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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
Diabetics Face Increased Treatment-resistant Hypertension Risk
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 – Patients with treatment-resistant hypertension and diabetes face a significantly increased risk for major cardiovascular adverse events, compared with those without diabetes, a study has shown.
The combined rate of death, myocardial infarction, and stroke was 6.2% among patients with treatment-resistant hypertension (TRH) and diabetes, and 3.8% in patients with TRH but no diabetes during 2 years of follow-up of more than 8,000 patients enrolled in a German registry, Dr. Stefanie Friedrich reported at the annual meeting of the European Association for the Study of Diabetes.
"Patients with treatment-resistant hypertension, and in particular patients with diabetes, need to have their blood pressure reduced to less than 140/90 mm Hg, combined with other organ-protective therapies, to improve their outcomes," said Dr. Friedrich of the division of nephrology and hypertension at Alexander-Friedrich University in Erlangen-Nürnberg (Germany).
"If you don’t succeed with blood pressure control with drugs, you should move along to another alternative like renal denervation with no inertia," said Dr. Roland E. Schmieder, professor and chief of nephrology and hypertension at the university and a collaborator with Dr. Friedrich on this study. "In this registry nothing happened for many of these resistant patients during 2 years. I would recommend waiting no more than about 6 months if patients remain hypertensive despite maximum medical therapy. If drugs do not succeed after 6 months, you need to go to the next step, which for some patients could be renal denervation," he said in an interview. "This should be the approach for all patients with treatment-resistant hypertension, but especially when patients have diabetes."
Data on renal denervation show that it is as effective in patients with diabetes as in those without diabetes, Dr. Schmieder said. Renal denervation devices first became available for routine European use in 2010, but remain investigational in the United States.
Their study used data collected from the nearly 15,000 patients enrolled in the Registry for Ambulant Therapy With RAS-Inhibitors in Hypertensive-Patients in Germany (3A registry). The registry enrolled patients with either newly diagnosed hypertension or established hypertension that required treatment intensification at 899 physician practices in Germany during October 2008 through April 2009. The study assigned patients to receive aliskiren (Tekturna), an ACE inhibitor, or an angiotensin receptor blocker in a 4:1:1 ratio, but otherwise participating physicians were allowed to manage these patients by whichever regimen they preferred. The current analysis focused on the 8,698 patients from the 3A registry who had 2-year follow-up, and the 2,772 patients from this group with TRH, defined as an office-measured blood pressure of 140/90 mm Hg or higher despite treatment with at least three antihypertensive medications.
The TRH subgroup included 1,170 with either type 1 or type 2 diabetes, 47% of all patients with diabetes followed in the registry for 2 years, and 1,602 patients without diabetes, 26% of the enrolled patients without diabetes followed for 2 years. These TRH prevalence rates show that "resistant hypertension is common in outpatients, especially patients with diabetes," Dr. Friedrich said. At the time they entered the registry, the TRH patients had an average blood pressure of 162/91 mm Hg, with similar averages in both the diabetic and nondiabetic subgroups. At entry, the patients with diabetes averaged 71 years of age, while those without diabetes were an average of 68 years old. The median duration of hypertension was 11 years in the diabetes patients and 8 years in those without diabetes.
After 2 years, 55% of the TRH patients with diabetes and 48% of those without diabetes remained at blood pressures above the goal of less than 140/90 mm Hg. The average level of hemoglobin A1c among the diabetes patients was 6.8% at baseline, and 6.9% after 2 years.
In addition to having a significantly greater rate of combined adverse cardiac and cerebrovascular events at 2 years, the patients with diabetes also had significantly more events for each of the three outcomes included in this composite: The rate of all-cause death was 4.4% in the patients with diabetes and 2.9% in those without; the incidence of myocardial infarction was 1.3% in the diabetes patients and 0.6% in the others; and stroke incidence was 1.4% in the patients with diabetes and 0.8% in those without, Dr. Friedrich reported.
The German 3A registry is sponsored by Novartis. Dr. Friedrich said she had no relevant financial disclosures. Dr. Schmieder has been a consultant to, and a speaker on behalf of, Medtronic, a company that markets a renal denervation device.
To earn 0.25 hours AMA PRA Category 1 credit after reading this article, take the post-test here.
On Twitter @mitchelzoler
The relatively high rate of major adverse cardiac and cerebrovascular events seen in patients with diabetes and treatment-resistant hypertension in this study is worrying, but several different approaches could potentially improve outcomes in these patients.
|
|
The clearest message is that physicians need to do a better job getting their hypertensive patients to take all their prescribed medications. Patients who need four drugs to control their blood pressure will often take only a fraction of the pills they are supposed to take. A lot of treatment-resistant hypertension results from poor patient compliance or physician negligence.
Another option that my colleagues and I have recently explored is slow breathing, at a rate of about 15 breaths per minute, as is often done in yoga. My associates and I published results 2 years ago showing that deep breathing can improve the blunted baroreflex sensitivity often seen in patients with diabetes (Diabetologia 2011;54:1862-70). This approach may also be effective for reducing blood pressure in patients who are not ideally responsive to antihypertensive drugs. With deep breathing, patients can exert some control over their autonomic nervous system.
Another nondrug option is renal denervation, but for the time being I see this as a last resort. I have reservations about widely using renal denervation right now because I believe it remains investigational. There is no way to assess the effect of denervation treatment at the time it is delivered, the long-term consequences of the treatment are not yet fully known, and in many patients the effect is modest, especially when measured with ambulatory blood pressure monitoring. For some patients with treatment-resistant hypertension, renal denervation may be the only option for getting their blood pressure to their target level, but for the time being, I would use it very cautiously.
Dr. Per-Henrik Groop is professor and head of nephrology at the University of Helsinki (Finland). He made these comments in an interview. He has been a consultant to, or a speaker on behalf of, Boehringer Ingelheim, Novartis, Cebeix, Novo Nordisk, Merck, Abbott, Genzyme, and Eli Lilly.
The relatively high rate of major adverse cardiac and cerebrovascular events seen in patients with diabetes and treatment-resistant hypertension in this study is worrying, but several different approaches could potentially improve outcomes in these patients.
|
|
|
The clearest message is that physicians need to do a better job getting their hypertensive patients to take all their prescribed medications. Patients who need four drugs to control their blood pressure will often take only a fraction of the pills they are supposed to take. A lot of treatment-resistant hypertension results from poor patient compliance or physician negligence.
Another option that my colleagues and I have recently explored is slow breathing, at a rate of about 15 breaths per minute, as is often done in yoga. My associates and I published results 2 years ago showing that deep breathing can improve the blunted baroreflex sensitivity often seen in patients with diabetes (Diabetologia 2011;54:1862-70). This approach may also be effective for reducing blood pressure in patients who are not ideally responsive to antihypertensive drugs. With deep breathing, patients can exert some control over their autonomic nervous system.
Another nondrug option is renal denervation, but for the time being I see this as a last resort. I have reservations about widely using renal denervation right now because I believe it remains investigational. There is no way to assess the effect of denervation treatment at the time it is delivered, the long-term consequences of the treatment are not yet fully known, and in many patients the effect is modest, especially when measured with ambulatory blood pressure monitoring. For some patients with treatment-resistant hypertension, renal denervation may be the only option for getting their blood pressure to their target level, but for the time being, I would use it very cautiously.
Dr. Per-Henrik Groop is professor and head of nephrology at the University of Helsinki (Finland). He made these comments in an interview. He has been a consultant to, or a speaker on behalf of, Boehringer Ingelheim, Novartis, Cebeix, Novo Nordisk, Merck, Abbott, Genzyme, and Eli Lilly.
The relatively high rate of major adverse cardiac and cerebrovascular events seen in patients with diabetes and treatment-resistant hypertension in this study is worrying, but several different approaches could potentially improve outcomes in these patients.
|
|
|
The clearest message is that physicians need to do a better job getting their hypertensive patients to take all their prescribed medications. Patients who need four drugs to control their blood pressure will often take only a fraction of the pills they are supposed to take. A lot of treatment-resistant hypertension results from poor patient compliance or physician negligence.
Another option that my colleagues and I have recently explored is slow breathing, at a rate of about 15 breaths per minute, as is often done in yoga. My associates and I published results 2 years ago showing that deep breathing can improve the blunted baroreflex sensitivity often seen in patients with diabetes (Diabetologia 2011;54:1862-70). This approach may also be effective for reducing blood pressure in patients who are not ideally responsive to antihypertensive drugs. With deep breathing, patients can exert some control over their autonomic nervous system.
Another nondrug option is renal denervation, but for the time being I see this as a last resort. I have reservations about widely using renal denervation right now because I believe it remains investigational. There is no way to assess the effect of denervation treatment at the time it is delivered, the long-term consequences of the treatment are not yet fully known, and in many patients the effect is modest, especially when measured with ambulatory blood pressure monitoring. For some patients with treatment-resistant hypertension, renal denervation may be the only option for getting their blood pressure to their target level, but for the time being, I would use it very cautiously.
Dr. Per-Henrik Groop is professor and head of nephrology at the University of Helsinki (Finland). He made these comments in an interview. He has been a consultant to, or a speaker on behalf of, Boehringer Ingelheim, Novartis, Cebeix, Novo Nordisk, Merck, Abbott, Genzyme, and Eli Lilly.
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 – Patients with treatment-resistant hypertension and diabetes face a significantly increased risk for major cardiovascular adverse events, compared with those without diabetes, a study has shown.
The combined rate of death, myocardial infarction, and stroke was 6.2% among patients with treatment-resistant hypertension (TRH) and diabetes, and 3.8% in patients with TRH but no diabetes during 2 years of follow-up of more than 8,000 patients enrolled in a German registry, Dr. Stefanie Friedrich reported at the annual meeting of the European Association for the Study of Diabetes.
"Patients with treatment-resistant hypertension, and in particular patients with diabetes, need to have their blood pressure reduced to less than 140/90 mm Hg, combined with other organ-protective therapies, to improve their outcomes," said Dr. Friedrich of the division of nephrology and hypertension at Alexander-Friedrich University in Erlangen-Nürnberg (Germany).
"If you don’t succeed with blood pressure control with drugs, you should move along to another alternative like renal denervation with no inertia," said Dr. Roland E. Schmieder, professor and chief of nephrology and hypertension at the university and a collaborator with Dr. Friedrich on this study. "In this registry nothing happened for many of these resistant patients during 2 years. I would recommend waiting no more than about 6 months if patients remain hypertensive despite maximum medical therapy. If drugs do not succeed after 6 months, you need to go to the next step, which for some patients could be renal denervation," he said in an interview. "This should be the approach for all patients with treatment-resistant hypertension, but especially when patients have diabetes."
Data on renal denervation show that it is as effective in patients with diabetes as in those without diabetes, Dr. Schmieder said. Renal denervation devices first became available for routine European use in 2010, but remain investigational in the United States.
Their study used data collected from the nearly 15,000 patients enrolled in the Registry for Ambulant Therapy With RAS-Inhibitors in Hypertensive-Patients in Germany (3A registry). The registry enrolled patients with either newly diagnosed hypertension or established hypertension that required treatment intensification at 899 physician practices in Germany during October 2008 through April 2009. The study assigned patients to receive aliskiren (Tekturna), an ACE inhibitor, or an angiotensin receptor blocker in a 4:1:1 ratio, but otherwise participating physicians were allowed to manage these patients by whichever regimen they preferred. The current analysis focused on the 8,698 patients from the 3A registry who had 2-year follow-up, and the 2,772 patients from this group with TRH, defined as an office-measured blood pressure of 140/90 mm Hg or higher despite treatment with at least three antihypertensive medications.
The TRH subgroup included 1,170 with either type 1 or type 2 diabetes, 47% of all patients with diabetes followed in the registry for 2 years, and 1,602 patients without diabetes, 26% of the enrolled patients without diabetes followed for 2 years. These TRH prevalence rates show that "resistant hypertension is common in outpatients, especially patients with diabetes," Dr. Friedrich said. At the time they entered the registry, the TRH patients had an average blood pressure of 162/91 mm Hg, with similar averages in both the diabetic and nondiabetic subgroups. At entry, the patients with diabetes averaged 71 years of age, while those without diabetes were an average of 68 years old. The median duration of hypertension was 11 years in the diabetes patients and 8 years in those without diabetes.
After 2 years, 55% of the TRH patients with diabetes and 48% of those without diabetes remained at blood pressures above the goal of less than 140/90 mm Hg. The average level of hemoglobin A1c among the diabetes patients was 6.8% at baseline, and 6.9% after 2 years.
In addition to having a significantly greater rate of combined adverse cardiac and cerebrovascular events at 2 years, the patients with diabetes also had significantly more events for each of the three outcomes included in this composite: The rate of all-cause death was 4.4% in the patients with diabetes and 2.9% in those without; the incidence of myocardial infarction was 1.3% in the diabetes patients and 0.6% in the others; and stroke incidence was 1.4% in the patients with diabetes and 0.8% in those without, Dr. Friedrich reported.
The German 3A registry is sponsored by Novartis. Dr. Friedrich said she had no relevant financial disclosures. Dr. Schmieder has been a consultant to, and a speaker on behalf of, Medtronic, a company that markets a renal denervation device.
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 – Patients with treatment-resistant hypertension and diabetes face a significantly increased risk for major cardiovascular adverse events, compared with those without diabetes, a study has shown.
The combined rate of death, myocardial infarction, and stroke was 6.2% among patients with treatment-resistant hypertension (TRH) and diabetes, and 3.8% in patients with TRH but no diabetes during 2 years of follow-up of more than 8,000 patients enrolled in a German registry, Dr. Stefanie Friedrich reported at the annual meeting of the European Association for the Study of Diabetes.
"Patients with treatment-resistant hypertension, and in particular patients with diabetes, need to have their blood pressure reduced to less than 140/90 mm Hg, combined with other organ-protective therapies, to improve their outcomes," said Dr. Friedrich of the division of nephrology and hypertension at Alexander-Friedrich University in Erlangen-Nürnberg (Germany).
"If you don’t succeed with blood pressure control with drugs, you should move along to another alternative like renal denervation with no inertia," said Dr. Roland E. Schmieder, professor and chief of nephrology and hypertension at the university and a collaborator with Dr. Friedrich on this study. "In this registry nothing happened for many of these resistant patients during 2 years. I would recommend waiting no more than about 6 months if patients remain hypertensive despite maximum medical therapy. If drugs do not succeed after 6 months, you need to go to the next step, which for some patients could be renal denervation," he said in an interview. "This should be the approach for all patients with treatment-resistant hypertension, but especially when patients have diabetes."
Data on renal denervation show that it is as effective in patients with diabetes as in those without diabetes, Dr. Schmieder said. Renal denervation devices first became available for routine European use in 2010, but remain investigational in the United States.
Their study used data collected from the nearly 15,000 patients enrolled in the Registry for Ambulant Therapy With RAS-Inhibitors in Hypertensive-Patients in Germany (3A registry). The registry enrolled patients with either newly diagnosed hypertension or established hypertension that required treatment intensification at 899 physician practices in Germany during October 2008 through April 2009. The study assigned patients to receive aliskiren (Tekturna), an ACE inhibitor, or an angiotensin receptor blocker in a 4:1:1 ratio, but otherwise participating physicians were allowed to manage these patients by whichever regimen they preferred. The current analysis focused on the 8,698 patients from the 3A registry who had 2-year follow-up, and the 2,772 patients from this group with TRH, defined as an office-measured blood pressure of 140/90 mm Hg or higher despite treatment with at least three antihypertensive medications.
The TRH subgroup included 1,170 with either type 1 or type 2 diabetes, 47% of all patients with diabetes followed in the registry for 2 years, and 1,602 patients without diabetes, 26% of the enrolled patients without diabetes followed for 2 years. These TRH prevalence rates show that "resistant hypertension is common in outpatients, especially patients with diabetes," Dr. Friedrich said. At the time they entered the registry, the TRH patients had an average blood pressure of 162/91 mm Hg, with similar averages in both the diabetic and nondiabetic subgroups. At entry, the patients with diabetes averaged 71 years of age, while those without diabetes were an average of 68 years old. The median duration of hypertension was 11 years in the diabetes patients and 8 years in those without diabetes.
After 2 years, 55% of the TRH patients with diabetes and 48% of those without diabetes remained at blood pressures above the goal of less than 140/90 mm Hg. The average level of hemoglobin A1c among the diabetes patients was 6.8% at baseline, and 6.9% after 2 years.
In addition to having a significantly greater rate of combined adverse cardiac and cerebrovascular events at 2 years, the patients with diabetes also had significantly more events for each of the three outcomes included in this composite: The rate of all-cause death was 4.4% in the patients with diabetes and 2.9% in those without; the incidence of myocardial infarction was 1.3% in the diabetes patients and 0.6% in the others; and stroke incidence was 1.4% in the patients with diabetes and 0.8% in those without, Dr. Friedrich reported.
The German 3A registry is sponsored by Novartis. Dr. Friedrich said she had no relevant financial disclosures. Dr. Schmieder has been a consultant to, and a speaker on behalf of, Medtronic, a company that markets a renal denervation device.
To earn 0.25 hours AMA PRA Category 1 credit after reading this article, take the post-test here.
On Twitter @mitchelzoler
AT THE EASD ANNUAL MEETING
Diabetics face increased treatment-resistant hypertension risk
BARCELONA – Patients with treatment-resistant hypertension and diabetes face a significantly increased risk for major cardiovascular adverse events, compared with those without diabetes, a study has shown.
The combined rate of death, myocardial infarction, and stroke was 6.2% among patients with treatment-resistant hypertension (TRH) and diabetes, and 3.8% in patients with TRH but no diabetes during 2 years of follow-up of more than 8,000 patients enrolled in a German registry, Dr. Stefanie Friedrich reported at the annual meeting of the European Association for the Study of Diabetes.
"Patients with treatment-resistant hypertension, and in particular patients with diabetes, need to have their blood pressure reduced to less than 140/90 mm Hg, combined with other organ-protective therapies, to improve their outcomes," said Dr. Friedrich of the division of nephrology and hypertension at Alexander-Friedrich University in Erlangen-Nürnberg (Germany).
"If you don’t succeed with blood pressure control with drugs, you should move along to another alternative like renal denervation with no inertia," said Dr. Roland E. Schmieder, professor and chief of nephrology and hypertension at the university and a collaborator with Dr. Friedrich on this study. "In this registry nothing happened for many of these resistant patients during 2 years. I would recommend waiting no more than about 6 months if patients remain hypertensive despite maximum medical therapy. If drugs do not succeed after 6 months, you need to go to the next step, which for some patients could be renal denervation," he said in an interview. "This should be the approach for all patients with treatment-resistant hypertension, but especially when patients have diabetes."
Data on renal denervation show that it is as effective in patients with diabetes as in those without diabetes, Dr. Schmieder said. Renal denervation devices first became available for routine European use in 2010, but remain investigational in the United States.
Their study used data collected from the nearly 15,000 patients enrolled in the Registry for Ambulant Therapy With RAS-Inhibitors in Hypertensive-Patients in Germany (3A registry). The registry enrolled patients with either newly diagnosed hypertension or established hypertension that required treatment intensification at 899 physician practices in Germany during October 2008 through April 2009. The study assigned patients to receive aliskiren (Tekturna), an ACE inhibitor, or an angiotensin receptor blocker in a 4:1:1 ratio, but otherwise participating physicians were allowed to manage these patients by whichever regimen they preferred. The current analysis focused on the 8,698 patients from the 3A registry who had 2-year follow-up, and the 2,772 patients from this group with TRH, defined as an office-measured blood pressure of 140/90 mm Hg or higher despite treatment with at least three antihypertensive medications.
The TRH subgroup included 1,170 with either type 1 or type 2 diabetes, 47% of all patients with diabetes followed in the registry for 2 years, and 1,602 patients without diabetes, 26% of the enrolled patients without diabetes followed for 2 years. These TRH prevalence rates show that "resistant hypertension is common in outpatients, especially patients with diabetes," Dr. Friedrich said. At the time they entered the registry, the TRH patients had an average blood pressure of 162/91 mm Hg, with similar averages in both the diabetic and nondiabetic subgroups. At entry, the patients with diabetes averaged 71 years of age, while those without diabetes were an average of 68 years old. The median duration of hypertension was 11 years in the diabetes patients and 8 years in those without diabetes.
After 2 years, 55% of the TRH patients with diabetes and 48% of those without diabetes remained at blood pressures above the goal of less than 140/90 mm Hg. The average level of hemoglobin A1c among the diabetes patients was 6.8% at baseline, and 6.9% after 2 years.
In addition to having a significantly greater rate of combined adverse cardiac and cerebrovascular events at 2 years, the patients with diabetes also had significantly more events for each of the three outcomes included in this composite: The rate of all-cause death was 4.4% in the patients with diabetes and 2.9% in those without; the incidence of myocardial infarction was 1.3% in the diabetes patients and 0.6% in the others; and stroke incidence was 1.4% in the patients with diabetes and 0.8% in those without, Dr. Friedrich reported.
The German 3A registry is sponsored by Novartis. Dr. Friedrich said she had no relevant financial disclosures. Dr. Schmieder has been a consultant to, and a speaker on behalf of, Medtronic, a company that markets a renal denervation device.
