Michele G. Sullivan

Despite advances in the treatment of acute myocardial infarction, 30-day rehospitalization rates remained fairly constant from 1987 to 2010.

Rehospitalizations ranged from a high of 23% in 1987 to a low of 19% in 2010 – but that difference was not statistically significant, Dr. Shannon Dunlay and her colleagues reported in the July 3 issue of Annals of Internal Medicine

During that period, treatment advances were obvious. There was a significant decrease in fibrinolysis and significant increases in angiography, reperfusion, and percutaneous coronary intervention (PCI). But those improvements didn’t affect 30-day readmission rates, and in fact, seem to be a driver of them, the researchers, led by Dr. Dunlay, a cardiology fellow at the Mayo Clinic, Rochester, Minn., wrote.

"Angiography, reperfusion, and revascularization are mainstays of therapy in acute MI, and complications are associated with a high risk for rehospitalization," they wrote.

They also noted that "as the prevalence of such comorbid conditions as diabetes and COPD [chronic obstructive pulmonary disease] increases over time, rehospitalizations after acute MI may continue to shift toward noncardiovascular causes." Other medical comorbidities, including hypertension, hyperlipidemia, and obesity, were also significantly associated with readmission rates (Ann. Intern. Med. 2012; 157:11-18).

The authors found that 43% of the readmissions were related to the incident heart attack or its treatment, 30% were unrelated, and a relationship was unclear in 27%.

The review encompassed 3,010 cases extracted from the Rochester Epidemiology Project, a database that links patient records from three facilities in Olmstead County, Minn. The patients’ mean age was 67 years and did not change over the study period.

In-hospital survival improved over time (89% in 1987 and 96% in 2010).

There were significant changes in comorbid conditions from 1987 to 2010, including hypertension (61%-69%), hyperlipidemia (50%-68%), diabetes (22%-24%), and obesity [a body mass index of at least 30 kg/m²] (33%-38%).

Treatment changes included a significant decrease in fibrinolysis (28%-1%), and significant increases in reperfusion/revascularization (64%-69%), PCI (51%-63%), and angiography (76%-85%). The median length of stay dropped from 5 days to 3 days – also a significant change.

Increasing rates of complications were associated with these changes in treatment, the records showed. Ten percent of patients who underwent PCI had a complication. These included vascular or bleeding complications (6%), stroke (0.3%), and renal failure (5%). Of the vascular or bleeding complications, 63% were access site complications, most of which were groin hematomas.

The complication rate was low among patient receiving fibrinolysis (2%). Two percent of patients who had a coronary artery bypass graft (CABG) procedure had an associated stroke. The complication rate was 8% among patients who had angiography, with or without reperfusion. Most of those (5%) had acute renal failure, with three patients requiring dialysis. The other patients had vascular or bleeding complications.

Thirty-day rehospitalizations were required in 561 patients (19%), who were admitted a total of 643 times – 484 patients were admitted once, 72 twice, and 5 three times. Three percent (87) of the patients died within 30 days; among these, 19 were in a readmission when they died.

Readmission rates were 23% from 1987 to 1992; 22% from 1993 to 1998; 22% from 1999 to 2004; and 19% from 2005 to 2010.

The most common reasons for rehospitalization were ischemic heart disease (15%), respiratory or other chest symptoms (10%), heart failure (9%), and cardiac arrhythmias (6%). Other reasons included procedural complications (92%); fluid/electrolyte problems (2%); and hypotension, pneumonia, embolism/thrombosis, and stroke or transient ischemic attack (about 1%) each.

Angiography was performed in 24% of readmissions and PCI in 9%. Of these, 25% were repeat PCIs of the same vessel.

There were 44 CABG procedures among the readmitted group (28 planned). Forty-five percent of those undergoing a revascularization had been treated medically during their initial hospitalization.

Some treatments significantly increased the risk of 30-day readmission; most of that association was driven by procedural complications:

• Angiography with complications: hazard ratio, 2.40.

• Reperfusions with revascularization, with complications: HR, 2.12.

Some medical comorbidities also showed significant associations with readmission:

• Diabetes: HR, 1.34.

• Chronic obstructive pulmonary disease: HR, 1.43.

• Heart failure: HR, 1.12.

"Compared with our previous report on rehospitalizations after incident heart failure diagnosis in Olmsted County, COPD, diabetes, and anemia were common risk factors for rehospitalization among patients with incident MI and heart failure," the authors said. These risk factors "may be of particular importance as future targets in preventing rehospitalizations in patients hospitalized with cardiovascular disease."

The National Institutes of Health sponsored the study. The researchers reported having no relevant financial conflicts of interests.

Despite advances in the treatment of acute myocardial infarction, 30-day rehospitalization rates remained fairly constant from 1987 to 2010.

Rehospitalizations ranged from a high of 23% in 1987 to a low of 19% in 2010 – but that difference was not statistically significant, Dr. Shannon Dunlay and her colleagues reported in the July 3 issue of Annals of Internal Medicine

During that period, treatment advances were obvious. There was a significant decrease in fibrinolysis and significant increases in angiography, reperfusion, and percutaneous coronary intervention (PCI). But those improvements didn’t affect 30-day readmission rates, and in fact, seem to be a driver of them, the researchers, led by Dr. Dunlay, a cardiology fellow at the Mayo Clinic, Rochester, Minn., wrote.

"Angiography, reperfusion, and revascularization are mainstays of therapy in acute MI, and complications are associated with a high risk for rehospitalization," they wrote.

They also noted that "as the prevalence of such comorbid conditions as diabetes and COPD [chronic obstructive pulmonary disease] increases over time, rehospitalizations after acute MI may continue to shift toward noncardiovascular causes." Other medical comorbidities, including hypertension, hyperlipidemia, and obesity, were also significantly associated with readmission rates (Ann. Intern. Med. 2012; 157:11-18).

The authors found that 43% of the readmissions were related to the incident heart attack or its treatment, 30% were unrelated, and a relationship was unclear in 27%.

The review encompassed 3,010 cases extracted from the Rochester Epidemiology Project, a database that links patient records from three facilities in Olmstead County, Minn. The patients’ mean age was 67 years and did not change over the study period.

In-hospital survival improved over time (89% in 1987 and 96% in 2010).

There were significant changes in comorbid conditions from 1987 to 2010, including hypertension (61%-69%), hyperlipidemia (50%-68%), diabetes (22%-24%), and obesity [a body mass index of at least 30 kg/m²] (33%-38%).

Treatment changes included a significant decrease in fibrinolysis (28%-1%), and significant increases in reperfusion/revascularization (64%-69%), PCI (51%-63%), and angiography (76%-85%). The median length of stay dropped from 5 days to 3 days – also a significant change.

Increasing rates of complications were associated with these changes in treatment, the records showed. Ten percent of patients who underwent PCI had a complication. These included vascular or bleeding complications (6%), stroke (0.3%), and renal failure (5%). Of the vascular or bleeding complications, 63% were access site complications, most of which were groin hematomas.

The complication rate was low among patient receiving fibrinolysis (2%). Two percent of patients who had a coronary artery bypass graft (CABG) procedure had an associated stroke. The complication rate was 8% among patients who had angiography, with or without reperfusion. Most of those (5%) had acute renal failure, with three patients requiring dialysis. The other patients had vascular or bleeding complications.

Thirty-day rehospitalizations were required in 561 patients (19%), who were admitted a total of 643 times – 484 patients were admitted once, 72 twice, and 5 three times. Three percent (87) of the patients died within 30 days; among these, 19 were in a readmission when they died.

Readmission rates were 23% from 1987 to 1992; 22% from 1993 to 1998; 22% from 1999 to 2004; and 19% from 2005 to 2010.

The most common reasons for rehospitalization were ischemic heart disease (15%), respiratory or other chest symptoms (10%), heart failure (9%), and cardiac arrhythmias (6%). Other reasons included procedural complications (92%); fluid/electrolyte problems (2%); and hypotension, pneumonia, embolism/thrombosis, and stroke or transient ischemic attack (about 1%) each.

Angiography was performed in 24% of readmissions and PCI in 9%. Of these, 25% were repeat PCIs of the same vessel.

There were 44 CABG procedures among the readmitted group (28 planned). Forty-five percent of those undergoing a revascularization had been treated medically during their initial hospitalization.

Some treatments significantly increased the risk of 30-day readmission; most of that association was driven by procedural complications:

• Angiography with complications: hazard ratio, 2.40.

• Reperfusions with revascularization, with complications: HR, 2.12.

Some medical comorbidities also showed significant associations with readmission:

• Diabetes: HR, 1.34.

• Chronic obstructive pulmonary disease: HR, 1.43.

• Heart failure: HR, 1.12.

"Compared with our previous report on rehospitalizations after incident heart failure diagnosis in Olmsted County, COPD, diabetes, and anemia were common risk factors for rehospitalization among patients with incident MI and heart failure," the authors said. These risk factors "may be of particular importance as future targets in preventing rehospitalizations in patients hospitalized with cardiovascular disease."

The National Institutes of Health sponsored the study. The researchers reported having no relevant financial conflicts of interests.

Despite advances in the treatment of acute myocardial infarction, 30-day rehospitalization rates remained fairly constant from 1987 to 2010.

Rehospitalizations ranged from a high of 23% in 1987 to a low of 19% in 2010 – but that difference was not statistically significant, Dr. Shannon Dunlay and her colleagues reported in the July 3 issue of Annals of Internal Medicine

During that period, treatment advances were obvious. There was a significant decrease in fibrinolysis and significant increases in angiography, reperfusion, and percutaneous coronary intervention (PCI). But those improvements didn’t affect 30-day readmission rates, and in fact, seem to be a driver of them, the researchers, led by Dr. Dunlay, a cardiology fellow at the Mayo Clinic, Rochester, Minn., wrote.

"Angiography, reperfusion, and revascularization are mainstays of therapy in acute MI, and complications are associated with a high risk for rehospitalization," they wrote.

They also noted that "as the prevalence of such comorbid conditions as diabetes and COPD [chronic obstructive pulmonary disease] increases over time, rehospitalizations after acute MI may continue to shift toward noncardiovascular causes." Other medical comorbidities, including hypertension, hyperlipidemia, and obesity, were also significantly associated with readmission rates (Ann. Intern. Med. 2012; 157:11-18).

The authors found that 43% of the readmissions were related to the incident heart attack or its treatment, 30% were unrelated, and a relationship was unclear in 27%.

The review encompassed 3,010 cases extracted from the Rochester Epidemiology Project, a database that links patient records from three facilities in Olmstead County, Minn. The patients’ mean age was 67 years and did not change over the study period.

In-hospital survival improved over time (89% in 1987 and 96% in 2010).

There were significant changes in comorbid conditions from 1987 to 2010, including hypertension (61%-69%), hyperlipidemia (50%-68%), diabetes (22%-24%), and obesity [a body mass index of at least 30 kg/m²] (33%-38%).

Treatment changes included a significant decrease in fibrinolysis (28%-1%), and significant increases in reperfusion/revascularization (64%-69%), PCI (51%-63%), and angiography (76%-85%). The median length of stay dropped from 5 days to 3 days – also a significant change.

Increasing rates of complications were associated with these changes in treatment, the records showed. Ten percent of patients who underwent PCI had a complication. These included vascular or bleeding complications (6%), stroke (0.3%), and renal failure (5%). Of the vascular or bleeding complications, 63% were access site complications, most of which were groin hematomas.

The complication rate was low among patient receiving fibrinolysis (2%). Two percent of patients who had a coronary artery bypass graft (CABG) procedure had an associated stroke. The complication rate was 8% among patients who had angiography, with or without reperfusion. Most of those (5%) had acute renal failure, with three patients requiring dialysis. The other patients had vascular or bleeding complications.

Thirty-day rehospitalizations were required in 561 patients (19%), who were admitted a total of 643 times – 484 patients were admitted once, 72 twice, and 5 three times. Three percent (87) of the patients died within 30 days; among these, 19 were in a readmission when they died.

Readmission rates were 23% from 1987 to 1992; 22% from 1993 to 1998; 22% from 1999 to 2004; and 19% from 2005 to 2010.

The most common reasons for rehospitalization were ischemic heart disease (15%), respiratory or other chest symptoms (10%), heart failure (9%), and cardiac arrhythmias (6%). Other reasons included procedural complications (92%); fluid/electrolyte problems (2%); and hypotension, pneumonia, embolism/thrombosis, and stroke or transient ischemic attack (about 1%) each.

Angiography was performed in 24% of readmissions and PCI in 9%. Of these, 25% were repeat PCIs of the same vessel.

There were 44 CABG procedures among the readmitted group (28 planned). Forty-five percent of those undergoing a revascularization had been treated medically during their initial hospitalization.

Some treatments significantly increased the risk of 30-day readmission; most of that association was driven by procedural complications:

• Angiography with complications: hazard ratio, 2.40.

• Reperfusions with revascularization, with complications: HR, 2.12.

Some medical comorbidities also showed significant associations with readmission:

• Diabetes: HR, 1.34.

• Chronic obstructive pulmonary disease: HR, 1.43.

• Heart failure: HR, 1.12.

"Compared with our previous report on rehospitalizations after incident heart failure diagnosis in Olmsted County, COPD, diabetes, and anemia were common risk factors for rehospitalization among patients with incident MI and heart failure," the authors said. These risk factors "may be of particular importance as future targets in preventing rehospitalizations in patients hospitalized with cardiovascular disease."

The National Institutes of Health sponsored the study. The researchers reported having no relevant financial conflicts of interests.

The American Heart Association is adding atrial fibrillation to its "Get With the Guidelines" program.

Get With the Guidelines has not previously addressed atrial fibrillation. But the current lack of a consistent treatment paradigm suggests the need for a unified strategy, Dr. Lee H. Schwamm said in a press statement.

