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Mitchel is a reporter for MDedge based in the Philadelphia area. He started with the company in 1992, when it was International Medical News Group (IMNG), and has since covered a range of medical specialties. Mitchel trained as a virologist at Roswell Park Memorial Institute in Buffalo, and then worked briefly as a researcher at Boston Children's Hospital before pivoting to journalism as a AAAS Mass Media Fellow in 1980. His first reporting job was with Science Digest magazine, and from the mid-1980s to early-1990s he was a reporter with Medical World News. @mitchelzoler
Fibromyalgia patients may harbor fewer small-nerve fibers
BARCELONA – Many patients with fibromyalgia syndrome have an unusually low number of small-nerve fibers in their skin, a finding that may provide important new insights into the pathology, etiology, and possible treatment of what has been a poorly understood disorder, according to Dr. Claudia Sommer.
"With three different methods, we showed pathologic changes in small-nerve fibers" in the skin of patients diagnosed with fibromyalgia, she said at the annual congress of the European College of Neuropsychopharmacology. These somatic findings are too strong to allow classification of these patients with fibromyalgia as having a "somatoform pain disorder." She suggested that the nerve deficits in patients’ skin could reflect systemic nerve damage that causes the deep pain that fibromyalgia patients have in muscles, tendons, and joints. "What we see in the skin may also exist elsewhere," said Dr. Sommer, professor of neurology at the University Clinic of Würzburg (Germany).
Three other, independent research groups have recently made similar findings of small-nerve deficits in the skin of fibromyalgia patients, including researchers at Massachusetts General Hospital in Boston (Pain 2013;154:2310-6), further boosting the likelihood that impaired small-nerve function is real and a key feature of at least some fibromyalgia patients, Dr. Sommer said.
The finding led her to develop a new model for the pathogenesis of these cases: An adverse life event or other predisposing factor leads to a more proinflammatory cytokine profile that causes small-nerve fiber damage and ongoing pain system activity that produces central sensitization and changes in central pain processing.
"This is just a model, but we can work on this and test hypotheses," she said. "We are a long way from finding new treatments, but trying to understand what causes damage to nerve fibers may give a start, something a new treatment could be directed against."
Dr. Sommer and her associates studied 25 patients who had been diagnosed with fibromyalgia, 10 diagnosed with unipolar depression, and 25 healthy controls who were matched by age and sex with the fibromyalgia patients. The participants ranged from 39 to 75 years old, and those with either depression or fibromyalgia had been diagnosed for an average of more than 20 years.
Compared with the controls, patients with fibromyalgia had significantly increased detection thresholds to warm and cold when quantitative sensory testing was used, while the depressed patients had no significant difference compared with the controls. Measurement of pain-related evoked potentials showed increased latency on stimulation of the feet and reduced amplitudes on stimulation of the feet, hands, and face in fibromyalgia patients compared with both the controls and the patients with depression.
The researchers also found reduced numbers of total and regenerating intraepidermal, unmyelinated nerve fibers in skin biopsies from the lower leg and upper thigh of the patients with fibromyalgia compared with the controls and the patients with depression. The nerve fiber count averaged 5 fibers/mm2 in the patients with fibromyalgia, about 7/mm2 in patients with depression, and about 8/mm2 in the controls. The difference between the fibromyalgia patients and the controls was statistically significant.
Dr. Sommer and her associates also published these results in Brain (2013;136:1857-67).
Dr. Sommer said she has received honoraria for being a speaker on behalf of Allergan, Astella, Baxter, CSL Behring, Eli Lilly, Genzyme, GlaxoSmithKline, and Pfizer.
On Twitter @mitchelzoler
BARCELONA – Many patients with fibromyalgia syndrome have an unusually low number of small-nerve fibers in their skin, a finding that may provide important new insights into the pathology, etiology, and possible treatment of what has been a poorly understood disorder, according to Dr. Claudia Sommer.
"With three different methods, we showed pathologic changes in small-nerve fibers" in the skin of patients diagnosed with fibromyalgia, she said at the annual congress of the European College of Neuropsychopharmacology. These somatic findings are too strong to allow classification of these patients with fibromyalgia as having a "somatoform pain disorder." She suggested that the nerve deficits in patients’ skin could reflect systemic nerve damage that causes the deep pain that fibromyalgia patients have in muscles, tendons, and joints. "What we see in the skin may also exist elsewhere," said Dr. Sommer, professor of neurology at the University Clinic of Würzburg (Germany).
Three other, independent research groups have recently made similar findings of small-nerve deficits in the skin of fibromyalgia patients, including researchers at Massachusetts General Hospital in Boston (Pain 2013;154:2310-6), further boosting the likelihood that impaired small-nerve function is real and a key feature of at least some fibromyalgia patients, Dr. Sommer said.
The finding led her to develop a new model for the pathogenesis of these cases: An adverse life event or other predisposing factor leads to a more proinflammatory cytokine profile that causes small-nerve fiber damage and ongoing pain system activity that produces central sensitization and changes in central pain processing.
"This is just a model, but we can work on this and test hypotheses," she said. "We are a long way from finding new treatments, but trying to understand what causes damage to nerve fibers may give a start, something a new treatment could be directed against."
Dr. Sommer and her associates studied 25 patients who had been diagnosed with fibromyalgia, 10 diagnosed with unipolar depression, and 25 healthy controls who were matched by age and sex with the fibromyalgia patients. The participants ranged from 39 to 75 years old, and those with either depression or fibromyalgia had been diagnosed for an average of more than 20 years.
Compared with the controls, patients with fibromyalgia had significantly increased detection thresholds to warm and cold when quantitative sensory testing was used, while the depressed patients had no significant difference compared with the controls. Measurement of pain-related evoked potentials showed increased latency on stimulation of the feet and reduced amplitudes on stimulation of the feet, hands, and face in fibromyalgia patients compared with both the controls and the patients with depression.
The researchers also found reduced numbers of total and regenerating intraepidermal, unmyelinated nerve fibers in skin biopsies from the lower leg and upper thigh of the patients with fibromyalgia compared with the controls and the patients with depression. The nerve fiber count averaged 5 fibers/mm2 in the patients with fibromyalgia, about 7/mm2 in patients with depression, and about 8/mm2 in the controls. The difference between the fibromyalgia patients and the controls was statistically significant.
Dr. Sommer and her associates also published these results in Brain (2013;136:1857-67).
