatric surgery] are not valid," Dr. Sjötröm declared. "Baseline BMI does not predict any treatment effect examined so far. We should give more importance to metabolic variables to select the patients who would benefit the most from bariatric surgery."
SOS has been supported by grants from Astra Zeneca, Cederroth, Hoffman-La Roche, Johnson & Johnson, and Sanofi-Aventis. Dr. Sjötröm has been a speaker for Astra Zeneca and Johnson & Johnson, and he serves on the board of Lenimen.
On Twitter @mitchelzoler
BARCELONA – Patients with type 2 diabetes who undergo bariatric surgery benefit from an increasingly reduced incidence of macro- and microvascular complications over the ensuing 20 years compared with matched controls, based on 20-year follow-up of more than 600 patients treated in Sweden.
The rate of complications that were prevented accelerated during 20 years of follow-up even though the prevalence of patients in remission from type 2 diabetes following bariatric surgery fell over time, with a nadir in remission reached at 20 years, Dr. Lars Sjötröm reported at the annual meeting of the European Association for the Study of Diabetes.
Dr. Sjötröm and his associates previously reported results from the Swedish Obese Subjects (SOS) study showing that among the subgroup of patients who entered the study with diabetes, 72% were in remission from diabetes 2 years after bariatric surgery, and 36% were still in remission 10 years after surgery (N. Engl. J. Med. 2004;351:2683-93). Longer follow-up data he reported at the meeting show that after 15 years the remission rate dropped further to 30%, and after 20 years just 18% of the starting population remained in remission of their diabetes. After 20 years, roughly three-quarters of the patients who initially went into remission of their diabetes had relapsed back into active diabetes.
Despite this, the incidence of macro- and microvascular complications continued to fall compared with the control patients, reported Dr. Sjötröm, professor of medicine at the University of Gothenburg, Sweden, and lead investigator of SOS. The rate of complications of the eyes, kidneys, peripheral nerves, or peripheral circulation that required hospitalization was about 8% in the surgery patients and 12% in the controls after 10 years, and after 20 years the rates were about 20% in the surgery patients and 45% in the controls, a 54% relative risk reduction in favor of surgery that appeared greater than after 10 years. His group previously reported a similar finding for the incidence of myocardial infarctions (Diabetes Care 2012;35:2613-7).
"I think you should operate on patients with diabetes; we saw a drop in their complications," he said. "Even when patients relapse, their cardiovascular risk factors are still improved. This may be why we see an effect on complications despite the patients relapsing. Even with all the relapses, the effect of surgery on diabetic complications remains strong after 20 years." Gastric bypass surgery appeared to offer a feasible operation that also resulted in good diabetes control, he added.
The SOS enrolled 607 patients with diabetes out of the 4,047 total patients in the study. The diabetes subgroup comprised 345 who underwent some form of bariatric surgery, and 262 matched controls who did not receive surgery. Their average age was 50 years, their average body mass index was 40 kg/m2, and they had diabetes for an average of 3 years.
In addition to producing diabetes remission and preventing complications, surgery also blunted the incidence of new-onset diabetes. A prior report from SOS showed prevention of new-onset diabetes in the surgery group through the first 15 years of follow-up, (N. Engl. J. Med. 2012;367:695-704), and after 20 years this effect "remained quite strong," with a 77% relative risk reduction in incident diabetes during 20 years of follow-up compared with the controls, Dr. Sjötröm reported.
He also called for scaling back body mass index criteria for performing bariatric surgery because the benefits following surgery appeared similar in patients with relatively low BMIs. He cited a recent analysis his group ran on the 233 patients from SOS who did not meet current criteria for bariatric surgery because their BMI was too low. The average BMI in this subgroup was 36 kg/m2, and 104 of these patients underwent bariatric surgery (Diabetes Care 2013;36:1335-40). This exploratory analysis of SOS results showed that the benefits from bariatric surgery were similar in patients with lower BMIs and in patients with higher BMIs who meet the standard surgical criteria.
"Current BMI-based eligibility criteria [for bariatric surgery] are not valid," Dr. Sjötröm declared. "Baseline BMI does not predict any treatment effect examined so far. We should give more importance to metabolic variables to select the patients who would benefit the most from bariatric surgery."
SOS has been supported by grants from Astra Zeneca, Cederroth, Hoffman-La Roche, Johnson & Johnson, and Sanofi-Aventis. Dr. Sjötröm has been a speaker for Astra Zeneca and Johnson & Johnson, and he serves on the board of Lenimen.
On Twitter @mitchelzoler
BARCELONA – Patients with type 2 diabetes who undergo bariatric surgery benefit from an increasingly reduced incidence of macro- and microvascular complications over the ensuing 20 years compared with matched controls, based on 20-year follow-up of more than 600 patients treated in Sweden.