On Twitter @mitchelzoler
The relatively high rate of major adverse cardiac and cerebrovascular events seen in patients with diabetes and treatment-resistant hypertension in this study is worrying, but several different approaches could potentially improve outcomes in these patients.
|
|
|
The clearest message is that physicians need to do a better job getting their hypertensive patients to take all their prescribed medications. Patients who need four drugs to control their blood pressure will often take only a fraction of the pills they are supposed to take. A lot of treatment-resistant hypertension results from poor patient compliance or physician negligence.
Another option that my colleagues and I have recently explored is slow breathing, at a rate of about 15 breaths per minute, as is often done in yoga. My associates and I published results 2 years ago showing that deep breathing can improve the blunted baroreflex sensitivity often seen in patients with diabetes (Diabetologia 2011;54:1862-70). This approach may also be effective for reducing blood pressure in patients who are not ideally responsive to antihypertensive drugs. With deep breathing, patients can exert some control over their autonomic nervous system.
The relatively high rate of major adverse cardiac and cerebrovascular events seen in patients with diabetes and treatment-resistant hypertension in this study is worrying, but several different approaches could potentially improve outcomes in these patients.
|
|
|
The clearest message is that physicians need to do a better job getting their hypertensive patients to take all their prescribed medications. Patients who need four drugs to control their blood pressure will often take only a fraction of the pills they are supposed to take. A lot of treatment-resistant hypertension results from poor patient compliance or physician negligence.
Another option that my colleagues and I have recently explored is slow breathing, at a rate of about 15 breaths per minute, as is often done in yoga. My associates and I published results 2 years ago showing that deep breathing can improve the blunted baroreflex sensitivity often seen in patients with diabetes (Diabetologia 2011;54:1862-70). This approach may also be effective for reducing blood pressure in patients who are not ideally responsive to antihypertensive drugs. With deep breathing, patients can exert some control over their autonomic nervous system.
The relatively high rate of major adverse cardiac and cerebrovascular events seen in patients with diabetes and treatment-resistant hypertension in this study is worrying, but several different approaches could potentially improve outcomes in these patients.
|
|
|
The clearest message is that physicians need to do a better job getting their hypertensive patients to take all their prescribed medications. Patients who need four drugs to control their blood pressure will often take only a fraction of the pills they are supposed to take. A lot of treatment-resistant hypertension results from poor patient compliance or physician negligence.
Another option that my colleagues and I have recently explored is slow breathing, at a rate of about 15 breaths per minute, as is often done in yoga. My associates and I published results 2 years ago showing that deep breathing can improve the blunted baroreflex sensitivity often seen in patients with diabetes (Diabetologia 2011;54:1862-70). This approach may also be effective for reducing blood pressure in patients who are not ideally responsive to antihypertensive drugs. With deep breathing, patients can exert some control over their autonomic nervous system.
BARCELONA – Patients with treatment-resistant hypertension and diabetes face a significantly increased risk for major cardiovascular adverse events, compared with those without diabetes, a study has shown.
The combined rate of death, myocardial infarction, and stroke was 6.2% among patients with treatment-resistant hypertension (TRH) and diabetes, and 3.8% in patients with TRH but no diabetes during 2 years of follow-up of more than 8,000 patients enrolled in a German registry, Dr. Stefanie Friedrich reported at the annual meeting of the European Association for the Study of Diabetes.
"Patients with treatment-resistant hypertension, and in particular patients with diabetes, need to have their blood pressure reduced to less than 140/90 mm Hg, combined with other organ-protective therapies, to improve their outcomes," said Dr. Friedrich of the division of nephrology and hypertension at Alexander-Friedrich University in Erlangen-Nürnberg (Germany).
"If you don’t succeed with blood pressure control with drugs, you should move along to another alternative like renal denervation with no inertia," said Dr. Roland E. Schmieder, professor and chief of nephrology and hypertension at the university and a collaborator with Dr. Friedrich on this study. "In this registry nothing happened for many of these resistant patients during 2 years. I would recommend waiting no more than about 6 months if patients remain hypertensive despite maximum medical therapy. If drugs do not succeed after 6 months, you need to go to the next step, which for some patients could be renal denervation," he said in an interview. "This should be the approach for all patients with treatment-resistant hypertension, but especially when patients have diabetes."
Data on renal denervation show that it is as effective in patients with diabetes as in those without diabetes, Dr. Schmieder said. Renal denervation devices first became available for routine European use in 2010, but remain investigational in the United States.
Their study used data collected from the nearly 15,000 patients enrolled in the Registry for Ambulant Therapy With RAS-Inhibitors in Hypertensive-Patients in Germany (3A registry). The registry enrolled patients with either newly diagnosed hypertension or established hypertension that required treatment intensification at 899 physician practices in Germany during October 2008 through April 2009. The study assigned patients to receive aliskiren (Tekturna), an ACE inhibitor, or an angiotensin receptor blocker in a 4:1:1 ratio, but otherwise participating physicians were allowed to manage these patients by whichever regimen they preferred. The current analysis focused on the 8,698 patients from the 3A registry who had 2-year follow-up, and the 2,772 patients from this group with TRH, defined as an office-measured blood pressure of 140/90 mm Hg or higher despite treatment with at least three antihypertensive medications.
The TRH subgroup included 1,170 with either type 1 or type 2 diabetes, 47% of all patients with diabetes followed in the registry for 2 years, and 1,602 patients without diabetes, 26% of the enrolled patients without diabetes followed for 2 years. These TRH prevalence rates show that "resistant hypertension is common in outpatients, especially patients with diabetes," Dr. Friedrich said. At the time they entered the registry, the TRH patients had an average blood pressure of 162/91 mm Hg, with similar averages in both the diabetic and nondiabetic subgroups. At entry, the patients with diabetes averaged 71 years of age, while those without diabetes were an average of 68 years old. The median duration of hypertension was 11 years in the diabetes patients and 8 years in those without diabetes.
After 2 years, 55% of the TRH patients with diabetes and 48% of those without diabetes remained at blood pressures above the goal of less than 140/90 mm Hg. The average level of hemoglobin A1c among the diabetes patients was 6.8% at baseline, and 6.9% after 2 years.
In addition to having a significantly greater rate of combined adverse cardiac and cerebrovascular events at 2 years, the patients with diabetes also had significantly more events for each of the three outcomes included in this composite: The rate of all-cause death was 4.4% in the patients with diabetes and 2.9% in those without; the incidence of myocardial infarction was 1.3% in the diabetes patients and 0.6% in the others; and stroke incidence was 1.4% in the patients with diabetes and 0.8% in those without, Dr. Friedrich reported.
The German 3A registry is sponsored by Novartis. Dr. Friedrich said she had no relevant financial disclosures. Dr. Schmieder has been a consultant to, and a speaker on behalf of, Medtronic, a company that markets a renal denervation device.
On Twitter @mitchelzoler
BARCELONA – Patients with treatment-resistant hypertension and diabetes face a significantly increased risk for major cardiovascular adverse events, compared with those without diabetes, a study has shown.
The combined rate of death, myocardial infarction, and stroke was 6.2% among patients with treatment-resistant hypertension (TRH) and diabetes, and 3.8% in patients with TRH but no diabetes during 2 years of follow-up of more than 8,000 patients enrolled in a German registry, Dr. Stefanie Friedrich reported at the annual meeting of the European Association for the Study of Diabetes.
"Patients with treatment-resistant hypertension, and in particular patients with diabetes, need to have their blood pressure reduced to less than 140/90 mm Hg, combined with other organ-protective therapies, to improve their outcomes," said Dr. Friedrich of the division of nephrology and hypertension at Alexander-Friedrich University in Erlangen-Nürnberg (Germany).
"If you don’t succeed with blood pressure control with drugs, you should move along to another alternative like renal denervation with no inertia," said Dr. Roland E. Schmieder, professor and chief of nephrology and hypertension at the university and a collaborator with Dr. Friedrich on this study. "In this registry nothing happened for many of these resistant patients during 2 years. I would recommend waiting no more than about 6 months if patients remain hypertensive despite maximum medical therapy. If drugs do not succeed after 6 months, you need to go to the next step, which for some patients could be renal denervation," he said in an interview. "This should be the approach for all patients with treatment-resistant hypertension, but especially when patients have diabetes."
Data on renal denervation show that it is as effective in patients with diabetes as in those without diabetes, Dr. Schmieder said. Renal denervation devices first became available for routine European use in 2010, but remain investigational in the United States.
Their study used data collected from the nearly 15,000 patients enrolled in the Registry for Ambulant Therapy With RAS-Inhibitors in Hypertensive-Patients in Germany (3A registry). The registry enrolled patients with either newly diagnosed hypertension or established hypertension that required treatment intensification at 899 physician practices in Germany during October 2008 through April 2009. The study assigned patients to receive aliskiren (Tekturna), an ACE inhibitor, or an angiotensin receptor blocker in a 4:1:1 ratio, but otherwise participating physicians were allowed to manage these patients by whichever regimen they preferred. The current analysis focused on the 8,698 patients from the 3A registry who had 2-year follow-up, and the 2,772 patients from this group with TRH, defined as an office-measured blood pressure of 140/90 mm Hg or higher despite treatment with at least three antihypertensive medications.
The TRH subgroup included 1,170 with either type 1 or type 2 diabetes, 47% of all patients with diabetes followed in the registry for 2 years, and 1,602 patients without diabetes, 26% of the enrolled patients without diabetes followed for 2 years. These TRH prevalence rates show that "resistant hypertension is common in outpatients, especially patients with diabetes," Dr. Friedrich said. At the time they entered the registry, the TRH patients had an average blood pressure of 162/91 mm Hg, with similar averages in both the diabetic and nondiabetic subgroups. At entry, the patients with diabetes averaged 71 years of age, while those without diabetes were an average of 68 years old. The median duration of hypertension was 11 years in the diabetes patients and 8 years in those without diabetes.
After 2 years, 55% of the TRH patients with diabetes and 48% of those without diabetes remained at blood pressures above the goal of less than 140/90 mm Hg. The average level of hemoglobin A1c among the diabetes patients was 6.8% at baseline, and 6.9% after 2 years.
In addition to having a significantly greater rate of combined adverse cardiac and cerebrovascular events at 2 years, the patients with diabetes also had significantly more events for each of the three outcomes included in this composite: The rate of all-cause death was 4.4% in the patients with diabetes and 2.9% in those without; the incidence of myocardial infarction was 1.3% in the diabetes patients and 0.6% in the others; and stroke incidence was 1.4% in the patients with diabetes and 0.8% in those without, Dr. Friedrich reported.
The German 3A registry is sponsored by Novartis. Dr. Friedrich said she had no relevant financial disclosures. Dr. Schmieder has been a consultant to, and a speaker on behalf of, Medtronic, a company that markets a renal denervation device.
On Twitter @mitchelzoler
AT THE EASD ANNUAL MEETING
Major finding: Diabetes patients with treatment-resistant hypertension had a 6.2% combined rate of death, myocardial infarction, and stroke over a 2-year period, compared with a 3.8% rate in nondiabetics.
Data source: The 3A registry, which enrolled nearly 15,000 patients with diabetes from 899 physician practices in Germany.
Disclosures: The German 3A registry is sponsored by Novartis. Dr. Friedrich said she had no relevant financial disclosures. Dr. Schmieder has been a consultant to, and a speaker on behalf of, Medtronic, which markets a renal denervation device.
ED in type 1 diabetes often resolves
BARCELONA – If a man with type 1 diabetes develops erectile dysfunction, the first appearance spontaneously resolves more than half the time, according to data collected from nearly 700 men followed for 16 years.
But of those men whose first erectile dysfunction (ED) episode resolves, more than half will experience a recurrence. Furthermore, although these recurrences may resolve as well, the likelihood of resolution falls over time, and the chance of resolution also drops as repeated cycles of ED and resolution accumulate, Dr. Hunter Wessells said at the annual meeting of the European Association for the Study of Diabetes.
Factors affecting this pattern of ED onset and resolution appear to include modifiable risks such as glycemic control, blood pressure, and body mass index, and a "point of no return" for ED resolution "may be postulated based on patient’s age, level of hemoglobin A1c, and duration of ED," said Dr. Wessells, professor and chairman of urology at the University of Washington in Seattle.
The findings suggest that a window of opportunity exists when ED first appears to boost the chance of resolution through improved glycemic control and other interventions.
"I counsel men with type 1 diabetes and new-onset ED that with increased exercise, better blood pressure control, weight loss, and better glycemic control they have a good chance of reversing their ED," Dr. Wessells said in an interview. "It’s an opportunity to intervene. We don’t yet have firm evidence for this, but as a clinician I give this advice. We need to run a clinical trial to show whether, for example, lowering HbA1c can reverse ED. If you have a man with ED and an HbA1c of 10%, if you bring him down to 7% I think you could probably reverse his ED, but currently that is just my speculation."
Dr. Wessells and his associates used data collected from men during the Diabetes Control and Complications Trial (DCCT) – which enrolled 1,441 men and women with type 1 diabetes starting in 1983 at 29 centers in the United States and Canada – and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study, which extended the follow-up of more than 90% of the originally-enrolled patients.
Their new analysis focused on 683 men who were followed for 16 years; their average age at their most recent follow-up was 50 years. During follow-up, the men completed an annual survey, which included a question that asked whether or not they had impotence, and a second question of whether or not they were using a drug for ED. Men who answered yes to either question were considered to have ED.
In this cohort, 326 men (48%) never developed ED, 77 (11%) had a single episode during follow-up that later resolved, 158 (23%) had two or more episodes of ED occurrences followed by resolution, and 122 men (18%) developed ED and never had resolution. By the end of the 16 years of follow-up, the majority of men who had multiple episodes of ED onset and resolution had progressed to unremitting ED.
The results showed that among the 357 men in this cohort who developed ED, 235 (66%) had resolution of their first episode.
To explore potential correlates of ED onset and resolution, they further analyzed the subgroup of 333 men from this group with at least 7 years of completed information on their ED status (although all men were followed for 16 years, many had years when they did not supply survey information). The researchers found that, on average, the men whose ED resolved were slightly younger than those whose ED did not resolve, and they had a lower BMI. In addition, men with a single ED episode had an average HbA1c of 8.1%, compared with 8.4% among those with multiple episodes of ED and resolution, and an average 8.8% level in men whose ED never resolved. The prevalence of an HbA1c level of 8% or higher was 47% in men with a single, transient episode, 66% in those with multiple transient episodes, and 71% among men whose ED never resolved.
The results also showed that when ED persisted for more than a year, the chance of subsequent resolution fell with time. Men with 2 consecutive years of reporting ED had a 50% rate of resolution the next year. The resolution rate continued to fall as the duration of ED increased, and when men had 5 consecutive years reporting ED, 25% had resolution the following year. "By the fifth year, ED status was essentially set," Dr. Wessells said.
Dr. Wessells said that he had no disclosures. The DCCT and EDIC trials were sponsored by the National Institutes of Health
On Twitter @mitchelzoler
BARCELONA – If a man with type 1 diabetes develops erectile dysfunction, the first appearance spontaneously resolves more than half the time, according to data collected from nearly 700 men followed for 16 years.
But of those men whose first erectile dysfunction (ED) episode resolves, more than half will experience a recurrence. Furthermore, although these recurrences may resolve as well, the likelihood of resolution falls over time, and the chance of resolution also drops as repeated cycles of ED and resolution accumulate, Dr. Hunter Wessells said at the annual meeting of the European Association for the Study of Diabetes.
Factors affecting this pattern of ED onset and resolution appear to include modifiable risks such as glycemic control, blood pressure, and body mass index, and a "point of no return" for ED resolution "may be postulated based on patient’s age, level of hemoglobin A1c, and duration of ED," said Dr. Wessells, professor and chairman of urology at the University of Washington in Seattle.
The findings suggest that a window of opportunity exists when ED first appears to boost the chance of resolution through improved glycemic control and other interventions.
"I counsel men with type 1 diabetes and new-onset ED that with increased exercise, better blood pressure control, weight loss, and better glycemic control they have a good chance of reversing their ED," Dr. Wessells said in an interview. "It’s an opportunity to intervene. We don’t yet have firm evidence for this, but as a clinician I give this advice. We need to run a clinical trial to show whether, for example, lowering HbA1c can reverse ED. If you have a man with ED and an HbA1c of 10%, if you bring him down to 7% I think you could probably reverse his ED, but currently that is just my speculation."
Dr. Wessells and his associates used data collected from men during the Diabetes Control and Complications Trial (DCCT) – which enrolled 1,441 men and women with type 1 diabetes starting in 1983 at 29 centers in the United States and Canada – and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study, which extended the follow-up of more than 90% of the originally-enrolled patients.
Their new analysis focused on 683 men who were followed for 16 years; their average age at their most recent follow-up was 50 years. During follow-up, the men completed an annual survey, which included a question that asked whether or not they had impotence, and a second question of whether or not they were using a drug for ED. Men who answered yes to either question were considered to have ED.
In this cohort, 326 men (48%) never developed ED, 77 (11%) had a single episode during follow-up that later resolved, 158 (23%) had two or more episodes of ED occurrences followed by resolution, and 122 men (18%) developed ED and never had resolution. By the end of the 16 years of follow-up, the majority of men who had multiple episodes of ED onset and resolution had progressed to unremitting ED.
The results showed that among the 357 men in this cohort who developed ED, 235 (66%) had resolution of their first episode.
To explore potential correlates of ED onset and resolution, they further analyzed the subgroup of 333 men from this group with at least 7 years of completed information on their ED status (although all men were followed for 16 years, many had years when they did not supply survey information). The researchers found that, on average, the men whose ED resolved were slightly younger than those whose ED did not resolve, and they had a lower BMI. In addition, men with a single ED episode had an average HbA1c of 8.1%, compared with 8.4% among those with multiple episodes of ED and resolution, and an average 8.8% level in men whose ED never resolved. The prevalence of an HbA1c level of 8% or higher was 47% in men with a single, transient episode, 66% in those with multiple transient episodes, and 71% among men whose ED never resolved.
The results also showed that when ED persisted for more than a year, the chance of subsequent resolution fell with time. Men with 2 consecutive years of reporting ED had a 50% rate of resolution the next year. The resolution rate continued to fall as the duration of ED increased, and when men had 5 consecutive years reporting ED, 25% had resolution the following year. "By the fifth year, ED status was essentially set," Dr. Wessells said.
Dr. Wessells said that he had no disclosures. The DCCT and EDIC trials were sponsored by the National Institutes of Health
On Twitter @mitchelzoler
BARCELONA – If a man with type 1 diabetes develops erectile dysfunction, the first appearance spontaneously resolves more than half the time, according to data collected from nearly 700 men followed for 16 years.
But of those men whose first erectile dysfunction (ED) episode resolves, more than half will experience a recurrence. Furthermore, although these recurrences may resolve as well, the likelihood of resolution falls over time, and the chance of resolution also drops as repeated cycles of ED and resolution accumulate, Dr. Hunter Wessells said at the annual meeting of the European Association for the Study of Diabetes.
Factors affecting this pattern of ED onset and resolution appear to include modifiable risks such as glycemic control, blood pressure, and body mass index, and a "point of no return" for ED resolution "may be postulated based on patient’s age, level of hemoglobin A1c, and duration of ED," said Dr. Wessells, professor and chairman of urology at the University of Washington in Seattle.
The findings suggest that a window of opportunity exists when ED first appears to boost the chance of resolution through improved glycemic control and other interventions.
"I counsel men with type 1 diabetes and new-onset ED that with increased exercise, better blood pressure control, weight loss, and better glycemic control they have a good chance of reversing their ED," Dr. Wessells said in an interview. "It’s an opportunity to intervene. We don’t yet have firm evidence for this, but as a clinician I give this advice. We need to run a clinical trial to show whether, for example, lowering HbA1c can reverse ED. If you have a man with ED and an HbA1c of 10%, if you bring him down to 7% I think you could probably reverse his ED, but currently that is just my speculation."
Dr. Wessells and his associates used data collected from men during the Diabetes Control and Complications Trial (DCCT) – which enrolled 1,441 men and women with type 1 diabetes starting in 1983 at 29 centers in the United States and Canada – and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study, which extended the follow-up of more than 90% of the originally-enrolled patients.
Their new analysis focused on 683 men who were followed for 16 years; their average age at their most recent follow-up was 50 years. During follow-up, the men completed an annual survey, which included a question that asked whether or not they had impotence, and a second question of whether or not they were using a drug for ED. Men who answered yes to either question were considered to have ED.
In this cohort, 326 men (48%) never developed ED, 77 (11%) had a single episode during follow-up that later resolved, 158 (23%) had two or more episodes of ED occurrences followed by resolution, and 122 men (18%) developed ED and never had resolution. By the end of the 16 years of follow-up, the majority of men who had multiple episodes of ED onset and resolution had progressed to unremitting ED.
The results showed that among the 357 men in this cohort who developed ED, 235 (66%) had resolution of their first episode.
To explore potential correlates of ED onset and resolution, they further analyzed the subgroup of 333 men from this group with at least 7 years of completed information on their ED status (although all men were followed for 16 years, many had years when they did not supply survey information). The researchers found that, on average, the men whose ED resolved were slightly younger than those whose ED did not resolve, and they had a lower BMI. In addition, men with a single ED episode had an average HbA1c of 8.1%, compared with 8.4% among those with multiple episodes of ED and resolution, and an average 8.8% level in men whose ED never resolved. The prevalence of an HbA1c level of 8% or higher was 47% in men with a single, transient episode, 66% in those with multiple transient episodes, and 71% among men whose ED never resolved.