Dr. Sommer said she has received honoraria for being a speaker on behalf of Allergan, Astella, Baxter, CSL Behring, Eli Lilly, Genzyme, GlaxoSmithKline, and Pfizer.
On Twitter @mitchelzoler
BARCELONA – Many patients with fibromyalgia syndrome have an unusually low number of small-nerve fibers in their skin, a finding that may provide important new insights into the pathology, etiology, and possible treatment of what has been a poorly understood disorder, according to Dr. Claudia Sommer.
"With three different methods, we showed pathologic changes in small-nerve fibers" in the skin of patients diagnosed with fibromyalgia, she said at the annual congress of the European College of Neuropsychopharmacology. These somatic findings are too strong to allow classification of these patients with fibromyalgia as having a "somatoform pain disorder." She suggested that the nerve deficits in patients’ skin could reflect systemic nerve damage that causes the deep pain that fibromyalgia patients have in muscles, tendons, and joints. "What we see in the skin may also exist elsewhere," said Dr. Sommer, professor of neurology at the University Clinic of Würzburg (Germany).
Three other, independent research groups have recently made similar findings of small-nerve deficits in the skin of fibromyalgia patients, including researchers at Massachusetts General Hospital in Boston (Pain 2013;154:2310-6), further boosting the likelihood that impaired small-nerve function is real and a key feature of at least some fibromyalgia patients, Dr. Sommer said.
The finding led her to develop a new model for the pathogenesis of these cases: An adverse life event or other predisposing factor leads to a more proinflammatory cytokine profile that causes small-nerve fiber damage and ongoing pain system activity that produces central sensitization and changes in central pain processing.
"This is just a model, but we can work on this and test hypotheses," she said. "We are a long way from finding new treatments, but trying to understand what causes damage to nerve fibers may give a start, something a new treatment could be directed against."
Dr. Sommer and her associates studied 25 patients who had been diagnosed with fibromyalgia, 10 diagnosed with unipolar depression, and 25 healthy controls who were matched by age and sex with the fibromyalgia patients. The participants ranged from 39 to 75 years old, and those with either depression or fibromyalgia had been diagnosed for an average of more than 20 years.
Compared with the controls, patients with fibromyalgia had significantly increased detection thresholds to warm and cold when quantitative sensory testing was used, while the depressed patients had no significant difference compared with the controls. Measurement of pain-related evoked potentials showed increased latency on stimulation of the feet and reduced amplitudes on stimulation of the feet, hands, and face in fibromyalgia patients compared with both the controls and the patients with depression.
The researchers also found reduced numbers of total and regenerating intraepidermal, unmyelinated nerve fibers in skin biopsies from the lower leg and upper thigh of the patients with fibromyalgia compared with the controls and the patients with depression. The nerve fiber count averaged 5 fibers/mm2 in the patients with fibromyalgia, about 7/mm2 in patients with depression, and about 8/mm2 in the controls. The difference between the fibromyalgia patients and the controls was statistically significant.
Dr. Sommer and her associates also published these results in Brain (2013;136:1857-67).
Dr. Sommer said she has received honoraria for being a speaker on behalf of Allergan, Astella, Baxter, CSL Behring, Eli Lilly, Genzyme, GlaxoSmithKline, and Pfizer.
On Twitter @mitchelzoler
AT THE ECNP CONGRESS
Major finding: Skin biopsies from patients with fibromyalgia averaged 5 fibers/mm2 compared with 8 fibers/mm2 in matched control patients.
Data source: A single-center study of 25 adults diagnosed with fibromyalgia syndrome and 25 healthy controls matched by age and sex.
Disclosures: Dr. Sommer that she has received honoraria for being a speaker on behalf of Allergan, Astella, Baxter, CSL Behring, Eli Lilly, Genzyme, GlaxoSmithKline, and Pfizer.
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.
Did the DSM-5 pathologize what’s normal?
Some elements of the DSM-5, released nearly 6 months ago now, follow a tricky path between giving the psychiatric community useful, new diagnostic tools and pathologizing what is part of the normal range of human behavior, but despite that, the manual seems to generally succeed in "better classifying the patients who come to psychiatrists," said Dr. Guy Goodwin, head of the psychiatry department at the University of Oxford (England).
Dr. Goodwin spoke in an unusual press conference during the annual Congress of the European College of Neuropsychopharmacology (ECNP) in Barcelona in October. The topic was the still somewhat new Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), and the role of diagnosis in psychiatry, which did not link to any report or talk at the meeting. The press conference seemed mostly a way for Dr. Goodwin, who became president of the ECNP during the meeting, and two other participants to give their thoughts on the DSM-5 and shifting views on psychiatric diagnoses, especially in children.
Dr. Goodwin ultimately called himself "sort of pro-DSM-5" and said that the key test of whether the diagnostic changes made by the DSM-5 were a step forward or not will come with time, as psychiatrists determine whether following the DSM-5 results in better diagnosis and patient care.
He offered an example of what he said some have characterized as a disorder "invented" by the DSM-5, disruptive mood dysregulation disorder (DMDD). It was an interesting choice for Dr. Goodwin to highlight, as he is not a pediatric specialist, although he noted it ties to his practice of treating patients with bipolar disorder because DMDD was designed as a replacement diagnosis for many children previously diagnosed with bipolar disorder. DMDD also has a history of controversy going back several years to when the DSM-5 writing group struggled with how to deal with what many saw as overdiagnosis of bipolar disease in children.
The DSM-5 "is trying to stop" the diagnosis of bipolar disease by U.S. psychiatrists in children as young as 3 years old "by inventing a disorder that describes these problematic children." DMDD is "a diagnosis that takes you into areas of judgment that many people are uncomfortable with," such as deciding whether outbursts by children are "grossly out of proportion" to the situation, Dr. Goodwin said. "It’s specific to the United States, and I think the rest of the world has difficulty with this. You’ve added another diagnosis that’s carved out of normal childhood experience. This is the difficulty for people with the perspective that all diagnoses are bad labels."
But Dr. Goodwin also noted that the DSM-5 "set the bar high" when designing the diagnosis. "U.S. psychiatrists see this as a way to stop the pathologizing of normal life" by creating a high threshold for diagnosis that is rarely met.
Dr. Goodwin also stressed that psychiatric diagnoses are not inherently bad for patients. Research findings, including work he collaborated on, showed that patients generally welcome a diagnosis and don’t feel stigmatized by it.