The rate of complications that were prevented accelerated during 20 years of follow-up even though the prevalence of patients in remission from type 2 diabetes following bariatric surgery fell over time, with a nadir in remission reached at 20 years, Dr. Lars Sjötröm reported at the annual meeting of the European Association for the Study of Diabetes.
Dr. Sjötröm and his associates previously reported results from the Swedish Obese Subjects (SOS) study showing that among the subgroup of patients who entered the study with diabetes, 72% were in remission from diabetes 2 years after bariatric surgery, and 36% were still in remission 10 years after surgery (N. Engl. J. Med. 2004;351:2683-93). Longer follow-up data he reported at the meeting show that after 15 years the remission rate dropped further to 30%, and after 20 years just 18% of the starting population remained in remission of their diabetes. After 20 years, roughly three-quarters of the patients who initially went into remission of their diabetes had relapsed back into active diabetes.
Despite this, the incidence of macro- and microvascular complications continued to fall compared with the control patients, reported Dr. Sjötröm, professor of medicine at the University of Gothenburg, Sweden, and lead investigator of SOS. The rate of complications of the eyes, kidneys, peripheral nerves, or peripheral circulation that required hospitalization was about 8% in the surgery patients and 12% in the controls after 10 years, and after 20 years the rates were about 20% in the surgery patients and 45% in the controls, a 54% relative risk reduction in favor of surgery that appeared greater than after 10 years. His group previously reported a similar finding for the incidence of myocardial infarctions (Diabetes Care 2012;35:2613-7).
"I think you should operate on patients with diabetes; we saw a drop in their complications," he said. "Even when patients relapse, their cardiovascular risk factors are still improved. This may be why we see an effect on complications despite the patients relapsing. Even with all the relapses, the effect of surgery on diabetic complications remains strong after 20 years." Gastric bypass surgery appeared to offer a feasible operation that also resulted in good diabetes control, he added.
The SOS enrolled 607 patients with diabetes out of the 4,047 total patients in the study. The diabetes subgroup comprised 345 who underwent some form of bariatric surgery, and 262 matched controls who did not receive surgery. Their average age was 50 years, their average body mass index was 40 kg/m2, and they had diabetes for an average of 3 years.
In addition to producing diabetes remission and preventing complications, surgery also blunted the incidence of new-onset diabetes. A prior report from SOS showed prevention of new-onset diabetes in the surgery group through the first 15 years of follow-up, (N. Engl. J. Med. 2012;367:695-704), and after 20 years this effect "remained quite strong," with a 77% relative risk reduction in incident diabetes during 20 years of follow-up compared with the controls, Dr. Sjötröm reported.
He also called for scaling back body mass index criteria for performing bariatric surgery because the benefits following surgery appeared similar in patients with relatively low BMIs. He cited a recent analysis his group ran on the 233 patients from SOS who did not meet current criteria for bariatric surgery because their BMI was too low. The average BMI in this subgroup was 36 kg/m2, and 104 of these patients underwent bariatric surgery (Diabetes Care 2013;36:1335-40). This exploratory analysis of SOS results showed that the benefits from bariatric surgery were similar in patients with lower BMIs and in patients with higher BMIs who meet the standard surgical criteria.
"Current BMI-based eligibility criteria [for bariatric surgery] are not valid," Dr. Sjötröm declared. "Baseline BMI does not predict any treatment effect examined so far. We should give more importance to metabolic variables to select the patients who would benefit the most from bariatric surgery."
SOS has been supported by grants from Astra Zeneca, Cederroth, Hoffman-La Roche, Johnson & Johnson, and Sanofi-Aventis. Dr. Sjötröm has been a speaker for Astra Zeneca and Johnson & Johnson, and he serves on the board of Lenimen.
On Twitter @mitchelzoler
AT THE EASD ANNUAL MEETING
Major finding: At 20-years follow-up, the incidence of microvascular complications was cut 54% in bariatric surgery patients compared with controls.
Data source: The SOS study of 4,047 obese patients who underwent bariatric surgery or matched controls. The study had a subgroup of 607 patients with diabetes.
Disclosures: SOS has been supported by grants from Astra Zeneca, Cederroth, Hoffman-La Roche, Johnson & Johnson, and Sanofi-Aventis. Dr. Sjötröm has been a speaker for Astra Zeneca and Johnson & Johnson, and he serves on the board of Lenimen.