The results also showed that when ED persisted for more than a year, the chance of subsequent resolution fell with time. Men with 2 consecutive years of reporting ED had a 50% rate of resolution the next year. The resolution rate continued to fall as the duration of ED increased, and when men had 5 consecutive years reporting ED, 25% had resolution the following year. "By the fifth year, ED status was essentially set," Dr. Wessells said.
Dr. Wessells said that he had no disclosures. The DCCT and EDIC trials were sponsored by the National Institutes of Health
On Twitter @mitchelzoler
AT THE EASD ANNUAL MEETING
Major finding: Two-thirds of men with type 1 diabetes who developed erectile dysfunction later recovered sexual function, but many had subsequent recurrences.
Data source: The DCCT and EDIC trials, which followed 683 men with type 1 diabetes for 16 years.
Disclosures: Dr. Wessells said that he had no disclosures. The DCCT and EDIC trials were sponsored by the National Institutes of Health.
M. genitalium demands new STI treatment strategy
VIENNA – Mycoplasma genitalium is a new bad boy of sexually transmitted infections, prompting experts to rethink how to treat nongonococcal urethritis, pelvic inflammatory disease, and other infections caused by the pathogen.
The full scope of M. genitalium in sexually transmitted infections (STI) of men and women is just now becoming clear – as are the treatment demands of M. genitalium’s susceptibility profile. Given that it’s notoriously hard to culture and that genetic-based assays are only recently available and not yet sold commercially, reliable management of M. genitalium depends on the fluoroquinolone moxifloxacin. Yet the threat of widespread resistance to that drug looms, with no good back-up agents currently available.
Because successful treatment of M. genitalium differs sharply from that of gonorrhea and Chlamydia trachomatis – the other two pathogens most common in urethritis, cervicitis, and pelvic inflammatory disease – clinicians increasingly confront infections unresponsive to or persistent despite a course of doxycycline or azithromycin (Zithromax).
Podium talks from a series of researchers in the United States and Europe at the joint meeting of the International Society for Sexually Transmitted Diseases Research and the International Union Against Sexually Transmitted Infections documented the STI niche that M. genitalium occupies and how well various antibiotics work against the pathogen.
"M. genitalium is associated with 15%-22% of nongonococcal urethritis cases, and 10%-15% of cervicitis cases, and in many settings is more common that Neisseria gonorrhoeae with treatment outcomes often far worse," said Lisa E. Manhart, Ph.D., an epidemiologist at the University of Washington, Seattle. "There is no characteristic clinical syndrome for M. genitalium infections; they look very similar to Chlamydia. Clinical judgment is the only option for treatment decisions in many settings, and no FDA-approved diagnostic test [for M. genitalium] exists."
Persistent cases of nongonococcal urethritis, cervicitis, and possibly pelvic inflammatory disease could benefit from treatment with moxifloxacin (Avelox), Dr. Manhart noted. But "it is becoming clear that resistance in M. genitalium develops rapidly."
"M. genitalium is an important STI, and guidelines should reflect this; but there is no good evidence base for optimal treatment. Optimal treatment is a moving target," said Dr. Jørgen S. Jensen, a researcher at the Statens Serum Institut in Copenhagen.
"Widespread use of azithromycin and moxifloxacin will select for multidrug-resistant strains; the time for single-drug, one-dose regimens is probably over," said Dr. Jensen, specifically referring to the common practice of treating nongonococcal urethritis with a single dose of azithromycin.
M. genitalium invades U.S.
Dr. Manhart and a second U.S. researcher, Dr. Harold C. Wiesenfeld from the University of Pittsburgh, each reported new data at the meeting showing how common M. genitalium STI infections have become among U.S. patients.
Dr. Manhart presented new data from the MEGA (Mycoplasma Genitalium Antibiotic Susceptibility and Treatment) trial, which enrolled 606 men with nongonococcal urethritis (NGU) at an STI clinic in Seattle. The study’s primary endpoint was a comparison of 100 mg doxycycline b.i.d. for 7 days and a single 1-g dose of azithromycin.
The two regimens produced similar cure rates – 76% in the doxycycline arm, and 80% in the azithromycin arm, Dr. Manhart and her associates reported earlier this year (Clin. Infec. Dis. 2013;56:934-42). The initial report also identified M. genitalium in 13% of those men – identified using an in-house polymerase chain reaction assay – compared with 24% who tested positive for Chlamydia and 23% infected with Ureaplasma urealyticum biovar.
The new analyses Dr. Manhart reported tracked the outcomes of patients infected with M. genitalium. Treatment with either of the standard doxycycline or azithromycin regimens failed about half the time, Dr. Manhart said: 29% of men with doxycycline-resistant infections who were retreated with azithromycin as part of the study’s extended protocol carried M. genitalium, and 70% of the men who failed initial azithromycin treatment who were then retreated with doxycycline had persistent infection with M. genitalium.
Results from the extended portion of the study also showed that treatment with moxifloxacin was the answer for most of the otherwise unresponsive M. genitalium infections, but it wasn’t perfect. The M. genitalium infection persisted in 12%-15% of those men after a full course of moxifloxacin.
The full results suggest that moxifloxacin is potentially effective for treating various persistent STIs, not only NGU but also cervicitis and possibly pelvic inflammatory disease (PID). But resistance to moxifloxacin develops "rapidly," meaning that surveillance for resistance is needed, as well as new drug alternatives, she said.
New suspect in acute PID?
Although Dr. Manhart hedged on the role of M. genitalium in PID, results from a different U.S. study created a strong case for a role in acute PID.
M. genitalium appeared in 28 (18%) of 157 diagnosed women with acute PID who were enrolled in a study that had primarily focused on comparing two antibiotic regimens, and in 30% of those women with histologically proven acute PID. Using an in-house transcription-mediated assay for M. genitalium, researchers at the University of Pittsburgh found that endometrial identification of M. genitalium linked independently with a fourfold increased prevalence of histologically confirmed acute PID.
Those numbers for M. genitalium put it in the same ball park in the study with the two traditional heavy hitters of acute PID, N. gonorrhoeae and C. trachomatis. By establishing a significant role for M. genitalium in acute PID, the data immediately called into question the standard empiric therapies for acute PID.
"The PID treatments we use fall short for eradicating M. genitalium," said Dr. Wiesenfeld, an ob.gyn. and infectious diseases physician at the University of Pittsburgh, who reported the results. "Whether these findings [affect] treatment guidelines for acute PID remains to be seen; but if it is truly important to treat M. genitalium, it will completely turn around our treatment regimens."
The looming dilemma is that the azithromycin or doxycycline used for gonorrhea will not stop many of the infections by M. genitalium, while the moxifloxacin that can handle most M. genitalium today does not eradicate N. gonorrhoeae.
However, it’s premature to consider routinely testing or screening for M. genitalium in patients with PID or other possible forms of M. genitalium infection, Dr. Wiesenfeld cautioned. That’s in part because of the current logistical limitations on testing, and in part because the long-term impact of M. genitalium infection on reproductive health is not yet established. Longer follow-up of women in the study should shed more light on the natural history of the patients who received treatments that did not eradicate M. genitalium.
"If M. genitalium turns out to be associated with PID, it is the single organism that is not covered by current treatment with a cephalosporin, doxycycline, and metronidazole," said Sharon L. Hillier, Ph. D., in an interview during the meeting. "We are very concerned about it because it is a fairly sizable fraction of the STIs we’ve seen in these women with acute PID," said Dr. Hillier, professor of ob.gyn. and reproductive sciences at the University of Pittsburgh and a collaborator with Dr. Wiesenfeld on his study.
Dr. Hillier agreed that the key question to address is the fertility risk to women from having PID caused by M. genitalium.
"It’s so common that it might have a huge population impact," she said. "We know fertility outcomes are bad from gonorrhea and Chlamydia." The fertility risk from M. genitalium "will be what makes us decide if we need to add another treatment."
Adding moxifloxacin to routine, empiric treatment for acute PID would be an especially tough call if it also meant dropping doxycycline, a drug that is otherwise attractive because of its low cost and broad spectrum of activity against other PID pathogens.
"It remains to be seen what we should do for empiric therapy for women who walk in with PID, what is the best way to try to preserve her fertility," Dr. Hillier said. "We simply don’t know right now, but it’s been a huge topic of conversation."
Changing the treatment strategies
While the best initial management strategy for acute PID remains unclear, the specter of M. genitalium has already changed the management strategy used by Dr. Paddy Horner to treat men with NGU, said Dr. Horner, a physician in the school of social and community medicine at the University of Bristol, U.K.
These days, his preferred approach is what he calls "infection-specific" first-line therapy: Before treatment begins, he eliminates purely empiric therapy by employing a commercially available, nucleic-acid amplification test for gonorrhea and Chlamydia at the first encounter and getting the result in 30 minutes.
That means treating men who test positive for Chlamydia with a week of doxycycline first, or starting with a 5-day course of azithromycin for men who are Chlamydia negative. However, he advised using a single, 1-g dosage of azithromycin with caution, because of the prevalence of macrolide resistance. But Dr. Horner also admitted that no evidence has proven the superiority of the 5-day alternative that starts with a 1-g dose followed by 500 mg daily for 4 more days. Men who test positive for N. gonorrhoeae should receive 1 g of azithromycin plus 500 mg ceftriaxone.
If the urethritis persists 2 weeks later, Dr. Horner recommended treating patients empirically with a combination of moxifloxacin and metronidazole to cover possible infection by either M. genitalium or U. urealyticum.
In theory, this overall approach has the potential to resolve 89% of infections after the first round of treatment and 99% after the second round, with low potential for generating resistant strains of M. genitalium, based on pathogen prevalence and susceptibility profiles that Dr. Horner sees in Bristol. Those outcomes are an improvement on the cure rates and resistance risks when initial treatment is applied completely empirically, he explained.
Infection-specific treatment would work even better once rapid, point-of-care genetic tests become available for M. genitalium and U. urealyticum, Dr. Horner said.
Dr. Manhart, Dr. Wiesenfeld, and Dr. Hillier had no disclosures. Dr. Jensen said that his institution provides diagnostic testing for M. genitalium commercially and also evaluates various new antimicrobials under contract. Dr. Horner said that he has been a consultant to or received research support from Aquarius Population Health, Cepheid, Hologic, and Siemens.
On Twitter @mitchelzoler
VIENNA – Mycoplasma genitalium is a new bad boy of sexually transmitted infections, prompting experts to rethink how to treat nongonococcal urethritis, pelvic inflammatory disease, and other infections caused by the pathogen.
The full scope of M. genitalium in sexually transmitted infections (STI) of men and women is just now becoming clear – as are the treatment demands of M. genitalium’s susceptibility profile. Given that it’s notoriously hard to culture and that genetic-based assays are only recently available and not yet sold commercially, reliable management of M. genitalium depends on the fluoroquinolone moxifloxacin. Yet the threat of widespread resistance to that drug looms, with no good back-up agents currently available.
Because successful treatment of M. genitalium differs sharply from that of gonorrhea and Chlamydia trachomatis – the other two pathogens most common in urethritis, cervicitis, and pelvic inflammatory disease – clinicians increasingly confront infections unresponsive to or persistent despite a course of doxycycline or azithromycin (Zithromax).
Podium talks from a series of researchers in the United States and Europe at the joint meeting of the International Society for Sexually Transmitted Diseases Research and the International Union Against Sexually Transmitted Infections documented the STI niche that M. genitalium occupies and how well various antibiotics work against the pathogen.
"M. genitalium is associated with 15%-22% of nongonococcal urethritis cases, and 10%-15% of cervicitis cases, and in many settings is more common that Neisseria gonorrhoeae with treatment outcomes often far worse," said Lisa E. Manhart, Ph.D., an epidemiologist at the University of Washington, Seattle. "There is no characteristic clinical syndrome for M. genitalium infections; they look very similar to Chlamydia. Clinical judgment is the only option for treatment decisions in many settings, and no FDA-approved diagnostic test [for M. genitalium] exists."
Persistent cases of nongonococcal urethritis, cervicitis, and possibly pelvic inflammatory disease could benefit from treatment with moxifloxacin (Avelox), Dr. Manhart noted. But "it is becoming clear that resistance in M. genitalium develops rapidly."
"M. genitalium is an important STI, and guidelines should reflect this; but there is no good evidence base for optimal treatment. Optimal treatment is a moving target," said Dr. Jørgen S. Jensen, a researcher at the Statens Serum Institut in Copenhagen.
"Widespread use of azithromycin and moxifloxacin will select for multidrug-resistant strains; the time for single-drug, one-dose regimens is probably over," said Dr. Jensen, specifically referring to the common practice of treating nongonococcal urethritis with a single dose of azithromycin.
M. genitalium invades U.S.
Dr. Manhart and a second U.S. researcher, Dr. Harold C. Wiesenfeld from the University of Pittsburgh, each reported new data at the meeting showing how common M. genitalium STI infections have become among U.S. patients.
Dr. Manhart presented new data from the MEGA (Mycoplasma Genitalium Antibiotic Susceptibility and Treatment) trial, which enrolled 606 men with nongonococcal urethritis (NGU) at an STI clinic in Seattle. The study’s primary endpoint was a comparison of 100 mg doxycycline b.i.d. for 7 days and a single 1-g dose of azithromycin.
The two regimens produced similar cure rates – 76% in the doxycycline arm, and 80% in the azithromycin arm, Dr. Manhart and her associates reported earlier this year (Clin. Infec. Dis. 2013;56:934-42). The initial report also identified M. genitalium in 13% of those men – identified using an in-house polymerase chain reaction assay – compared with 24% who tested positive for Chlamydia and 23% infected with Ureaplasma urealyticum biovar.
The new analyses Dr. Manhart reported tracked the outcomes of patients infected with M. genitalium. Treatment with either of the standard doxycycline or azithromycin regimens failed about half the time, Dr. Manhart said: 29% of men with doxycycline-resistant infections who were retreated with azithromycin as part of the study’s extended protocol carried M. genitalium, and 70% of the men who failed initial azithromycin treatment who were then retreated with doxycycline had persistent infection with M. genitalium.
Results from the extended portion of the study also showed that treatment with moxifloxacin was the answer for most of the otherwise unresponsive M. genitalium infections, but it wasn’t perfect. The M. genitalium infection persisted in 12%-15% of those men after a full course of moxifloxacin.
The full results suggest that moxifloxacin is potentially effective for treating various persistent STIs, not only NGU but also cervicitis and possibly pelvic inflammatory disease (PID). But resistance to moxifloxacin develops "rapidly," meaning that surveillance for resistance is needed, as well as new drug alternatives, she said.
New suspect in acute PID?
Although Dr. Manhart hedged on the role of M. genitalium in PID, results from a different U.S. study created a strong case for a role in acute PID.
M. genitalium appeared in 28 (18%) of 157 diagnosed women with acute PID who were enrolled in a study that had primarily focused on comparing two antibiotic regimens, and in 30% of those women with histologically proven acute PID. Using an in-house transcription-mediated assay for M. genitalium, researchers at the University of Pittsburgh found that endometrial identification of M. genitalium linked independently with a fourfold increased prevalence of histologically confirmed acute PID.
Those numbers for M. genitalium put it in the same ball park in the study with the two traditional heavy hitters of acute PID, N. gonorrhoeae and C. trachomatis. By establishing a significant role for M. genitalium in acute PID, the data immediately called into question the standard empiric therapies for acute PID.
"The PID treatments we use fall short for eradicating M. genitalium," said Dr. Wiesenfeld, an ob.gyn. and infectious diseases physician at the University of Pittsburgh, who reported the results. "Whether these findings [affect] treatment guidelines for acute PID remains to be seen; but if it is truly important to treat M. genitalium, it will completely turn around our treatment regimens."
The looming dilemma is that the azithromycin or doxycycline used for gonorrhea will not stop many of the infections by M. genitalium, while the moxifloxacin that can handle most M. genitalium today does not eradicate N. gonorrhoeae.
However, it’s premature to consider routinely testing or screening for M. genitalium in patients with PID or other possible forms of M. genitalium infection, Dr. Wiesenfeld cautioned. That’s in part because of the current logistical limitations on testing, and in part because the long-term impact of M. genitalium infection on reproductive health is not yet established. Longer follow-up of women in the study should shed more light on the natural history of the patients who received treatments that did not eradicate M. genitalium.
"If M. genitalium turns out to be associated with PID, it is the single organism that is not covered by current treatment with a cephalosporin, doxycycline, and metronidazole," said Sharon L. Hillier, Ph. D., in an interview during the meeting. "We are very concerned about it because it is a fairly sizable fraction of the STIs we’ve seen in these women with acute PID," said Dr. Hillier, professor of ob.gyn. and reproductive sciences at the University of Pittsburgh and a collaborator with Dr. Wiesenfeld on his study.
Dr. Hillier agreed that the key question to address is the fertility risk to women from having PID caused by M. genitalium.
"It’s so common that it might have a huge population impact," she said. "We know fertility outcomes are bad from gonorrhea and Chlamydia." The fertility risk from M. genitalium "will be what makes us decide if we need to add another treatment."
Adding moxifloxacin to routine, empiric treatment for acute PID would be an especially tough call if it also meant dropping doxycycline, a drug that is otherwise attractive because of its low cost and broad spectrum of activity against other PID pathogens.
"It remains to be seen what we should do for empiric therapy for women who walk in with PID, what is the best way to try to preserve her fertility," Dr. Hillier said. "We simply don’t know right now, but it’s been a huge topic of conversation."
Changing the treatment strategies
While the best initial management strategy for acute PID remains unclear, the specter of M. genitalium has already changed the management strategy used by Dr. Paddy Horner to treat men with NGU, said Dr. Horner, a physician in the school of social and community medicine at the University of Bristol, U.K.
These days, his preferred approach is what he calls "infection-specific" first-line therapy: Before treatment begins, he eliminates purely empiric therapy by employing a commercially available, nucleic-acid amplification test for gonorrhea and Chlamydia at the first encounter and getting the result in 30 minutes.
That means treating men who test positive for Chlamydia with a week of doxycycline first, or starting with a 5-day course of azithromycin for men who are Chlamydia negative. However, he advised using a single, 1-g dosage of azithromycin with caution, because of the prevalence of macrolide resistance. But Dr. Horner also admitted that no evidence has proven the superiority of the 5-day alternative that starts with a 1-g dose followed by 500 mg daily for 4 more days. Men who test positive for N. gonorrhoeae should receive 1 g of azithromycin plus 500 mg ceftriaxone.
If the urethritis persists 2 weeks later, Dr. Horner recommended treating patients empirically with a combination of moxifloxacin and metronidazole to cover possible infection by either M. genitalium or U. urealyticum.
In theory, this overall approach has the potential to resolve 89% of infections after the first round of treatment and 99% after the second round, with low potential for generating resistant strains of M. genitalium, based on pathogen prevalence and susceptibility profiles that Dr. Horner sees in Bristol. Those outcomes are an improvement on the cure rates and resistance risks when initial treatment is applied completely empirically, he explained.
Infection-specific treatment would work even better once rapid, point-of-care genetic tests become available for M. genitalium and U. urealyticum, Dr. Horner said.
Dr. Manhart, Dr. Wiesenfeld, and Dr. Hillier had no disclosures. Dr. Jensen said that his institution provides diagnostic testing for M. genitalium commercially and also evaluates various new antimicrobials under contract. Dr. Horner said that he has been a consultant to or received research support from Aquarius Population Health, Cepheid, Hologic, and Siemens.
On Twitter @mitchelzoler
VIENNA – Mycoplasma genitalium is a new bad boy of sexually transmitted infections, prompting experts to rethink how to treat nongonococcal urethritis, pelvic inflammatory disease, and other infections caused by the pathogen.
The full scope of M. genitalium in sexually transmitted infections (STI) of men and women is just now becoming clear – as are the treatment demands of M. genitalium’s susceptibility profile. Given that it’s notoriously hard to culture and that genetic-based assays are only recently available and not yet sold commercially, reliable management of M. genitalium depends on the fluoroquinolone moxifloxacin. Yet the threat of widespread resistance to that drug looms, with no good back-up agents currently available.
Because successful treatment of M. genitalium differs sharply from that of gonorrhea and Chlamydia trachomatis – the other two pathogens most common in urethritis, cervicitis, and pelvic inflammatory disease – clinicians increasingly confront infections unresponsive to or persistent despite a course of doxycycline or azithromycin (Zithromax).
Podium talks from a series of researchers in the United States and Europe at the joint meeting of the International Society for Sexually Transmitted Diseases Research and the International Union Against Sexually Transmitted Infections documented the STI niche that M. genitalium occupies and how well various antibiotics work against the pathogen.
"M. genitalium is associated with 15%-22% of nongonococcal urethritis cases, and 10%-15% of cervicitis cases, and in many settings is more common that Neisseria gonorrhoeae with treatment outcomes often far worse," said Lisa E. Manhart, Ph.D., an epidemiologist at the University of Washington, Seattle. "There is no characteristic clinical syndrome for M. genitalium infections; they look very similar to Chlamydia. Clinical judgment is the only option for treatment decisions in many settings, and no FDA-approved diagnostic test [for M. genitalium] exists."