"Diagnoses are useful, because they give patients a starting point for understanding their problems and give clinicians a starting point for understanding" the best way to manage each patient, he said. "What patients want is an explanation of their situation."
A second speaker at the press conference, Dr. Celso Arango, head of child and adolescent psychiatry at a university hospital in Madrid and president-elect of ECNP, offered his own take on diagnosing psychiatric disorders in children that indirectly added another dimension to questions about DMDD’s validity and role.
Although psychiatric disorders are usually first diagnosed in adults, "they start much earlier. More than 70% of mental illnesses present first symptoms during childhood," said Dr. Arango. "The earlier we intervene, the lower the risk of a more severe disorder." He cited recent study results documenting the cost effectiveness of early intervention in children diagnosed with psychosis.
The DMDD diagnosis "may or may not be useful. If you count kids with this new diagnosis and find that it’s useful, that it’s a precursor for later problems, and is something we need to take seriously and treat, then it may be a prelude to successful intervention," Dr. Goodwin said.
On Twitter @mitchelzoler
Some elements of the DSM-5, released nearly 6 months ago now, follow a tricky path between giving the psychiatric community useful, new diagnostic tools and pathologizing what is part of the normal range of human behavior, but despite that, the manual seems to generally succeed in "better classifying the patients who come to psychiatrists," said Dr. Guy Goodwin, head of the psychiatry department at the University of Oxford (England).
Dr. Goodwin spoke in an unusual press conference during the annual Congress of the European College of Neuropsychopharmacology (ECNP) in Barcelona in October. The topic was the still somewhat new Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), and the role of diagnosis in psychiatry, which did not link to any report or talk at the meeting. The press conference seemed mostly a way for Dr. Goodwin, who became president of the ECNP during the meeting, and two other participants to give their thoughts on the DSM-5 and shifting views on psychiatric diagnoses, especially in children.
Dr. Goodwin ultimately called himself "sort of pro-DSM-5" and said that the key test of whether the diagnostic changes made by the DSM-5 were a step forward or not will come with time, as psychiatrists determine whether following the DSM-5 results in better diagnosis and patient care.
He offered an example of what he said some have characterized as a disorder "invented" by the DSM-5, disruptive mood dysregulation disorder (DMDD). It was an interesting choice for Dr. Goodwin to highlight, as he is not a pediatric specialist, although he noted it ties to his practice of treating patients with bipolar disorder because DMDD was designed as a replacement diagnosis for many children previously diagnosed with bipolar disorder. DMDD also has a history of controversy going back several years to when the DSM-5 writing group struggled with how to deal with what many saw as overdiagnosis of bipolar disease in children.
The DSM-5 "is trying to stop" the diagnosis of bipolar disease by U.S. psychiatrists in children as young as 3 years old "by inventing a disorder that describes these problematic children." DMDD is "a diagnosis that takes you into areas of judgment that many people are uncomfortable with," such as deciding whether outbursts by children are "grossly out of proportion" to the situation, Dr. Goodwin said. "It’s specific to the United States, and I think the rest of the world has difficulty with this. You’ve added another diagnosis that’s carved out of normal childhood experience. This is the difficulty for people with the perspective that all diagnoses are bad labels."
But Dr. Goodwin also noted that the DSM-5 "set the bar high" when designing the diagnosis. "U.S. psychiatrists see this as a way to stop the pathologizing of normal life" by creating a high threshold for diagnosis that is rarely met.
Dr. Goodwin also stressed that psychiatric diagnoses are not inherently bad for patients. Research findings, including work he collaborated on, showed that patients generally welcome a diagnosis and don’t feel stigmatized by it.
"Diagnoses are useful, because they give patients a starting point for understanding their problems and give clinicians a starting point for understanding" the best way to manage each patient, he said. "What patients want is an explanation of their situation."
A second speaker at the press conference, Dr. Celso Arango, head of child and adolescent psychiatry at a university hospital in Madrid and president-elect of ECNP, offered his own take on diagnosing psychiatric disorders in children that indirectly added another dimension to questions about DMDD’s validity and role.
Although psychiatric disorders are usually first diagnosed in adults, "they start much earlier. More than 70% of mental illnesses present first symptoms during childhood," said Dr. Arango. "The earlier we intervene, the lower the risk of a more severe disorder." He cited recent study results documenting the cost effectiveness of early intervention in children diagnosed with psychosis.
The DMDD diagnosis "may or may not be useful. If you count kids with this new diagnosis and find that it’s useful, that it’s a precursor for later problems, and is something we need to take seriously and treat, then it may be a prelude to successful intervention," Dr. Goodwin said.
On Twitter @mitchelzoler
Some elements of the DSM-5, released nearly 6 months ago now, follow a tricky path between giving the psychiatric community useful, new diagnostic tools and pathologizing what is part of the normal range of human behavior, but despite that, the manual seems to generally succeed in "better classifying the patients who come to psychiatrists," said Dr. Guy Goodwin, head of the psychiatry department at the University of Oxford (England).
Dr. Goodwin spoke in an unusual press conference during the annual Congress of the European College of Neuropsychopharmacology (ECNP) in Barcelona in October. The topic was the still somewhat new Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), and the role of diagnosis in psychiatry, which did not link to any report or talk at the meeting. The press conference seemed mostly a way for Dr. Goodwin, who became president of the ECNP during the meeting, and two other participants to give their thoughts on the DSM-5 and shifting views on psychiatric diagnoses, especially in children.
Dr. Goodwin ultimately called himself "sort of pro-DSM-5" and said that the key test of whether the diagnostic changes made by the DSM-5 were a step forward or not will come with time, as psychiatrists determine whether following the DSM-5 results in better diagnosis and patient care.
He offered an example of what he said some have characterized as a disorder "invented" by the DSM-5, disruptive mood dysregulation disorder (DMDD). It was an interesting choice for Dr. Goodwin to highlight, as he is not a pediatric specialist, although he noted it ties to his practice of treating patients with bipolar disorder because DMDD was designed as a replacement diagnosis for many children previously diagnosed with bipolar disorder. DMDD also has a history of controversy going back several years to when the DSM-5 writing group struggled with how to deal with what many saw as overdiagnosis of bipolar disease in children.