Drug Combo in New-onset Diabetes
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 A1c 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 HbA1c 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 HbA1c 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 HbA1c 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 HbA1c, 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, HbA1c, and weight. Their daily home blood glucose monitoring data were also reviewed. The primary endpoint was treatment failure, defined as an HbA1c 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 HbA1c 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, HbA1c 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 HbA1c 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 HbA1c 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 HbA1c 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 HbA1c 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 HbA1c 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.
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 A1c 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 HbA1c 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 HbA1c 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 HbA1c 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 HbA1c, 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, HbA1c, and weight. Their daily home blood glucose monitoring data were also reviewed. The primary endpoint was treatment failure, defined as an HbA1c 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 HbA1c 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, HbA1c 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 HbA1c 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 HbA1c 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 HbA1c 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 HbA1c 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 HbA1c 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.
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 A1c 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 HbA1c 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 HbA1c 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 HbA1c 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 HbA1c, 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, HbA1c, and weight. Their daily home blood glucose monitoring data were also reviewed. The primary endpoint was treatment failure, defined as an HbA1c 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 HbA1c 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, HbA1c 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 HbA1c 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 HbA1c 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 HbA1c 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 HbA1c 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 HbA1c 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.
AT THE EASD ANNUAL MEETING
Drug combo tops sequential therapy in new-onset diabetes
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 A1c 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 HbA1c 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 HbA1c 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 HbA1c 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 HbA1c, 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, HbA1c, and weight. Their daily home blood glucose monitoring data were also reviewed. The primary endpoint was treatment failure, defined as an HbA1c 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 HbA1c 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, HbA1c 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 HbA1c 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 HbA1c 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 HbA1c 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 HbA1c 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 HbA1c 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.
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 A1c 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 HbA1c 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 HbA1c 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 HbA1c 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 HbA1c, 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, HbA1c, and weight. Their daily home blood glucose monitoring data were also reviewed. The primary endpoint was treatment failure, defined as an HbA1c 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 HbA1c 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, HbA1c 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 HbA1c 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 HbA1c 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 HbA1c 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 HbA1c 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 HbA1c 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.
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 A1c 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 HbA1c 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 HbA1c 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 HbA1c 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 HbA1c, 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, HbA1c, and weight. Their daily home blood glucose monitoring data were also reviewed. The primary endpoint was treatment failure, defined as an HbA1c 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 HbA1c 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, HbA1c 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 HbA1c 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 HbA1c 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 HbA1c 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 HbA1c 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 HbA1c 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.
AT THE EASD ANNUAL MEETING
Major finding: Newly diagnosed type 2 diabetes patients who took a triple-drug therapy were 84% less likely to fail treatment by 24 months than patients who took conventional, stepwise therapy.
Data source: The results are 2-year interim data from a 3-year, open-label, randomized trial containing 169 patients.
Disclosures: 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.
Type 2 diabetes encompasses three distinct subtypes
BARCELONA – Not all type 2 diabetes is the same, and pathophysiologic differences among diabetes subtypes mean that different type 2 patients need different treatment.
"Several specific causes of hyperglycemia are hidden behind the clinical diagnosis of type 2 diabetes," Dr. Henning Beck-Nielsen said at the annual meeting of the European Association for the Study of Diabetes.
"Patients with type 2 diabetes can be divided into three basic pathophysiologic phenotypes: classic type 2 diabetes, insulinopenic type 2 diabetes, and hyperinsulinemic type 2 diabetes." He and his associates identified these and other, less common subtypes by systematically studying more than 1,000 Danish patients newly diagnosed with type 2 diabetes who were entered into a national registry that now totals 40,000 patients.
"We recommend that clinicians measure both GAD [glutamic acid decarboxylase] antibodies and fasting C-peptide in newly diagnosed patients with type 2 diabetes to properly classify the phenotypes," said Dr. Beck-Nielsen, professor and head of the endocrinology research unit at Odense (Denmark) University Hospital. "Measuring C-peptide gives a lot of information."
Patients with the insulinopenic form of type 2 diabetes should receive insulin treatment, those with the hyperinsulinemic form should ideally be treated with a sensitizer drug, while patients with a combination of both defects – classic type 2 diabetes – should be treated according to current recommendations (Diabetes Care 2012;35:1364-79), he said in an interview.
Dr. Beck-Nielsen and his associates studied the first 1,048 Danish patients newly diagnosed with type 2 diabetes by a general practitioner or in an outpatient clinic and enrolled in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) study. The patients averaged 61 years old, and slightly more than half were men.
Initial analysis identified 918 (87%) of the patients with true type 2 diabetes. Another 6% had steroid-associated diabetes; 4% had diabetes secondary to pancreatitis; 3% were positive for GAD antibodies showing they had latent autoimmune diabetes of adulthood (LADA); and a small number of patients had rare disorders.