"While scientifically proven therapies and approaches to treatment exist for patients with atrial fibrillation, wide gaps, variations and disparities remain in the quality of care for people with this common heart rhythm disorder," said Dr. Schwamm, chairman of the Get With the Guidelines National Steering Committee and professor of neurology at Harvard Medical School in Boston. "By improving the care of patients with atrial fibrillation through the GWTG program, we can save lives and prevent serious complications, such as stroke."

The atrial fibrillation program will provide the "blueprint" for an atrial fibrillation treatment strategy. While its primary function is as a clinical improvement guide, the program will also serve as a data collection tool, according to the statement.

"[Data collection] gives participating hospitals feedback on their practice and patient outcomes and can be used to develop new evidence-based guidelines for in-hospital care for AF patients."

GWTG programs have consistently improved care in a number of cardiac disorders, as well as stroke care.

"Our Get With the Guidelines suite is the ideal home for a nationwide atrial fibrillation quality improvement module, because participation in these programs has proven to make a difference in the quality of care and outcomes for patients with heart disease and stroke," Schwamm said. "In the last decade, numerous scientific studies have shown Get With the Guidelines participating hospitals are more likely to adhere to national guideline-recommended therapies than other U.S. hospitals."

Last year, the American Heart Association and the American College of Cardiology collaborated on an updated evidence review of atrial fibrillation treatment recommendations.

The association already offers a number of clinical and patient resources on its website.

"Get With the Guidelines" is the largest national hospital-based program dedicated to quality of care improvement for patients with cardiovascular disease, including targeted initiatives in stroke, heart failure and resuscitation. More than 42% of U.S. hospitals participate in the quality initiative.

Enrollment in the new atrial fibrillation module should begin within the next year. Boehringer Ingelheim will provide funding to support the American Heart Association’s GWTG–Atrial Fibrillation program.

The American Heart Association is adding atrial fibrillation to its "Get With the Guidelines" program.

Get With the Guidelines has not previously addressed atrial fibrillation. But the current lack of a consistent treatment paradigm suggests the need for a unified strategy, Dr. Lee H. Schwamm said in a press statement.

"While scientifically proven therapies and approaches to treatment exist for patients with atrial fibrillation, wide gaps, variations and disparities remain in the quality of care for people with this common heart rhythm disorder," said Dr. Schwamm, chairman of the Get With the Guidelines National Steering Committee and professor of neurology at Harvard Medical School in Boston. "By improving the care of patients with atrial fibrillation through the GWTG program, we can save lives and prevent serious complications, such as stroke."

The atrial fibrillation program will provide the "blueprint" for an atrial fibrillation treatment strategy. While its primary function is as a clinical improvement guide, the program will also serve as a data collection tool, according to the statement.

"[Data collection] gives participating hospitals feedback on their practice and patient outcomes and can be used to develop new evidence-based guidelines for in-hospital care for AF patients."

GWTG programs have consistently improved care in a number of cardiac disorders, as well as stroke care.

"Our Get With the Guidelines suite is the ideal home for a nationwide atrial fibrillation quality improvement module, because participation in these programs has proven to make a difference in the quality of care and outcomes for patients with heart disease and stroke," Schwamm said. "In the last decade, numerous scientific studies have shown Get With the Guidelines participating hospitals are more likely to adhere to national guideline-recommended therapies than other U.S. hospitals."

Last year, the American Heart Association and the American College of Cardiology collaborated on an updated evidence review of atrial fibrillation treatment recommendations.

The association already offers a number of clinical and patient resources on its website.

"Get With the Guidelines" is the largest national hospital-based program dedicated to quality of care improvement for patients with cardiovascular disease, including targeted initiatives in stroke, heart failure and resuscitation. More than 42% of U.S. hospitals participate in the quality initiative.

Enrollment in the new atrial fibrillation module should begin within the next year. Boehringer Ingelheim will provide funding to support the American Heart Association’s GWTG–Atrial Fibrillation program.

The American Heart Association is adding atrial fibrillation to its "Get With the Guidelines" program.

Get With the Guidelines has not previously addressed atrial fibrillation. But the current lack of a consistent treatment paradigm suggests the need for a unified strategy, Dr. Lee H. Schwamm said in a press statement.

"While scientifically proven therapies and approaches to treatment exist for patients with atrial fibrillation, wide gaps, variations and disparities remain in the quality of care for people with this common heart rhythm disorder," said Dr. Schwamm, chairman of the Get With the Guidelines National Steering Committee and professor of neurology at Harvard Medical School in Boston. "By improving the care of patients with atrial fibrillation through the GWTG program, we can save lives and prevent serious complications, such as stroke."

The atrial fibrillation program will provide the "blueprint" for an atrial fibrillation treatment strategy. While its primary function is as a clinical improvement guide, the program will also serve as a data collection tool, according to the statement.

"[Data collection] gives participating hospitals feedback on their practice and patient outcomes and can be used to develop new evidence-based guidelines for in-hospital care for AF patients."

GWTG programs have consistently improved care in a number of cardiac disorders, as well as stroke care.

"Our Get With the Guidelines suite is the ideal home for a nationwide atrial fibrillation quality improvement module, because participation in these programs has proven to make a difference in the quality of care and outcomes for patients with heart disease and stroke," Schwamm said. "In the last decade, numerous scientific studies have shown Get With the Guidelines participating hospitals are more likely to adhere to national guideline-recommended therapies than other U.S. hospitals."

Last year, the American Heart Association and the American College of Cardiology collaborated on an updated evidence review of atrial fibrillation treatment recommendations.

The association already offers a number of clinical and patient resources on its website.

"Get With the Guidelines" is the largest national hospital-based program dedicated to quality of care improvement for patients with cardiovascular disease, including targeted initiatives in stroke, heart failure and resuscitation. More than 42% of U.S. hospitals participate in the quality initiative.

Enrollment in the new atrial fibrillation module should begin within the next year. Boehringer Ingelheim will provide funding to support the American Heart Association’s GWTG–Atrial Fibrillation program.

ATLANTA – Men with type 1 diabetes might not express an elevated level of prostate specific antigen, even if they have an early prostate cancer, suggest findings from a subanalysis of patients with type 1 diabetes.

In that prospective study, poor glycemic control was associated with decreased PSA levels, irrespective of age or body size, Dr. James Hotaling said during a poster session at the annual meeting of the American Urological Association.

"It’s well known that patients with type 2 diabetes have a decreased risk of prostate cancers as well as lower PSAs," said Dr. Hotaling of the University of Washington, Seattle.

"This lower PSA is thought to stem from a greater volume of distribution because many of these men are overweight or morbidly obese – and some hypothesize that they have lower testosterone because of the obesity and that this contributes to these findings."

Dr. Hotaling and his colleagues sought to determine whether men with type 1 diabetes showed a similar pattern. To do this, they examined data from year 17 of the Epidemiology of Diabetes Interventions and Complications (EDIC) study. EDIC began in 1994 and is the observational follow-up study of 1,441 participants in the earlier Diabetes Control and Complications Trial (DCCT).

PSA concentrations were measured in 627 men during year 17. The investigators stratified the subjects by both age (younger than 40 years, 41-59 years, and 60 years and older) and body mass index (normal, overweight, obese).

The subjects were a mean age of 52 years at the time of PSA measurement. Their mean HbA_1c was 8%, and the mean PSA 0.93 ng/mL.

PSA levels increased with age, from a low of 0.56 ng/mL in the youngest patients to a mean of 1.38 ng/mL in the oldest group.

PSA levels significantly decreased as HbA_1c increased. The mean PSA was 1.05 ng/mL when blood sugar was less than 7.5% and 0.76 ng/mL when blood sugar was above 8.5%.

"Each 10% increase in HbA_1c levels was associated with a PSA reduction of 1.37ng/mL," Dr. Hotaling said. "This association was independent of age and body size."

Our findings suggest that metabolic differences related to diabetes may affect the ability to detect early-stage prostate cancer. This finding also could represent a potentially modifiable risk factor that could be addressed.

The physiologic relationship between hyperglycemia and low PSA is not completely known, he added. "Proposed mechanisms are that hyperinsulinemia and insulin resistance lead to increased estradiol, which causes decreased testosterone and sex hormone–binding globulin, thus leading to a decreased PSA concentration."

EDIC is sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Hotaling reported having no financial disclosures.

ATLANTA – Men with type 1 diabetes might not express an elevated level of prostate specific antigen, even if they have an early prostate cancer, suggest findings from a subanalysis of patients with type 1 diabetes.

In that prospective study, poor glycemic control was associated with decreased PSA levels, irrespective of age or body size, Dr. James Hotaling said during a poster session at the annual meeting of the American Urological Association.

"It’s well known that patients with type 2 diabetes have a decreased risk of prostate cancers as well as lower PSAs," said Dr. Hotaling of the University of Washington, Seattle.

"This lower PSA is thought to stem from a greater volume of distribution because many of these men are overweight or morbidly obese – and some hypothesize that they have lower testosterone because of the obesity and that this contributes to these findings."

Dr. Hotaling and his colleagues sought to determine whether men with type 1 diabetes showed a similar pattern. To do this, they examined data from year 17 of the Epidemiology of Diabetes Interventions and Complications (EDIC) study. EDIC began in 1994 and is the observational follow-up study of 1,441 participants in the earlier Diabetes Control and Complications Trial (DCCT).

PSA concentrations were measured in 627 men during year 17. The investigators stratified the subjects by both age (younger than 40 years, 41-59 years, and 60 years and older) and body mass index (normal, overweight, obese).

The subjects were a mean age of 52 years at the time of PSA measurement. Their mean HbA_1c was 8%, and the mean PSA 0.93 ng/mL.

PSA levels increased with age, from a low of 0.56 ng/mL in the youngest patients to a mean of 1.38 ng/mL in the oldest group.

PSA levels significantly decreased as HbA_1c increased. The mean PSA was 1.05 ng/mL when blood sugar was less than 7.5% and 0.76 ng/mL when blood sugar was above 8.5%.

"Each 10% increase in HbA_1c levels was associated with a PSA reduction of 1.37ng/mL," Dr. Hotaling said. "This association was independent of age and body size."

Our findings suggest that metabolic differences related to diabetes may affect the ability to detect early-stage prostate cancer. This finding also could represent a potentially modifiable risk factor that could be addressed.

The physiologic relationship between hyperglycemia and low PSA is not completely known, he added. "Proposed mechanisms are that hyperinsulinemia and insulin resistance lead to increased estradiol, which causes decreased testosterone and sex hormone–binding globulin, thus leading to a decreased PSA concentration."

EDIC is sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Hotaling reported having no financial disclosures.

ATLANTA – Men with type 1 diabetes might not express an elevated level of prostate specific antigen, even if they have an early prostate cancer, suggest findings from a subanalysis of patients with type 1 diabetes.

In that prospective study, poor glycemic control was associated with decreased PSA levels, irrespective of age or body size, Dr. James Hotaling said during a poster session at the annual meeting of the American Urological Association.

"It’s well known that patients with type 2 diabetes have a decreased risk of prostate cancers as well as lower PSAs," said Dr. Hotaling of the University of Washington, Seattle.

"This lower PSA is thought to stem from a greater volume of distribution because many of these men are overweight or morbidly obese – and some hypothesize that they have lower testosterone because of the obesity and that this contributes to these findings."

Dr. Hotaling and his colleagues sought to determine whether men with type 1 diabetes showed a similar pattern. To do this, they examined data from year 17 of the Epidemiology of Diabetes Interventions and Complications (EDIC) study. EDIC began in 1994 and is the observational follow-up study of 1,441 participants in the earlier Diabetes Control and Complications Trial (DCCT).

PSA concentrations were measured in 627 men during year 17. The investigators stratified the subjects by both age (younger than 40 years, 41-59 years, and 60 years and older) and body mass index (normal, overweight, obese).

The subjects were a mean age of 52 years at the time of PSA measurement. Their mean HbA_1c was 8%, and the mean PSA 0.93 ng/mL.

PSA levels increased with age, from a low of 0.56 ng/mL in the youngest patients to a mean of 1.38 ng/mL in the oldest group.

PSA levels significantly decreased as HbA_1c increased. The mean PSA was 1.05 ng/mL when blood sugar was less than 7.5% and 0.76 ng/mL when blood sugar was above 8.5%.

"Each 10% increase in HbA_1c levels was associated with a PSA reduction of 1.37ng/mL," Dr. Hotaling said. "This association was independent of age and body size."

Our findings suggest that metabolic differences related to diabetes may affect the ability to detect early-stage prostate cancer. This finding also could represent a potentially modifiable risk factor that could be addressed.

The physiologic relationship between hyperglycemia and low PSA is not completely known, he added. "Proposed mechanisms are that hyperinsulinemia and insulin resistance lead to increased estradiol, which causes decreased testosterone and sex hormone–binding globulin, thus leading to a decreased PSA concentration."

EDIC is sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Hotaling reported having no financial disclosures.

ATLANTA – Interstitial cystitis and chronic pelvic pain may be more common in males than assumed.

A national telephone survey shows that about 2 million U.S. men may suffer from either of the disorders, Dr. Anne Suskind said during a poster session at the annual meeting of the American Urological Association.

"We found that anywhere from 1% to 2.5% of men report symptoms suggestive of interstitial cystitis and a similar number report symptoms suggestive of chronic prostatitis or chronic pelvic pain," said Dr. Suskind, a fellow at the University of Michigan, Ann Arbor. "The degree of overlap is less than 20%"

Dr. Suskind and her colleagues conducted a telephone survey similar to the RAND IC Epidemiology Study (RICE) survey of women. That study – the largest interstitial cystitis epidemiology study ever undertaken – found that up to 6.5% of U.S. women may have the disorder.