Persistent cases of nongonococcal urethritis, cervicitis, and possibly pelvic inflammatory disease could benefit from treatment with moxifloxacin (Avelox), Dr. Manhart noted. But "it is becoming clear that resistance in M. genitalium develops rapidly."
"M. genitalium is an important STI, and guidelines should reflect this; but there is no good evidence base for optimal treatment. Optimal treatment is a moving target," said Dr. Jørgen S. Jensen, a researcher at the Statens Serum Institut in Copenhagen.
"Widespread use of azithromycin and moxifloxacin will select for multidrug-resistant strains; the time for single-drug, one-dose regimens is probably over," said Dr. Jensen, specifically referring to the common practice of treating nongonococcal urethritis with a single dose of azithromycin.
M. genitalium invades U.S.
Dr. Manhart and a second U.S. researcher, Dr. Harold C. Wiesenfeld from the University of Pittsburgh, each reported new data at the meeting showing how common M. genitalium STI infections have become among U.S. patients.
Dr. Manhart presented new data from the MEGA (Mycoplasma Genitalium Antibiotic Susceptibility and Treatment) trial, which enrolled 606 men with nongonococcal urethritis (NGU) at an STI clinic in Seattle. The study’s primary endpoint was a comparison of 100 mg doxycycline b.i.d. for 7 days and a single 1-g dose of azithromycin.
The two regimens produced similar cure rates – 76% in the doxycycline arm, and 80% in the azithromycin arm, Dr. Manhart and her associates reported earlier this year (Clin. Infec. Dis. 2013;56:934-42). The initial report also identified M. genitalium in 13% of those men – identified using an in-house polymerase chain reaction assay – compared with 24% who tested positive for Chlamydia and 23% infected with Ureaplasma urealyticum biovar.
The new analyses Dr. Manhart reported tracked the outcomes of patients infected with M. genitalium. Treatment with either of the standard doxycycline or azithromycin regimens failed about half the time, Dr. Manhart said: 29% of men with doxycycline-resistant infections who were retreated with azithromycin as part of the study’s extended protocol carried M. genitalium, and 70% of the men who failed initial azithromycin treatment who were then retreated with doxycycline had persistent infection with M. genitalium.
Results from the extended portion of the study also showed that treatment with moxifloxacin was the answer for most of the otherwise unresponsive M. genitalium infections, but it wasn’t perfect. The M. genitalium infection persisted in 12%-15% of those men after a full course of moxifloxacin.
The full results suggest that moxifloxacin is potentially effective for treating various persistent STIs, not only NGU but also cervicitis and possibly pelvic inflammatory disease (PID). But resistance to moxifloxacin develops "rapidly," meaning that surveillance for resistance is needed, as well as new drug alternatives, she said.
New suspect in acute PID?
Although Dr. Manhart hedged on the role of M. genitalium in PID, results from a different U.S. study created a strong case for a role in acute PID.
M. genitalium appeared in 28 (18%) of 157 diagnosed women with acute PID who were enrolled in a study that had primarily focused on comparing two antibiotic regimens, and in 30% of those women with histologically proven acute PID. Using an in-house transcription-mediated assay for M. genitalium, researchers at the University of Pittsburgh found that endometrial identification of M. genitalium linked independently with a fourfold increased prevalence of histologically confirmed acute PID.
Those numbers for M. genitalium put it in the same ball park in the study with the two traditional heavy hitters of acute PID, N. gonorrhoeae and C. trachomatis. By establishing a significant role for M. genitalium in acute PID, the data immediately called into question the standard empiric therapies for acute PID.
"The PID treatments we use fall short for eradicating M. genitalium," said Dr. Wiesenfeld, an ob.gyn. and infectious diseases physician at the University of Pittsburgh, who reported the results. "Whether these findings [affect] treatment guidelines for acute PID remains to be seen; but if it is truly important to treat M. genitalium, it will completely turn around our treatment regimens."
The looming dilemma is that the azithromycin or doxycycline used for gonorrhea will not stop many of the infections by M. genitalium, while the moxifloxacin that can handle most M. genitalium today does not eradicate N. gonorrhoeae.
However, it’s premature to consider routinely testing or screening for M. genitalium in patients with PID or other possible forms of M. genitalium infection, Dr. Wiesenfeld cautioned. That’s in part because of the current logistical limitations on testing, and in part because the long-term impact of M. genitalium infection on reproductive health is not yet established. Longer follow-up of women in the study should shed more light on the natural history of the patients who received treatments that did not eradicate M. genitalium.
"If M. genitalium turns out to be associated with PID, it is the single organism that is not covered by current treatment with a cephalosporin, doxycycline, and metronidazole," said Sharon L. Hillier, Ph. D., in an interview during the meeting. "We are very concerned about it because it is a fairly sizable fraction of the STIs we’ve seen in these women with acute PID," said Dr. Hillier, professor of ob.gyn. and reproductive sciences at the University of Pittsburgh and a collaborator with Dr. Wiesenfeld on his study.
Dr. Hillier agreed that the key question to address is the fertility risk to women from having PID caused by M. genitalium.
"It’s so common that it might have a huge population impact," she said. "We know fertility outcomes are bad from gonorrhea and Chlamydia." The fertility risk from M. genitalium "will be what makes us decide if we need to add another treatment."
Adding moxifloxacin to routine, empiric treatment for acute PID would be an especially tough call if it also meant dropping doxycycline, a drug that is otherwise attractive because of its low cost and broad spectrum of activity against other PID pathogens.
"It remains to be seen what we should do for empiric therapy for women who walk in with PID, what is the best way to try to preserve her fertility," Dr. Hillier said. "We simply don’t know right now, but it’s been a huge topic of conversation."
Changing the treatment strategies
While the best initial management strategy for acute PID remains unclear, the specter of M. genitalium has already changed the management strategy used by Dr. Paddy Horner to treat men with NGU, said Dr. Horner, a physician in the school of social and community medicine at the University of Bristol, U.K.
These days, his preferred approach is what he calls "infection-specific" first-line therapy: Before treatment begins, he eliminates purely empiric therapy by employing a commercially available, nucleic-acid amplification test for gonorrhea and Chlamydia at the first encounter and getting the result in 30 minutes.
That means treating men who test positive for Chlamydia with a week of doxycycline first, or starting with a 5-day course of azithromycin for men who are Chlamydia negative. However, he advised using a single, 1-g dosage of azithromycin with caution, because of the prevalence of macrolide resistance. But Dr. Horner also admitted that no evidence has proven the superiority of the 5-day alternative that starts with a 1-g dose followed by 500 mg daily for 4 more days. Men who test positive for N. gonorrhoeae should receive 1 g of azithromycin plus 500 mg ceftriaxone.
If the urethritis persists 2 weeks later, Dr. Horner recommended treating patients empirically with a combination of moxifloxacin and metronidazole to cover possible infection by either M. genitalium or U. urealyticum.
In theory, this overall approach has the potential to resolve 89% of infections after the first round of treatment and 99% after the second round, with low potential for generating resistant strains of M. genitalium, based on pathogen prevalence and susceptibility profiles that Dr. Horner sees in Bristol. Those outcomes are an improvement on the cure rates and resistance risks when initial treatment is applied completely empirically, he explained.
Infection-specific treatment would work even better once rapid, point-of-care genetic tests become available for M. genitalium and U. urealyticum, Dr. Horner said.
Dr. Manhart, Dr. Wiesenfeld, and Dr. Hillier had no disclosures. Dr. Jensen said that his institution provides diagnostic testing for M. genitalium commercially and also evaluates various new antimicrobials under contract. Dr. Horner said that he has been a consultant to or received research support from Aquarius Population Health, Cepheid, Hologic, and Siemens.
On Twitter @mitchelzoler
EXPERT ANALYSIS FROM THE STI & AIDS WORLD CONGRESS 2013
M. genitalium demands new STI treatment strategy
VIENNA – Mycoplasma genitalium is a new bad boy of sexually transmitted infections, prompting experts to rethink how to treat nongonococcal urethritis, pelvic inflammatory disease, and other infections caused by the pathogen.
The full scope of M. genitalium in sexually transmitted infections (STI) of men and women is just now becoming clear – as are the treatment demands of M. genitalium’s susceptibility profile. Given that it’s notoriously hard to culture and that genetic-based assays are only recently available and not yet sold commercially, reliable management of M. genitalium depends on the fluoroquinolone moxifloxacin. Yet the threat of widespread resistance to that drug looms, with no good back-up agents currently available.
Because successful treatment of M. genitalium differs sharply from that of gonorrhea and Chlamydia trachomatis – the other two pathogens most common in urethritis, cervicitis, and pelvic inflammatory disease – clinicians increasingly confront infections unresponsive to or persistent despite a course of doxycycline or azithromycin (Zithromax).
Podium talks from a series of researchers in the United States and Europe at the joint meeting of the International Society for Sexually Transmitted Diseases Research and the International Union Against Sexually Transmitted Infections documented the STI niche that M. genitalium occupies and how well various antibiotics work against the pathogen.
"M. genitalium is associated with 15%-22% of nongonococcal urethritis cases, and 10%-15% of cervicitis cases, and in many settings is more common that Neisseria gonorrhoeae with treatment outcomes often far worse," said Lisa E. Manhart, Ph.D., an epidemiologist at the University of Washington, Seattle. "There is no characteristic clinical syndrome for M. genitalium infections; they look very similar to Chlamydia. Clinical judgment is the only option for treatment decisions in many settings, and no FDA-approved diagnostic test [for M. genitalium] exists."
Persistent cases of nongonococcal urethritis, cervicitis, and possibly pelvic inflammatory disease could benefit from treatment with moxifloxacin (Avelox), Dr. Manhart noted. But "it is becoming clear that resistance in M. genitalium develops rapidly."
"M. genitalium is an important STI, and guidelines should reflect this; but there is no good evidence base for optimal treatment. Optimal treatment is a moving target," said Dr. Jørgen S. Jensen, a researcher at the Statens Serum Institut in Copenhagen.
"Widespread use of azithromycin and moxifloxacin will select for multidrug-resistant strains; the time for single-drug, one-dose regimens is probably over," said Dr. Jensen, specifically referring to the common practice of treating nongonococcal urethritis with a single dose of azithromycin.
M. genitalium invades U.S.
Dr. Manhart and a second U.S. researcher, Dr. Harold C. Wiesenfeld from the University of Pittsburgh, each reported new data at the meeting showing how common M. genitalium STI infections have become among U.S. patients.
Dr. Manhart presented new data from the MEGA (Mycoplasma Genitalium Antibiotic Susceptibility and Treatment) trial, which enrolled 606 men with nongonococcal urethritis (NGU) at an STI clinic in Seattle. The study’s primary endpoint was a comparison of 100 mg doxycycline b.i.d. for 7 days and a single 1-g dose of azithromycin.
The two regimens produced similar cure rates – 76% in the doxycycline arm, and 80% in the azithromycin arm, Dr. Manhart and her associates reported earlier this year (Clin. Infec. Dis. 2013;56:934-42). The initial report also identified M. genitalium in 13% of those men – identified using an in-house polymerase chain reaction assay – compared with 24% who tested positive for Chlamydia and 23% infected with Ureaplasma urealyticum biovar.
The new analyses Dr. Manhart reported tracked the outcomes of patients infected with M. genitalium. Treatment with either of the standard doxycycline or azithromycin regimens failed about half the time, Dr. Manhart said: 29% of men with doxycycline-resistant infections who were retreated with azithromycin as part of the study’s extended protocol carried M. genitalium, and 70% of the men who failed initial azithromycin treatment who were then retreated with doxycycline had persistent infection with M. genitalium.
Results from the extended portion of the study also showed that treatment with moxifloxacin was the answer for most of the otherwise unresponsive M. genitalium infections, but it wasn’t perfect. The M. genitalium infection persisted in 12%-15% of those men after a full course of moxifloxacin.
The full results suggest that moxifloxacin is potentially effective for treating various persistent STIs, not only NGU but also cervicitis and possibly pelvic inflammatory disease (PID). But resistance to moxifloxacin develops "rapidly," meaning that surveillance for resistance is needed, as well as new drug alternatives, she said.
New suspect in acute PID?
Although Dr. Manhart hedged on the role of M. genitalium in PID, results from a different U.S. study created a strong case for a role in acute PID.
M. genitalium appeared in 28 (18%) of 157 diagnosed women with acute PID who were enrolled in a study that had primarily focused on comparing two antibiotic regimens, and in 30% of those women with histologically proven acute PID. Using an in-house transcription-mediated assay for M. genitalium, researchers at the University of Pittsburgh found that endometrial identification of M. genitalium linked independently with a fourfold increased prevalence of histologically confirmed acute PID.
Those numbers for M. genitalium put it in the same ball park in the study with the two traditional heavy hitters of acute PID, N. gonorrhoeae and C. trachomatis. By establishing a significant role for M. genitalium in acute PID, the data immediately called into question the standard empiric therapies for acute PID.
"The PID treatments we use fall short for eradicating M. genitalium," said Dr. Wiesenfeld, an ob.gyn. and infectious diseases physician at the University of Pittsburgh, who reported the results. "Whether these findings [affect] treatment guidelines for acute PID remains to be seen; but if it is truly important to treat M. genitalium, it will completely turn around our treatment regimens."
The looming dilemma is that the azithromycin or doxycycline used for gonorrhea will not stop many of the infections by M. genitalium, while the moxifloxacin that can handle most M. genitalium today does not eradicate N. gonorrhoeae.
However, it’s premature to consider routinely testing or screening for M. genitalium in patients with PID or other possible forms of M. genitalium infection, Dr. Wiesenfeld cautioned. That’s in part because of the current logistical limitations on testing, and in part because the long-term impact of M. genitalium infection on reproductive health is not yet established. Longer follow-up of women in the study should shed more light on the natural history of the patients who received treatments that did not eradicate M. genitalium.
"If M. genitalium turns out to be associated with PID, it is the single organism that is not covered by current treatment with a cephalosporin, doxycycline, and metronidazole," said Sharon L. Hillier, Ph. D., in an interview during the meeting. "We are very concerned about it because it is a fairly sizable fraction of the STIs we’ve seen in these women with acute PID," said Dr. Hillier, professor of ob.gyn. and reproductive sciences at the University of Pittsburgh and a collaborator with Dr. Wiesenfeld on his study.
Dr. Hillier agreed that the key question to address is the fertility risk to women from having PID caused by M. genitalium.
"It’s so common that it might have a huge population impact," she said. "We know fertility outcomes are bad from gonorrhea and Chlamydia." The fertility risk from M. genitalium "will be what makes us decide if we need to add another treatment."
Adding moxifloxacin to routine, empiric treatment for acute PID would be an especially tough call if it also meant dropping doxycycline, a drug that is otherwise attractive because of its low cost and broad spectrum of activity against other PID pathogens.
"It remains to be seen what we should do for empiric therapy for women who walk in with PID, what is the best way to try to preserve her fertility," Dr. Hillier said. "We simply don’t know right now, but it’s been a huge topic of conversation."
Changing the treatment strategies
While the best initial management strategy for acute PID remains unclear, the specter of M. genitalium has already changed the management strategy used by Dr. Paddy Horner to treat men with NGU, said Dr. Horner, a physician in the school of social and community medicine at the University of Bristol, U.K.
These days, his preferred approach is what he calls "infection-specific" first-line therapy: Before treatment begins, he eliminates purely empiric therapy by employing a commercially available, nucleic-acid amplification test for gonorrhea and Chlamydia at the first encounter and getting the result in 30 minutes.
That means treating men who test positive for Chlamydia with a week of doxycycline first, or starting with a 5-day course of azithromycin for men who are Chlamydia negative. However, he advised using a single, 1-g dosage of azithromycin with caution, because of the prevalence of macrolide resistance. But Dr. Horner also admitted that no evidence has proven the superiority of the 5-day alternative that starts with a 1-g dose followed by 500 mg daily for 4 more days. Men who test positive for N. gonorrhoeae should receive 1 g of azithromycin plus 500 mg ceftriaxone.
If the urethritis persists 2 weeks later, Dr. Horner recommended treating patients empirically with a combination of moxifloxacin and metronidazole to cover possible infection by either M. genitalium or U. urealyticum.
In theory, this overall approach has the potential to resolve 89% of infections after the first round of treatment and 99% after the second round, with low potential for generating resistant strains of M. genitalium, based on pathogen prevalence and susceptibility profiles that Dr. Horner sees in Bristol. Those outcomes are an improvement on the cure rates and resistance risks when initial treatment is applied completely empirically, he explained.
Infection-specific treatment would work even better once rapid, point-of-care genetic tests become available for M. genitalium and U. urealyticum, Dr. Horner said.
Dr. Manhart, Dr. Wiesenfeld, and Dr. Hillier had no disclosures. Dr. Jensen said that his institution provides diagnostic testing for M. genitalium commercially and also evaluates various new antimicrobials under contract. Dr. Horner said that he has been a consultant to or received research support from Aquarius Population Health, Cepheid, Hologic, and Siemens.
On Twitter @mitchelzoler
VIENNA – Mycoplasma genitalium is a new bad boy of sexually transmitted infections, prompting experts to rethink how to treat nongonococcal urethritis, pelvic inflammatory disease, and other infections caused by the pathogen.
The full scope of M. genitalium in sexually transmitted infections (STI) of men and women is just now becoming clear – as are the treatment demands of M. genitalium’s susceptibility profile. Given that it’s notoriously hard to culture and that genetic-based assays are only recently available and not yet sold commercially, reliable management of M. genitalium depends on the fluoroquinolone moxifloxacin. Yet the threat of widespread resistance to that drug looms, with no good back-up agents currently available.
Because successful treatment of M. genitalium differs sharply from that of gonorrhea and Chlamydia trachomatis – the other two pathogens most common in urethritis, cervicitis, and pelvic inflammatory disease – clinicians increasingly confront infections unresponsive to or persistent despite a course of doxycycline or azithromycin (Zithromax).
Podium talks from a series of researchers in the United States and Europe at the joint meeting of the International Society for Sexually Transmitted Diseases Research and the International Union Against Sexually Transmitted Infections documented the STI niche that M. genitalium occupies and how well various antibiotics work against the pathogen.
"M. genitalium is associated with 15%-22% of nongonococcal urethritis cases, and 10%-15% of cervicitis cases, and in many settings is more common that Neisseria gonorrhoeae with treatment outcomes often far worse," said Lisa E. Manhart, Ph.D., an epidemiologist at the University of Washington, Seattle. "There is no characteristic clinical syndrome for M. genitalium infections; they look very similar to Chlamydia. Clinical judgment is the only option for treatment decisions in many settings, and no FDA-approved diagnostic test [for M. genitalium] exists."
Persistent cases of nongonococcal urethritis, cervicitis, and possibly pelvic inflammatory disease could benefit from treatment with moxifloxacin (Avelox), Dr. Manhart noted. But "it is becoming clear that resistance in M. genitalium develops rapidly."
"M. genitalium is an important STI, and guidelines should reflect this; but there is no good evidence base for optimal treatment. Optimal treatment is a moving target," said Dr. Jørgen S. Jensen, a researcher at the Statens Serum Institut in Copenhagen.
"Widespread use of azithromycin and moxifloxacin will select for multidrug-resistant strains; the time for single-drug, one-dose regimens is probably over," said Dr. Jensen, specifically referring to the common practice of treating nongonococcal urethritis with a single dose of azithromycin.
M. genitalium invades U.S.
Dr. Manhart and a second U.S. researcher, Dr. Harold C. Wiesenfeld from the University of Pittsburgh, each reported new data at the meeting showing how common M. genitalium STI infections have become among U.S. patients.
Dr. Manhart presented new data from the MEGA (Mycoplasma Genitalium Antibiotic Susceptibility and Treatment) trial, which enrolled 606 men with nongonococcal urethritis (NGU) at an STI clinic in Seattle. The study’s primary endpoint was a comparison of 100 mg doxycycline b.i.d. for 7 days and a single 1-g dose of azithromycin.
The two regimens produced similar cure rates – 76% in the doxycycline arm, and 80% in the azithromycin arm, Dr. Manhart and her associates reported earlier this year (Clin. Infec. Dis. 2013;56:934-42). The initial report also identified M. genitalium in 13% of those men – identified using an in-house polymerase chain reaction assay – compared with 24% who tested positive for Chlamydia and 23% infected with Ureaplasma urealyticum biovar.
The new analyses Dr. Manhart reported tracked the outcomes of patients infected with M. genitalium. Treatment with either of the standard doxycycline or azithromycin regimens failed about half the time, Dr. Manhart said: 29% of men with doxycycline-resistant infections who were retreated with azithromycin as part of the study’s extended protocol carried M. genitalium, and 70% of the men who failed initial azithromycin treatment who were then retreated with doxycycline had persistent infection with M. genitalium.
Results from the extended portion of the study also showed that treatment with moxifloxacin was the answer for most of the otherwise unresponsive M. genitalium infections, but it wasn’t perfect. The M. genitalium infection persisted in 12%-15% of those men after a full course of moxifloxacin.
The full results suggest that moxifloxacin is potentially effective for treating various persistent STIs, not only NGU but also cervicitis and possibly pelvic inflammatory disease (PID). But resistance to moxifloxacin develops "rapidly," meaning that surveillance for resistance is needed, as well as new drug alternatives, she said.
New suspect in acute PID?