The DSM-5 "is trying to stop" the diagnosis of bipolar disease by U.S. psychiatrists in children as young as 3 years old "by inventing a disorder that describes these problematic children." DMDD is "a diagnosis that takes you into areas of judgment that many people are uncomfortable with," such as deciding whether outbursts by children are "grossly out of proportion" to the situation, Dr. Goodwin said. "It’s specific to the United States, and I think the rest of the world has difficulty with this. You’ve added another diagnosis that’s carved out of normal childhood experience. This is the difficulty for people with the perspective that all diagnoses are bad labels."
But Dr. Goodwin also noted that the DSM-5 "set the bar high" when designing the diagnosis. "U.S. psychiatrists see this as a way to stop the pathologizing of normal life" by creating a high threshold for diagnosis that is rarely met.
Dr. Goodwin also stressed that psychiatric diagnoses are not inherently bad for patients. Research findings, including work he collaborated on, showed that patients generally welcome a diagnosis and don’t feel stigmatized by it.
"Diagnoses are useful, because they give patients a starting point for understanding their problems and give clinicians a starting point for understanding" the best way to manage each patient, he said. "What patients want is an explanation of their situation."
A second speaker at the press conference, Dr. Celso Arango, head of child and adolescent psychiatry at a university hospital in Madrid and president-elect of ECNP, offered his own take on diagnosing psychiatric disorders in children that indirectly added another dimension to questions about DMDD’s validity and role.
Although psychiatric disorders are usually first diagnosed in adults, "they start much earlier. More than 70% of mental illnesses present first symptoms during childhood," said Dr. Arango. "The earlier we intervene, the lower the risk of a more severe disorder." He cited recent study results documenting the cost effectiveness of early intervention in children diagnosed with psychosis.
The DMDD diagnosis "may or may not be useful. If you count kids with this new diagnosis and find that it’s useful, that it’s a precursor for later problems, and is something we need to take seriously and treat, then it may be a prelude to successful intervention," Dr. Goodwin said.
On Twitter @mitchelzoler
NMDA blocker lanicemine safely reduces depression
BARCELONA – Lanicemine, a new drug active in the glutamate neurotransmitter system, showed safety and efficacy for treating major depressive disorder during 3 weeks of treatment in a multicenter, U.S. phase II study with 152 patients.
In addition, 3 weeks of lanicemine treatment did not result in any marked psychomimetic effects such as those produced by ketamine, an anesthetic and related drug that first showed clinical antidepressant effects more than a decade ago and led to lanicemine’s testing, Dr. Gerard Sanacora said at the annual congress of the European College of Neuropsychopharmacology.
With the new lanicemine results, "I think we’re getting closer to a proof of concept that an NMDA [N-methyl-D-aspartate] receptor antagonist could be useful for development of antidepressant drugs," said Dr. Sanacora, professor of psychiatry and director of the depression research program at Yale University in New Haven, Conn.
"The results are encouraging. The study adds a lot" to addressing whether treatments targeted at the NMDA receptor can help patients with mood disorder, he said in an interview.
The study enrolled 152 patients diagnosed with major depressive disorder and poor responses to at least two antidepressants at 30 U.S. centers. While patients remained on their entry drugs, the researchers administered 100 or 150 mg lanicemine or placebo as an intravenous infusion three times a week for 3 weeks. At 3 weeks, the change from baseline in total Montgomery Åsberg Depression Rating Scale (MADRS) score, the primary endpoint, was about a 13-point decline with either dosage of lanicemine and a decline of about 8 points with placebo, a 5-point increased reduction with either lanicemine dosage that was statistically significant for each dosage.
The 100-mg dosage showed more consistent efficacy than the higher dosage. The 100-mg dosage produced significantly greater reductions from baseline, compared with placebo after 2 weeks on treatment, and also at 4 and 5 weeks after treatment began, when patients no longer received infusions. The higher lanicemine dosage did not show significant effects compared with placebo at these other time points.
Lanicemine treatment, especially the 100-mg dosage, also showed efficacy by several secondary measures. For example, the proportion of patients who recorded a clinical global impression of much improved or very much improved was 65% with the 100-mg dosage at weeks 3, 4, and 5 after treatment began, significantly better than the 25%-30% rates at the same time points in the placebo group. Dr. Sanacora and his associates also published their results online (Mol. Psychiatry 2013 [doi:10.1038/mp.2013.130]).
During the study, neither lanicemine dosage produced any clinically meaningful difference compared with placebo for dissociative symptoms, and lanicemine was generally well tolerated. The most common adverse effect was dizziness around the time of infusion, which occurred in a third to half of the lanicemine patients, compared with 12% of those on placebo. Lanicemine "looked dramatically different from ketamine," Dr. Sanacora said.
He also downplayed the barrier that treatment by infusion presents. "There is such an unmet need" for patients with severe depression who fail to respond to existing drugs that infusion is not a major issue, he said. But "several companies are trying to develop novel formulations of NMDA receptor–targeted drugs" that might be active orally or intranasally.
The study was funded by AstraZeneca, the company developing lanicemine. Dr. Sanacora said he has been a consultant to and has received research support from AstraZeneca and several other drug companies. Some of Dr. Sanacora’s associates on this study were AstraZeneca employees.
On Twitter @mitchelzoler
BARCELONA – Lanicemine, a new drug active in the glutamate neurotransmitter system, showed safety and efficacy for treating major depressive disorder during 3 weeks of treatment in a multicenter, U.S. phase II study with 152 patients.
In addition, 3 weeks of lanicemine treatment did not result in any marked psychomimetic effects such as those produced by ketamine, an anesthetic and related drug that first showed clinical antidepressant effects more than a decade ago and led to lanicemine’s testing, Dr. Gerard Sanacora said at the annual congress of the European College of Neuropsychopharmacology.
With the new lanicemine results, "I think we’re getting closer to a proof of concept that an NMDA [N-methyl-D-aspartate] receptor antagonist could be useful for development of antidepressant drugs," said Dr. Sanacora, professor of psychiatry and director of the depression research program at Yale University in New Haven, Conn.
"The results are encouraging. The study adds a lot" to addressing whether treatments targeted at the NMDA receptor can help patients with mood disorder, he said in an interview.