Among the 918 with true type 2 diabetes, the Odense researchers used data collected on fasting levels of C-peptide and plasma glucose to make a homeostasis model assessment (HOMA2) and derive from it information on insulin sensitivity and beta-cell activity.
Roughly half the patients had classic type 2 diabetes, about a third had the hyperinsulinemic form, and fewer than a quarter had the insulinopenic form (but not type 1 diabetes or LADA). These clusterings appeared independent of age and sex, but patients with classic type 2 diabetes or the hyperinsulinemic form had a greater prevalence of metabolic syndrome and increased waist circumference.
Patients with insulinopenic type 2 diabetes had an average body mass index of 26.9 kg/m2, were sensitive to insulin, and had a relatively low prevalence of cardiovascular disease, compared with the other two types. Cardiovascular disease prevalence was highest among the hyperinsulinemic patients, who were generally obese and had a 25% cardiovascular disease prevalence compared with a 13% rate in those with insulinopenic diabetes, and an 18% rate in those with classic type 2 diabetes.
Dr. Beck-Nielsen said that he has received research support from Novo Nordisk.
On Twitter @mitchelzoler
BARCELONA – Not all type 2 diabetes is the same, and pathophysiologic differences among diabetes subtypes mean that different type 2 patients need different treatment.
"Several specific causes of hyperglycemia are hidden behind the clinical diagnosis of type 2 diabetes," Dr. Henning Beck-Nielsen said at the annual meeting of the European Association for the Study of Diabetes.
"Patients with type 2 diabetes can be divided into three basic pathophysiologic phenotypes: classic type 2 diabetes, insulinopenic type 2 diabetes, and hyperinsulinemic type 2 diabetes." He and his associates identified these and other, less common subtypes by systematically studying more than 1,000 Danish patients newly diagnosed with type 2 diabetes who were entered into a national registry that now totals 40,000 patients.
"We recommend that clinicians measure both GAD [glutamic acid decarboxylase] antibodies and fasting C-peptide in newly diagnosed patients with type 2 diabetes to properly classify the phenotypes," said Dr. Beck-Nielsen, professor and head of the endocrinology research unit at Odense (Denmark) University Hospital. "Measuring C-peptide gives a lot of information."
Patients with the insulinopenic form of type 2 diabetes should receive insulin treatment, those with the hyperinsulinemic form should ideally be treated with a sensitizer drug, while patients with a combination of both defects – classic type 2 diabetes – should be treated according to current recommendations (Diabetes Care 2012;35:1364-79), he said in an interview.
Dr. Beck-Nielsen and his associates studied the first 1,048 Danish patients newly diagnosed with type 2 diabetes by a general practitioner or in an outpatient clinic and enrolled in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) study. The patients averaged 61 years old, and slightly more than half were men.
Initial analysis identified 918 (87%) of the patients with true type 2 diabetes. Another 6% had steroid-associated diabetes; 4% had diabetes secondary to pancreatitis; 3% were positive for GAD antibodies showing they had latent autoimmune diabetes of adulthood (LADA); and a small number of patients had rare disorders.
Among the 918 with true type 2 diabetes, the Odense researchers used data collected on fasting levels of C-peptide and plasma glucose to make a homeostasis model assessment (HOMA2) and derive from it information on insulin sensitivity and beta-cell activity.
Roughly half the patients had classic type 2 diabetes, about a third had the hyperinsulinemic form, and fewer than a quarter had the insulinopenic form (but not type 1 diabetes or LADA). These clusterings appeared independent of age and sex, but patients with classic type 2 diabetes or the hyperinsulinemic form had a greater prevalence of metabolic syndrome and increased waist circumference.
Patients with insulinopenic type 2 diabetes had an average body mass index of 26.9 kg/m2, were sensitive to insulin, and had a relatively low prevalence of cardiovascular disease, compared with the other two types. Cardiovascular disease prevalence was highest among the hyperinsulinemic patients, who were generally obese and had a 25% cardiovascular disease prevalence compared with a 13% rate in those with insulinopenic diabetes, and an 18% rate in those with classic type 2 diabetes.
Dr. Beck-Nielsen said that he has received research support from Novo Nordisk.
On Twitter @mitchelzoler
BARCELONA – Not all type 2 diabetes is the same, and pathophysiologic differences among diabetes subtypes mean that different type 2 patients need different treatment.
"Several specific causes of hyperglycemia are hidden behind the clinical diagnosis of type 2 diabetes," Dr. Henning Beck-Nielsen said at the annual meeting of the European Association for the Study of Diabetes.