Although Dr. Manhart hedged on the role of M. genitalium in PID, results from a different U.S. study created a strong case for a role in acute PID.
M. genitalium appeared in 28 (18%) of 157 diagnosed women with acute PID who were enrolled in a study that had primarily focused on comparing two antibiotic regimens, and in 30% of those women with histologically proven acute PID. Using an in-house transcription-mediated assay for M. genitalium, researchers at the University of Pittsburgh found that endometrial identification of M. genitalium linked independently with a fourfold increased prevalence of histologically confirmed acute PID.
Those numbers for M. genitalium put it in the same ball park in the study with the two traditional heavy hitters of acute PID, N. gonorrhoeae and C. trachomatis. By establishing a significant role for M. genitalium in acute PID, the data immediately called into question the standard empiric therapies for acute PID.
"The PID treatments we use fall short for eradicating M. genitalium," said Dr. Wiesenfeld, an ob.gyn. and infectious diseases physician at the University of Pittsburgh, who reported the results. "Whether these findings [affect] treatment guidelines for acute PID remains to be seen; but if it is truly important to treat M. genitalium, it will completely turn around our treatment regimens."
The looming dilemma is that the azithromycin or doxycycline used for gonorrhea will not stop many of the infections by M. genitalium, while the moxifloxacin that can handle most M. genitalium today does not eradicate N. gonorrhoeae.
However, it’s premature to consider routinely testing or screening for M. genitalium in patients with PID or other possible forms of M. genitalium infection, Dr. Wiesenfeld cautioned. That’s in part because of the current logistical limitations on testing, and in part because the long-term impact of M. genitalium infection on reproductive health is not yet established. Longer follow-up of women in the study should shed more light on the natural history of the patients who received treatments that did not eradicate M. genitalium.
"If M. genitalium turns out to be associated with PID, it is the single organism that is not covered by current treatment with a cephalosporin, doxycycline, and metronidazole," said Sharon L. Hillier, Ph. D., in an interview during the meeting. "We are very concerned about it because it is a fairly sizable fraction of the STIs we’ve seen in these women with acute PID," said Dr. Hillier, professor of ob.gyn. and reproductive sciences at the University of Pittsburgh and a collaborator with Dr. Wiesenfeld on his study.
Dr. Hillier agreed that the key question to address is the fertility risk to women from having PID caused by M. genitalium.
"It’s so common that it might have a huge population impact," she said. "We know fertility outcomes are bad from gonorrhea and Chlamydia." The fertility risk from M. genitalium "will be what makes us decide if we need to add another treatment."
Adding moxifloxacin to routine, empiric treatment for acute PID would be an especially tough call if it also meant dropping doxycycline, a drug that is otherwise attractive because of its low cost and broad spectrum of activity against other PID pathogens.
"It remains to be seen what we should do for empiric therapy for women who walk in with PID, what is the best way to try to preserve her fertility," Dr. Hillier said. "We simply don’t know right now, but it’s been a huge topic of conversation."
Changing the treatment strategies
While the best initial management strategy for acute PID remains unclear, the specter of M. genitalium has already changed the management strategy used by Dr. Paddy Horner to treat men with NGU, said Dr. Horner, a physician in the school of social and community medicine at the University of Bristol, U.K.
These days, his preferred approach is what he calls "infection-specific" first-line therapy: Before treatment begins, he eliminates purely empiric therapy by employing a commercially available, nucleic-acid amplification test for gonorrhea and Chlamydia at the first encounter and getting the result in 30 minutes.
That means treating men who test positive for Chlamydia with a week of doxycycline first, or starting with a 5-day course of azithromycin for men who are Chlamydia negative. However, he advised using a single, 1-g dosage of azithromycin with caution, because of the prevalence of macrolide resistance. But Dr. Horner also admitted that no evidence has proven the superiority of the 5-day alternative that starts with a 1-g dose followed by 500 mg daily for 4 more days. Men who test positive for N. gonorrhoeae should receive 1 g of azithromycin plus 500 mg ceftriaxone.
If the urethritis persists 2 weeks later, Dr. Horner recommended treating patients empirically with a combination of moxifloxacin and metronidazole to cover possible infection by either M. genitalium or U. urealyticum.
In theory, this overall approach has the potential to resolve 89% of infections after the first round of treatment and 99% after the second round, with low potential for generating resistant strains of M. genitalium, based on pathogen prevalence and susceptibility profiles that Dr. Horner sees in Bristol. Those outcomes are an improvement on the cure rates and resistance risks when initial treatment is applied completely empirically, he explained.
Infection-specific treatment would work even better once rapid, point-of-care genetic tests become available for M. genitalium and U. urealyticum, Dr. Horner said.
Dr. Manhart, Dr. Wiesenfeld, and Dr. Hillier had no disclosures. Dr. Jensen said that his institution provides diagnostic testing for M. genitalium commercially and also evaluates various new antimicrobials under contract. Dr. Horner said that he has been a consultant to or received research support from Aquarius Population Health, Cepheid, Hologic, and Siemens.
On Twitter @mitchelzoler
VIENNA – Mycoplasma genitalium is a new bad boy of sexually transmitted infections, prompting experts to rethink how to treat nongonococcal urethritis, pelvic inflammatory disease, and other infections caused by the pathogen.
The full scope of M. genitalium in sexually transmitted infections (STI) of men and women is just now becoming clear – as are the treatment demands of M. genitalium’s susceptibility profile. Given that it’s notoriously hard to culture and that genetic-based assays are only recently available and not yet sold commercially, reliable management of M. genitalium depends on the fluoroquinolone moxifloxacin. Yet the threat of widespread resistance to that drug looms, with no good back-up agents currently available.
Because successful treatment of M. genitalium differs sharply from that of gonorrhea and Chlamydia trachomatis – the other two pathogens most common in urethritis, cervicitis, and pelvic inflammatory disease – clinicians increasingly confront infections unresponsive to or persistent despite a course of doxycycline or azithromycin (Zithromax).
Podium talks from a series of researchers in the United States and Europe at the joint meeting of the International Society for Sexually Transmitted Diseases Research and the International Union Against Sexually Transmitted Infections documented the STI niche that M. genitalium occupies and how well various antibiotics work against the pathogen.
"M. genitalium is associated with 15%-22% of nongonococcal urethritis cases, and 10%-15% of cervicitis cases, and in many settings is more common that Neisseria gonorrhoeae with treatment outcomes often far worse," said Lisa E. Manhart, Ph.D., an epidemiologist at the University of Washington, Seattle. "There is no characteristic clinical syndrome for M. genitalium infections; they look very similar to Chlamydia. Clinical judgment is the only option for treatment decisions in many settings, and no FDA-approved diagnostic test [for M. genitalium] exists."
Persistent cases of nongonococcal urethritis, cervicitis, and possibly pelvic inflammatory disease could benefit from treatment with moxifloxacin (Avelox), Dr. Manhart noted. But "it is becoming clear that resistance in M. genitalium develops rapidly."
"M. genitalium is an important STI, and guidelines should reflect this; but there is no good evidence base for optimal treatment. Optimal treatment is a moving target," said Dr. Jørgen S. Jensen, a researcher at the Statens Serum Institut in Copenhagen.
"Widespread use of azithromycin and moxifloxacin will select for multidrug-resistant strains; the time for single-drug, one-dose regimens is probably over," said Dr. Jensen, specifically referring to the common practice of treating nongonococcal urethritis with a single dose of azithromycin.
M. genitalium invades U.S.
Dr. Manhart and a second U.S. researcher, Dr. Harold C. Wiesenfeld from the University of Pittsburgh, each reported new data at the meeting showing how common M. genitalium STI infections have become among U.S. patients.
Dr. Manhart presented new data from the MEGA (Mycoplasma Genitalium Antibiotic Susceptibility and Treatment) trial, which enrolled 606 men with nongonococcal urethritis (NGU) at an STI clinic in Seattle. The study’s primary endpoint was a comparison of 100 mg doxycycline b.i.d. for 7 days and a single 1-g dose of azithromycin.
The two regimens produced similar cure rates – 76% in the doxycycline arm, and 80% in the azithromycin arm, Dr. Manhart and her associates reported earlier this year (Clin. Infec. Dis. 2013;56:934-42). The initial report also identified M. genitalium in 13% of those men – identified using an in-house polymerase chain reaction assay – compared with 24% who tested positive for Chlamydia and 23% infected with Ureaplasma urealyticum biovar.
The new analyses Dr. Manhart reported tracked the outcomes of patients infected with M. genitalium. Treatment with either of the standard doxycycline or azithromycin regimens failed about half the time, Dr. Manhart said: 29% of men with doxycycline-resistant infections who were retreated with azithromycin as part of the study’s extended protocol carried M. genitalium, and 70% of the men who failed initial azithromycin treatment who were then retreated with doxycycline had persistent infection with M. genitalium.
Results from the extended portion of the study also showed that treatment with moxifloxacin was the answer for most of the otherwise unresponsive M. genitalium infections, but it wasn’t perfect. The M. genitalium infection persisted in 12%-15% of those men after a full course of moxifloxacin.
The full results suggest that moxifloxacin is potentially effective for treating various persistent STIs, not only NGU but also cervicitis and possibly pelvic inflammatory disease (PID). But resistance to moxifloxacin develops "rapidly," meaning that surveillance for resistance is needed, as well as new drug alternatives, she said.
New suspect in acute PID?
Although Dr. Manhart hedged on the role of M. genitalium in PID, results from a different U.S. study created a strong case for a role in acute PID.
M. genitalium appeared in 28 (18%) of 157 diagnosed women with acute PID who were enrolled in a study that had primarily focused on comparing two antibiotic regimens, and in 30% of those women with histologically proven acute PID. Using an in-house transcription-mediated assay for M. genitalium, researchers at the University of Pittsburgh found that endometrial identification of M. genitalium linked independently with a fourfold increased prevalence of histologically confirmed acute PID.
Those numbers for M. genitalium put it in the same ball park in the study with the two traditional heavy hitters of acute PID, N. gonorrhoeae and C. trachomatis. By establishing a significant role for M. genitalium in acute PID, the data immediately called into question the standard empiric therapies for acute PID.
"The PID treatments we use fall short for eradicating M. genitalium," said Dr. Wiesenfeld, an ob.gyn. and infectious diseases physician at the University of Pittsburgh, who reported the results. "Whether these findings [affect] treatment guidelines for acute PID remains to be seen; but if it is truly important to treat M. genitalium, it will completely turn around our treatment regimens."
The looming dilemma is that the azithromycin or doxycycline used for gonorrhea will not stop many of the infections by M. genitalium, while the moxifloxacin that can handle most M. genitalium today does not eradicate N. gonorrhoeae.
However, it’s premature to consider routinely testing or screening for M. genitalium in patients with PID or other possible forms of M. genitalium infection, Dr. Wiesenfeld cautioned. That’s in part because of the current logistical limitations on testing, and in part because the long-term impact of M. genitalium infection on reproductive health is not yet established. Longer follow-up of women in the study should shed more light on the natural history of the patients who received treatments that did not eradicate M. genitalium.
"If M. genitalium turns out to be associated with PID, it is the single organism that is not covered by current treatment with a cephalosporin, doxycycline, and metronidazole," said Sharon L. Hillier, Ph. D., in an interview during the meeting. "We are very concerned about it because it is a fairly sizable fraction of the STIs we’ve seen in these women with acute PID," said Dr. Hillier, professor of ob.gyn. and reproductive sciences at the University of Pittsburgh and a collaborator with Dr. Wiesenfeld on his study.
Dr. Hillier agreed that the key question to address is the fertility risk to women from having PID caused by M. genitalium.
"It’s so common that it might have a huge population impact," she said. "We know fertility outcomes are bad from gonorrhea and Chlamydia." The fertility risk from M. genitalium "will be what makes us decide if we need to add another treatment."
Adding moxifloxacin to routine, empiric treatment for acute PID would be an especially tough call if it also meant dropping doxycycline, a drug that is otherwise attractive because of its low cost and broad spectrum of activity against other PID pathogens.
"It remains to be seen what we should do for empiric therapy for women who walk in with PID, what is the best way to try to preserve her fertility," Dr. Hillier said. "We simply don’t know right now, but it’s been a huge topic of conversation."
Changing the treatment strategies
While the best initial management strategy for acute PID remains unclear, the specter of M. genitalium has already changed the management strategy used by Dr. Paddy Horner to treat men with NGU, said Dr. Horner, a physician in the school of social and community medicine at the University of Bristol, U.K.
These days, his preferred approach is what he calls "infection-specific" first-line therapy: Before treatment begins, he eliminates purely empiric therapy by employing a commercially available, nucleic-acid amplification test for gonorrhea and Chlamydia at the first encounter and getting the result in 30 minutes.
That means treating men who test positive for Chlamydia with a week of doxycycline first, or starting with a 5-day course of azithromycin for men who are Chlamydia negative. However, he advised using a single, 1-g dosage of azithromycin with caution, because of the prevalence of macrolide resistance. But Dr. Horner also admitted that no evidence has proven the superiority of the 5-day alternative that starts with a 1-g dose followed by 500 mg daily for 4 more days. Men who test positive for N. gonorrhoeae should receive 1 g of azithromycin plus 500 mg ceftriaxone.
If the urethritis persists 2 weeks later, Dr. Horner recommended treating patients empirically with a combination of moxifloxacin and metronidazole to cover possible infection by either M. genitalium or U. urealyticum.
In theory, this overall approach has the potential to resolve 89% of infections after the first round of treatment and 99% after the second round, with low potential for generating resistant strains of M. genitalium, based on pathogen prevalence and susceptibility profiles that Dr. Horner sees in Bristol. Those outcomes are an improvement on the cure rates and resistance risks when initial treatment is applied completely empirically, he explained.
Infection-specific treatment would work even better once rapid, point-of-care genetic tests become available for M. genitalium and U. urealyticum, Dr. Horner said.
Dr. Manhart, Dr. Wiesenfeld, and Dr. Hillier had no disclosures. Dr. Jensen said that his institution provides diagnostic testing for M. genitalium commercially and also evaluates various new antimicrobials under contract. Dr. Horner said that he has been a consultant to or received research support from Aquarius Population Health, Cepheid, Hologic, and Siemens.
On Twitter @mitchelzoler
EXPERT ANALYSIS FROM THE STI & AIDS WORLD CONGRESS 2013
Albiglutide shows safety, efficacy, slight weight loss in pivotal diabetes trial
BARCELONA – Treatment of patients with type 2 diabetes with albiglutide plus metformin produced a significantly greater rate of glycemic control compared with three other oral regimens in a pivotal trial with more than 1,000 patients treated and followed for up to 2 years.
After 2 years of treatment, 59% of patients randomized to albiglutide, an investigational glucagonlike peptide–1 (GLP-1) receptor agonist, and metformin had a hemoglobin A1c level below 7.5%, compared with 49% of patients randomized to glimepiride plus metformin, 44% of patients randomized to sitagliptin plus metformin, and 28% who received metformin plus placebo. The differences between albiglutide and each of the three other study groups were statistically significant, Dr. Murray W. Stewart reported at the annual meeting of the European Association for the Study of Diabetes.
In addition, albiglutide treatment produced no severe hypoglycemic episodes and resulted in a relatively modest 5% incidence of nausea and vomiting during the first 8 weeks on treatment, "generally consistent with the known profile" of GLP-1 receptor agonists, Dr. Stewart said. During the second year of treatment, the incidence of nausea or vomiting in albiglutide-treated patients declined to a steady rate of about 1%-2%, similar to that of patients on sitagliptin or metformin plus placebo, and less than the 3%-4% rate seen among patients on glimepiride during the final 6 months of the study, he said. Dr. Stewart is senior vice president for metabolic pathways and cardiovascular therapy at GlaxoSmithKline, the company developing albiglutide.
The HARMONY 3 trial randomized 1,049 patients with type 2 diabetes and hyperglycemia, with an average HbA1c level of 8.1%. The study started all patients on metformin and up-titrated their regimen to a maximum tolerated dosage over 2 weeks, and also started all patients on a diet and exercise regimen for a week prior to randomization. After these two run-in treatments began, the investigators randomized patients to receive either 30 mg of albiglutide by injection once a week, sitagliptin (Januvia, a dipeptidyl peptidase–4 inhibitor) at 100 mg orally once per day, glimepiride (Amaryl, a sulfonylurea) at 2-4 mg orally once a day, or a weekly placebo injection. About two thirds of patients completed the study’s full 2 years of treatment. Study patients averaged about 55 years old, their mean body mass index was 33 kg/m2, and they had type 2 diabetes for an average of about 6 years.
After 2 years, the average HbA1c level was about 7.5% in the patients on albiglutide, 7.8% in the patients on sitagliptin or glimepiride, and 8.4% among those on metformin plus placebo. All patients lost an average of about 1 kg of weight at 2 years compared with baseline except those who receive glimepiride, whose weight increased by an average of about 1 kg. The incidence of patients having their HbA1c rise to 8.5%, requiring the initiation of insulin therapy, was 26% in patients on albiglutide, 33% of those on glimepiride, 36% among those on sitagliptin, and 59% of those on metformin plus placebo, all significant differences between albiglutide and each of the three comparator arms.
Symptomatic hypoglycemia occurred in 3% of the albiglutide patients, similar to the rates in the sitagliptin and placebo subgroups, and less than the 18% rate among patients who received glimepiride. Injection-site reactions occurred in 17% of the albiglutide patients, but these were mostly mild or moderate, and 21 patients on this drug developed antialbiglutide antibodies. Two patients on albiglutide had probable pancreatitis that was at least possibly related to their treatment, and one patient developed thyroid cancer.
The HARMONY 3 trial is one of several pivotal trials recently completed for albiglutide. GlaxoSmithKline initially filed an application with the Food and Drug Administration for approval of albiglutide last January. The goal date for an FDA decision is currently next April.
HARMONY 3 was sponsored by GlaxoSmithKline. Dr. Stewart is an employee of the company.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
In this study, albiglutide showed less weight loss than we have seen in the results from studies of other GLP-1 receptor agonists; on the other hand, it was relatively free of adverse events other than some episodes of nausea and vomiting, which may be an attractive feature for some patients.
It is still too soon to know how this entire class of drugs will fit into the algorithm for treating patients with type 2 diabetes. The GLP-1 receptor agonists seem to produce glycemic control that is at least as good as that produced by insulin, but without causing severe hypoglycemia or much hypoglycemia of any kind, and also leading to a small amount of weight loss. The potential exists for the GLP-1 receptor agonists to supplant metformin as a first-line drug, but with a few qualifications.
|
|
First, the most convincing evidence to support early use of the GLP-1 receptor agonists would be if they are shown in the future to be significantly better at preventing complications than metformin, especially cardiovascular and microvascular events.
There is also the issue of administration by injection. Some patients don’t like injections, and others may hesitate until they try it and find it is not very difficult. But patients who accept this route of delivery may find the GLP-1 receptor agonists to be effective and relatively safe. Of course, there is also the issue of the drug’s costs. Generic metformin will hold a price edge over all these new drugs for many years to come.
Dr. Michael A. Nauck is head of the Diabetes Center in Bad Lauterberg, Germany. He made these comments in an interview. He has been a coinvestigator on other trials of albiglutide and a consultant to GlaxoSmithKline, the company developing this drug, as well as a consultant to several other companies that are developing or that market drugs for patients with diabetes.
In this study, albiglutide showed less weight loss than we have seen in the results from studies of other GLP-1 receptor agonists; on the other hand, it was relatively free of adverse events other than some episodes of nausea and vomiting, which may be an attractive feature for some patients.
It is still too soon to know how this entire class of drugs will fit into the algorithm for treating patients with type 2 diabetes. The GLP-1 receptor agonists seem to produce glycemic control that is at least as good as that produced by insulin, but without causing severe hypoglycemia or much hypoglycemia of any kind, and also leading to a small amount of weight loss. The potential exists for the GLP-1 receptor agonists to supplant metformin as a first-line drug, but with a few qualifications.
|
|
|
First, the most convincing evidence to support early use of the GLP-1 receptor agonists would be if they are shown in the future to be significantly better at preventing complications than metformin, especially cardiovascular and microvascular events.
There is also the issue of administration by injection. Some patients don’t like injections, and others may hesitate until they try it and find it is not very difficult. But patients who accept this route of delivery may find the GLP-1 receptor agonists to be effective and relatively safe. Of course, there is also the issue of the drug’s costs. Generic metformin will hold a price edge over all these new drugs for many years to come.
Dr. Michael A. Nauck is head of the Diabetes Center in Bad Lauterberg, Germany. He made these comments in an interview. He has been a coinvestigator on other trials of albiglutide and a consultant to GlaxoSmithKline, the company developing this drug, as well as a consultant to several other companies that are developing or that market drugs for patients with diabetes.
In this study, albiglutide showed less weight loss than we have seen in the results from studies of other GLP-1 receptor agonists; on the other hand, it was relatively free of adverse events other than some episodes of nausea and vomiting, which may be an attractive feature for some patients.
It is still too soon to know how this entire class of drugs will fit into the algorithm for treating patients with type 2 diabetes. The GLP-1 receptor agonists seem to produce glycemic control that is at least as good as that produced by insulin, but without causing severe hypoglycemia or much hypoglycemia of any kind, and also leading to a small amount of weight loss. The potential exists for the GLP-1 receptor agonists to supplant metformin as a first-line drug, but with a few qualifications.
|
|
|
First, the most convincing evidence to support early use of the GLP-1 receptor agonists would be if they are shown in the future to be significantly better at preventing complications than metformin, especially cardiovascular and microvascular events.