The study enrolled 152 patients diagnosed with major depressive disorder and poor responses to at least two antidepressants at 30 U.S. centers. While patients remained on their entry drugs, the researchers administered 100 or 150 mg lanicemine or placebo as an intravenous infusion three times a week for 3 weeks. At 3 weeks, the change from baseline in total Montgomery Åsberg Depression Rating Scale (MADRS) score, the primary endpoint, was about a 13-point decline with either dosage of lanicemine and a decline of about 8 points with placebo, a 5-point increased reduction with either lanicemine dosage that was statistically significant for each dosage.
The 100-mg dosage showed more consistent efficacy than the higher dosage. The 100-mg dosage produced significantly greater reductions from baseline, compared with placebo after 2 weeks on treatment, and also at 4 and 5 weeks after treatment began, when patients no longer received infusions. The higher lanicemine dosage did not show significant effects compared with placebo at these other time points.
Lanicemine treatment, especially the 100-mg dosage, also showed efficacy by several secondary measures. For example, the proportion of patients who recorded a clinical global impression of much improved or very much improved was 65% with the 100-mg dosage at weeks 3, 4, and 5 after treatment began, significantly better than the 25%-30% rates at the same time points in the placebo group. Dr. Sanacora and his associates also published their results online (Mol. Psychiatry 2013 [doi:10.1038/mp.2013.130]).
During the study, neither lanicemine dosage produced any clinically meaningful difference compared with placebo for dissociative symptoms, and lanicemine was generally well tolerated. The most common adverse effect was dizziness around the time of infusion, which occurred in a third to half of the lanicemine patients, compared with 12% of those on placebo. Lanicemine "looked dramatically different from ketamine," Dr. Sanacora said.
He also downplayed the barrier that treatment by infusion presents. "There is such an unmet need" for patients with severe depression who fail to respond to existing drugs that infusion is not a major issue, he said. But "several companies are trying to develop novel formulations of NMDA receptor–targeted drugs" that might be active orally or intranasally.
The study was funded by AstraZeneca, the company developing lanicemine. Dr. Sanacora said he has been a consultant to and has received research support from AstraZeneca and several other drug companies. Some of Dr. Sanacora’s associates on this study were AstraZeneca employees.
On Twitter @mitchelzoler
BARCELONA – Lanicemine, a new drug active in the glutamate neurotransmitter system, showed safety and efficacy for treating major depressive disorder during 3 weeks of treatment in a multicenter, U.S. phase II study with 152 patients.
In addition, 3 weeks of lanicemine treatment did not result in any marked psychomimetic effects such as those produced by ketamine, an anesthetic and related drug that first showed clinical antidepressant effects more than a decade ago and led to lanicemine’s testing, Dr. Gerard Sanacora said at the annual congress of the European College of Neuropsychopharmacology.
With the new lanicemine results, "I think we’re getting closer to a proof of concept that an NMDA [N-methyl-D-aspartate] receptor antagonist could be useful for development of antidepressant drugs," said Dr. Sanacora, professor of psychiatry and director of the depression research program at Yale University in New Haven, Conn.
"The results are encouraging. The study adds a lot" to addressing whether treatments targeted at the NMDA receptor can help patients with mood disorder, he said in an interview.
The study enrolled 152 patients diagnosed with major depressive disorder and poor responses to at least two antidepressants at 30 U.S. centers. While patients remained on their entry drugs, the researchers administered 100 or 150 mg lanicemine or placebo as an intravenous infusion three times a week for 3 weeks. At 3 weeks, the change from baseline in total Montgomery Åsberg Depression Rating Scale (MADRS) score, the primary endpoint, was about a 13-point decline with either dosage of lanicemine and a decline of about 8 points with placebo, a 5-point increased reduction with either lanicemine dosage that was statistically significant for each dosage.
The 100-mg dosage showed more consistent efficacy than the higher dosage. The 100-mg dosage produced significantly greater reductions from baseline, compared with placebo after 2 weeks on treatment, and also at 4 and 5 weeks after treatment began, when patients no longer received infusions. The higher lanicemine dosage did not show significant effects compared with placebo at these other time points.
Lanicemine treatment, especially the 100-mg dosage, also showed efficacy by several secondary measures. For example, the proportion of patients who recorded a clinical global impression of much improved or very much improved was 65% with the 100-mg dosage at weeks 3, 4, and 5 after treatment began, significantly better than the 25%-30% rates at the same time points in the placebo group. Dr. Sanacora and his associates also published their results online (Mol. Psychiatry 2013 [doi:10.1038/mp.2013.130]).
During the study, neither lanicemine dosage produced any clinically meaningful difference compared with placebo for dissociative symptoms, and lanicemine was generally well tolerated. The most common adverse effect was dizziness around the time of infusion, which occurred in a third to half of the lanicemine patients, compared with 12% of those on placebo. Lanicemine "looked dramatically different from ketamine," Dr. Sanacora said.
He also downplayed the barrier that treatment by infusion presents. "There is such an unmet need" for patients with severe depression who fail to respond to existing drugs that infusion is not a major issue, he said. But "several companies are trying to develop novel formulations of NMDA receptor–targeted drugs" that might be active orally or intranasally.
The study was funded by AstraZeneca, the company developing lanicemine. Dr. Sanacora said he has been a consultant to and has received research support from AstraZeneca and several other drug companies. Some of Dr. Sanacora’s associates on this study were AstraZeneca employees.
On Twitter @mitchelzoler
AT THE ANNUAL ENCP CONGRESS
Major finding: Treatment with lanicemine produced an average 5-point greater reduction in depression score from baseline, compared with placebo.
Data source: A phase II study that randomized 152 patients with major depressive disorder to either of two lanicemine dosages or placebo for 3 weeks at 30 U.S. centers.
Disclosures: The study was funded by AstraZeneca, the company developing lanicemine. Dr. Sanacora said he has been a consultant to and has received research support from AstraZeneca and several other drug companies. Some of Dr. Sanacora’s associates in the study were AstraZeneca employees.
Atomoxetine may lead to improved driving for adults with ADHD
BARCELONA – Adults with attention-deficit/hyperactivity disorder who undergo treatment for their most intrusive symptoms also might benefit by having their driving improve.
Most adults with attention-deficit/hyperactivity disorder (ADHD) do not seek treatment because of their driving; most usually want their disorder to intrude less into their work life, education, or relationships. However, a poor driving record is common among ADHD patients. In addition, driving performance improved significantly during treatment with atomoxetine in a controlled study with 43 patients.
These are the first study results to show that atomoxetine treatment can improve driving performance in real traffic in adults with ADHD, Dr. Esther Sobanski said at the annual congress of the European College of Neuropsychopharmacology.