The male-targeted survey used versions of the RICE validated definitions to assess problems in men. Chronic prostatitis was considered a value of greater than 5 on the National Institute of Health Chronic Prostatitis Symptom Index, plus ejaculatory or perineal pain.

Researchers contacted 6,072 households, asking if the male resident would be willing to answer a survey about President Obama’s performance. If the answer was yes, the survey ensued, with questions about any urinary tract pain attached at the end of the political questions.

Initially, 296 men screened positive for the bladder symptoms; 149 of these men met inclusionary diagnostic criteria for interstitial cystitis or prostatitis. Of these, 52 were excluded from the final analysis.

Based on the remaining sample of 97 subjects, 23% met the high specificity definition of interstitial cystitis/ bladder pain syndrome, 16% met the case definition of chronic prostatitis/chronic pelvic pain syndrome, and 8% met both definitions.

By extrapolating the numbers to the entire U.S. adult male population, Dr. Suskind concluded that up to 2 million men would meet the diagnostic definition for either of the disorders. A further analysis showed that the overlap between the two conditions was small – about 17% – indicating that they could be easily diagnostically differentiated.

"These conditions appear to be more widespread in men than many of us have believed," she concluded.

Dr. Suskind reported having no financial disclosures.

ATLANTA – Interstitial cystitis and chronic pelvic pain may be more common in males than assumed.

A national telephone survey shows that about 2 million U.S. men may suffer from either of the disorders, Dr. Anne Suskind said during a poster session at the annual meeting of the American Urological Association.

"We found that anywhere from 1% to 2.5% of men report symptoms suggestive of interstitial cystitis and a similar number report symptoms suggestive of chronic prostatitis or chronic pelvic pain," said Dr. Suskind, a fellow at the University of Michigan, Ann Arbor. "The degree of overlap is less than 20%"

Dr. Suskind and her colleagues conducted a telephone survey similar to the RAND IC Epidemiology Study (RICE) survey of women. That study – the largest interstitial cystitis epidemiology study ever undertaken – found that up to 6.5% of U.S. women may have the disorder.

The male-targeted survey used versions of the RICE validated definitions to assess problems in men. Chronic prostatitis was considered a value of greater than 5 on the National Institute of Health Chronic Prostatitis Symptom Index, plus ejaculatory or perineal pain.

Researchers contacted 6,072 households, asking if the male resident would be willing to answer a survey about President Obama’s performance. If the answer was yes, the survey ensued, with questions about any urinary tract pain attached at the end of the political questions.

Initially, 296 men screened positive for the bladder symptoms; 149 of these men met inclusionary diagnostic criteria for interstitial cystitis or prostatitis. Of these, 52 were excluded from the final analysis.

Based on the remaining sample of 97 subjects, 23% met the high specificity definition of interstitial cystitis/ bladder pain syndrome, 16% met the case definition of chronic prostatitis/chronic pelvic pain syndrome, and 8% met both definitions.

By extrapolating the numbers to the entire U.S. adult male population, Dr. Suskind concluded that up to 2 million men would meet the diagnostic definition for either of the disorders. A further analysis showed that the overlap between the two conditions was small – about 17% – indicating that they could be easily diagnostically differentiated.

"These conditions appear to be more widespread in men than many of us have believed," she concluded.

Dr. Suskind reported having no financial disclosures.

ATLANTA – Interstitial cystitis and chronic pelvic pain may be more common in males than assumed.

A national telephone survey shows that about 2 million U.S. men may suffer from either of the disorders, Dr. Anne Suskind said during a poster session at the annual meeting of the American Urological Association.

"We found that anywhere from 1% to 2.5% of men report symptoms suggestive of interstitial cystitis and a similar number report symptoms suggestive of chronic prostatitis or chronic pelvic pain," said Dr. Suskind, a fellow at the University of Michigan, Ann Arbor. "The degree of overlap is less than 20%"

Dr. Suskind and her colleagues conducted a telephone survey similar to the RAND IC Epidemiology Study (RICE) survey of women. That study – the largest interstitial cystitis epidemiology study ever undertaken – found that up to 6.5% of U.S. women may have the disorder.

The male-targeted survey used versions of the RICE validated definitions to assess problems in men. Chronic prostatitis was considered a value of greater than 5 on the National Institute of Health Chronic Prostatitis Symptom Index, plus ejaculatory or perineal pain.

Researchers contacted 6,072 households, asking if the male resident would be willing to answer a survey about President Obama’s performance. If the answer was yes, the survey ensued, with questions about any urinary tract pain attached at the end of the political questions.

Initially, 296 men screened positive for the bladder symptoms; 149 of these men met inclusionary diagnostic criteria for interstitial cystitis or prostatitis. Of these, 52 were excluded from the final analysis.

Based on the remaining sample of 97 subjects, 23% met the high specificity definition of interstitial cystitis/ bladder pain syndrome, 16% met the case definition of chronic prostatitis/chronic pelvic pain syndrome, and 8% met both definitions.

By extrapolating the numbers to the entire U.S. adult male population, Dr. Suskind concluded that up to 2 million men would meet the diagnostic definition for either of the disorders. A further analysis showed that the overlap between the two conditions was small – about 17% – indicating that they could be easily diagnostically differentiated.

"These conditions appear to be more widespread in men than many of us have believed," she concluded.

Dr. Suskind reported having no financial disclosures.

ATLANTA – Men younger than age 55 who have served in the U.S. armed forces are almost three times as likely to report urinary incontinence as are their nonmilitary peers.

The association between military service and incontinence remained statistically significant even after investigators controlled for age, medications, and medical comorbidities – including prostate problems, Dr. Alayne Markland said at the annual meeting of the American Urological Society. Additionally, in the youngest group of men, the presence of posttraumatic stress disorder was associated with a threefold increase of any lower urinary tract symptom.

"One implication of this finding is the need for additional screening for men who are members of the armed forces, especially those who are returning from the current wars," said Dr. Markland, an internist at the Birmingham (Ala.) VA Medical Center. "This is something we need to ask about."

Dr. Markland reviewed data from the 2005-2006 and 2007-2008 cycles of the NHANES (National Health and Nutritional Examination Survey). Those cycles included queries about lower urinary tract symptoms, and provided an opportunity for respondents to rate any problems as mild, moderate, or severe.

The survey population included 5,287 men who were older than age 20. Military exposure was assessed by asking whether the respondent had ever served in any branch of the U.S. armed forces.

The investigators divided respondents into three age groups, correlated with the timing of military conflicts in which they might have served: 70 years or older (World War II or the Korean War); 55-59 (Vietnam War); and younger than 55 (Gulf War, Iraq, or Afghanistan). The groupings also allowed some comparison based on health concerns that are known to be associated with each conflict. For example, Vietnam-era vets could have been exposed to the defoliant Agent Orange and have a higher prevalence of diabetes and cancer than exists in the general population. Middle-aged veterans sometimes report Gulf War syndrome, and younger veterans report posttraumatic stress disorder and traumatic brain injury.

Among the entire survey population, the rate of any incontinence was 10%. About a quarter of the respondents reported having some military exposure. The rate of incontinence among these men was 19%, a significant difference.

Urgency was the most common problem, reported by 15% of veterans and 8% of civilians. The rates of stress and mixed incontinence were 4% and 2%, respectively.

Moderate to severe symptoms also were more common among the veterans (19% vs. 3%), whereas 1% of each group reported severe incontinence.

However, Dr. Markland said, when the group was broken down by age, the youngest group was driving the difference. Men aged 55 years and younger were three times more likely to report any urinary incontinence than were the nonmilitary population. The difference remained significant even after investigators controlled for ethnicity, socioeconomic level, body mass index, diabetes, and heart disease.

In another model that included prostate enlargement and cancer, the youngest veterans still had a threefold increase in the risk of incontinence.

Dr. Markland then examined the youngest group more carefully. Their average age was 26 years. Posttraumatic stress disorder was common, affecting 28% of them; 16% of this population reported some form of lower urinary tract problem. In fact, the presence of PTSD was associated with a threefold increase of any lower urinary tract symptom.

The association might be related to adrenergic or anticholinergic medication used to treat PTSD, Dr. Markland said. But even after investigators controlled for this, the youngest veterans had a 20% higher risk of any lower urinary tract symptom.

Because NHANES doesn’t collect any detailed information about military experience, there’s no way to tease out any cause and effect information, she said. But Dr. Christopher Amling, a moderator at the session, suggested that modern war injuries could be playing a part.

"Normally, you would expect to see much higher rates of this among an older population," said Dr. Amling, chief of urology at the Oregon Health and Science University, Portland. "What’s remarkable to me is that this is occurring in this younger population. To me, this suggests something about the recent conflicts – perhaps there is a greater risk of spinal cord or limb injuries."

Or, he said, the difference could be as simple as reluctance among older men to discuss their urinary problems. "Maybe they’re just more embarrassed to say anything about it."

However, Dr. Markland said, younger veterans are returning from the Middle East conflicts with different kinds of injuries than have been seen in past wars.

"Traumatic brain injury is a big issue, and we are still trying to recognize the more subtle presentations of blast injuries."

And, she said, the very armor that protects soldiers may contribute to problems when they survive an injury. "The Kevlar protection shields the thorax and abdomen, so although more people are surviving, we’re seeing many more limbs blown off, as well as TBI. We can keep soldiers from being killed, but anything that injures the brain can cause dysfunctional voiding."

Dr. Markland and Dr. Amling said they had no financial disclosures.

ATLANTA – Men younger than age 55 who have served in the U.S. armed forces are almost three times as likely to report urinary incontinence as are their nonmilitary peers.

The association between military service and incontinence remained statistically significant even after investigators controlled for age, medications, and medical comorbidities – including prostate problems, Dr. Alayne Markland said at the annual meeting of the American Urological Society. Additionally, in the youngest group of men, the presence of posttraumatic stress disorder was associated with a threefold increase of any lower urinary tract symptom.

"One implication of this finding is the need for additional screening for men who are members of the armed forces, especially those who are returning from the current wars," said Dr. Markland, an internist at the Birmingham (Ala.) VA Medical Center. "This is something we need to ask about."

Dr. Markland reviewed data from the 2005-2006 and 2007-2008 cycles of the NHANES (National Health and Nutritional Examination Survey). Those cycles included queries about lower urinary tract symptoms, and provided an opportunity for respondents to rate any problems as mild, moderate, or severe.

The survey population included 5,287 men who were older than age 20. Military exposure was assessed by asking whether the respondent had ever served in any branch of the U.S. armed forces.

The investigators divided respondents into three age groups, correlated with the timing of military conflicts in which they might have served: 70 years or older (World War II or the Korean War); 55-59 (Vietnam War); and younger than 55 (Gulf War, Iraq, or Afghanistan). The groupings also allowed some comparison based on health concerns that are known to be associated with each conflict. For example, Vietnam-era vets could have been exposed to the defoliant Agent Orange and have a higher prevalence of diabetes and cancer than exists in the general population. Middle-aged veterans sometimes report Gulf War syndrome, and younger veterans report posttraumatic stress disorder and traumatic brain injury.

Among the entire survey population, the rate of any incontinence was 10%. About a quarter of the respondents reported having some military exposure. The rate of incontinence among these men was 19%, a significant difference.

Urgency was the most common problem, reported by 15% of veterans and 8% of civilians. The rates of stress and mixed incontinence were 4% and 2%, respectively.

Moderate to severe symptoms also were more common among the veterans (19% vs. 3%), whereas 1% of each group reported severe incontinence.

However, Dr. Markland said, when the group was broken down by age, the youngest group was driving the difference. Men aged 55 years and younger were three times more likely to report any urinary incontinence than were the nonmilitary population. The difference remained significant even after investigators controlled for ethnicity, socioeconomic level, body mass index, diabetes, and heart disease.

In another model that included prostate enlargement and cancer, the youngest veterans still had a threefold increase in the risk of incontinence.

Dr. Markland then examined the youngest group more carefully. Their average age was 26 years. Posttraumatic stress disorder was common, affecting 28% of them; 16% of this population reported some form of lower urinary tract problem. In fact, the presence of PTSD was associated with a threefold increase of any lower urinary tract symptom.

The association might be related to adrenergic or anticholinergic medication used to treat PTSD, Dr. Markland said. But even after investigators controlled for this, the youngest veterans had a 20% higher risk of any lower urinary tract symptom.

Because NHANES doesn’t collect any detailed information about military experience, there’s no way to tease out any cause and effect information, she said. But Dr. Christopher Amling, a moderator at the session, suggested that modern war injuries could be playing a part.

"Normally, you would expect to see much higher rates of this among an older population," said Dr. Amling, chief of urology at the Oregon Health and Science University, Portland. "What’s remarkable to me is that this is occurring in this younger population. To me, this suggests something about the recent conflicts – perhaps there is a greater risk of spinal cord or limb injuries."

Or, he said, the difference could be as simple as reluctance among older men to discuss their urinary problems. "Maybe they’re just more embarrassed to say anything about it."

However, Dr. Markland said, younger veterans are returning from the Middle East conflicts with different kinds of injuries than have been seen in past wars.

"Traumatic brain injury is a big issue, and we are still trying to recognize the more subtle presentations of blast injuries."

And, she said, the very armor that protects soldiers may contribute to problems when they survive an injury. "The Kevlar protection shields the thorax and abdomen, so although more people are surviving, we’re seeing many more limbs blown off, as well as TBI. We can keep soldiers from being killed, but anything that injures the brain can cause dysfunctional voiding."

Dr. Markland and Dr. Amling said they had no financial disclosures.