There is also the issue of administration by injection. Some patients don’t like injections, and others may hesitate until they try it and find it is not very difficult. But patients who accept this route of delivery may find the GLP-1 receptor agonists to be effective and relatively safe. Of course, there is also the issue of the drug’s costs. Generic metformin will hold a price edge over all these new drugs for many years to come.
Dr. Michael A. Nauck is head of the Diabetes Center in Bad Lauterberg, Germany. He made these comments in an interview. He has been a coinvestigator on other trials of albiglutide and a consultant to GlaxoSmithKline, the company developing this drug, as well as a consultant to several other companies that are developing or that market drugs for patients with diabetes.
BARCELONA – Treatment of patients with type 2 diabetes with albiglutide plus metformin produced a significantly greater rate of glycemic control compared with three other oral regimens in a pivotal trial with more than 1,000 patients treated and followed for up to 2 years.
After 2 years of treatment, 59% of patients randomized to albiglutide, an investigational glucagonlike peptide–1 (GLP-1) receptor agonist, and metformin had a hemoglobin A1c level below 7.5%, compared with 49% of patients randomized to glimepiride plus metformin, 44% of patients randomized to sitagliptin plus metformin, and 28% who received metformin plus placebo. The differences between albiglutide and each of the three other study groups were statistically significant, Dr. Murray W. Stewart reported at the annual meeting of the European Association for the Study of Diabetes.
In addition, albiglutide treatment produced no severe hypoglycemic episodes and resulted in a relatively modest 5% incidence of nausea and vomiting during the first 8 weeks on treatment, "generally consistent with the known profile" of GLP-1 receptor agonists, Dr. Stewart said. During the second year of treatment, the incidence of nausea or vomiting in albiglutide-treated patients declined to a steady rate of about 1%-2%, similar to that of patients on sitagliptin or metformin plus placebo, and less than the 3%-4% rate seen among patients on glimepiride during the final 6 months of the study, he said. Dr. Stewart is senior vice president for metabolic pathways and cardiovascular therapy at GlaxoSmithKline, the company developing albiglutide.
The HARMONY 3 trial randomized 1,049 patients with type 2 diabetes and hyperglycemia, with an average HbA1c level of 8.1%. The study started all patients on metformin and up-titrated their regimen to a maximum tolerated dosage over 2 weeks, and also started all patients on a diet and exercise regimen for a week prior to randomization. After these two run-in treatments began, the investigators randomized patients to receive either 30 mg of albiglutide by injection once a week, sitagliptin (Januvia, a dipeptidyl peptidase–4 inhibitor) at 100 mg orally once per day, glimepiride (Amaryl, a sulfonylurea) at 2-4 mg orally once a day, or a weekly placebo injection. About two thirds of patients completed the study’s full 2 years of treatment. Study patients averaged about 55 years old, their mean body mass index was 33 kg/m2, and they had type 2 diabetes for an average of about 6 years.
After 2 years, the average HbA1c level was about 7.5% in the patients on albiglutide, 7.8% in the patients on sitagliptin or glimepiride, and 8.4% among those on metformin plus placebo. All patients lost an average of about 1 kg of weight at 2 years compared with baseline except those who receive glimepiride, whose weight increased by an average of about 1 kg. The incidence of patients having their HbA1c rise to 8.5%, requiring the initiation of insulin therapy, was 26% in patients on albiglutide, 33% of those on glimepiride, 36% among those on sitagliptin, and 59% of those on metformin plus placebo, all significant differences between albiglutide and each of the three comparator arms.
Symptomatic hypoglycemia occurred in 3% of the albiglutide patients, similar to the rates in the sitagliptin and placebo subgroups, and less than the 18% rate among patients who received glimepiride. Injection-site reactions occurred in 17% of the albiglutide patients, but these were mostly mild or moderate, and 21 patients on this drug developed antialbiglutide antibodies. Two patients on albiglutide had probable pancreatitis that was at least possibly related to their treatment, and one patient developed thyroid cancer.
The HARMONY 3 trial is one of several pivotal trials recently completed for albiglutide. GlaxoSmithKline initially filed an application with the Food and Drug Administration for approval of albiglutide last January. The goal date for an FDA decision is currently next April.
HARMONY 3 was sponsored by GlaxoSmithKline. Dr. Stewart is an employee of the company.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
BARCELONA – Treatment of patients with type 2 diabetes with albiglutide plus metformin produced a significantly greater rate of glycemic control compared with three other oral regimens in a pivotal trial with more than 1,000 patients treated and followed for up to 2 years.
After 2 years of treatment, 59% of patients randomized to albiglutide, an investigational glucagonlike peptide–1 (GLP-1) receptor agonist, and metformin had a hemoglobin A1c level below 7.5%, compared with 49% of patients randomized to glimepiride plus metformin, 44% of patients randomized to sitagliptin plus metformin, and 28% who received metformin plus placebo. The differences between albiglutide and each of the three other study groups were statistically significant, Dr. Murray W. Stewart reported at the annual meeting of the European Association for the Study of Diabetes.
In addition, albiglutide treatment produced no severe hypoglycemic episodes and resulted in a relatively modest 5% incidence of nausea and vomiting during the first 8 weeks on treatment, "generally consistent with the known profile" of GLP-1 receptor agonists, Dr. Stewart said. During the second year of treatment, the incidence of nausea or vomiting in albiglutide-treated patients declined to a steady rate of about 1%-2%, similar to that of patients on sitagliptin or metformin plus placebo, and less than the 3%-4% rate seen among patients on glimepiride during the final 6 months of the study, he said. Dr. Stewart is senior vice president for metabolic pathways and cardiovascular therapy at GlaxoSmithKline, the company developing albiglutide.
The HARMONY 3 trial randomized 1,049 patients with type 2 diabetes and hyperglycemia, with an average HbA1c level of 8.1%. The study started all patients on metformin and up-titrated their regimen to a maximum tolerated dosage over 2 weeks, and also started all patients on a diet and exercise regimen for a week prior to randomization. After these two run-in treatments began, the investigators randomized patients to receive either 30 mg of albiglutide by injection once a week, sitagliptin (Januvia, a dipeptidyl peptidase–4 inhibitor) at 100 mg orally once per day, glimepiride (Amaryl, a sulfonylurea) at 2-4 mg orally once a day, or a weekly placebo injection. About two thirds of patients completed the study’s full 2 years of treatment. Study patients averaged about 55 years old, their mean body mass index was 33 kg/m2, and they had type 2 diabetes for an average of about 6 years.
After 2 years, the average HbA1c level was about 7.5% in the patients on albiglutide, 7.8% in the patients on sitagliptin or glimepiride, and 8.4% among those on metformin plus placebo. All patients lost an average of about 1 kg of weight at 2 years compared with baseline except those who receive glimepiride, whose weight increased by an average of about 1 kg. The incidence of patients having their HbA1c rise to 8.5%, requiring the initiation of insulin therapy, was 26% in patients on albiglutide, 33% of those on glimepiride, 36% among those on sitagliptin, and 59% of those on metformin plus placebo, all significant differences between albiglutide and each of the three comparator arms.
Symptomatic hypoglycemia occurred in 3% of the albiglutide patients, similar to the rates in the sitagliptin and placebo subgroups, and less than the 18% rate among patients who received glimepiride. Injection-site reactions occurred in 17% of the albiglutide patients, but these were mostly mild or moderate, and 21 patients on this drug developed antialbiglutide antibodies. Two patients on albiglutide had probable pancreatitis that was at least possibly related to their treatment, and one patient developed thyroid cancer.
The HARMONY 3 trial is one of several pivotal trials recently completed for albiglutide. GlaxoSmithKline initially filed an application with the Food and Drug Administration for approval of albiglutide last January. The goal date for an FDA decision is currently next April.
HARMONY 3 was sponsored by GlaxoSmithKline. Dr. Stewart is an employee of the company.
mzoler@frontlinemedcom.com
On Twitter @mitchelzoler
AT THE EASD ANNUAL MEETING
Major finding: Treatment with metformin plus albiglutide dropped HbA1c below 7.5% in 59% of patients, compared with 28% for metformin plus placebo.
Data source: HARMONY 3, which randomized 1,049 patients with type 2 diabetes to treatment with metformin plus albiglutide, sitagliptin, glimepiride, or placebo and followed them for up to 2 years.
Disclosures: HARMONY 3 was sponsored by GlaxoSmithKline. Dr. Stewart is an employee of the company.
TAVR shows large survival benefit in diabetes patients
AMSTERDAM – Transcatheter aortic valve replacement produced dramatically better 1-year survival, compared with surgical valve replacement, among high-risk patients with diabetes in a new, post hoc analysis of data collected in the first PARTNER trial.
The 145 patients with any type of diabetes who underwent transcatheter aortic valve replacement (TAVR) in the operable, cohort A of the first Placement of Aortic Transcatheter Valves (PARTNER) trial had an 18% all-cause mortality rate during 1-year follow-up, compared with a 27% rate among the 130 patients who underwent surgical aortic valve replacement (SAVR), a difference in this post hoc analysis that reached statistical significance.
The finding of a 9-percentage-point difference in mortality in the diabetic subgroup treated with TAVR, a 40% relative risk reduction compared with SAVR, contrasts with the overall, primary finding of the PARTNER I cohort A trial, which showed that TAVR and SAVR produced similar mortality rates in high surgical-risk patients after 1 year (N. Engl. J. Med. 2011;364:2187-98).
TAVR use in patients with diabetes also resulted in a statistically significant reduction in the 1-year incidence of renal failure requiring dialysis, a 4% rate compared with an 11% among the SAVR patients, Dr. Brian R. Lindman reported at the annual congress of the European Society of Cardiology. This also contrasted with the overall PARTNER results when patients without diabetes were included, which showed no difference in renal outcomes between TAVR and SAVR.
The results "raise the possibility that TAVR may be the preferred approach for patients with diabetes," said Dr. Lindman. But he cautioned that because this was a post hoc analysis, the results need confirmation in a prospective study.
Despite this caveat, Dr. Lindman said that the finding can’t be completely ignored when treatment options are discussed with patients who have severe aortic stenosis. "Going forward, I think this is something we’ll need to think about, and we might lean more toward TAVR for patients with diabetes. But we’d like to see some confirmatory evidence in the PARTNER II cohort A trial," he said in an interview. Investigators from the PARTNER II trial, which is randomizing patients with moderate surgical risk, have said that the cohort A results are expected in 2015.
"Although hypothesis-generating only, this result is good news for patients with diabetes," said Dr. William Wijns, codirector of the cardiovascular center at O.L.V. Hospital in Aalst, Belgium.
Dr. Lindman also cautioned that investigators collected limited data on patients’ diabetes status in PARTNER I. The data did not include information on diabetes type, hemoglobin A1c or blood glucose levels, or treatment received. He also acknowledged that the 42% prevalence of diabetes in the study cohort was unexpectedly high, but noted that if this meant that some patients with a questionable diabetes diagnosis entered the analysis, this should have diminished the mortality difference between TAVR and SAVR.
The 275 patients with diabetes in PARTNER I cohort A averaged 82 years of age, and just over a third were women. The subgroups of patients with diabetes randomized to TAVR and to SAVR showed no significant differences for any physiologic or cardiovascular measure or in the prevalence of various comorbidities.
The analysis also showed a statistically significant reduced rate of 1-year mortality in the subgroup treated with transfemoral TAVR compared with SAVR, and in the subgroup of patients with diabetes treated with transapical TAVR compared with SAVR. The 1-year rate of stroke was an identical 3.5% in the patients with diabetes treated with TAVR and in those treated with SAVR. Patients treated with SAVR had a higher incidence of a major bleeding event during follow-up compared with the TAVR patients, while the TAVR patients had a significantly higher rate of major vascular complications during follow-up. Both findings were consistent with the overall PARTNER I cohort A results, said Dr. Lindman, a cardiologist at Washington University in St. Louis.
The diabetes patients who underwent TAVR showed their striking reduction in 1-year mortality despite having the same problem with postprocedural aortic regurgitation as seen in the overall PARTNER I trial. At 6 months after treatment, 9% of the TAVR patients had moderate or severe aortic regurgitation, and 54% had mild regurgitation, compared with rates of 1% moderate or severe and 6% mild in the SAVR patients.
Dr. Lindman speculated that increased inflammation and oxidative stress in patients with diabetes may interact with the stresses of heart surgery to produce the excess mortality seen after SAVR in patients with diabetes. Results from prior studies had documented worsened survival in patients with diabetes who undergo heart surgery, he said.
The PARTNER trial was sponsored by Edwards Lifesciences, which markets the TAVR device used in the study. Dr. Lindman was an investigator in PARTNER and said that he had no disclosures.
On Twitter @mitchelzoler
AMSTERDAM – Transcatheter aortic valve replacement produced dramatically better 1-year survival, compared with surgical valve replacement, among high-risk patients with diabetes in a new, post hoc analysis of data collected in the first PARTNER trial.
The 145 patients with any type of diabetes who underwent transcatheter aortic valve replacement (TAVR) in the operable, cohort A of the first Placement of Aortic Transcatheter Valves (PARTNER) trial had an 18% all-cause mortality rate during 1-year follow-up, compared with a 27% rate among the 130 patients who underwent surgical aortic valve replacement (SAVR), a difference in this post hoc analysis that reached statistical significance.
The finding of a 9-percentage-point difference in mortality in the diabetic subgroup treated with TAVR, a 40% relative risk reduction compared with SAVR, contrasts with the overall, primary finding of the PARTNER I cohort A trial, which showed that TAVR and SAVR produced similar mortality rates in high surgical-risk patients after 1 year (N. Engl. J. Med. 2011;364:2187-98).
TAVR use in patients with diabetes also resulted in a statistically significant reduction in the 1-year incidence of renal failure requiring dialysis, a 4% rate compared with an 11% among the SAVR patients, Dr. Brian R. Lindman reported at the annual congress of the European Society of Cardiology. This also contrasted with the overall PARTNER results when patients without diabetes were included, which showed no difference in renal outcomes between TAVR and SAVR.
The results "raise the possibility that TAVR may be the preferred approach for patients with diabetes," said Dr. Lindman. But he cautioned that because this was a post hoc analysis, the results need confirmation in a prospective study.
Despite this caveat, Dr. Lindman said that the finding can’t be completely ignored when treatment options are discussed with patients who have severe aortic stenosis. "Going forward, I think this is something we’ll need to think about, and we might lean more toward TAVR for patients with diabetes. But we’d like to see some confirmatory evidence in the PARTNER II cohort A trial," he said in an interview. Investigators from the PARTNER II trial, which is randomizing patients with moderate surgical risk, have said that the cohort A results are expected in 2015.
"Although hypothesis-generating only, this result is good news for patients with diabetes," said Dr. William Wijns, codirector of the cardiovascular center at O.L.V. Hospital in Aalst, Belgium.
Dr. Lindman also cautioned that investigators collected limited data on patients’ diabetes status in PARTNER I. The data did not include information on diabetes type, hemoglobin A1c or blood glucose levels, or treatment received. He also acknowledged that the 42% prevalence of diabetes in the study cohort was unexpectedly high, but noted that if this meant that some patients with a questionable diabetes diagnosis entered the analysis, this should have diminished the mortality difference between TAVR and SAVR.
The 275 patients with diabetes in PARTNER I cohort A averaged 82 years of age, and just over a third were women. The subgroups of patients with diabetes randomized to TAVR and to SAVR showed no significant differences for any physiologic or cardiovascular measure or in the prevalence of various comorbidities.
The analysis also showed a statistically significant reduced rate of 1-year mortality in the subgroup treated with transfemoral TAVR compared with SAVR, and in the subgroup of patients with diabetes treated with transapical TAVR compared with SAVR. The 1-year rate of stroke was an identical 3.5% in the patients with diabetes treated with TAVR and in those treated with SAVR. Patients treated with SAVR had a higher incidence of a major bleeding event during follow-up compared with the TAVR patients, while the TAVR patients had a significantly higher rate of major vascular complications during follow-up. Both findings were consistent with the overall PARTNER I cohort A results, said Dr. Lindman, a cardiologist at Washington University in St. Louis.
The diabetes patients who underwent TAVR showed their striking reduction in 1-year mortality despite having the same problem with postprocedural aortic regurgitation as seen in the overall PARTNER I trial. At 6 months after treatment, 9% of the TAVR patients had moderate or severe aortic regurgitation, and 54% had mild regurgitation, compared with rates of 1% moderate or severe and 6% mild in the SAVR patients.
Dr. Lindman speculated that increased inflammation and oxidative stress in patients with diabetes may interact with the stresses of heart surgery to produce the excess mortality seen after SAVR in patients with diabetes. Results from prior studies had documented worsened survival in patients with diabetes who undergo heart surgery, he said.
The PARTNER trial was sponsored by Edwards Lifesciences, which markets the TAVR device used in the study. Dr. Lindman was an investigator in PARTNER and said that he had no disclosures.
On Twitter @mitchelzoler
AMSTERDAM – Transcatheter aortic valve replacement produced dramatically better 1-year survival, compared with surgical valve replacement, among high-risk patients with diabetes in a new, post hoc analysis of data collected in the first PARTNER trial.
The 145 patients with any type of diabetes who underwent transcatheter aortic valve replacement (TAVR) in the operable, cohort A of the first Placement of Aortic Transcatheter Valves (PARTNER) trial had an 18% all-cause mortality rate during 1-year follow-up, compared with a 27% rate among the 130 patients who underwent surgical aortic valve replacement (SAVR), a difference in this post hoc analysis that reached statistical significance.
The finding of a 9-percentage-point difference in mortality in the diabetic subgroup treated with TAVR, a 40% relative risk reduction compared with SAVR, contrasts with the overall, primary finding of the PARTNER I cohort A trial, which showed that TAVR and SAVR produced similar mortality rates in high surgical-risk patients after 1 year (N. Engl. J. Med. 2011;364:2187-98).
TAVR use in patients with diabetes also resulted in a statistically significant reduction in the 1-year incidence of renal failure requiring dialysis, a 4% rate compared with an 11% among the SAVR patients, Dr. Brian R. Lindman reported at the annual congress of the European Society of Cardiology. This also contrasted with the overall PARTNER results when patients without diabetes were included, which showed no difference in renal outcomes between TAVR and SAVR.
The results "raise the possibility that TAVR may be the preferred approach for patients with diabetes," said Dr. Lindman. But he cautioned that because this was a post hoc analysis, the results need confirmation in a prospective study.
Despite this caveat, Dr. Lindman said that the finding can’t be completely ignored when treatment options are discussed with patients who have severe aortic stenosis. "Going forward, I think this is something we’ll need to think about, and we might lean more toward TAVR for patients with diabetes. But we’d like to see some confirmatory evidence in the PARTNER II cohort A trial," he said in an interview. Investigators from the PARTNER II trial, which is randomizing patients with moderate surgical risk, have said that the cohort A results are expected in 2015.
"Although hypothesis-generating only, this result is good news for patients with diabetes," said Dr. William Wijns, codirector of the cardiovascular center at O.L.V. Hospital in Aalst, Belgium.
Dr. Lindman also cautioned that investigators collected limited data on patients’ diabetes status in PARTNER I. The data did not include information on diabetes type, hemoglobin A1c or blood glucose levels, or treatment received. He also acknowledged that the 42% prevalence of diabetes in the study cohort was unexpectedly high, but noted that if this meant that some patients with a questionable diabetes diagnosis entered the analysis, this should have diminished the mortality difference between TAVR and SAVR.
The 275 patients with diabetes in PARTNER I cohort A averaged 82 years of age, and just over a third were women. The subgroups of patients with diabetes randomized to TAVR and to SAVR showed no significant differences for any physiologic or cardiovascular measure or in the prevalence of various comorbidities.
The analysis also showed a statistically significant reduced rate of 1-year mortality in the subgroup treated with transfemoral TAVR compared with SAVR, and in the subgroup of patients with diabetes treated with transapical TAVR compared with SAVR. The 1-year rate of stroke was an identical 3.5% in the patients with diabetes treated with TAVR and in those treated with SAVR. Patients treated with SAVR had a higher incidence of a major bleeding event during follow-up compared with the TAVR patients, while the TAVR patients had a significantly higher rate of major vascular complications during follow-up. Both findings were consistent with the overall PARTNER I cohort A results, said Dr. Lindman, a cardiologist at Washington University in St. Louis.
The diabetes patients who underwent TAVR showed their striking reduction in 1-year mortality despite having the same problem with postprocedural aortic regurgitation as seen in the overall PARTNER I trial. At 6 months after treatment, 9% of the TAVR patients had moderate or severe aortic regurgitation, and 54% had mild regurgitation, compared with rates of 1% moderate or severe and 6% mild in the SAVR patients.
Dr. Lindman speculated that increased inflammation and oxidative stress in patients with diabetes may interact with the stresses of heart surgery to produce the excess mortality seen after SAVR in patients with diabetes. Results from prior studies had documented worsened survival in patients with diabetes who undergo heart surgery, he said.
The PARTNER trial was sponsored by Edwards Lifesciences, which markets the TAVR device used in the study. Dr. Lindman was an investigator in PARTNER and said that he had no disclosures.