Atomoxetine, which is approved in the United States and in Europe for treating ADHD in adults and children, also has shown efficacy in controlled studies for treating patients with ADHD and social anxiety disorder (Depress. Anxiety 2009;26:212-21), and partial efficacy for patients with ADHD and alcohol-use disorder (Drug Alcohol Depend. 2008;96:145-54). The drug probably is similar in efficacy and safety to methylphenidate but without methylphenidate’s long clinical track record, Dr. Sobanski said.
"We are trying to figure out whom to treat with atomoxetine and whom to treat with methylphenidate," she said in an interview. "There is no evidence base now, so we are trying to figure out" whether certain types of ADHD patients respond better to one drug or the other.
The study enrolled adults diagnosed with ADHD at an outpatient mental health clinic in Mannheim, Germany, who were 18-50 years old and had a valid German driver’s license. After a 4-week tapering-dosage washout of entry medications, patients underwent baseline testing and then randomized to 18 mg/day atomoxetine or placebo. The atomoxetine dosage gradually ramped up over 4 weeks to 80 mg/day, which continued for 8 weeks until follow-up testing occurred. Enrolled patients averaged about 35 years old.
After 8 weeks of full treatment, the 22 atomoxetine patients showed statistically significant reductions in their average rates of false reactions for three different measures: orientation to traffic, attention to traffic, and driver skills. For each of these, the rate of false reactions fell by more than half, compared with the baseline rate, reported Dr. Sobanski, a psychiatrist at the Central Institute of Mental Health in Mannheim. False reactions by a fourth measure, risk-related self-control, also fell by more than half, but this trend was not statistically significant. In contrast, the placebo group showed virtually no change from baseline by all four measures. The rate of "critical traffic situations" recorded by participants in their daily diaries also fell by about half in the atomoxetine patients but not in the placebo group. Dr. Sobanski and her associates recently published their findings (Eur. Psychiatry 2013;28:379-85).
Prior research documented that adults with ADHD have three to four times more traffic accidents and double the traffic violations (especially speeding) than does the general adult population, Dr. Sobanski said. But driving problems usually are not what bring patients to treatment. "Most patients with ADHD get interventions for other reasons, but our findings show that their driving benefits, too."
The study was funded by Eli Lilly, which markets atomoxetine (Strattera). Dr. Sobanski said she has been an adviser to and received support from Eli Lilly and also from Medice, Shire, and Novartis.
On Twitter @mitchelzoler
BARCELONA – Adults with attention-deficit/hyperactivity disorder who undergo treatment for their most intrusive symptoms also might benefit by having their driving improve.
Most adults with attention-deficit/hyperactivity disorder (ADHD) do not seek treatment because of their driving; most usually want their disorder to intrude less into their work life, education, or relationships. However, a poor driving record is common among ADHD patients. In addition, driving performance improved significantly during treatment with atomoxetine in a controlled study with 43 patients.
These are the first study results to show that atomoxetine treatment can improve driving performance in real traffic in adults with ADHD, Dr. Esther Sobanski said at the annual congress of the European College of Neuropsychopharmacology.
Atomoxetine, which is approved in the United States and in Europe for treating ADHD in adults and children, also has shown efficacy in controlled studies for treating patients with ADHD and social anxiety disorder (Depress. Anxiety 2009;26:212-21), and partial efficacy for patients with ADHD and alcohol-use disorder (Drug Alcohol Depend. 2008;96:145-54). The drug probably is similar in efficacy and safety to methylphenidate but without methylphenidate’s long clinical track record, Dr. Sobanski said.
"We are trying to figure out whom to treat with atomoxetine and whom to treat with methylphenidate," she said in an interview. "There is no evidence base now, so we are trying to figure out" whether certain types of ADHD patients respond better to one drug or the other.
The study enrolled adults diagnosed with ADHD at an outpatient mental health clinic in Mannheim, Germany, who were 18-50 years old and had a valid German driver’s license. After a 4-week tapering-dosage washout of entry medications, patients underwent baseline testing and then randomized to 18 mg/day atomoxetine or placebo. The atomoxetine dosage gradually ramped up over 4 weeks to 80 mg/day, which continued for 8 weeks until follow-up testing occurred. Enrolled patients averaged about 35 years old.
After 8 weeks of full treatment, the 22 atomoxetine patients showed statistically significant reductions in their average rates of false reactions for three different measures: orientation to traffic, attention to traffic, and driver skills. For each of these, the rate of false reactions fell by more than half, compared with the baseline rate, reported Dr. Sobanski, a psychiatrist at the Central Institute of Mental Health in Mannheim. False reactions by a fourth measure, risk-related self-control, also fell by more than half, but this trend was not statistically significant. In contrast, the placebo group showed virtually no change from baseline by all four measures. The rate of "critical traffic situations" recorded by participants in their daily diaries also fell by about half in the atomoxetine patients but not in the placebo group. Dr. Sobanski and her associates recently published their findings (Eur. Psychiatry 2013;28:379-85).
Prior research documented that adults with ADHD have three to four times more traffic accidents and double the traffic violations (especially speeding) than does the general adult population, Dr. Sobanski said. But driving problems usually are not what bring patients to treatment. "Most patients with ADHD get interventions for other reasons, but our findings show that their driving benefits, too."
The study was funded by Eli Lilly, which markets atomoxetine (Strattera). Dr. Sobanski said she has been an adviser to and received support from Eli Lilly and also from Medice, Shire, and Novartis.
On Twitter @mitchelzoler
BARCELONA – Adults with attention-deficit/hyperactivity disorder who undergo treatment for their most intrusive symptoms also might benefit by having their driving improve.
Most adults with attention-deficit/hyperactivity disorder (ADHD) do not seek treatment because of their driving; most usually want their disorder to intrude less into their work life, education, or relationships. However, a poor driving record is common among ADHD patients. In addition, driving performance improved significantly during treatment with atomoxetine in a controlled study with 43 patients.
These are the first study results to show that atomoxetine treatment can improve driving performance in real traffic in adults with ADHD, Dr. Esther Sobanski said at the annual congress of the European College of Neuropsychopharmacology.