"Patients with type 2 diabetes can be divided into three basic pathophysiologic phenotypes: classic type 2 diabetes, insulinopenic type 2 diabetes, and hyperinsulinemic type 2 diabetes." He and his associates identified these and other, less common subtypes by systematically studying more than 1,000 Danish patients newly diagnosed with type 2 diabetes who were entered into a national registry that now totals 40,000 patients.
"We recommend that clinicians measure both GAD [glutamic acid decarboxylase] antibodies and fasting C-peptide in newly diagnosed patients with type 2 diabetes to properly classify the phenotypes," said Dr. Beck-Nielsen, professor and head of the endocrinology research unit at Odense (Denmark) University Hospital. "Measuring C-peptide gives a lot of information."
Patients with the insulinopenic form of type 2 diabetes should receive insulin treatment, those with the hyperinsulinemic form should ideally be treated with a sensitizer drug, while patients with a combination of both defects – classic type 2 diabetes – should be treated according to current recommendations (Diabetes Care 2012;35:1364-79), he said in an interview.
Dr. Beck-Nielsen and his associates studied the first 1,048 Danish patients newly diagnosed with type 2 diabetes by a general practitioner or in an outpatient clinic and enrolled in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) study. The patients averaged 61 years old, and slightly more than half were men.
Initial analysis identified 918 (87%) of the patients with true type 2 diabetes. Another 6% had steroid-associated diabetes; 4% had diabetes secondary to pancreatitis; 3% were positive for GAD antibodies showing they had latent autoimmune diabetes of adulthood (LADA); and a small number of patients had rare disorders.
Among the 918 with true type 2 diabetes, the Odense researchers used data collected on fasting levels of C-peptide and plasma glucose to make a homeostasis model assessment (HOMA2) and derive from it information on insulin sensitivity and beta-cell activity.
Roughly half the patients had classic type 2 diabetes, about a third had the hyperinsulinemic form, and fewer than a quarter had the insulinopenic form (but not type 1 diabetes or LADA). These clusterings appeared independent of age and sex, but patients with classic type 2 diabetes or the hyperinsulinemic form had a greater prevalence of metabolic syndrome and increased waist circumference.
Patients with insulinopenic type 2 diabetes had an average body mass index of 26.9 kg/m2, were sensitive to insulin, and had a relatively low prevalence of cardiovascular disease, compared with the other two types. Cardiovascular disease prevalence was highest among the hyperinsulinemic patients, who were generally obese and had a 25% cardiovascular disease prevalence compared with a 13% rate in those with insulinopenic diabetes, and an 18% rate in those with classic type 2 diabetes.
Dr. Beck-Nielsen said that he has received research support from Novo Nordisk.
On Twitter @mitchelzoler
AT THE EASD ANNUAL MEETING
Major finding: Patients with type 2 diabetes can have an insulinopenic form, a hyperinsulinemic form, or a classic form with both defects.
Data source: The first 1,048 patients enrolled in the Danish Centre for Strategic Research in Type 2 Diabetes study.
Disclosures: Dr. Beck-Nielsen said that he has received research support from Novo Nordisk.
Diabetics face increased treatment-resistant hypertension risk
BARCELONA – Patients with treatment-resistant hypertension and diabetes face a significantly increased risk for major cardiovascular adverse events, compared with those without diabetes, a study has shown.
The combined rate of death, myocardial infarction, and stroke was 6.2% among patients with treatment-resistant hypertension (TRH) and diabetes, and 3.8% in patients with TRH but no diabetes during 2 years of follow-up of more than 8,000 patients enrolled in a German registry, Dr. Stefanie Friedrich reported at the annual meeting of the European Association for the Study of Diabetes.
"Patients with treatment-resistant hypertension, and in particular patients with diabetes, need to have their blood pressure reduced to less than 140/90 mm Hg, combined with other organ-protective therapies, to improve their outcomes," said Dr. Friedrich of the division of nephrology and hypertension at Alexander-Friedrich University in Erlangen-Nürnberg (Germany).
"If you don’t succeed with blood pressure control with drugs, you should move along to another alternative like renal denervation with no inertia," said Dr. Roland E. Schmieder, professor and chief of nephrology and hypertension at the university and a collaborator with Dr. Friedrich on this study. "In this registry nothing happened for many of these resistant patients during 2 years. I would recommend waiting no more than about 6 months if patients remain hypertensive despite maximum medical therapy. If drugs do not succeed after 6 months, you need to go to the next step, which for some patients could be renal denervation," he said in an interview. "This should be the approach for all patients with treatment-resistant hypertension, but especially when patients have diabetes."
Data on renal denervation show that it is as effective in patients with diabetes as in those without diabetes, Dr. Schmieder said. Renal denervation devices first became available for routine European use in 2010, but remain investigational in the United States.