ATLANTA – Men younger than age 55 who have served in the U.S. armed forces are almost three times as likely to report urinary incontinence as are their nonmilitary peers.

The association between military service and incontinence remained statistically significant even after investigators controlled for age, medications, and medical comorbidities – including prostate problems, Dr. Alayne Markland said at the annual meeting of the American Urological Society. Additionally, in the youngest group of men, the presence of posttraumatic stress disorder was associated with a threefold increase of any lower urinary tract symptom.

"One implication of this finding is the need for additional screening for men who are members of the armed forces, especially those who are returning from the current wars," said Dr. Markland, an internist at the Birmingham (Ala.) VA Medical Center. "This is something we need to ask about."

Dr. Markland reviewed data from the 2005-2006 and 2007-2008 cycles of the NHANES (National Health and Nutritional Examination Survey). Those cycles included queries about lower urinary tract symptoms, and provided an opportunity for respondents to rate any problems as mild, moderate, or severe.

The survey population included 5,287 men who were older than age 20. Military exposure was assessed by asking whether the respondent had ever served in any branch of the U.S. armed forces.

The investigators divided respondents into three age groups, correlated with the timing of military conflicts in which they might have served: 70 years or older (World War II or the Korean War); 55-59 (Vietnam War); and younger than 55 (Gulf War, Iraq, or Afghanistan). The groupings also allowed some comparison based on health concerns that are known to be associated with each conflict. For example, Vietnam-era vets could have been exposed to the defoliant Agent Orange and have a higher prevalence of diabetes and cancer than exists in the general population. Middle-aged veterans sometimes report Gulf War syndrome, and younger veterans report posttraumatic stress disorder and traumatic brain injury.

Among the entire survey population, the rate of any incontinence was 10%. About a quarter of the respondents reported having some military exposure. The rate of incontinence among these men was 19%, a significant difference.

Urgency was the most common problem, reported by 15% of veterans and 8% of civilians. The rates of stress and mixed incontinence were 4% and 2%, respectively.

Moderate to severe symptoms also were more common among the veterans (19% vs. 3%), whereas 1% of each group reported severe incontinence.

However, Dr. Markland said, when the group was broken down by age, the youngest group was driving the difference. Men aged 55 years and younger were three times more likely to report any urinary incontinence than were the nonmilitary population. The difference remained significant even after investigators controlled for ethnicity, socioeconomic level, body mass index, diabetes, and heart disease.

In another model that included prostate enlargement and cancer, the youngest veterans still had a threefold increase in the risk of incontinence.

Dr. Markland then examined the youngest group more carefully. Their average age was 26 years. Posttraumatic stress disorder was common, affecting 28% of them; 16% of this population reported some form of lower urinary tract problem. In fact, the presence of PTSD was associated with a threefold increase of any lower urinary tract symptom.

The association might be related to adrenergic or anticholinergic medication used to treat PTSD, Dr. Markland said. But even after investigators controlled for this, the youngest veterans had a 20% higher risk of any lower urinary tract symptom.

Because NHANES doesn’t collect any detailed information about military experience, there’s no way to tease out any cause and effect information, she said. But Dr. Christopher Amling, a moderator at the session, suggested that modern war injuries could be playing a part.

"Normally, you would expect to see much higher rates of this among an older population," said Dr. Amling, chief of urology at the Oregon Health and Science University, Portland. "What’s remarkable to me is that this is occurring in this younger population. To me, this suggests something about the recent conflicts – perhaps there is a greater risk of spinal cord or limb injuries."

Or, he said, the difference could be as simple as reluctance among older men to discuss their urinary problems. "Maybe they’re just more embarrassed to say anything about it."

However, Dr. Markland said, younger veterans are returning from the Middle East conflicts with different kinds of injuries than have been seen in past wars.

"Traumatic brain injury is a big issue, and we are still trying to recognize the more subtle presentations of blast injuries."

And, she said, the very armor that protects soldiers may contribute to problems when they survive an injury. "The Kevlar protection shields the thorax and abdomen, so although more people are surviving, we’re seeing many more limbs blown off, as well as TBI. We can keep soldiers from being killed, but anything that injures the brain can cause dysfunctional voiding."

Dr. Markland and Dr. Amling said they had no financial disclosures.

PHILADELPHIA – Daily insulin glargine for patients with diabetes appears to have no effect on the occurrence of breast, prostate, colorectal, lung, pancreatic, or any other type of cancer.

Studies of three large administrative databases agree: Compared with other forms of insulin, glargine (Lantus) confers absolutely no increase in the risk of any of these cancers.

Since 2009, when four articles simultaneously raised the specter of a glargine-cancer connection, researchers, physicians, and patients have struggled with concerns that the compound could impart its own health risks. These questions must be answered as definitively as possible, Peter Boyle, Ph.D., said at the annual scientific sessions of the American Diabetes Association.

Not doing so could have devastating consequences.

"None of our results support this hypothesis that short-term use of glargine is associated with any form of cancer."

"The big worry is that by 2030, we will have more than 500 million people living with diabetes. Many of them will require insulin. Without it, they will die unnecessarily prematurely. If we don’t take a more regulated approach [into researching the cancer association], and use a lot of common sense while doing so, there could be a shortage of a drug that we absolutely need to treat this very common disease."

Dr. Boyle is the primary investigator of the Northern European Study of Insulin and Cancer, the largest-yet registry study of glargine and NPH insulin, and their relation to cancer. His study, combined with the two others presented at the same session, comprised more than 615,000 patients, with well over 1.5 million patient/years of follow-up data.

Dr. Boyle examined the glargine-cancer connection in 447,821 patients with diabetes who used daily insulin. This study had the longest follow-up of the trio – 3 years for patients using glargine and 3.5 years for those using other types of insulin.

It was conducted in five countries: Scotland, Norway, Sweden, Denmark, and Finland. This study also had the longest follow-up time – 3 years for patients using glargine and 3.5 years for those using other insulins. It compared cancer incidence in two groups: patients taking glargine or other insulin for the first time, and patients who switched from another insulin to glargine.

Over the study period, 17,800 new cases of cancer developed, said Dr. Boyle, president of the International Prevention Research Institute, Lyon, France. "In none of the individual cancers, nor in the overall analysis, did we see any evidence at all of an increased risk of cancer associated with the use of glargine, compared with other forms of insulin. Even though we saw some inconsistencies [in cancer incidence] across the different countries, none of the risk analyses came anywhere close to meeting statistical significance."

The overall risk for colorectal cancer in patients taking glargine, compared with other forms of insulin, was 0.86 – a finding consistent over all the study centers.

Findings for prostate cancer were less consistent, but this was most likely because some of the countries in the study conduct many prostate cancer screenings, "while in other countries, PSA testing is virtually verboten," Dr. Boyle said. Nevertheless, the overall risk for prostate cancer in glargine vs. other insulins was 1.11 – still not statistically significant.

Breast cancers showed a similar finding, with an overall relative risk of 1.12 for glargine, compared with other forms of insulin.

A predefined exploratory analysis examined risks associated with lung and pancreatic cancer. For glargine vs. other forms of insulin, the overall relative risk for lung cancer was 0.97; for pancreatic cancer, the relative risk was 0.99.

"There is just nothing there at all," Dr. Boyle said.

"The big worry is that by 2030, we will have more than 500 million people living with diabetes."

The second portion of the analysis examined cancer risk in light of exposure length. Breast cancer was the only type that showed any signal, and that was a confusing one, he said. While in most countries, the risk declined with time, "In the Scottish data, increasing use was associated with increasing hazard. This really is terribly inconsistent, and we need to look into it in greater detail."

However, he said, the contradictory finding perfectly illustrates the trouble with using large surveillance databases to make any kind of prediction about drug/adverse event associations.

"Quite frankly, these administrative databases were not designed for epidemiologic studies. We’ve got to do our best to come up with real findings that mean something rather than just torturing the data until something shows up. Critical bits of information are missing from these pictures. We don’t know why a patient might change from one therapy to another, for instance. There are a lot of questions like that, and these are the first things that a clinician needs to know."

Dr. Laurel Habel, a senior researcher at Kaiser Permanente, presented similar findings of no increased cancer risk from glargine exposure. Her study was based on Kaiser’s northern and southern California claims and coding databases. The study group comprised 115,000 patients with diabetes – 100,000 took NPH insulin, 27,000 took glargine, and 12,000 took both. The median follow-up time was 2.3 years for glargine and 3.6 years for NPH.

"We found no evidence of increased prostate or colorectal cancer for glargine users, whether they were new users or whether they had switched to it," she said.

In a time exposure analysis of breast cancer risk, those who had been on glargine at baseline had a "suggestion of a very modest increase in risk, of 1.6." after 24 months. Curiously, she said, there was no risk increase for patients who had been on glargine for at least 2 years after switching from another insulin.

"We can’t think of any biological reason why we would only see this in the new users, so it might be a case of confounding," she said. "None of our results support this hypothesis that short-term use of glargine is associated with any form of cancer."

For prostate and colorectal cancers, there were no significant associations in any of the analyses, or in the time-dependent comparisons

Dr. Til Stürmer of the University of North Carolina at Chapel Hill presented the smallest study, but had results entirely consistent with those of his colleagues. Again, the comparison group of 52,553 patients was drawn from a large healthcare database. Median follow-up was 1.5 years for both the glargine and other insulin groups.

In looking at the relative risks of breast, prostate, colon. and all cancer, Dr. Stürmer found no significant associations with either new glargine users or those who switched medications. Compared with other insulins, glargine had a relative risk of 1.1 for breast cancer, 1.2 for prostate cancer, 0.9 for colon cancer, and 1.1 for all forms of cancer.

"In a subgroup looking at breast cancer stratified by time [0-6 months, 6-12 months, 12-24 months and longer than 24 months] the hazard ratios jumped around the null, but we only had 14 cancers in 4,000 person/years," he added.

All of the registry studies received support from Sanofi. Other than this funding, none of the presenters had any financial declarations relevant to their studies.

PHILADELPHIA – Daily insulin glargine for patients with diabetes appears to have no effect on the occurrence of breast, prostate, colorectal, lung, pancreatic, or any other type of cancer.

Studies of three large administrative databases agree: Compared with other forms of insulin, glargine (Lantus) confers absolutely no increase in the risk of any of these cancers.

Since 2009, when four articles simultaneously raised the specter of a glargine-cancer connection, researchers, physicians, and patients have struggled with concerns that the compound could impart its own health risks. These questions must be answered as definitively as possible, Peter Boyle, Ph.D., said at the annual scientific sessions of the American Diabetes Association.

Not doing so could have devastating consequences.

"None of our results support this hypothesis that short-term use of glargine is associated with any form of cancer."

"The big worry is that by 2030, we will have more than 500 million people living with diabetes. Many of them will require insulin. Without it, they will die unnecessarily prematurely. If we don’t take a more regulated approach [into researching the cancer association], and use a lot of common sense while doing so, there could be a shortage of a drug that we absolutely need to treat this very common disease."

Dr. Boyle is the primary investigator of the Northern European Study of Insulin and Cancer, the largest-yet registry study of glargine and NPH insulin, and their relation to cancer. His study, combined with the two others presented at the same session, comprised more than 615,000 patients, with well over 1.5 million patient/years of follow-up data.

Dr. Boyle examined the glargine-cancer connection in 447,821 patients with diabetes who used daily insulin. This study had the longest follow-up of the trio – 3 years for patients using glargine and 3.5 years for those using other types of insulin.

It was conducted in five countries: Scotland, Norway, Sweden, Denmark, and Finland. This study also had the longest follow-up time – 3 years for patients using glargine and 3.5 years for those using other insulins. It compared cancer incidence in two groups: patients taking glargine or other insulin for the first time, and patients who switched from another insulin to glargine.

Over the study period, 17,800 new cases of cancer developed, said Dr. Boyle, president of the International Prevention Research Institute, Lyon, France. "In none of the individual cancers, nor in the overall analysis, did we see any evidence at all of an increased risk of cancer associated with the use of glargine, compared with other forms of insulin. Even though we saw some inconsistencies [in cancer incidence] across the different countries, none of the risk analyses came anywhere close to meeting statistical significance."

The overall risk for colorectal cancer in patients taking glargine, compared with other forms of insulin, was 0.86 – a finding consistent over all the study centers.

Findings for prostate cancer were less consistent, but this was most likely because some of the countries in the study conduct many prostate cancer screenings, "while in other countries, PSA testing is virtually verboten," Dr. Boyle said. Nevertheless, the overall risk for prostate cancer in glargine vs. other insulins was 1.11 – still not statistically significant.

Breast cancers showed a similar finding, with an overall relative risk of 1.12 for glargine, compared with other forms of insulin.

A predefined exploratory analysis examined risks associated with lung and pancreatic cancer. For glargine vs. other forms of insulin, the overall relative risk for lung cancer was 0.97; for pancreatic cancer, the relative risk was 0.99.

"There is just nothing there at all," Dr. Boyle said.

"The big worry is that by 2030, we will have more than 500 million people living with diabetes."

The second portion of the analysis examined cancer risk in light of exposure length. Breast cancer was the only type that showed any signal, and that was a confusing one, he said. While in most countries, the risk declined with time, "In the Scottish data, increasing use was associated with increasing hazard. This really is terribly inconsistent, and we need to look into it in greater detail."

However, he said, the contradictory finding perfectly illustrates the trouble with using large surveillance databases to make any kind of prediction about drug/adverse event associations.

"Quite frankly, these administrative databases were not designed for epidemiologic studies. We’ve got to do our best to come up with real findings that mean something rather than just torturing the data until something shows up. Critical bits of information are missing from these pictures. We don’t know why a patient might change from one therapy to another, for instance. There are a lot of questions like that, and these are the first things that a clinician needs to know."