Atomoxetine, which is approved in the United States and in Europe for treating ADHD in adults and children, also has shown efficacy in controlled studies for treating patients with ADHD and social anxiety disorder (Depress. Anxiety 2009;26:212-21), and partial efficacy for patients with ADHD and alcohol-use disorder (Drug Alcohol Depend. 2008;96:145-54). The drug probably is similar in efficacy and safety to methylphenidate but without methylphenidate’s long clinical track record, Dr. Sobanski said.
"We are trying to figure out whom to treat with atomoxetine and whom to treat with methylphenidate," she said in an interview. "There is no evidence base now, so we are trying to figure out" whether certain types of ADHD patients respond better to one drug or the other.
The study enrolled adults diagnosed with ADHD at an outpatient mental health clinic in Mannheim, Germany, who were 18-50 years old and had a valid German driver’s license. After a 4-week tapering-dosage washout of entry medications, patients underwent baseline testing and then randomized to 18 mg/day atomoxetine or placebo. The atomoxetine dosage gradually ramped up over 4 weeks to 80 mg/day, which continued for 8 weeks until follow-up testing occurred. Enrolled patients averaged about 35 years old.
After 8 weeks of full treatment, the 22 atomoxetine patients showed statistically significant reductions in their average rates of false reactions for three different measures: orientation to traffic, attention to traffic, and driver skills. For each of these, the rate of false reactions fell by more than half, compared with the baseline rate, reported Dr. Sobanski, a psychiatrist at the Central Institute of Mental Health in Mannheim. False reactions by a fourth measure, risk-related self-control, also fell by more than half, but this trend was not statistically significant. In contrast, the placebo group showed virtually no change from baseline by all four measures. The rate of "critical traffic situations" recorded by participants in their daily diaries also fell by about half in the atomoxetine patients but not in the placebo group. Dr. Sobanski and her associates recently published their findings (Eur. Psychiatry 2013;28:379-85).
Prior research documented that adults with ADHD have three to four times more traffic accidents and double the traffic violations (especially speeding) than does the general adult population, Dr. Sobanski said. But driving problems usually are not what bring patients to treatment. "Most patients with ADHD get interventions for other reasons, but our findings show that their driving benefits, too."
The study was funded by Eli Lilly, which markets atomoxetine (Strattera). Dr. Sobanski said she has been an adviser to and received support from Eli Lilly and also from Medice, Shire, and Novartis.
On Twitter @mitchelzoler
AT THE ANNUAL ECNP CONGRESS
Major finding: After 8 weeks treatment with atomoxetine, attention-deficit/hyperactivity disorder patients showed significant improvement over placebo in three measures of driving attention.
Data source: The study randomized 43 patients to treatment with 80 mg/day atomoxetine or placebo for 8 weeks in a single-center German study.
Disclosures: The study was funded by Eli Lilly, which markets atomoxetine (Strattera). Dr. Sobanski said she has been an adviser to and received support from Eli Lilly and also from Medice, Shire, and Novartis.
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
Armodafinil shows bipolar depression efficacy
BARCELONA – Armodafinil, a drug with Food and Drug Administration approval to treat excessive sleepiness and narcolepsy, showed efficacy for improving concentration, energy, and appetite in a controlled study of nearly 400 patients with bipolar I depression.
"I think [armodafinil] is clinically useful because its efficacy appears complementary to the efficacy we see from other compounds," Dr. Joseph R. Calabrese said at the annual congress of the European College of Neuropsychopharmacology.
In addition to showing useful efficacy compared with placebo as adjunctive treatment, armodafinil also had a "very, very benign" adverse effect profile – its 6% dropout rate because of adverse effects was not statistically significant from the 4% rate in placebo patients.
Armodafinil is the R-enantiomer of modafinil, which means the two agents are essentially the same. "I think off-label use [of armodafinil] is okay, because there are a lot of [safety] data for modafinil," Dr. Calabrese said in an interview.
Armodafinil (Nuvigil) has FDA approval for treating shift-work disorder, narcolepsy, and treated obstructed sleep apnea. He foresees no push for formal labeling of armodafinil for bipolar I depression because three phase III trials were run and only one was positive for efficacy. The two trials that failed to prove efficacy fell short not because of a blunted drug effect but because of an unexpectedly high response in the placebo group. This design flaw in two of the three pivotal trials likely doomed any hope of getting armodafinil labeled for this indication, he said.
"There is a role for armodafinil. It is something to try for patients" who need help in the things it affects, said Dr. Calabrese, professor of psychiatry and head of the mood disorders program at Case Western Reserve University in Cleveland. "It has stimulant-like properties that can improve concentration" and can help patients who are on another drug causing sedation, he added.
The study he ran enrolled patients who had cycled into a new major depressive episode after treatment with antimanic drugs for at least 4 weeks. Most patients were on antimanic monotherapy during the study, about 10% were on two antimanic drugs, and two patients were on three drugs. The researchers randomized 198 patients to receive 150 mg of armodafinil daily and 199 to placebo. An additional 32 patients initially received 200 mg armodafinil daily, but that arm was discontinued because of adverse effects.
After 8 weeks, the study’s primary endpoint – change in average, total clinician-rated, 30-item Inventory of Depressive Symptomatology (IDS) score – showed a 21.7 point drop with armodafinil and a 17.9 point drop with placebo, a statistically significant difference. The incidence of responder patients, those with at least a 50% reduction from their baseline IDS score, was 46% in the armodafinil arm and 34% in the placebo arm, a statistically significant difference and indicating a number needed to treat of nine to achieve one additional response over placebo.
The results also showed that the improvements in IDS score focused on five of the score’s 30 individual items: panic and phobic symptoms, appetite, concentration and decision making, energy and fatigability, and leaden paralysis and physical energy. In contrast, armodafinil had no apparent effect on core symptoms of depression. Armodafinil also produced no worsening of anxiety, sleep, or switch rates, and no meaningful trends toward gain or loss of weight.
The study was sponsored by Teva, which markets armodafinil (Nuvigil). Dr. Calabrese said that he has been a consultant to and received research support from Teva and more than a dozen other drug companies.
On Twitter @mitchelzoler
BARCELONA – Armodafinil, a drug with Food and Drug Administration approval to treat excessive sleepiness and narcolepsy, showed efficacy for improving concentration, energy, and appetite in a controlled study of nearly 400 patients with bipolar I depression.
"I think [armodafinil] is clinically useful because its efficacy appears complementary to the efficacy we see from other compounds," Dr. Joseph R. Calabrese said at the annual congress of the European College of Neuropsychopharmacology.