Their study used data collected from the nearly 15,000 patients enrolled in the Registry for Ambulant Therapy With RAS-Inhibitors in Hypertensive-Patients in Germany (3A registry). The registry enrolled patients with either newly diagnosed hypertension or established hypertension that required treatment intensification at 899 physician practices in Germany during October 2008 through April 2009. The study assigned patients to receive aliskiren (Tekturna), an ACE inhibitor, or an angiotensin receptor blocker in a 4:1:1 ratio, but otherwise participating physicians were allowed to manage these patients by whichever regimen they preferred. The current analysis focused on the 8,698 patients from the 3A registry who had 2-year follow-up, and the 2,772 patients from this group with TRH, defined as an office-measured blood pressure of 140/90 mm Hg or higher despite treatment with at least three antihypertensive medications.
The TRH subgroup included 1,170 with either type 1 or type 2 diabetes, 47% of all patients with diabetes followed in the registry for 2 years, and 1,602 patients without diabetes, 26% of the enrolled patients without diabetes followed for 2 years. These TRH prevalence rates show that "resistant hypertension is common in outpatients, especially patients with diabetes," Dr. Friedrich said. At the time they entered the registry, the TRH patients had an average blood pressure of 162/91 mm Hg, with similar averages in both the diabetic and nondiabetic subgroups. At entry, the patients with diabetes averaged 71 years of age, while those without diabetes were an average of 68 years old. The median duration of hypertension was 11 years in the diabetes patients and 8 years in those without diabetes.
After 2 years, 55% of the TRH patients with diabetes and 48% of those without diabetes remained at blood pressures above the goal of less than 140/90 mm Hg. The average level of hemoglobin A1c among the diabetes patients was 6.8% at baseline, and 6.9% after 2 years.
In addition to having a significantly greater rate of combined adverse cardiac and cerebrovascular events at 2 years, the patients with diabetes also had significantly more events for each of the three outcomes included in this composite: The rate of all-cause death was 4.4% in the patients with diabetes and 2.9% in those without; the incidence of myocardial infarction was 1.3% in the diabetes patients and 0.6% in the others; and stroke incidence was 1.4% in the patients with diabetes and 0.8% in those without, Dr. Friedrich reported.
The German 3A registry is sponsored by Novartis. Dr. Friedrich said she had no relevant financial disclosures. Dr. Schmieder has been a consultant to, and a speaker on behalf of, Medtronic, a company that markets a renal denervation device.
On Twitter @mitchelzoler
The relatively high rate of major adverse cardiac and cerebrovascular events seen in patients with diabetes and treatment-resistant hypertension in this study is worrying, but several different approaches could potentially improve outcomes in these patients.
 |
|
The clearest message is that physicians need to do a better job getting their hypertensive patients to take all their prescribed medications. Patients who need four drugs to control their blood pressure will often take only a fraction of the pills they are supposed to take. A lot of treatment-resistant hypertension results from poor patient compliance or physician negligence.
Another option that my colleagues and I have recently explored is slow breathing, at a rate of about 15 breaths per minute, as is often done in yoga. My associates and I published results 2 years ago showing that deep breathing can improve the blunted baroreflex sensitivity often seen in patients with diabetes (Diabetologia 2011;54:1862-70). This approach may also be effective for reducing blood pressure in patients who are not ideally responsive to antihypertensive drugs. With deep breathing, patients can exert some control over their autonomic nervous system.
The relatively high rate of major adverse cardiac and cerebrovascular events seen in patients with diabetes and treatment-resistant hypertension in this study is worrying, but several different approaches could potentially improve outcomes in these patients.
|
|
The clearest message is that physicians need to do a better job getting their hypertensive patients to take all their prescribed medications. Patients who need four drugs to control their blood pressure will often take only a fraction of the pills they are supposed to take. A lot of treatment-resistant hypertension results from poor patient compliance or physician negligence.
Another option that my colleagues and I have recently explored is slow breathing, at a rate of about 15 breaths per minute, as is often done in yoga. My associates and I published results 2 years ago showing that deep breathing can improve the blunted baroreflex sensitivity often seen in patients with diabetes (Diabetologia 2011;54:1862-70). This approach may also be effective for reducing blood pressure in patients who are not ideally responsive to antihypertensive drugs. With deep breathing, patients can exert some control over their autonomic nervous system.
The relatively high rate of major adverse cardiac and cerebrovascular events seen in patients with diabetes and treatment-resistant hypertension in this study is worrying, but several different approaches could potentially improve outcomes in these patients.
|
|
The clearest message is that physicians need to do a better job getting their hypertensive patients to take all their prescribed medications. Patients who need four drugs to control their blood pressure will often take only a fraction of the pills they are supposed to take. A lot of treatment-resistant hypertension results from poor patient compliance or physician negligence.