Dr. Laurel Habel, a senior researcher at Kaiser Permanente, presented similar findings of no increased cancer risk from glargine exposure. Her study was based on Kaiser’s northern and southern California claims and coding databases. The study group comprised 115,000 patients with diabetes – 100,000 took NPH insulin, 27,000 took glargine, and 12,000 took both. The median follow-up time was 2.3 years for glargine and 3.6 years for NPH.

"We found no evidence of increased prostate or colorectal cancer for glargine users, whether they were new users or whether they had switched to it," she said.

In a time exposure analysis of breast cancer risk, those who had been on glargine at baseline had a "suggestion of a very modest increase in risk, of 1.6." after 24 months. Curiously, she said, there was no risk increase for patients who had been on glargine for at least 2 years after switching from another insulin.

"We can’t think of any biological reason why we would only see this in the new users, so it might be a case of confounding," she said. "None of our results support this hypothesis that short-term use of glargine is associated with any form of cancer."

For prostate and colorectal cancers, there were no significant associations in any of the analyses, or in the time-dependent comparisons

Dr. Til Stürmer of the University of North Carolina at Chapel Hill presented the smallest study, but had results entirely consistent with those of his colleagues. Again, the comparison group of 52,553 patients was drawn from a large healthcare database. Median follow-up was 1.5 years for both the glargine and other insulin groups.

In looking at the relative risks of breast, prostate, colon. and all cancer, Dr. Stürmer found no significant associations with either new glargine users or those who switched medications. Compared with other insulins, glargine had a relative risk of 1.1 for breast cancer, 1.2 for prostate cancer, 0.9 for colon cancer, and 1.1 for all forms of cancer.

"In a subgroup looking at breast cancer stratified by time [0-6 months, 6-12 months, 12-24 months and longer than 24 months] the hazard ratios jumped around the null, but we only had 14 cancers in 4,000 person/years," he added.

All of the registry studies received support from Sanofi. Other than this funding, none of the presenters had any financial declarations relevant to their studies.

PHILADELPHIA – Daily insulin glargine for patients with diabetes appears to have no effect on the occurrence of breast, prostate, colorectal, lung, pancreatic, or any other type of cancer.

Studies of three large administrative databases agree: Compared with other forms of insulin, glargine (Lantus) confers absolutely no increase in the risk of any of these cancers.

Since 2009, when four articles simultaneously raised the specter of a glargine-cancer connection, researchers, physicians, and patients have struggled with concerns that the compound could impart its own health risks. These questions must be answered as definitively as possible, Peter Boyle, Ph.D., said at the annual scientific sessions of the American Diabetes Association.

Not doing so could have devastating consequences.

"None of our results support this hypothesis that short-term use of glargine is associated with any form of cancer."

"The big worry is that by 2030, we will have more than 500 million people living with diabetes. Many of them will require insulin. Without it, they will die unnecessarily prematurely. If we don’t take a more regulated approach [into researching the cancer association], and use a lot of common sense while doing so, there could be a shortage of a drug that we absolutely need to treat this very common disease."

Dr. Boyle is the primary investigator of the Northern European Study of Insulin and Cancer, the largest-yet registry study of glargine and NPH insulin, and their relation to cancer. His study, combined with the two others presented at the same session, comprised more than 615,000 patients, with well over 1.5 million patient/years of follow-up data.

Dr. Boyle examined the glargine-cancer connection in 447,821 patients with diabetes who used daily insulin. This study had the longest follow-up of the trio – 3 years for patients using glargine and 3.5 years for those using other types of insulin.

It was conducted in five countries: Scotland, Norway, Sweden, Denmark, and Finland. This study also had the longest follow-up time – 3 years for patients using glargine and 3.5 years for those using other insulins. It compared cancer incidence in two groups: patients taking glargine or other insulin for the first time, and patients who switched from another insulin to glargine.

Over the study period, 17,800 new cases of cancer developed, said Dr. Boyle, president of the International Prevention Research Institute, Lyon, France. "In none of the individual cancers, nor in the overall analysis, did we see any evidence at all of an increased risk of cancer associated with the use of glargine, compared with other forms of insulin. Even though we saw some inconsistencies [in cancer incidence] across the different countries, none of the risk analyses came anywhere close to meeting statistical significance."

The overall risk for colorectal cancer in patients taking glargine, compared with other forms of insulin, was 0.86 – a finding consistent over all the study centers.

Findings for prostate cancer were less consistent, but this was most likely because some of the countries in the study conduct many prostate cancer screenings, "while in other countries, PSA testing is virtually verboten," Dr. Boyle said. Nevertheless, the overall risk for prostate cancer in glargine vs. other insulins was 1.11 – still not statistically significant.

Breast cancers showed a similar finding, with an overall relative risk of 1.12 for glargine, compared with other forms of insulin.

A predefined exploratory analysis examined risks associated with lung and pancreatic cancer. For glargine vs. other forms of insulin, the overall relative risk for lung cancer was 0.97; for pancreatic cancer, the relative risk was 0.99.

"There is just nothing there at all," Dr. Boyle said.

"The big worry is that by 2030, we will have more than 500 million people living with diabetes."

The second portion of the analysis examined cancer risk in light of exposure length. Breast cancer was the only type that showed any signal, and that was a confusing one, he said. While in most countries, the risk declined with time, "In the Scottish data, increasing use was associated with increasing hazard. This really is terribly inconsistent, and we need to look into it in greater detail."

However, he said, the contradictory finding perfectly illustrates the trouble with using large surveillance databases to make any kind of prediction about drug/adverse event associations.

"Quite frankly, these administrative databases were not designed for epidemiologic studies. We’ve got to do our best to come up with real findings that mean something rather than just torturing the data until something shows up. Critical bits of information are missing from these pictures. We don’t know why a patient might change from one therapy to another, for instance. There are a lot of questions like that, and these are the first things that a clinician needs to know."

Dr. Laurel Habel, a senior researcher at Kaiser Permanente, presented similar findings of no increased cancer risk from glargine exposure. Her study was based on Kaiser’s northern and southern California claims and coding databases. The study group comprised 115,000 patients with diabetes – 100,000 took NPH insulin, 27,000 took glargine, and 12,000 took both. The median follow-up time was 2.3 years for glargine and 3.6 years for NPH.

"We found no evidence of increased prostate or colorectal cancer for glargine users, whether they were new users or whether they had switched to it," she said.

In a time exposure analysis of breast cancer risk, those who had been on glargine at baseline had a "suggestion of a very modest increase in risk, of 1.6." after 24 months. Curiously, she said, there was no risk increase for patients who had been on glargine for at least 2 years after switching from another insulin.

"We can’t think of any biological reason why we would only see this in the new users, so it might be a case of confounding," she said. "None of our results support this hypothesis that short-term use of glargine is associated with any form of cancer."

For prostate and colorectal cancers, there were no significant associations in any of the analyses, or in the time-dependent comparisons

Dr. Til Stürmer of the University of North Carolina at Chapel Hill presented the smallest study, but had results entirely consistent with those of his colleagues. Again, the comparison group of 52,553 patients was drawn from a large healthcare database. Median follow-up was 1.5 years for both the glargine and other insulin groups.

In looking at the relative risks of breast, prostate, colon. and all cancer, Dr. Stürmer found no significant associations with either new glargine users or those who switched medications. Compared with other insulins, glargine had a relative risk of 1.1 for breast cancer, 1.2 for prostate cancer, 0.9 for colon cancer, and 1.1 for all forms of cancer.

"In a subgroup looking at breast cancer stratified by time [0-6 months, 6-12 months, 12-24 months and longer than 24 months] the hazard ratios jumped around the null, but we only had 14 cancers in 4,000 person/years," he added.

All of the registry studies received support from Sanofi. Other than this funding, none of the presenters had any financial declarations relevant to their studies.

PHILADELPHIA – The prevalence of type 2 diabetes, once considered an almost exclusively adult-onset disease, increased by 21% from 2001 to 2009 among Americans younger than 20 years.

The prevalence of type 1 diabetes increased by 23% over the same time period, Dr. Dana Dabelea reported at the annual meeting of the American Diabetes Association.

"Every year, we see about 15,000 new cases of type 1 and 3,700 new cases of type 2 diabetes, and the numbers of children living with these diseases are increasing," she said at a press briefing.

Although type 1 diabetes remains "an extremely rare" and very dangerous condition, evidence continues to emerge that type 2 diabetes is anything but benign, said Dr. Dabelea, a professor of epidemiology at the University of Colorado at Denver, Aurora.

"It’s believed that this increase we’re seeing is making type 2 more and more a pediatric condition," she said. "In youth, this disease is associated with early signs and symptoms of chronic complications that may increase lifelong comorbidities, reduce quality life and life expectancy, and increase health care costs."

Dr. Dabelea and her coinvestigators discussed new data from the SEARCH for Diabetes in Youth study. The registry study was launched in 2000, and is expected to continue at least through 2015. It’s being conducted in five centers in the United States.

The primary aim is to track the prevalence of new diabetes cases, providing the first national picture of the rising epidemic. Subanalyses look at the diseases’ complications and comorbidities, associations between diabetes and lifestyle, and the impact of nutrition on the diseases.

The new data suggest that from 2001 to 2009, almost 189,000 U.S. residents aged younger than 20 years had diabetes (about 168,000 with type 1 and about 19,000 with type 2).

The prevalence of both types of diabetes has increased in both boys and girls and across all races and ethnicities. The prevalence of type 1 in the study population rose from 1.55 per 1,000 in 2001 to 2.03 per 1,000 in 2009, a statistically significant difference. The prevalence of type 2 during that period rose significantly from 2.9 per 10,000 to 3.6 per 10,000.

"Although the proportion was highest in Native Americans and blacks, the increase was also observed in whites and Hispanics," Dr. Dabelea said. "This may suggest that pediatric type 2 diabetes is plateauing in the traditionally high-risk groups, but still increasing in other groups."

SEARCH investigators presented a number of substudy findings at the meeting, including the following:

• Young people with either form of the disease may show signs of impending kidney damage. In a group of 5,000 patients with a 4-year diabetes history, up to 17% had albuminuria. The numbers were highest in children with insulin resistance but no diabetes autoantibodies (17%), and lowest (8%) in those with diabetes autoantibodies who were insulin sensitive.

• Television time seems directly tied to blood glucose and lipid levels in both types of diabetes. In a cohort of 1,400 SEARCH patients aged younger than 10 years, HbA_1c increased as TV time increased. Triglyceride levels were significantly higher in children who watched TV for 3 or more hours each day than in those who watched less.

• Peripheral neuropathy strikes children with diabetes at about the same rate as it does adults. "Our findings suggest that children, adolescents, and young adults with diabetes are not only at risk for diabetic peripheral neuropathy, but that many already show measurable signs of it," the authors noted.

• Among a subset of 222 SEARCH subjects, there were early indications that cardiovascular parasympathetic nerves were impaired, perhaps predisposing children with diabetes to future cardiovascular disease.

SEARCH is being sponsored by the Centers for Disease Control and Prevention and the National Institutes of Health. Dr. Dabelea did not have any financial disclosures.

PHILADELPHIA – The prevalence of type 2 diabetes, once considered an almost exclusively adult-onset disease, increased by 21% from 2001 to 2009 among Americans younger than 20 years.

The prevalence of type 1 diabetes increased by 23% over the same time period, Dr. Dana Dabelea reported at the annual meeting of the American Diabetes Association.

"Every year, we see about 15,000 new cases of type 1 and 3,700 new cases of type 2 diabetes, and the numbers of children living with these diseases are increasing," she said at a press briefing.

Although type 1 diabetes remains "an extremely rare" and very dangerous condition, evidence continues to emerge that type 2 diabetes is anything but benign, said Dr. Dabelea, a professor of epidemiology at the University of Colorado at Denver, Aurora.

"It’s believed that this increase we’re seeing is making type 2 more and more a pediatric condition," she said. "In youth, this disease is associated with early signs and symptoms of chronic complications that may increase lifelong comorbidities, reduce quality life and life expectancy, and increase health care costs."

Dr. Dabelea and her coinvestigators discussed new data from the SEARCH for Diabetes in Youth study. The registry study was launched in 2000, and is expected to continue at least through 2015. It’s being conducted in five centers in the United States.

The primary aim is to track the prevalence of new diabetes cases, providing the first national picture of the rising epidemic. Subanalyses look at the diseases’ complications and comorbidities, associations between diabetes and lifestyle, and the impact of nutrition on the diseases.

The new data suggest that from 2001 to 2009, almost 189,000 U.S. residents aged younger than 20 years had diabetes (about 168,000 with type 1 and about 19,000 with type 2).

The prevalence of both types of diabetes has increased in both boys and girls and across all races and ethnicities. The prevalence of type 1 in the study population rose from 1.55 per 1,000 in 2001 to 2.03 per 1,000 in 2009, a statistically significant difference. The prevalence of type 2 during that period rose significantly from 2.9 per 10,000 to 3.6 per 10,000.

"Although the proportion was highest in Native Americans and blacks, the increase was also observed in whites and Hispanics," Dr. Dabelea said. "This may suggest that pediatric type 2 diabetes is plateauing in the traditionally high-risk groups, but still increasing in other groups."

SEARCH investigators presented a number of substudy findings at the meeting, including the following:

• Young people with either form of the disease may show signs of impending kidney damage. In a group of 5,000 patients with a 4-year diabetes history, up to 17% had albuminuria. The numbers were highest in children with insulin resistance but no diabetes autoantibodies (17%), and lowest (8%) in those with diabetes autoantibodies who were insulin sensitive.