On Twitter @mitchelzoler
AT THE ESC CONGRESS 2013
Major finding: In patients with diabetes, 1-year mortality was 18% after TAVR and 27% after SAVR in a post hoc analysis.
Data source: The PARTNER I cohort A study, which enrolled 699 high-risk patients with severe aortic stenosis to treatment with aortic valve replacement by the transcatheter or surgical approach, including 275 patients with diabetes.
Disclosures: The trial was sponsored by Edwards Lifesciences, which markets the TAVR device used in the study. Dr. Lindman was an investigator in PARTNER, and said that he had no disclosures.
Full-dose beta-blockers still show heart failure benefit
AMSTERDAM – Patients with heart failure appeared to continue to benefit from full-dose beta-blocker therapy against a background of optimal, contemporary treatment, based on an analysis of data collected from an 1,800-patient trial of cardiac resynchronization therapy.
Dr. L. Brent Mitchell, who presented this finding at the annual congress of the European Society of Cardiology, acknowledged that assessing the efficacy of drugs in a study that did not randomize patients based on their use of those drugs had questionable validity and was vulnerable to unidentified confounding, but he also noted that data on the role of beta-blockers in contemporary heart failure management were unlikely to come from any other source.
"You need some tool to ask whether beta-blockers are still useful," said Dr. Mitchell, professor of cardiac sciences at the University of Calgary (Alta.). "The purpose of this analysis was to ask if beta-blockers at full dosages are still better than not using a full-dose beta-blocker despite all the other treatments" that patients received while in the study during 2003-2009. The analysis showed that those receiving full-dosage or nearly full-dosage beta-blocker regimens had a one-third cut in all-cause death or heart failure hospitalization, compared with patients receiving less than half the recommended dosage, after adjustment for many baseline differences between these two subgroups.
The analysis also showed that just half of the nearly 1,500 patients who received treatment with a beta-blocker in this cohort received an adequate dosage, defined as at least 50% of the level recommended by the European Society of Cardiology in heart failure treatment guidelines issued last year (Euro. Heart J. 2012;33:1787-847). Two-thirds of the patients on carvedilol received at least half of the recommended target dosage of 50 mg/day. In contrast, about a third of patients being treated with either bisoprolol or metoprolol received a dosage that was at least half the target dosage (10 mg/day for bisoprolol, 200 mg/day for metoprolol).
The analysis used data collected in the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT), which enrolled 1,798 patients primarily with New York Heart Association class II heart failure at 34 centers worldwide. When the primary endpoint of RAFT was evaluated, treatment with cardiac resynchronization therapy (CRT) with defibrillator capability was more effective at preventing death or heart failure hospitalization in the study population than was an implanted defibrillator alone against a background of optimal medical treatment (N. Engl. J. Med. 2010;363:2385-95).
Dr. Mitchell and his associates focused on 1,474 patients who all received beta-blocker treatment while in RAFT. Like the entire RAFT population, 97% of these patients also received treatment with an ACE inhibitor or angiotensin receptor blocker, and 42% received treatment with spironolactone, and their average left ventricular ejection fraction was 23%.
The patients in this group who were undertreated with beta-blockers were significantly older and had a significantly greater prevalence of New York Heart Association class III heart failure and heart failure with an ischemic etiology compared with those who received at least 50% of the target dosage.
In a regression model that adjusted for all measured baseline differences, patients treated with at least half of the recommended dosage had an incidence of mortality or heart failure hospitalization during an average 40 months of follow-up that was 33% below the rate among patients on lower beta-blocker dosages, a statistically significant difference. This 33% relative risk reduction with adequate beta-blocker treatment is "indistinguishable" from the risk reductions seen with placebo in the major beta-blocker efficacy trials in heart failure patients during the 1990s, Dr. Mitchell noted. "This suggests that beta-blocker treatment still has potency," he said.
Other significant, independent predictors of the primary outcome in this model were prior coronary artery bypass, which boosted the risk by 63%; a history of ischemic heart disease, which raised the risk by 39%; having peripheral vascular disease, which increased the risk by 36%; and receiving CRT, which cut the risk by 33%. In addition, adverse outcomes rose 10% for each reduction of 5 mL/min per 1.73 m2 in estimated glomerular filtration rate.
The impact of underdosing was roughly similar across all three beta-blockers, bisoprolol, carvedilol, and metoprolol. The adverse effect of underdosing was mitigated to some extent when patients also received CRT.
RAFT was partially funded by Medtronic of Canada. Dr. Mitchell said he had no relevant financial disclosures.
On Twitter @mitchelzoler
A post hoc analysis of the nonrandomized interventions that patients receive during randomized clinical trials is generally discouraged. Patients treated with lower dosages of hemodynamically active drugs like beta-blockers are often sicker and have a worse prognosis. This problem can be seen in the baseline characteristics of the two subgroups in this analysis, which revealed many significant differences between the two. Performing statistical compensations to counterbalance these differences is very uncertain.
In addition, a few years ago, my associates and I ran the Systolic Heart Failure Treatment With the If inhibitor Ivabradine Trial (SHIFT) (Lancet 2010;376:875-85) to assess the efficacy and safety of ivabradine to lower heart rate and improve outcomes in optimally treated heart failure patients. In SHIFT we saw a relationship similar to the one seen in RAFT by the current investigators: Patients on lower dosages of beta-blockers were sicker and at higher risk than patients on higher beta-blocker dosages. In our analyses, adjusting for differences in heart rate eliminated the link between beta-blocker dosage and outcomes. We found that the entire treatment effect could be explained by differences in patient heart rate.
Dr. Karl Swedberg is a professor of medicine at the University of Gothenburg (Sweden). He was lead investigator for the SHIFT trial, which was funded by Servier, the company that markets ivabradine (Procoralan). He made these comments as designated discussant for Dr. Mitchell’s report.
A post hoc analysis of the nonrandomized interventions that patients receive during randomized clinical trials is generally discouraged. Patients treated with lower dosages of hemodynamically active drugs like beta-blockers are often sicker and have a worse prognosis. This problem can be seen in the baseline characteristics of the two subgroups in this analysis, which revealed many significant differences between the two. Performing statistical compensations to counterbalance these differences is very uncertain.
In addition, a few years ago, my associates and I ran the Systolic Heart Failure Treatment With the If inhibitor Ivabradine Trial (SHIFT) (Lancet 2010;376:875-85) to assess the efficacy and safety of ivabradine to lower heart rate and improve outcomes in optimally treated heart failure patients. In SHIFT we saw a relationship similar to the one seen in RAFT by the current investigators: Patients on lower dosages of beta-blockers were sicker and at higher risk than patients on higher beta-blocker dosages. In our analyses, adjusting for differences in heart rate eliminated the link between beta-blocker dosage and outcomes. We found that the entire treatment effect could be explained by differences in patient heart rate.
Dr. Karl Swedberg is a professor of medicine at the University of Gothenburg (Sweden). He was lead investigator for the SHIFT trial, which was funded by Servier, the company that markets ivabradine (Procoralan). He made these comments as designated discussant for Dr. Mitchell’s report.
A post hoc analysis of the nonrandomized interventions that patients receive during randomized clinical trials is generally discouraged. Patients treated with lower dosages of hemodynamically active drugs like beta-blockers are often sicker and have a worse prognosis. This problem can be seen in the baseline characteristics of the two subgroups in this analysis, which revealed many significant differences between the two. Performing statistical compensations to counterbalance these differences is very uncertain.
In addition, a few years ago, my associates and I ran the Systolic Heart Failure Treatment With the If inhibitor Ivabradine Trial (SHIFT) (Lancet 2010;376:875-85) to assess the efficacy and safety of ivabradine to lower heart rate and improve outcomes in optimally treated heart failure patients. In SHIFT we saw a relationship similar to the one seen in RAFT by the current investigators: Patients on lower dosages of beta-blockers were sicker and at higher risk than patients on higher beta-blocker dosages. In our analyses, adjusting for differences in heart rate eliminated the link between beta-blocker dosage and outcomes. We found that the entire treatment effect could be explained by differences in patient heart rate.
Dr. Karl Swedberg is a professor of medicine at the University of Gothenburg (Sweden). He was lead investigator for the SHIFT trial, which was funded by Servier, the company that markets ivabradine (Procoralan). He made these comments as designated discussant for Dr. Mitchell’s report.
AMSTERDAM – Patients with heart failure appeared to continue to benefit from full-dose beta-blocker therapy against a background of optimal, contemporary treatment, based on an analysis of data collected from an 1,800-patient trial of cardiac resynchronization therapy.
Dr. L. Brent Mitchell, who presented this finding at the annual congress of the European Society of Cardiology, acknowledged that assessing the efficacy of drugs in a study that did not randomize patients based on their use of those drugs had questionable validity and was vulnerable to unidentified confounding, but he also noted that data on the role of beta-blockers in contemporary heart failure management were unlikely to come from any other source.
"You need some tool to ask whether beta-blockers are still useful," said Dr. Mitchell, professor of cardiac sciences at the University of Calgary (Alta.). "The purpose of this analysis was to ask if beta-blockers at full dosages are still better than not using a full-dose beta-blocker despite all the other treatments" that patients received while in the study during 2003-2009. The analysis showed that those receiving full-dosage or nearly full-dosage beta-blocker regimens had a one-third cut in all-cause death or heart failure hospitalization, compared with patients receiving less than half the recommended dosage, after adjustment for many baseline differences between these two subgroups.
The analysis also showed that just half of the nearly 1,500 patients who received treatment with a beta-blocker in this cohort received an adequate dosage, defined as at least 50% of the level recommended by the European Society of Cardiology in heart failure treatment guidelines issued last year (Euro. Heart J. 2012;33:1787-847). Two-thirds of the patients on carvedilol received at least half of the recommended target dosage of 50 mg/day. In contrast, about a third of patients being treated with either bisoprolol or metoprolol received a dosage that was at least half the target dosage (10 mg/day for bisoprolol, 200 mg/day for metoprolol).
The analysis used data collected in the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT), which enrolled 1,798 patients primarily with New York Heart Association class II heart failure at 34 centers worldwide. When the primary endpoint of RAFT was evaluated, treatment with cardiac resynchronization therapy (CRT) with defibrillator capability was more effective at preventing death or heart failure hospitalization in the study population than was an implanted defibrillator alone against a background of optimal medical treatment (N. Engl. J. Med. 2010;363:2385-95).
Dr. Mitchell and his associates focused on 1,474 patients who all received beta-blocker treatment while in RAFT. Like the entire RAFT population, 97% of these patients also received treatment with an ACE inhibitor or angiotensin receptor blocker, and 42% received treatment with spironolactone, and their average left ventricular ejection fraction was 23%.
The patients in this group who were undertreated with beta-blockers were significantly older and had a significantly greater prevalence of New York Heart Association class III heart failure and heart failure with an ischemic etiology compared with those who received at least 50% of the target dosage.
In a regression model that adjusted for all measured baseline differences, patients treated with at least half of the recommended dosage had an incidence of mortality or heart failure hospitalization during an average 40 months of follow-up that was 33% below the rate among patients on lower beta-blocker dosages, a statistically significant difference. This 33% relative risk reduction with adequate beta-blocker treatment is "indistinguishable" from the risk reductions seen with placebo in the major beta-blocker efficacy trials in heart failure patients during the 1990s, Dr. Mitchell noted. "This suggests that beta-blocker treatment still has potency," he said.
Other significant, independent predictors of the primary outcome in this model were prior coronary artery bypass, which boosted the risk by 63%; a history of ischemic heart disease, which raised the risk by 39%; having peripheral vascular disease, which increased the risk by 36%; and receiving CRT, which cut the risk by 33%. In addition, adverse outcomes rose 10% for each reduction of 5 mL/min per 1.73 m2 in estimated glomerular filtration rate.
The impact of underdosing was roughly similar across all three beta-blockers, bisoprolol, carvedilol, and metoprolol. The adverse effect of underdosing was mitigated to some extent when patients also received CRT.
RAFT was partially funded by Medtronic of Canada. Dr. Mitchell said he had no relevant financial disclosures.
On Twitter @mitchelzoler
AMSTERDAM – Patients with heart failure appeared to continue to benefit from full-dose beta-blocker therapy against a background of optimal, contemporary treatment, based on an analysis of data collected from an 1,800-patient trial of cardiac resynchronization therapy.
Dr. L. Brent Mitchell, who presented this finding at the annual congress of the European Society of Cardiology, acknowledged that assessing the efficacy of drugs in a study that did not randomize patients based on their use of those drugs had questionable validity and was vulnerable to unidentified confounding, but he also noted that data on the role of beta-blockers in contemporary heart failure management were unlikely to come from any other source.
"You need some tool to ask whether beta-blockers are still useful," said Dr. Mitchell, professor of cardiac sciences at the University of Calgary (Alta.). "The purpose of this analysis was to ask if beta-blockers at full dosages are still better than not using a full-dose beta-blocker despite all the other treatments" that patients received while in the study during 2003-2009. The analysis showed that those receiving full-dosage or nearly full-dosage beta-blocker regimens had a one-third cut in all-cause death or heart failure hospitalization, compared with patients receiving less than half the recommended dosage, after adjustment for many baseline differences between these two subgroups.
The analysis also showed that just half of the nearly 1,500 patients who received treatment with a beta-blocker in this cohort received an adequate dosage, defined as at least 50% of the level recommended by the European Society of Cardiology in heart failure treatment guidelines issued last year (Euro. Heart J. 2012;33:1787-847). Two-thirds of the patients on carvedilol received at least half of the recommended target dosage of 50 mg/day. In contrast, about a third of patients being treated with either bisoprolol or metoprolol received a dosage that was at least half the target dosage (10 mg/day for bisoprolol, 200 mg/day for metoprolol).
The analysis used data collected in the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT), which enrolled 1,798 patients primarily with New York Heart Association class II heart failure at 34 centers worldwide. When the primary endpoint of RAFT was evaluated, treatment with cardiac resynchronization therapy (CRT) with defibrillator capability was more effective at preventing death or heart failure hospitalization in the study population than was an implanted defibrillator alone against a background of optimal medical treatment (N. Engl. J. Med. 2010;363:2385-95).
Dr. Mitchell and his associates focused on 1,474 patients who all received beta-blocker treatment while in RAFT. Like the entire RAFT population, 97% of these patients also received treatment with an ACE inhibitor or angiotensin receptor blocker, and 42% received treatment with spironolactone, and their average left ventricular ejection fraction was 23%.
The patients in this group who were undertreated with beta-blockers were significantly older and had a significantly greater prevalence of New York Heart Association class III heart failure and heart failure with an ischemic etiology compared with those who received at least 50% of the target dosage.
In a regression model that adjusted for all measured baseline differences, patients treated with at least half of the recommended dosage had an incidence of mortality or heart failure hospitalization during an average 40 months of follow-up that was 33% below the rate among patients on lower beta-blocker dosages, a statistically significant difference. This 33% relative risk reduction with adequate beta-blocker treatment is "indistinguishable" from the risk reductions seen with placebo in the major beta-blocker efficacy trials in heart failure patients during the 1990s, Dr. Mitchell noted. "This suggests that beta-blocker treatment still has potency," he said.
Other significant, independent predictors of the primary outcome in this model were prior coronary artery bypass, which boosted the risk by 63%; a history of ischemic heart disease, which raised the risk by 39%; having peripheral vascular disease, which increased the risk by 36%; and receiving CRT, which cut the risk by 33%. In addition, adverse outcomes rose 10% for each reduction of 5 mL/min per 1.73 m2 in estimated glomerular filtration rate.
The impact of underdosing was roughly similar across all three beta-blockers, bisoprolol, carvedilol, and metoprolol. The adverse effect of underdosing was mitigated to some extent when patients also received CRT.
RAFT was partially funded by Medtronic of Canada. Dr. Mitchell said he had no relevant financial disclosures.
On Twitter @mitchelzoler
AT THE ESC CONGRESS 2013
Major finding: Heart failure patients on recommended beta-blocker dosages had 33% fewer deaths or hospitalizations than did patients on lower dosages.
Data source: A post hoc subgroup analysis of results from RAFT, with 1,798 patients with heart failure at 34 worldwide sites.
Disclosures: RAFT was partially funded by Medtronic of Canada. Dr. Mitchell said he had no relevant financial disclosures.
Insulin-triggered hypoglycemia poses less danger
AMSTERDAM – When patients with dysglycemia had severe hypoglycemia while on treatment with basal insulin glargine, the episodes did not trigger as many adverse cardiovascular outcomes as did severe hypoglycemia during standard care with oral glucose-lowering drugs but no insulin.
"Hypoglycemia caused by insulin glargine–mediated glucose lowering is unlikely to cause cardiovascular outcomes," Dr. Linda G. Mellbin said at the European Society of Cardiology Congress 2013. The link between hypoglycemia and cardiovascular outcomes was up to two- to threefold lower in patients receiving insulin glargine treatment, compared with patients on standard oral regimens in data from more than 12,000 patients with early type 2 diabetes, impaired fasting glucose, or impaired glucose tolerance enrolled in a trial that compared insulin glargine with standard treatment, said Dr. Mellbin, a cardiologist at the Karolinska Institute in Stockholm.
"What was reassuring was that while insulin glargine caused more hypoglycemic events" compared with standard treatment in these patients, "the absolute number of fatal events was still lower with insulin, showing insulin is a very safe treatment," said Dr. Lars Rydén, professor of cardiology at the Karolinska Institute and a coinvestigator with Dr. Mellbin.
"The clinical implication is that you shouldn’t be afraid of insulin; patients should use it if they need it," Dr. Rydén said in an interview. "One reason people are afraid is because it causes hypoglycemia, but this [hypoglycemia] doesn’t seem to be very dangerous."
Dr. Mellbin, Dr. Rydén, and their associates studied data collected in the ORIGIN (Outcome Reduction With Initial Glargine Intervention) trial. Last year, the primary outcome of the study showed that in 12,537 patients with early type 2 diabetes or other indications of dysglycemia and at high risk for cardiovascular outcomes, treatment with basal insulin glargine (Lantus) had a neutral effect during a median 6 years follow-up, compared with standard care on the incidence of several cardiovascular outcomes: death, myocardial infarction, stroke, any revascularization procedure, or heart-failure hospitalization (N. Engl. J. Med. 2012;367:319-28). The new analysis focused on the 3,518 patients in ORIGIN who had at least one hypoglycemic episode during follow-up+ and included 472 patients with at least one severe hypoglycemic event.
Hypoglycemic episodes were more frequent in insulin-treated patients, who accounted for about three-quarters of all hypoglycemic episodes and as well as about three-quarters of the severe events.
The nonsevere hypoglycemic episodes were benign. In a propensity-score adjusted analysis, nonsevere hypoglycemia had no significant association with total mortality, cardiovascular death, arrhythmic death, or cardiovascular death plus nonfatal MI or stroke.
But severe hypoglycemic episodes, as well as severe nocturnal episodes, were significantly linked with increased rates for all these outcomes in the adjusted analysis. For example, patients who had at least one severe hypoglycemic event had a 58% increased incidence of cardiovascular death, MI, or stroke, and a 74% higher rate of total mortality, Dr. Mellbin reported at the meeting. Concurrent with her report, an article with the results was published online (Eur. Heart J. 2013 [doi:10.1093/eurheartj/eht332]).
Although more patients who received insulin had severe hypoglycemia, patients who had these episodes while on glargine had a substantially lower rate of death and other cardiovascular outcomes than did the patients who became hypoglycemic while on standard treatment. The standard-treatment patients who had a severe hypoglycemic episode were 70% more likely to have a subsequent primary-outcome event, compared with the patients who had severe hypoglycemia, while on glargine. The rate of all-cause death following severe hypoglycemia was more than twice as common in the standard care patients, compared with those who had severe hypoglycemia on glargine, and the rate of arrhythmia death was nearly threefold higher in the standard-care patients.
These findings explain why patients on insulin glargine did not have excess cardiovascular and mortality endpoints over standard treatment: Each hypoglycemic event while on insulin had less adverse consequence than when hypoglycemia occurred in patients on standard treatment. In the standard-treatment group, 29% of patients received a sulfonylurea, 28% received metformin, and 3% received another oral hypoglycemic drug. In the insulin glargine group use of oral drugs was very similar, but all patients also received insulin.
The finding that severe hypoglycemic events differ in their clinical impact depending on the treatment context in which they occur in the patients enrolled in ORIGIN could have several possible explanations, Dr. Rydén said. First, it’s possible that the more frequent, repeated episodes of hypoglycemia in the patients on insulin pre-conditioned their myocardium and prevented more severe reactions to subsequent hypoglycemic episodes.
Another possible explanation is an adverse effect from sulfonylurea drugs among patients on standard care. "Sulfonylureas may restrict the ability of the myocardium to adapt to ischemia, and it also prolongs the hypoglycemia," Dr. Rydén said. This explanation was endorsed by Dr. Peter Grant, a diabetologist and professor of medicine at the University of Leeds (U.K.). "It is difficult to believe that sulfonylureas are not having an adverse effect," he said as the designated discussant for Dr. Mellbin’s report. "These results tell us that hypoglycemia is an important determinant of outcome, and they raise questions about sulfonylureas," Dr. Grant said.