Another option that my colleagues and I have recently explored is slow breathing, at a rate of about 15 breaths per minute, as is often done in yoga. My associates and I published results 2 years ago showing that deep breathing can improve the blunted baroreflex sensitivity often seen in patients with diabetes (Diabetologia 2011;54:1862-70). This approach may also be effective for reducing blood pressure in patients who are not ideally responsive to antihypertensive drugs. With deep breathing, patients can exert some control over their autonomic nervous system.
BARCELONA – Patients with treatment-resistant hypertension and diabetes face a significantly increased risk for major cardiovascular adverse events, compared with those without diabetes, a study has shown.
The combined rate of death, myocardial infarction, and stroke was 6.2% among patients with treatment-resistant hypertension (TRH) and diabetes, and 3.8% in patients with TRH but no diabetes during 2 years of follow-up of more than 8,000 patients enrolled in a German registry, Dr. Stefanie Friedrich reported at the annual meeting of the European Association for the Study of Diabetes.
"Patients with treatment-resistant hypertension, and in particular patients with diabetes, need to have their blood pressure reduced to less than 140/90 mm Hg, combined with other organ-protective therapies, to improve their outcomes," said Dr. Friedrich of the division of nephrology and hypertension at Alexander-Friedrich University in Erlangen-Nürnberg (Germany).
"If you don’t succeed with blood pressure control with drugs, you should move along to another alternative like renal denervation with no inertia," said Dr. Roland E. Schmieder, professor and chief of nephrology and hypertension at the university and a collaborator with Dr. Friedrich on this study. "In this registry nothing happened for many of these resistant patients during 2 years. I would recommend waiting no more than about 6 months if patients remain hypertensive despite maximum medical therapy. If drugs do not succeed after 6 months, you need to go to the next step, which for some patients could be renal denervation," he said in an interview. "This should be the approach for all patients with treatment-resistant hypertension, but especially when patients have diabetes."
Data on renal denervation show that it is as effective in patients with diabetes as in those without diabetes, Dr. Schmieder said. Renal denervation devices first became available for routine European use in 2010, but remain investigational in the United States.
Their study used data collected from the nearly 15,000 patients enrolled in the Registry for Ambulant Therapy With RAS-Inhibitors in Hypertensive-Patients in Germany (3A registry). The registry enrolled patients with either newly diagnosed hypertension or established hypertension that required treatment intensification at 899 physician practices in Germany during October 2008 through April 2009. The study assigned patients to receive aliskiren (Tekturna), an ACE inhibitor, or an angiotensin receptor blocker in a 4:1:1 ratio, but otherwise participating physicians were allowed to manage these patients by whichever regimen they preferred. The current analysis focused on the 8,698 patients from the 3A registry who had 2-year follow-up, and the 2,772 patients from this group with TRH, defined as an office-measured blood pressure of 140/90 mm Hg or higher despite treatment with at least three antihypertensive medications.
The TRH subgroup included 1,170 with either type 1 or type 2 diabetes, 47% of all patients with diabetes followed in the registry for 2 years, and 1,602 patients without diabetes, 26% of the enrolled patients without diabetes followed for 2 years. These TRH prevalence rates show that "resistant hypertension is common in outpatients, especially patients with diabetes," Dr. Friedrich said. At the time they entered the registry, the TRH patients had an average blood pressure of 162/91 mm Hg, with similar averages in both the diabetic and nondiabetic subgroups. At entry, the patients with diabetes averaged 71 years of age, while those without diabetes were an average of 68 years old. The median duration of hypertension was 11 years in the diabetes patients and 8 years in those without diabetes.
After 2 years, 55% of the TRH patients with diabetes and 48% of those without diabetes remained at blood pressures above the goal of less than 140/90 mm Hg. The average level of hemoglobin A1c among the diabetes patients was 6.8% at baseline, and 6.9% after 2 years.
In addition to having a significantly greater rate of combined adverse cardiac and cerebrovascular events at 2 years, the patients with diabetes also had significantly more events for each of the three outcomes included in this composite: The rate of all-cause death was 4.4% in the patients with diabetes and 2.9% in those without; the incidence of myocardial infarction was 1.3% in the diabetes patients and 0.6% in the others; and stroke incidence was 1.4% in the patients with diabetes and 0.8% in those without, Dr. Friedrich reported.
The German 3A registry is sponsored by Novartis. Dr. Friedrich said she had no relevant financial disclosures. Dr. Schmieder has been a consultant to, and a speaker on behalf of, Medtronic, a company that markets a renal denervation device.