• Television time seems directly tied to blood glucose and lipid levels in both types of diabetes. In a cohort of 1,400 SEARCH patients aged younger than 10 years, HbA_1c increased as TV time increased. Triglyceride levels were significantly higher in children who watched TV for 3 or more hours each day than in those who watched less.

• Peripheral neuropathy strikes children with diabetes at about the same rate as it does adults. "Our findings suggest that children, adolescents, and young adults with diabetes are not only at risk for diabetic peripheral neuropathy, but that many already show measurable signs of it," the authors noted.

• Among a subset of 222 SEARCH subjects, there were early indications that cardiovascular parasympathetic nerves were impaired, perhaps predisposing children with diabetes to future cardiovascular disease.

SEARCH is being sponsored by the Centers for Disease Control and Prevention and the National Institutes of Health. Dr. Dabelea did not have any financial disclosures.

PHILADELPHIA – The prevalence of type 2 diabetes, once considered an almost exclusively adult-onset disease, increased by 21% from 2001 to 2009 among Americans younger than 20 years.

The prevalence of type 1 diabetes increased by 23% over the same time period, Dr. Dana Dabelea reported at the annual meeting of the American Diabetes Association.

"Every year, we see about 15,000 new cases of type 1 and 3,700 new cases of type 2 diabetes, and the numbers of children living with these diseases are increasing," she said at a press briefing.

Although type 1 diabetes remains "an extremely rare" and very dangerous condition, evidence continues to emerge that type 2 diabetes is anything but benign, said Dr. Dabelea, a professor of epidemiology at the University of Colorado at Denver, Aurora.

"It’s believed that this increase we’re seeing is making type 2 more and more a pediatric condition," she said. "In youth, this disease is associated with early signs and symptoms of chronic complications that may increase lifelong comorbidities, reduce quality life and life expectancy, and increase health care costs."

Dr. Dabelea and her coinvestigators discussed new data from the SEARCH for Diabetes in Youth study. The registry study was launched in 2000, and is expected to continue at least through 2015. It’s being conducted in five centers in the United States.

The primary aim is to track the prevalence of new diabetes cases, providing the first national picture of the rising epidemic. Subanalyses look at the diseases’ complications and comorbidities, associations between diabetes and lifestyle, and the impact of nutrition on the diseases.

The new data suggest that from 2001 to 2009, almost 189,000 U.S. residents aged younger than 20 years had diabetes (about 168,000 with type 1 and about 19,000 with type 2).

The prevalence of both types of diabetes has increased in both boys and girls and across all races and ethnicities. The prevalence of type 1 in the study population rose from 1.55 per 1,000 in 2001 to 2.03 per 1,000 in 2009, a statistically significant difference. The prevalence of type 2 during that period rose significantly from 2.9 per 10,000 to 3.6 per 10,000.

"Although the proportion was highest in Native Americans and blacks, the increase was also observed in whites and Hispanics," Dr. Dabelea said. "This may suggest that pediatric type 2 diabetes is plateauing in the traditionally high-risk groups, but still increasing in other groups."

SEARCH investigators presented a number of substudy findings at the meeting, including the following:

• Young people with either form of the disease may show signs of impending kidney damage. In a group of 5,000 patients with a 4-year diabetes history, up to 17% had albuminuria. The numbers were highest in children with insulin resistance but no diabetes autoantibodies (17%), and lowest (8%) in those with diabetes autoantibodies who were insulin sensitive.

• Television time seems directly tied to blood glucose and lipid levels in both types of diabetes. In a cohort of 1,400 SEARCH patients aged younger than 10 years, HbA_1c increased as TV time increased. Triglyceride levels were significantly higher in children who watched TV for 3 or more hours each day than in those who watched less.

• Peripheral neuropathy strikes children with diabetes at about the same rate as it does adults. "Our findings suggest that children, adolescents, and young adults with diabetes are not only at risk for diabetic peripheral neuropathy, but that many already show measurable signs of it," the authors noted.

• Among a subset of 222 SEARCH subjects, there were early indications that cardiovascular parasympathetic nerves were impaired, perhaps predisposing children with diabetes to future cardiovascular disease.

SEARCH is being sponsored by the Centers for Disease Control and Prevention and the National Institutes of Health. Dr. Dabelea did not have any financial disclosures.

PHILADELPHIA – Getting a firm, early grip on blood glucose confers the best chance for durable glycemic control in children with type 2 diabetes.

Any rapid increase in hemoglobin A_1c after initial stabilization probably signals the need to quickly gear up treatment, Dr. Sonia Caprio said at the annual scientific sessions of the American Diabetes Association.

"The best single predictor of treatment failure – regardless of therapy – is baseline [hemoglobin A_1c], even if it’s in the nondiabetic range" after stabilization, said Dr. Caprio, a professor of pediatric endocrinology at Yale University in New Haven, Conn. "A rapidly rising HbA_1c, even if it’s still in the normal range, is associated with failure, and suggests the need for more intense treatment."

These new findings from the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study mean that physicians may need new treatment markers for diabetes regimens in youth, she said. "We need to identify specific thresholds for intensifying therapy, perhaps at diagnosis, perhaps after a certain period of treatment, or when the patient reaches a certain HbA_1c threshold."

Dr. Caprio joined other TODAY investigators in a lively discussion of the study. TODAY’s primary end points were released in April; the ADA presentation not only broke down predictors of treatment failure, but pointed up a disturbing scenario of the medical comorbidities that already haunt children with type 2 diabetes.

Hypertension, enlarged hearts, retinopathy, dyslipidemia, and incipient kidney dysfunction were all common among the 699 children who participated in the study, said Dr. Neil White of Washington University, St. Louis. The problems occurred early and frequently.

"Within 7-8 months after diagnosis, 14% already had nonproliferative retinopathy. That number is similar to the amount found in the Diabetes Prevention Program study, for a population that was an average of 55 years old. These subjects are getting the signs of disease during childhood that older adults have."

TODAY examined three different treatment regimens among 699 children with newly diagnosed type 2 diabetes: metformin alone, metformin plus lifestyle modifications, and metformin plus rosiglitazone (N. Engl. J. Med. 2012 April 29 [doi:10.1056/NEJMoa1109333]).

The 60-month trial started all patients aged 10-17 years on metformin 2,000 mg/day. Randomization occurred after HbA_1c stabilized at 8% or lower with metformin therapy. The primary end point was time to the failure of glycemic control (defined as an HbA_1c of at least 8% for 6 months, or sustained metabolic decompensation that required insulin treatment).

Overall, nearly half of the cohort (46%) failed to maintain glycemic control; the median time to failure was 11 months. However, compared with the combination therapy group, significantly more of those taking metformin alone failed glycemic control (52% vs. 39%). The failure rate in the lifestyle intervention group was 47% – not significantly different from that of the metformin mono- or combination therapy groups.

The new analyses examined predictors of response, and looked at medical comorbidities among the patients. A seemingly innocuous increase in HbA_1c during the initial 6-month stabilization phase was the strongest predictor of whether a child would achieve a durable response to the long-term therapy, said Dr. Kenneth Copeland, a TODAY investigator and the Milburn Endowed Chair of Pediatrics at the University of Oklahoma Health Sciences Center, Oklahoma City.

In a univariate analysis, a number of baseline factors were associated with failure, including race (with blacks doing significantly worse than whites); the presence of depression; lower household income; lower insulinogenic index, and lower HbA_1c.

The baseline difference in HbA_1c was statistically significant, but still apparently small, he said. After initial stabilization, those who maintained and failed control still had blood glucose levels in the nondiabetic range (5.7% vs. 6.4%)

But in a multivariate model, only baseline HbA_1c strongly predicted response to long-term therapy. Those who maintained glucose control had very moderate HbA_1c increases, from a median of 6.4% to about 7% by the end of the study. Those who failed therapy had a much steeper increase, rising from 5.7% at baseline to about 7.3% at the end.

"Baseline HbA_1c appears to be the best predictor of failure, regardless of whether it is still in the nondiabetic range. A rapidly rising level – even in the normal range – is associated with incipient failure and may suggest the need to intensify treatment early."

The increases in blood sugar that arose during stabilization and treatment probably signaled beta-cell decline in an increasingly stressed pancreas, Dr. Caprio said. The analysis used two algorithms to assess beta-cell function: the insulinogenic index (the difference in blood glucose before and after insulin administration) and the oral disposition index (a measure of beta-cell function relative to insulin). The baseline for this analysis was the point of randomization, when glucose was stabilized at 8% or lower after 6 months of treatment.

"At 6 months, we saw a dramatic difference between the rosiglitazone/metformin arm and the other arms," with a 20% increase in insulin sensitivity compared with no change in the other groups. Thereafter, however, insulin sensitivity started to decrease in the rosiglitazone group, until it plateaued.

By the end of the study, beta-cell function was also similar between the groups, but those in the rosiglitazone group showed a slower decline during the treatment period. This indicated that rosiglitazone was able to stabilize function for at least a period of time. "In contrast, we saw a dramatic fall-off in the beta-cell function in the other two groups, although by 24 months there were no differences among any of them."

"The favorable changes relative to insulin sensitivity were responsible for the observed reduced failure rate in the rosiglitazone group; telling is that this profound degree of insulin resistance in obese youth with type 2 diabetes is unresponsive to the effect of metformin, alone or with lifestyle therapy," Dr. Caprio said.

Because metformin failed those children, the better alternative appears to be more aggressive treatment early in the disease. "The introduction of such aggressive therapy early in the course of the disease appears to slow the decline of beta-cell adaptation and improve the chance or durable control."

Children in TODAY were plagued with much the same medical issues as are adults with type 2 diabetes, said Dr. Neil White, chairman of the TODAY data safety and monitoring committee.

The subjects had a very short duration of diabetes, having been diagnosed 5-7 months before the metformin stabilization period. At that point, 34% already had hypertension. Abnormal LDL cholesterol levels were present in 10%, and high triglycerides in 54%. Some 20% had microalbuminuria, suggesting possible progression to kidney disease.

All of the children, regardless of their treatment group or outcome, showed somewhat abnormal left ventricular and right auricular measurements, noted Dr. White, who is also director of the pediatric clinical research unit at Washington University.

Echocardiography showed that the children had a left auricular diameter of up to 2.4 cm/m height, greater than the population median. All also had a left ventricular mass greater than the population median of 30 g/m², with some reaching almost 45 g/m².

"These youngsters had big hearts that are going to predispose them to heart disease in the future," Dr. White said.

At the end of the study, most children (523) underwent fundus photography to evaluate retinopathy. About 14% of them had some degree of nonproliferative retinopathy, putting the young group’s prevalence squarely in line with prevalence in adults with type 2 diabetes.

"This profound insulin resistance was a culprit ... against which metformin had no effect at all," Dr. Caprio said. "Even with the two best drugs we had at the time of this study – metformin and rosiglitazone – we were not able to improve outcomes in 50% of these kids."

Dr. Copeland agreed.

"The finding that 50% of our children failed therapy indicates that this is an incredibly tough disease to treat by any modality we have. Our target as a society needs to be ‘How do we prevent diabetes in children?’ because once they get it, it’s going to be really tough to intervene effectively."

TODAY was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. All of the presenters disclosed financial relationships with Daiichi Sankyo, but said these were not relevant to the TODAY study.

PHILADELPHIA – Getting a firm, early grip on blood glucose confers the best chance for durable glycemic control in children with type 2 diabetes.

Any rapid increase in hemoglobin A_1c after initial stabilization probably signals the need to quickly gear up treatment, Dr. Sonia Caprio said at the annual scientific sessions of the American Diabetes Association.

"The best single predictor of treatment failure – regardless of therapy – is baseline [hemoglobin A_1c], even if it’s in the nondiabetic range" after stabilization, said Dr. Caprio, a professor of pediatric endocrinology at Yale University in New Haven, Conn. "A rapidly rising HbA_1c, even if it’s still in the normal range, is associated with failure, and suggests the need for more intense treatment."

These new findings from the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study mean that physicians may need new treatment markers for diabetes regimens in youth, she said. "We need to identify specific thresholds for intensifying therapy, perhaps at diagnosis, perhaps after a certain period of treatment, or when the patient reaches a certain HbA_1c threshold."

Dr. Caprio joined other TODAY investigators in a lively discussion of the study. TODAY’s primary end points were released in April; the ADA presentation not only broke down predictors of treatment failure, but pointed up a disturbing scenario of the medical comorbidities that already haunt children with type 2 diabetes.

Hypertension, enlarged hearts, retinopathy, dyslipidemia, and incipient kidney dysfunction were all common among the 699 children who participated in the study, said Dr. Neil White of Washington University, St. Louis. The problems occurred early and frequently.

"Within 7-8 months after diagnosis, 14% already had nonproliferative retinopathy. That number is similar to the amount found in the Diabetes Prevention Program study, for a population that was an average of 55 years old. These subjects are getting the signs of disease during childhood that older adults have."

TODAY examined three different treatment regimens among 699 children with newly diagnosed type 2 diabetes: metformin alone, metformin plus lifestyle modifications, and metformin plus rosiglitazone (N. Engl. J. Med. 2012 April 29 [doi:10.1056/NEJMoa1109333]).

The 60-month trial started all patients aged 10-17 years on metformin 2,000 mg/day. Randomization occurred after HbA_1c stabilized at 8% or lower with metformin therapy. The primary end point was time to the failure of glycemic control (defined as an HbA_1c of at least 8% for 6 months, or sustained metabolic decompensation that required insulin treatment).

Overall, nearly half of the cohort (46%) failed to maintain glycemic control; the median time to failure was 11 months. However, compared with the combination therapy group, significantly more of those taking metformin alone failed glycemic control (52% vs. 39%). The failure rate in the lifestyle intervention group was 47% – not significantly different from that of the metformin mono- or combination therapy groups.