In addition to showing useful efficacy compared with placebo as adjunctive treatment, armodafinil also had a "very, very benign" adverse effect profile – its 6% dropout rate because of adverse effects was not statistically significant from the 4% rate in placebo patients.
Armodafinil is the R-enantiomer of modafinil, which means the two agents are essentially the same. "I think off-label use [of armodafinil] is okay, because there are a lot of [safety] data for modafinil," Dr. Calabrese said in an interview.
Armodafinil (Nuvigil) has FDA approval for treating shift-work disorder, narcolepsy, and treated obstructed sleep apnea. He foresees no push for formal labeling of armodafinil for bipolar I depression because three phase III trials were run and only one was positive for efficacy. The two trials that failed to prove efficacy fell short not because of a blunted drug effect but because of an unexpectedly high response in the placebo group. This design flaw in two of the three pivotal trials likely doomed any hope of getting armodafinil labeled for this indication, he said.
"There is a role for armodafinil. It is something to try for patients" who need help in the things it affects, said Dr. Calabrese, professor of psychiatry and head of the mood disorders program at Case Western Reserve University in Cleveland. "It has stimulant-like properties that can improve concentration" and can help patients who are on another drug causing sedation, he added.
The study he ran enrolled patients who had cycled into a new major depressive episode after treatment with antimanic drugs for at least 4 weeks. Most patients were on antimanic monotherapy during the study, about 10% were on two antimanic drugs, and two patients were on three drugs. The researchers randomized 198 patients to receive 150 mg of armodafinil daily and 199 to placebo. An additional 32 patients initially received 200 mg armodafinil daily, but that arm was discontinued because of adverse effects.
After 8 weeks, the study’s primary endpoint – change in average, total clinician-rated, 30-item Inventory of Depressive Symptomatology (IDS) score – showed a 21.7 point drop with armodafinil and a 17.9 point drop with placebo, a statistically significant difference. The incidence of responder patients, those with at least a 50% reduction from their baseline IDS score, was 46% in the armodafinil arm and 34% in the placebo arm, a statistically significant difference and indicating a number needed to treat of nine to achieve one additional response over placebo.
The results also showed that the improvements in IDS score focused on five of the score’s 30 individual items: panic and phobic symptoms, appetite, concentration and decision making, energy and fatigability, and leaden paralysis and physical energy. In contrast, armodafinil had no apparent effect on core symptoms of depression. Armodafinil also produced no worsening of anxiety, sleep, or switch rates, and no meaningful trends toward gain or loss of weight.
The study was sponsored by Teva, which markets armodafinil (Nuvigil). Dr. Calabrese said that he has been a consultant to and received research support from Teva and more than a dozen other drug companies.
On Twitter @mitchelzoler
BARCELONA – Armodafinil, a drug with Food and Drug Administration approval to treat excessive sleepiness and narcolepsy, showed efficacy for improving concentration, energy, and appetite in a controlled study of nearly 400 patients with bipolar I depression.
"I think [armodafinil] is clinically useful because its efficacy appears complementary to the efficacy we see from other compounds," Dr. Joseph R. Calabrese said at the annual congress of the European College of Neuropsychopharmacology.
In addition to showing useful efficacy compared with placebo as adjunctive treatment, armodafinil also had a "very, very benign" adverse effect profile – its 6% dropout rate because of adverse effects was not statistically significant from the 4% rate in placebo patients.
Armodafinil is the R-enantiomer of modafinil, which means the two agents are essentially the same. "I think off-label use [of armodafinil] is okay, because there are a lot of [safety] data for modafinil," Dr. Calabrese said in an interview.
Armodafinil (Nuvigil) has FDA approval for treating shift-work disorder, narcolepsy, and treated obstructed sleep apnea. He foresees no push for formal labeling of armodafinil for bipolar I depression because three phase III trials were run and only one was positive for efficacy. The two trials that failed to prove efficacy fell short not because of a blunted drug effect but because of an unexpectedly high response in the placebo group. This design flaw in two of the three pivotal trials likely doomed any hope of getting armodafinil labeled for this indication, he said.
"There is a role for armodafinil. It is something to try for patients" who need help in the things it affects, said Dr. Calabrese, professor of psychiatry and head of the mood disorders program at Case Western Reserve University in Cleveland. "It has stimulant-like properties that can improve concentration" and can help patients who are on another drug causing sedation, he added.
The study he ran enrolled patients who had cycled into a new major depressive episode after treatment with antimanic drugs for at least 4 weeks. Most patients were on antimanic monotherapy during the study, about 10% were on two antimanic drugs, and two patients were on three drugs. The researchers randomized 198 patients to receive 150 mg of armodafinil daily and 199 to placebo. An additional 32 patients initially received 200 mg armodafinil daily, but that arm was discontinued because of adverse effects.
After 8 weeks, the study’s primary endpoint – change in average, total clinician-rated, 30-item Inventory of Depressive Symptomatology (IDS) score – showed a 21.7 point drop with armodafinil and a 17.9 point drop with placebo, a statistically significant difference. The incidence of responder patients, those with at least a 50% reduction from their baseline IDS score, was 46% in the armodafinil arm and 34% in the placebo arm, a statistically significant difference and indicating a number needed to treat of nine to achieve one additional response over placebo.
The results also showed that the improvements in IDS score focused on five of the score’s 30 individual items: panic and phobic symptoms, appetite, concentration and decision making, energy and fatigability, and leaden paralysis and physical energy. In contrast, armodafinil had no apparent effect on core symptoms of depression. Armodafinil also produced no worsening of anxiety, sleep, or switch rates, and no meaningful trends toward gain or loss of weight.
The study was sponsored by Teva, which markets armodafinil (Nuvigil). Dr. Calabrese said that he has been a consultant to and received research support from Teva and more than a dozen other drug companies.
On Twitter @mitchelzoler
AT THE ECNP CONGRESS
Major finding: Adjunctive treatment of bipolar I depression with armodafinil produced a 46% depression response rate, compared with a 34% rate from placebo.
Data source: Randomized, placebo-controlled, multicenter study involving 397 patients with bipolar I depression treated for 8 weeks.
Disclosures: The study was sponsored by Teva, which markets armodafinil (Nuvigil). Dr. Calabrese said that he has been a consultant to and received research support from Teva and more than a dozen other drug companies.