On Twitter @mitchelzoler
BARCELONA – Patients with treatment-resistant hypertension and diabetes face a significantly increased risk for major cardiovascular adverse events, compared with those without diabetes, a study has shown.
The combined rate of death, myocardial infarction, and stroke was 6.2% among patients with treatment-resistant hypertension (TRH) and diabetes, and 3.8% in patients with TRH but no diabetes during 2 years of follow-up of more than 8,000 patients enrolled in a German registry, Dr. Stefanie Friedrich reported at the annual meeting of the European Association for the Study of Diabetes.
"Patients with treatment-resistant hypertension, and in particular patients with diabetes, need to have their blood pressure reduced to less than 140/90 mm Hg, combined with other organ-protective therapies, to improve their outcomes," said Dr. Friedrich of the division of nephrology and hypertension at Alexander-Friedrich University in Erlangen-Nürnberg (Germany).
"If you don’t succeed with blood pressure control with drugs, you should move along to another alternative like renal denervation with no inertia," said Dr. Roland E. Schmieder, professor and chief of nephrology and hypertension at the university and a collaborator with Dr. Friedrich on this study. "In this registry nothing happened for many of these resistant patients during 2 years. I would recommend waiting no more than about 6 months if patients remain hypertensive despite maximum medical therapy. If drugs do not succeed after 6 months, you need to go to the next step, which for some patients could be renal denervation," he said in an interview. "This should be the approach for all patients with treatment-resistant hypertension, but especially when patients have diabetes."
Data on renal denervation show that it is as effective in patients with diabetes as in those without diabetes, Dr. Schmieder said. Renal denervation devices first became available for routine European use in 2010, but remain investigational in the United States.
Their study used data collected from the nearly 15,000 patients enrolled in the Registry for Ambulant Therapy With RAS-Inhibitors in Hypertensive-Patients in Germany (3A registry). The registry enrolled patients with either newly diagnosed hypertension or established hypertension that required treatment intensification at 899 physician practices in Germany during October 2008 through April 2009. The study assigned patients to receive aliskiren (Tekturna), an ACE inhibitor, or an angiotensin receptor blocker in a 4:1:1 ratio, but otherwise participating physicians were allowed to manage these patients by whichever regimen they preferred. The current analysis focused on the 8,698 patients from the 3A registry who had 2-year follow-up, and the 2,772 patients from this group with TRH, defined as an office-measured blood pressure of 140/90 mm Hg or higher despite treatment with at least three antihypertensive medications.
The TRH subgroup included 1,170 with either type 1 or type 2 diabetes, 47% of all patients with diabetes followed in the registry for 2 years, and 1,602 patients without diabetes, 26% of the enrolled patients without diabetes followed for 2 years. These TRH prevalence rates show that "resistant hypertension is common in outpatients, especially patients with diabetes," Dr. Friedrich said. At the time they entered the registry, the TRH patients had an average blood pressure of 162/91 mm Hg, with similar averages in both the diabetic and nondiabetic subgroups. At entry, the patients with diabetes averaged 71 years of age, while those without diabetes were an average of 68 years old. The median duration of hypertension was 11 years in the diabetes patients and 8 years in those without diabetes.
After 2 years, 55% of the TRH patients with diabetes and 48% of those without diabetes remained at blood pressures above the goal of less than 140/90 mm Hg. The average level of hemoglobin A1c among the diabetes patients was 6.8% at baseline, and 6.9% after 2 years.
In addition to having a significantly greater rate of combined adverse cardiac and cerebrovascular events at 2 years, the patients with diabetes also had significantly more events for each of the three outcomes included in this composite: The rate of all-cause death was 4.4% in the patients with diabetes and 2.9% in those without; the incidence of myocardial infarction was 1.3% in the diabetes patients and 0.6% in the others; and stroke incidence was 1.4% in the patients with diabetes and 0.8% in those without, Dr. Friedrich reported.
The German 3A registry is sponsored by Novartis. Dr. Friedrich said she had no relevant financial disclosures. Dr. Schmieder has been a consultant to, and a speaker on behalf of, Medtronic, a company that markets a renal denervation device.
On Twitter @mitchelzoler
AT THE EASD ANNUAL MEETING
Major finding: Diabetes patients with treatment-resistant hypertension had a 6.2% combined rate of death, myocardial infarction, and stroke over a 2-year period, compared with a 3.8% rate in nondiabetics.
Data source: The 3A registry, which enrolled nearly 15,000 patients with diabetes from 899 physician practices in Germany.
Disclosures: The German 3A registry is sponsored by Novartis. Dr. Friedrich said she had no relevant financial disclosures. Dr. Schmieder has been a consultant to, and a speaker on behalf of, Medtronic, which markets a renal denervation device.