A third possible explanation is that increased mortality and poor cardiovascular prognosis and a tendency to develop hypoglycemia have a common, as-yet unidentified cause that has not been adjusted for in the models, Dr. Rydén said. "The relationship between severe hypoglycemia and cardiovascular outcomes is likely confounded by unmeasured risk factors," Dr. Mellbin said.
ORIGIN was funded by Sanofi, the company that markets insulin glargine (Lantus). Dr. Mellbin said that she has received lecture honoraria from Sanofi-Aventis and six other drug companies. Dr. Rydén said that he has received consulting and lecture honoraria from Sanofi-Aventis, Roche, Bristol-Myers Squibb, AstraZeneca, and Bayer. Dr. Grant said that he had no relevant disclosures.
On Twitter @mitchelzoler
AMSTERDAM – When patients with dysglycemia had severe hypoglycemia while on treatment with basal insulin glargine, the episodes did not trigger as many adverse cardiovascular outcomes as did severe hypoglycemia during standard care with oral glucose-lowering drugs but no insulin.
"Hypoglycemia caused by insulin glargine–mediated glucose lowering is unlikely to cause cardiovascular outcomes," Dr. Linda G. Mellbin said at the European Society of Cardiology Congress 2013. The link between hypoglycemia and cardiovascular outcomes was up to two- to threefold lower in patients receiving insulin glargine treatment, compared with patients on standard oral regimens in data from more than 12,000 patients with early type 2 diabetes, impaired fasting glucose, or impaired glucose tolerance enrolled in a trial that compared insulin glargine with standard treatment, said Dr. Mellbin, a cardiologist at the Karolinska Institute in Stockholm.
"What was reassuring was that while insulin glargine caused more hypoglycemic events" compared with standard treatment in these patients, "the absolute number of fatal events was still lower with insulin, showing insulin is a very safe treatment," said Dr. Lars Rydén, professor of cardiology at the Karolinska Institute and a coinvestigator with Dr. Mellbin.
"The clinical implication is that you shouldn’t be afraid of insulin; patients should use it if they need it," Dr. Rydén said in an interview. "One reason people are afraid is because it causes hypoglycemia, but this [hypoglycemia] doesn’t seem to be very dangerous."
Dr. Mellbin, Dr. Rydén, and their associates studied data collected in the ORIGIN (Outcome Reduction With Initial Glargine Intervention) trial. Last year, the primary outcome of the study showed that in 12,537 patients with early type 2 diabetes or other indications of dysglycemia and at high risk for cardiovascular outcomes, treatment with basal insulin glargine (Lantus) had a neutral effect during a median 6 years follow-up, compared with standard care on the incidence of several cardiovascular outcomes: death, myocardial infarction, stroke, any revascularization procedure, or heart-failure hospitalization (N. Engl. J. Med. 2012;367:319-28). The new analysis focused on the 3,518 patients in ORIGIN who had at least one hypoglycemic episode during follow-up+ and included 472 patients with at least one severe hypoglycemic event.
Hypoglycemic episodes were more frequent in insulin-treated patients, who accounted for about three-quarters of all hypoglycemic episodes and as well as about three-quarters of the severe events.
The nonsevere hypoglycemic episodes were benign. In a propensity-score adjusted analysis, nonsevere hypoglycemia had no significant association with total mortality, cardiovascular death, arrhythmic death, or cardiovascular death plus nonfatal MI or stroke.
But severe hypoglycemic episodes, as well as severe nocturnal episodes, were significantly linked with increased rates for all these outcomes in the adjusted analysis. For example, patients who had at least one severe hypoglycemic event had a 58% increased incidence of cardiovascular death, MI, or stroke, and a 74% higher rate of total mortality, Dr. Mellbin reported at the meeting. Concurrent with her report, an article with the results was published online (Eur. Heart J. 2013 [doi:10.1093/eurheartj/eht332]).
Although more patients who received insulin had severe hypoglycemia, patients who had these episodes while on glargine had a substantially lower rate of death and other cardiovascular outcomes than did the patients who became hypoglycemic while on standard treatment. The standard-treatment patients who had a severe hypoglycemic episode were 70% more likely to have a subsequent primary-outcome event, compared with the patients who had severe hypoglycemia, while on glargine. The rate of all-cause death following severe hypoglycemia was more than twice as common in the standard care patients, compared with those who had severe hypoglycemia on glargine, and the rate of arrhythmia death was nearly threefold higher in the standard-care patients.
These findings explain why patients on insulin glargine did not have excess cardiovascular and mortality endpoints over standard treatment: Each hypoglycemic event while on insulin had less adverse consequence than when hypoglycemia occurred in patients on standard treatment. In the standard-treatment group, 29% of patients received a sulfonylurea, 28% received metformin, and 3% received another oral hypoglycemic drug. In the insulin glargine group use of oral drugs was very similar, but all patients also received insulin.
The finding that severe hypoglycemic events differ in their clinical impact depending on the treatment context in which they occur in the patients enrolled in ORIGIN could have several possible explanations, Dr. Rydén said. First, it’s possible that the more frequent, repeated episodes of hypoglycemia in the patients on insulin pre-conditioned their myocardium and prevented more severe reactions to subsequent hypoglycemic episodes.
Another possible explanation is an adverse effect from sulfonylurea drugs among patients on standard care. "Sulfonylureas may restrict the ability of the myocardium to adapt to ischemia, and it also prolongs the hypoglycemia," Dr. Rydén said. This explanation was endorsed by Dr. Peter Grant, a diabetologist and professor of medicine at the University of Leeds (U.K.). "It is difficult to believe that sulfonylureas are not having an adverse effect," he said as the designated discussant for Dr. Mellbin’s report. "These results tell us that hypoglycemia is an important determinant of outcome, and they raise questions about sulfonylureas," Dr. Grant said.
A third possible explanation is that increased mortality and poor cardiovascular prognosis and a tendency to develop hypoglycemia have a common, as-yet unidentified cause that has not been adjusted for in the models, Dr. Rydén said. "The relationship between severe hypoglycemia and cardiovascular outcomes is likely confounded by unmeasured risk factors," Dr. Mellbin said.
ORIGIN was funded by Sanofi, the company that markets insulin glargine (Lantus). Dr. Mellbin said that she has received lecture honoraria from Sanofi-Aventis and six other drug companies. Dr. Rydén said that he has received consulting and lecture honoraria from Sanofi-Aventis, Roche, Bristol-Myers Squibb, AstraZeneca, and Bayer. Dr. Grant said that he had no relevant disclosures.
On Twitter @mitchelzoler
AMSTERDAM – When patients with dysglycemia had severe hypoglycemia while on treatment with basal insulin glargine, the episodes did not trigger as many adverse cardiovascular outcomes as did severe hypoglycemia during standard care with oral glucose-lowering drugs but no insulin.
"Hypoglycemia caused by insulin glargine–mediated glucose lowering is unlikely to cause cardiovascular outcomes," Dr. Linda G. Mellbin said at the European Society of Cardiology Congress 2013. The link between hypoglycemia and cardiovascular outcomes was up to two- to threefold lower in patients receiving insulin glargine treatment, compared with patients on standard oral regimens in data from more than 12,000 patients with early type 2 diabetes, impaired fasting glucose, or impaired glucose tolerance enrolled in a trial that compared insulin glargine with standard treatment, said Dr. Mellbin, a cardiologist at the Karolinska Institute in Stockholm.
"What was reassuring was that while insulin glargine caused more hypoglycemic events" compared with standard treatment in these patients, "the absolute number of fatal events was still lower with insulin, showing insulin is a very safe treatment," said Dr. Lars Rydén, professor of cardiology at the Karolinska Institute and a coinvestigator with Dr. Mellbin.
"The clinical implication is that you shouldn’t be afraid of insulin; patients should use it if they need it," Dr. Rydén said in an interview. "One reason people are afraid is because it causes hypoglycemia, but this [hypoglycemia] doesn’t seem to be very dangerous."
Dr. Mellbin, Dr. Rydén, and their associates studied data collected in the ORIGIN (Outcome Reduction With Initial Glargine Intervention) trial. Last year, the primary outcome of the study showed that in 12,537 patients with early type 2 diabetes or other indications of dysglycemia and at high risk for cardiovascular outcomes, treatment with basal insulin glargine (Lantus) had a neutral effect during a median 6 years follow-up, compared with standard care on the incidence of several cardiovascular outcomes: death, myocardial infarction, stroke, any revascularization procedure, or heart-failure hospitalization (N. Engl. J. Med. 2012;367:319-28). The new analysis focused on the 3,518 patients in ORIGIN who had at least one hypoglycemic episode during follow-up+ and included 472 patients with at least one severe hypoglycemic event.
Hypoglycemic episodes were more frequent in insulin-treated patients, who accounted for about three-quarters of all hypoglycemic episodes and as well as about three-quarters of the severe events.
The nonsevere hypoglycemic episodes were benign. In a propensity-score adjusted analysis, nonsevere hypoglycemia had no significant association with total mortality, cardiovascular death, arrhythmic death, or cardiovascular death plus nonfatal MI or stroke.
But severe hypoglycemic episodes, as well as severe nocturnal episodes, were significantly linked with increased rates for all these outcomes in the adjusted analysis. For example, patients who had at least one severe hypoglycemic event had a 58% increased incidence of cardiovascular death, MI, or stroke, and a 74% higher rate of total mortality, Dr. Mellbin reported at the meeting. Concurrent with her report, an article with the results was published online (Eur. Heart J. 2013 [doi:10.1093/eurheartj/eht332]).
Although more patients who received insulin had severe hypoglycemia, patients who had these episodes while on glargine had a substantially lower rate of death and other cardiovascular outcomes than did the patients who became hypoglycemic while on standard treatment. The standard-treatment patients who had a severe hypoglycemic episode were 70% more likely to have a subsequent primary-outcome event, compared with the patients who had severe hypoglycemia, while on glargine. The rate of all-cause death following severe hypoglycemia was more than twice as common in the standard care patients, compared with those who had severe hypoglycemia on glargine, and the rate of arrhythmia death was nearly threefold higher in the standard-care patients.
These findings explain why patients on insulin glargine did not have excess cardiovascular and mortality endpoints over standard treatment: Each hypoglycemic event while on insulin had less adverse consequence than when hypoglycemia occurred in patients on standard treatment. In the standard-treatment group, 29% of patients received a sulfonylurea, 28% received metformin, and 3% received another oral hypoglycemic drug. In the insulin glargine group use of oral drugs was very similar, but all patients also received insulin.
The finding that severe hypoglycemic events differ in their clinical impact depending on the treatment context in which they occur in the patients enrolled in ORIGIN could have several possible explanations, Dr. Rydén said. First, it’s possible that the more frequent, repeated episodes of hypoglycemia in the patients on insulin pre-conditioned their myocardium and prevented more severe reactions to subsequent hypoglycemic episodes.
Another possible explanation is an adverse effect from sulfonylurea drugs among patients on standard care. "Sulfonylureas may restrict the ability of the myocardium to adapt to ischemia, and it also prolongs the hypoglycemia," Dr. Rydén said. This explanation was endorsed by Dr. Peter Grant, a diabetologist and professor of medicine at the University of Leeds (U.K.). "It is difficult to believe that sulfonylureas are not having an adverse effect," he said as the designated discussant for Dr. Mellbin’s report. "These results tell us that hypoglycemia is an important determinant of outcome, and they raise questions about sulfonylureas," Dr. Grant said.
A third possible explanation is that increased mortality and poor cardiovascular prognosis and a tendency to develop hypoglycemia have a common, as-yet unidentified cause that has not been adjusted for in the models, Dr. Rydén said. "The relationship between severe hypoglycemia and cardiovascular outcomes is likely confounded by unmeasured risk factors," Dr. Mellbin said.
ORIGIN was funded by Sanofi, the company that markets insulin glargine (Lantus). Dr. Mellbin said that she has received lecture honoraria from Sanofi-Aventis and six other drug companies. Dr. Rydén said that he has received consulting and lecture honoraria from Sanofi-Aventis, Roche, Bristol-Myers Squibb, AstraZeneca, and Bayer. Dr. Grant said that he had no relevant disclosures.
On Twitter @mitchelzoler
AT ESC 2013
Major finding: Severe hypoglycemia during standard, oral dysglycemia treatment produced 70% more cardiovascular outcomes than did severe hypoglycemia during insulin treatment.
Data source: ORIGIN, a multicenter trial with 12,537 patients with early type 2 diabetes or dysglycemia randomized to treatment with basal insulin glargine or a standard, oral regimen.
Disclosures: ORIGIN was funded by Sanofi, the company that markets insulin glargine (Lantus). Dr. Mellbin said that she has received lecture honoraria from Sanofi-Aventis and six other drug companies. Dr. Rydén said that he has received consulting and lecture honoraria from Sanofi-Aventis, Roche, Bristol-Myers Squibb, AstraZeneca, and Bayer. Dr. Grant said that he had no relevant disclosures.
Statins Cut Limb Events in PAD Patients
AMSTERDAM – Treatment with a statin cut the relative rate of worsening peripheral artery disease by roughly 20% in a registry with nearly 6,000 peripheral artery disease patients.
But the registry data also showed that more than a third of patients with peripheral artery disease (PAD) failed to receive statin treatment, Dr. Dharam Kumbhani said at the annual Congress of the European Society of Cardiology.
"This is one of the first, and largest, studies to demonstrate an impact [of statin treatment] on adverse limb outcomes in patients with PAD, including worsening claudication, new critical limb ischemia, need for revascularization, and notably need for ischemic amputations. But despite having a class I recommendation for use in patients with PAD, data from this large, international registry suggest that statin use remains suboptimal," said Dr. Kumbhani, an interventional cardiologist at the University of Texas Southwestern Medical Center in Dallas.
"Future research should focus on improving patient and physician compliance with statin use across the entire spectrum of PAD patients," he said.
Concomitant coronary artery disease, as well as the specialty of the treating physician, seemed to link with statin use in these patients, Dr. Kumbhani added. "In PAD patients with CAD, statin use occurred in about 75%; in PAD patients without CAD, it was less than 50%."
Statins were most reliably prescribed to PAD patients by cardiologists, who administered the drugs to about 80% of all their PAD patients, regardless of concomitant CAD. In contrast, vascular surgeons prescribed statins to fewer than half their PAD patients, and in those who did not have concomitant CAD, statin use fell to less than a third. About 70% of all patients enrolled in the registry received their treatment from a primary care physician.
The data came from the Reduction of Atherothrombosis for Continued Health (REACH) registry, which followed more than 45,000 enrolled patients for at least 4 years at more than 3,600 centers in 29 countries; more than a quarter were U.S. patients (JAMA 2010;304:1350-7). Enrolled patients were at least 45 years old and had at least three atherosclerosis risk factors or established vascular disease in the coronary, cerebral, or peripheral domains. The enrolled patients included 5,861 with established, symptomatic PAD, of whom 3,643 (62%) were on statin treatment at the time they entered the registry.
During 4-year follow-up the rate of the primary systemic outcome – a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke – decreased by a statistically significant, relative 15% among patients on a statin compared with those not on a statin at baseline, in a propensity-score adjusted analysis.
Statin use linked with a statistically significant, 21% relative drop in worsening PAD events, compared with nonuse, in the propensity-score adjusted model. Adjusted analyses also showed statistically significant reductions for most of the individual outcomes that formed the composites, including a 27% relative reduction in nonfatal strokes and a 43% relative drop in limb amputations.
The systemic benefits seen in the registry from statin use in patients with PAD are consistent with results from randomized, controlled trials, but finding statin use also linked with decreased adverse limb outcomes is new, Dr. Kumbhani said.
The REACH registry is funded by Sanofi and Bristol-Myers Squibb. Dr. Kumbhani reported having no relevant financial disclosures.
On Twitter @mitchelzoler
AMSTERDAM – Treatment with a statin cut the relative rate of worsening peripheral artery disease by roughly 20% in a registry with nearly 6,000 peripheral artery disease patients.
But the registry data also showed that more than a third of patients with peripheral artery disease (PAD) failed to receive statin treatment, Dr. Dharam Kumbhani said at the annual Congress of the European Society of Cardiology.
"This is one of the first, and largest, studies to demonstrate an impact [of statin treatment] on adverse limb outcomes in patients with PAD, including worsening claudication, new critical limb ischemia, need for revascularization, and notably need for ischemic amputations. But despite having a class I recommendation for use in patients with PAD, data from this large, international registry suggest that statin use remains suboptimal," said Dr. Kumbhani, an interventional cardiologist at the University of Texas Southwestern Medical Center in Dallas.
"Future research should focus on improving patient and physician compliance with statin use across the entire spectrum of PAD patients," he said.
Concomitant coronary artery disease, as well as the specialty of the treating physician, seemed to link with statin use in these patients, Dr. Kumbhani added. "In PAD patients with CAD, statin use occurred in about 75%; in PAD patients without CAD, it was less than 50%."
Statins were most reliably prescribed to PAD patients by cardiologists, who administered the drugs to about 80% of all their PAD patients, regardless of concomitant CAD. In contrast, vascular surgeons prescribed statins to fewer than half their PAD patients, and in those who did not have concomitant CAD, statin use fell to less than a third. About 70% of all patients enrolled in the registry received their treatment from a primary care physician.
The data came from the Reduction of Atherothrombosis for Continued Health (REACH) registry, which followed more than 45,000 enrolled patients for at least 4 years at more than 3,600 centers in 29 countries; more than a quarter were U.S. patients (JAMA 2010;304:1350-7). Enrolled patients were at least 45 years old and had at least three atherosclerosis risk factors or established vascular disease in the coronary, cerebral, or peripheral domains. The enrolled patients included 5,861 with established, symptomatic PAD, of whom 3,643 (62%) were on statin treatment at the time they entered the registry.
During 4-year follow-up the rate of the primary systemic outcome – a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke – decreased by a statistically significant, relative 15% among patients on a statin compared with those not on a statin at baseline, in a propensity-score adjusted analysis.
Statin use linked with a statistically significant, 21% relative drop in worsening PAD events, compared with nonuse, in the propensity-score adjusted model. Adjusted analyses also showed statistically significant reductions for most of the individual outcomes that formed the composites, including a 27% relative reduction in nonfatal strokes and a 43% relative drop in limb amputations.
The systemic benefits seen in the registry from statin use in patients with PAD are consistent with results from randomized, controlled trials, but finding statin use also linked with decreased adverse limb outcomes is new, Dr. Kumbhani said.
The REACH registry is funded by Sanofi and Bristol-Myers Squibb. Dr. Kumbhani reported having no relevant financial disclosures.
On Twitter @mitchelzoler
AMSTERDAM – Treatment with a statin cut the relative rate of worsening peripheral artery disease by roughly 20% in a registry with nearly 6,000 peripheral artery disease patients.
But the registry data also showed that more than a third of patients with peripheral artery disease (PAD) failed to receive statin treatment, Dr. Dharam Kumbhani said at the annual Congress of the European Society of Cardiology.
"This is one of the first, and largest, studies to demonstrate an impact [of statin treatment] on adverse limb outcomes in patients with PAD, including worsening claudication, new critical limb ischemia, need for revascularization, and notably need for ischemic amputations. But despite having a class I recommendation for use in patients with PAD, data from this large, international registry suggest that statin use remains suboptimal," said Dr. Kumbhani, an interventional cardiologist at the University of Texas Southwestern Medical Center in Dallas.
"Future research should focus on improving patient and physician compliance with statin use across the entire spectrum of PAD patients," he said.
Concomitant coronary artery disease, as well as the specialty of the treating physician, seemed to link with statin use in these patients, Dr. Kumbhani added. "In PAD patients with CAD, statin use occurred in about 75%; in PAD patients without CAD, it was less than 50%."
Statins were most reliably prescribed to PAD patients by cardiologists, who administered the drugs to about 80% of all their PAD patients, regardless of concomitant CAD. In contrast, vascular surgeons prescribed statins to fewer than half their PAD patients, and in those who did not have concomitant CAD, statin use fell to less than a third. About 70% of all patients enrolled in the registry received their treatment from a primary care physician.
The data came from the Reduction of Atherothrombosis for Continued Health (REACH) registry, which followed more than 45,000 enrolled patients for at least 4 years at more than 3,600 centers in 29 countries; more than a quarter were U.S. patients (JAMA 2010;304:1350-7). Enrolled patients were at least 45 years old and had at least three atherosclerosis risk factors or established vascular disease in the coronary, cerebral, or peripheral domains. The enrolled patients included 5,861 with established, symptomatic PAD, of whom 3,643 (62%) were on statin treatment at the time they entered the registry.
During 4-year follow-up the rate of the primary systemic outcome – a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke – decreased by a statistically significant, relative 15% among patients on a statin compared with those not on a statin at baseline, in a propensity-score adjusted analysis.
Statin use linked with a statistically significant, 21% relative drop in worsening PAD events, compared with nonuse, in the propensity-score adjusted model. Adjusted analyses also showed statistically significant reductions for most of the individual outcomes that formed the composites, including a 27% relative reduction in nonfatal strokes and a 43% relative drop in limb amputations.
The systemic benefits seen in the registry from statin use in patients with PAD are consistent with results from randomized, controlled trials, but finding statin use also linked with decreased adverse limb outcomes is new, Dr. Kumbhani said.
The REACH registry is funded by Sanofi and Bristol-Myers Squibb. Dr. Kumbhani reported having no relevant financial disclosures.
On Twitter @mitchelzoler
AT THE ESC CONGRESS 2013