The new analyses examined predictors of response, and looked at medical comorbidities among the patients. A seemingly innocuous increase in HbA_1c during the initial 6-month stabilization phase was the strongest predictor of whether a child would achieve a durable response to the long-term therapy, said Dr. Kenneth Copeland, a TODAY investigator and the Milburn Endowed Chair of Pediatrics at the University of Oklahoma Health Sciences Center, Oklahoma City.

In a univariate analysis, a number of baseline factors were associated with failure, including race (with blacks doing significantly worse than whites); the presence of depression; lower household income; lower insulinogenic index, and lower HbA_1c.

The baseline difference in HbA_1c was statistically significant, but still apparently small, he said. After initial stabilization, those who maintained and failed control still had blood glucose levels in the nondiabetic range (5.7% vs. 6.4%)

But in a multivariate model, only baseline HbA_1c strongly predicted response to long-term therapy. Those who maintained glucose control had very moderate HbA_1c increases, from a median of 6.4% to about 7% by the end of the study. Those who failed therapy had a much steeper increase, rising from 5.7% at baseline to about 7.3% at the end.

"Baseline HbA_1c appears to be the best predictor of failure, regardless of whether it is still in the nondiabetic range. A rapidly rising level – even in the normal range – is associated with incipient failure and may suggest the need to intensify treatment early."

The increases in blood sugar that arose during stabilization and treatment probably signaled beta-cell decline in an increasingly stressed pancreas, Dr. Caprio said. The analysis used two algorithms to assess beta-cell function: the insulinogenic index (the difference in blood glucose before and after insulin administration) and the oral disposition index (a measure of beta-cell function relative to insulin). The baseline for this analysis was the point of randomization, when glucose was stabilized at 8% or lower after 6 months of treatment.

"At 6 months, we saw a dramatic difference between the rosiglitazone/metformin arm and the other arms," with a 20% increase in insulin sensitivity compared with no change in the other groups. Thereafter, however, insulin sensitivity started to decrease in the rosiglitazone group, until it plateaued.

By the end of the study, beta-cell function was also similar between the groups, but those in the rosiglitazone group showed a slower decline during the treatment period. This indicated that rosiglitazone was able to stabilize function for at least a period of time. "In contrast, we saw a dramatic fall-off in the beta-cell function in the other two groups, although by 24 months there were no differences among any of them."

"The favorable changes relative to insulin sensitivity were responsible for the observed reduced failure rate in the rosiglitazone group; telling is that this profound degree of insulin resistance in obese youth with type 2 diabetes is unresponsive to the effect of metformin, alone or with lifestyle therapy," Dr. Caprio said.

Because metformin failed those children, the better alternative appears to be more aggressive treatment early in the disease. "The introduction of such aggressive therapy early in the course of the disease appears to slow the decline of beta-cell adaptation and improve the chance or durable control."

Children in TODAY were plagued with much the same medical issues as are adults with type 2 diabetes, said Dr. Neil White, chairman of the TODAY data safety and monitoring committee.

The subjects had a very short duration of diabetes, having been diagnosed 5-7 months before the metformin stabilization period. At that point, 34% already had hypertension. Abnormal LDL cholesterol levels were present in 10%, and high triglycerides in 54%. Some 20% had microalbuminuria, suggesting possible progression to kidney disease.

All of the children, regardless of their treatment group or outcome, showed somewhat abnormal left ventricular and right auricular measurements, noted Dr. White, who is also director of the pediatric clinical research unit at Washington University.

Echocardiography showed that the children had a left auricular diameter of up to 2.4 cm/m height, greater than the population median. All also had a left ventricular mass greater than the population median of 30 g/m², with some reaching almost 45 g/m².

"These youngsters had big hearts that are going to predispose them to heart disease in the future," Dr. White said.

At the end of the study, most children (523) underwent fundus photography to evaluate retinopathy. About 14% of them had some degree of nonproliferative retinopathy, putting the young group’s prevalence squarely in line with prevalence in adults with type 2 diabetes.

"This profound insulin resistance was a culprit ... against which metformin had no effect at all," Dr. Caprio said. "Even with the two best drugs we had at the time of this study – metformin and rosiglitazone – we were not able to improve outcomes in 50% of these kids."

Dr. Copeland agreed.

"The finding that 50% of our children failed therapy indicates that this is an incredibly tough disease to treat by any modality we have. Our target as a society needs to be ‘How do we prevent diabetes in children?’ because once they get it, it’s going to be really tough to intervene effectively."

TODAY was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. All of the presenters disclosed financial relationships with Daiichi Sankyo, but said these were not relevant to the TODAY study.

PHILADELPHIA – Getting a firm, early grip on blood glucose confers the best chance for durable glycemic control in children with type 2 diabetes.

Any rapid increase in hemoglobin A_1c after initial stabilization probably signals the need to quickly gear up treatment, Dr. Sonia Caprio said at the annual scientific sessions of the American Diabetes Association.

"The best single predictor of treatment failure – regardless of therapy – is baseline [hemoglobin A_1c], even if it’s in the nondiabetic range" after stabilization, said Dr. Caprio, a professor of pediatric endocrinology at Yale University in New Haven, Conn. "A rapidly rising HbA_1c, even if it’s still in the normal range, is associated with failure, and suggests the need for more intense treatment."

These new findings from the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study mean that physicians may need new treatment markers for diabetes regimens in youth, she said. "We need to identify specific thresholds for intensifying therapy, perhaps at diagnosis, perhaps after a certain period of treatment, or when the patient reaches a certain HbA_1c threshold."

Dr. Caprio joined other TODAY investigators in a lively discussion of the study. TODAY’s primary end points were released in April; the ADA presentation not only broke down predictors of treatment failure, but pointed up a disturbing scenario of the medical comorbidities that already haunt children with type 2 diabetes.

Hypertension, enlarged hearts, retinopathy, dyslipidemia, and incipient kidney dysfunction were all common among the 699 children who participated in the study, said Dr. Neil White of Washington University, St. Louis. The problems occurred early and frequently.

"Within 7-8 months after diagnosis, 14% already had nonproliferative retinopathy. That number is similar to the amount found in the Diabetes Prevention Program study, for a population that was an average of 55 years old. These subjects are getting the signs of disease during childhood that older adults have."

TODAY examined three different treatment regimens among 699 children with newly diagnosed type 2 diabetes: metformin alone, metformin plus lifestyle modifications, and metformin plus rosiglitazone (N. Engl. J. Med. 2012 April 29 [doi:10.1056/NEJMoa1109333]).

The 60-month trial started all patients aged 10-17 years on metformin 2,000 mg/day. Randomization occurred after HbA_1c stabilized at 8% or lower with metformin therapy. The primary end point was time to the failure of glycemic control (defined as an HbA_1c of at least 8% for 6 months, or sustained metabolic decompensation that required insulin treatment).

Overall, nearly half of the cohort (46%) failed to maintain glycemic control; the median time to failure was 11 months. However, compared with the combination therapy group, significantly more of those taking metformin alone failed glycemic control (52% vs. 39%). The failure rate in the lifestyle intervention group was 47% – not significantly different from that of the metformin mono- or combination therapy groups.

The new analyses examined predictors of response, and looked at medical comorbidities among the patients. A seemingly innocuous increase in HbA_1c during the initial 6-month stabilization phase was the strongest predictor of whether a child would achieve a durable response to the long-term therapy, said Dr. Kenneth Copeland, a TODAY investigator and the Milburn Endowed Chair of Pediatrics at the University of Oklahoma Health Sciences Center, Oklahoma City.

In a univariate analysis, a number of baseline factors were associated with failure, including race (with blacks doing significantly worse than whites); the presence of depression; lower household income; lower insulinogenic index, and lower HbA_1c.

The baseline difference in HbA_1c was statistically significant, but still apparently small, he said. After initial stabilization, those who maintained and failed control still had blood glucose levels in the nondiabetic range (5.7% vs. 6.4%)

But in a multivariate model, only baseline HbA_1c strongly predicted response to long-term therapy. Those who maintained glucose control had very moderate HbA_1c increases, from a median of 6.4% to about 7% by the end of the study. Those who failed therapy had a much steeper increase, rising from 5.7% at baseline to about 7.3% at the end.

"Baseline HbA_1c appears to be the best predictor of failure, regardless of whether it is still in the nondiabetic range. A rapidly rising level – even in the normal range – is associated with incipient failure and may suggest the need to intensify treatment early."

The increases in blood sugar that arose during stabilization and treatment probably signaled beta-cell decline in an increasingly stressed pancreas, Dr. Caprio said. The analysis used two algorithms to assess beta-cell function: the insulinogenic index (the difference in blood glucose before and after insulin administration) and the oral disposition index (a measure of beta-cell function relative to insulin). The baseline for this analysis was the point of randomization, when glucose was stabilized at 8% or lower after 6 months of treatment.

"At 6 months, we saw a dramatic difference between the rosiglitazone/metformin arm and the other arms," with a 20% increase in insulin sensitivity compared with no change in the other groups. Thereafter, however, insulin sensitivity started to decrease in the rosiglitazone group, until it plateaued.

By the end of the study, beta-cell function was also similar between the groups, but those in the rosiglitazone group showed a slower decline during the treatment period. This indicated that rosiglitazone was able to stabilize function for at least a period of time. "In contrast, we saw a dramatic fall-off in the beta-cell function in the other two groups, although by 24 months there were no differences among any of them."

"The favorable changes relative to insulin sensitivity were responsible for the observed reduced failure rate in the rosiglitazone group; telling is that this profound degree of insulin resistance in obese youth with type 2 diabetes is unresponsive to the effect of metformin, alone or with lifestyle therapy," Dr. Caprio said.

Because metformin failed those children, the better alternative appears to be more aggressive treatment early in the disease. "The introduction of such aggressive therapy early in the course of the disease appears to slow the decline of beta-cell adaptation and improve the chance or durable control."

Children in TODAY were plagued with much the same medical issues as are adults with type 2 diabetes, said Dr. Neil White, chairman of the TODAY data safety and monitoring committee.

The subjects had a very short duration of diabetes, having been diagnosed 5-7 months before the metformin stabilization period. At that point, 34% already had hypertension. Abnormal LDL cholesterol levels were present in 10%, and high triglycerides in 54%. Some 20% had microalbuminuria, suggesting possible progression to kidney disease.

All of the children, regardless of their treatment group or outcome, showed somewhat abnormal left ventricular and right auricular measurements, noted Dr. White, who is also director of the pediatric clinical research unit at Washington University.

Echocardiography showed that the children had a left auricular diameter of up to 2.4 cm/m height, greater than the population median. All also had a left ventricular mass greater than the population median of 30 g/m², with some reaching almost 45 g/m².

"These youngsters had big hearts that are going to predispose them to heart disease in the future," Dr. White said.

At the end of the study, most children (523) underwent fundus photography to evaluate retinopathy. About 14% of them had some degree of nonproliferative retinopathy, putting the young group’s prevalence squarely in line with prevalence in adults with type 2 diabetes.

"This profound insulin resistance was a culprit ... against which metformin had no effect at all," Dr. Caprio said. "Even with the two best drugs we had at the time of this study – metformin and rosiglitazone – we were not able to improve outcomes in 50% of these kids."

Dr. Copeland agreed.

"The finding that 50% of our children failed therapy indicates that this is an incredibly tough disease to treat by any modality we have. Our target as a society needs to be ‘How do we prevent diabetes in children?’ because once they get it, it’s going to be really tough to intervene effectively."

TODAY was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. All of the presenters disclosed financial relationships with Daiichi Sankyo, but said these were not relevant to the TODAY study.

Combining the investigational drug delamanid with standard tuberculosis treatment significantly increased sputum-culture conversion rates in MDR tuberculosis, an international study demonstrated.

The results could be particularly good news for China, which now has one-quarter of the world’s cases of MDR TB, according to a second study.

In the delamanid study, the conversion proportion was 45% after 2 months of treatment among those who received the new drug plus standard therapy, compared with a 30% rate for standard therapy alone, Dr. Maria T. Gler and her coauthors reported in the June 7 issue of the New England Journal of Medicine.

"It is important to learn more about the use of delamanid in combination with other new and existing antimycobacterial agents to develop better regimens for multidrug-resistant tuberculosis," wrote Dr. Gler, of Makati Medical Center and the Tropical Disease Foundation, Makati City, Philippines, and her colleagues (N. Engl. J. Med. 2012;366:2151-60).

Delamanid, which inhibits mycolic acid synthesis, has shown effectiveness against drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis in preclinical tests.

The team investigated the drug’s effect at 200 mg/day and 400 mg/day, plus a background treatment regimen approved by the World Health Organization for multidrug-resistant (MDR) tuberculosis. A placebo group received only the background treatment – the current standard of care. The 2-month study was carried out in nine countries: China, Egypt, Estonia, Japan, Korea, Latvia, Peru, the Philippines, and the United States.

The study group included 481 patients with sputum culture–proven MDR tuberculosis infections. The patients’ mean age was 35 years. More than 90% of the group had received prior treatment for tuberculosis, including 50% who had already taken only first-line antitubercular agents and 40% who had received a second- or third-line agent. Only four of the patients were coinfected with HIV.

By the end of 2 months, both groups receiving delamanid had significantly higher proportions of sputum-culture conversion than the placebo groups. Similar conversion proportions occurred in both active groups: 45% of the 200-mg/day delamanid group, and 42% of the 400-mg/day group. Conversion in the placebo group (30%) was significantly less than in both of the active groups.

Time to conversion also differed significantly between the active and placebo groups, with conversion proportions beginning to separate by 30 days of treatment.

There were more adverse events in the delamanid groups, although the investigators found that only the incidence of QT prolongation was significantly less in the placebo group (4%) than in the 200- and 400-mg/day delamanid groups (10% and 13%, respectively). None of the arrhythmias were clinically significant, they noted.

There were no between-group differences in the rate of hepatotoxicity. One patient died from tuberculosis during the trial.

A longer trial is underway to more closely examine delamanid’s effect on the hard-to-treat disease in patients taking antiretroviral drugs for HIV infections.

MDR Need Greatest in China

Finding an effective treatment for MDR tuberculosis is especially important in China, which has the greatest number of cases in the world, Yanlin Zhao, Ph.D., reported in an accompanying study (N. Engl. J. Med. 2012;366:2161-70).

Dr. Zhao, of the Chinese Center for Disease Control and Prevention, and colleagues reported on a national disease survey conducted in 2007. The survey showed that about 110,000 MDR cases were reported that year, and that 8,200 showed extensive drug resistance (XDR) – defined as resistance to isoniazid, rifampin, ofloxacin, and kanamycin.

China’s prevalence rate of multidrug resistance among new cases of tuberculosis was 3.5 times greater than the global median, and nearly twice the global average.

"With the use of the World Health Organization estimate of multidrug-resistant tuberculosis in various countries as a reference, China has the highest annual number of cases of MDR tuberculosis in the world – a quarter of the cases worldwide," the authors wrote.

A numbers of factors were linked to drug-resistant disease. Patients with multiple previous treatments – with the most recent taken in a tuberculosis hospital – were at the highest risk.

Poor compliance also influenced drug resistance. In a subanalysis of 226 patients who had received prior treatment, 44% had not completed their prior regimen. Among the 127 patients who had completed treatment, 115 had relapsed TB, and 62% had received that last treatment in the Chinese Center for Disease Control (CDC) system.

"This finding points to the need for interventions that will increase the continuity of treatment and reduce the rate of treatment default, especially among patients treated within the hospital system," the authors noted.

Because national facilities provide limited follow-up, the Chinese Ministry of Health has strengthened the hospitals’ follow-up capabilities, the investigators added.

More needs to be done, however, they noted. China’s CDC system, which is responsible for monitoring patients with tuberculosis in the community, could test new approaches to improving adherence to treatment, such as mobile-phone text messaging, and expand such approaches if they prove to be effective.

Improvements are imperative, the study authors cautioned, as the future does not bode well. About 11% of new cases and 16% of previously treated cases are already resistant to either isoniazid or rifampin, "placing them one step away from having MDR tuberculosis."

In addition, in patients with MDR but not XDR tuberculosis, more than one-third of cases were resistant to either ofloxacin or kanamycin – leaving those patients also just one step away from XDR tuberculosis.

Dr. Gler has received consulting fees from Otsuka Novel Products, the company that sponsored the trial. Neither Dr. Zhao nor any of the coauthors had any financial disclosures.

Combining the investigational drug delamanid with standard tuberculosis treatment significantly increased sputum-culture conversion rates in MDR tuberculosis, an international study demonstrated.

The results could be particularly good news for China, which now has one-quarter of the world’s cases of MDR TB, according to a second study.

In the delamanid study, the conversion proportion was 45% after 2 months of treatment among those who received the new drug plus standard therapy, compared with a 30% rate for standard therapy alone, Dr. Maria T. Gler and her coauthors reported in the June 7 issue of the New England Journal of Medicine.

"It is important to learn more about the use of delamanid in combination with other new and existing antimycobacterial agents to develop better regimens for multidrug-resistant tuberculosis," wrote Dr. Gler, of Makati Medical Center and the Tropical Disease Foundation, Makati City, Philippines, and her colleagues (N. Engl. J. Med. 2012;366:2151-60).

Delamanid, which inhibits mycolic acid synthesis, has shown effectiveness against drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis in preclinical tests.

The team investigated the drug’s effect at 200 mg/day and 400 mg/day, plus a background treatment regimen approved by the World Health Organization for multidrug-resistant (MDR) tuberculosis. A placebo group received only the background treatment – the current standard of care. The 2-month study was carried out in nine countries: China, Egypt, Estonia, Japan, Korea, Latvia, Peru, the Philippines, and the United States.

The study group included 481 patients with sputum culture–proven MDR tuberculosis infections. The patients’ mean age was 35 years. More than 90% of the group had received prior treatment for tuberculosis, including 50% who had already taken only first-line antitubercular agents and 40% who had received a second- or third-line agent. Only four of the patients were coinfected with HIV.

By the end of 2 months, both groups receiving delamanid had significantly higher proportions of sputum-culture conversion than the placebo groups. Similar conversion proportions occurred in both active groups: 45% of the 200-mg/day delamanid group, and 42% of the 400-mg/day group. Conversion in the placebo group (30%) was significantly less than in both of the active groups.

Time to conversion also differed significantly between the active and placebo groups, with conversion proportions beginning to separate by 30 days of treatment.

There were more adverse events in the delamanid groups, although the investigators found that only the incidence of QT prolongation was significantly less in the placebo group (4%) than in the 200- and 400-mg/day delamanid groups (10% and 13%, respectively). None of the arrhythmias were clinically significant, they noted.

There were no between-group differences in the rate of hepatotoxicity. One patient died from tuberculosis during the trial.

A longer trial is underway to more closely examine delamanid’s effect on the hard-to-treat disease in patients taking antiretroviral drugs for HIV infections.

MDR Need Greatest in China

Finding an effective treatment for MDR tuberculosis is especially important in China, which has the greatest number of cases in the world, Yanlin Zhao, Ph.D., reported in an accompanying study (N. Engl. J. Med. 2012;366:2161-70).

Dr. Zhao, of the Chinese Center for Disease Control and Prevention, and colleagues reported on a national disease survey conducted in 2007. The survey showed that about 110,000 MDR cases were reported that year, and that 8,200 showed extensive drug resistance (XDR) – defined as resistance to isoniazid, rifampin, ofloxacin, and kanamycin.

China’s prevalence rate of multidrug resistance among new cases of tuberculosis was 3.5 times greater than the global median, and nearly twice the global average.

"With the use of the World Health Organization estimate of multidrug-resistant tuberculosis in various countries as a reference, China has the highest annual number of cases of MDR tuberculosis in the world – a quarter of the cases worldwide," the authors wrote.

A numbers of factors were linked to drug-resistant disease. Patients with multiple previous treatments – with the most recent taken in a tuberculosis hospital – were at the highest risk.

Poor compliance also influenced drug resistance. In a subanalysis of 226 patients who had received prior treatment, 44% had not completed their prior regimen. Among the 127 patients who had completed treatment, 115 had relapsed TB, and 62% had received that last treatment in the Chinese Center for Disease Control (CDC) system.

"This finding points to the need for interventions that will increase the continuity of treatment and reduce the rate of treatment default, especially among patients treated within the hospital system," the authors noted.

Because national facilities provide limited follow-up, the Chinese Ministry of Health has strengthened the hospitals’ follow-up capabilities, the investigators added.

More needs to be done, however, they noted. China’s CDC system, which is responsible for monitoring patients with tuberculosis in the community, could test new approaches to improving adherence to treatment, such as mobile-phone text messaging, and expand such approaches if they prove to be effective.

Improvements are imperative, the study authors cautioned, as the future does not bode well. About 11% of new cases and 16% of previously treated cases are already resistant to either isoniazid or rifampin, "placing them one step away from having MDR tuberculosis."

In addition, in patients with MDR but not XDR tuberculosis, more than one-third of cases were resistant to either ofloxacin or kanamycin – leaving those patients also just one step away from XDR tuberculosis.

Dr. Gler has received consulting fees from Otsuka Novel Products, the company that sponsored the trial. Neither Dr. Zhao nor any of the coauthors had any financial disclosures.

Combining the investigational drug delamanid with standard tuberculosis treatment significantly increased sputum-culture conversion rates in MDR tuberculosis, an international study demonstrated.

The results could be particularly good news for China, which now has one-quarter of the world’s cases of MDR TB, according to a second study.

In the delamanid study, the conversion proportion was 45% after 2 months of treatment among those who received the new drug plus standard therapy, compared with a 30% rate for standard therapy alone, Dr. Maria T. Gler and her coauthors reported in the June 7 issue of the New England Journal of Medicine.

"It is important to learn more about the use of delamanid in combination with other new and existing antimycobacterial agents to develop better regimens for multidrug-resistant tuberculosis," wrote Dr. Gler, of Makati Medical Center and the Tropical Disease Foundation, Makati City, Philippines, and her colleagues (N. Engl. J. Med. 2012;366:2151-60).

Delamanid, which inhibits mycolic acid synthesis, has shown effectiveness against drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis in preclinical tests.

The team investigated the drug’s effect at 200 mg/day and 400 mg/day, plus a background treatment regimen approved by the World Health Organization for multidrug-resistant (MDR) tuberculosis. A placebo group received only the background treatment – the current standard of care. The 2-month study was carried out in nine countries: China, Egypt, Estonia, Japan, Korea, Latvia, Peru, the Philippines, and the United States.

The study group included 481 patients with sputum culture–proven MDR tuberculosis infections. The patients’ mean age was 35 years. More than 90% of the group had received prior treatment for tuberculosis, including 50% who had already taken only first-line antitubercular agents and 40% who had received a second- or third-line agent. Only four of the patients were coinfected with HIV.

By the end of 2 months, both groups receiving delamanid had significantly higher proportions of sputum-culture conversion than the placebo groups. Similar conversion proportions occurred in both active groups: 45% of the 200-mg/day delamanid group, and 42% of the 400-mg/day group. Conversion in the placebo group (30%) was significantly less than in both of the active groups.

Time to conversion also differed significantly between the active and placebo groups, with conversion proportions beginning to separate by 30 days of treatment.

There were more adverse events in the delamanid groups, although the investigators found that only the incidence of QT prolongation was significantly less in the placebo group (4%) than in the 200- and 400-mg/day delamanid groups (10% and 13%, respectively). None of the arrhythmias were clinically significant, they noted.

There were no between-group differences in the rate of hepatotoxicity. One patient died from tuberculosis during the trial.

A longer trial is underway to more closely examine delamanid’s effect on the hard-to-treat disease in patients taking antiretroviral drugs for HIV infections.

MDR Need Greatest in China

Finding an effective treatment for MDR tuberculosis is especially important in China, which has the greatest number of cases in the world, Yanlin Zhao, Ph.D., reported in an accompanying study (N. Engl. J. Med. 2012;366:2161-70).

Dr. Zhao, of the Chinese Center for Disease Control and Prevention, and colleagues reported on a national disease survey conducted in 2007. The survey showed that about 110,000 MDR cases were reported that year, and that 8,200 showed extensive drug resistance (XDR) – defined as resistance to isoniazid, rifampin, ofloxacin, and kanamycin.

China’s prevalence rate of multidrug resistance among new cases of tuberculosis was 3.5 times greater than the global median, and nearly twice the global average.

"With the use of the World Health Organization estimate of multidrug-resistant tuberculosis in various countries as a reference, China has the highest annual number of cases of MDR tuberculosis in the world – a quarter of the cases worldwide," the authors wrote.

A numbers of factors were linked to drug-resistant disease. Patients with multiple previous treatments – with the most recent taken in a tuberculosis hospital – were at the highest risk.

Poor compliance also influenced drug resistance. In a subanalysis of 226 patients who had received prior treatment, 44% had not completed their prior regimen. Among the 127 patients who had completed treatment, 115 had relapsed TB, and 62% had received that last treatment in the Chinese Center for Disease Control (CDC) system.

"This finding points to the need for interventions that will increase the continuity of treatment and reduce the rate of treatment default, especially among patients treated within the hospital system," the authors noted.

Because national facilities provide limited follow-up, the Chinese Ministry of Health has strengthened the hospitals’ follow-up capabilities, the investigators added.

More needs to be done, however, they noted. China’s CDC system, which is responsible for monitoring patients with tuberculosis in the community, could test new approaches to improving adherence to treatment, such as mobile-phone text messaging, and expand such approaches if they prove to be effective.

Improvements are imperative, the study authors cautioned, as the future does not bode well. About 11% of new cases and 16% of previously treated cases are already resistant to either isoniazid or rifampin, "placing them one step away from having MDR tuberculosis."

In addition, in patients with MDR but not XDR tuberculosis, more than one-third of cases were resistant to either ofloxacin or kanamycin – leaving those patients also just one step away from XDR tuberculosis.

Dr. Gler has received consulting fees from Otsuka Novel Products, the company that sponsored the trial. Neither Dr. Zhao nor any of the coauthors had any financial disclosures.

ATLANTA – Children who are exposed to secondhand tobacco smoke have an increased risk of urinary urgency, frequency, and incontinence, prospective data from a small study have shown.

Among children with these bladder symptoms, 28% were exposed to tobacco smoke on a daily basis – 13% higher than the overall child exposure rate in New Jersey, Dr. Kelly Johnson said at the annual meeting of the American Urological Association.

In addition to irritating a child’s bladder, childhood exposure to tobacco smoke is directly linked to the development of bladder cancer as an adult, she said in a press briefing.

Dr. Johnson, chief urology resident at the Robert Wood Johnson University Hospital, New Brunswick, N.J., presented prospective data on 45 children, aged 4-17 years, who presented with irritative bladder symptoms – frequency, urgency, and incontinence.

She used the Harvard Children’s Health and the Children’s Neurotoxicant Exposure studies to classify tobacco smoke exposure. The patients’ symptom severity was scored with the Dysfunctional Voiding Scoring System and classified as very mild, mild, Drmoderate, or severe.

About half of the group (21) had very mild or mild symptoms, while the remainder had symptoms scored as moderate or severe.

None of the children with mild scores were exposed to secondhand smoke on a daily basis, and none had mothers who smoked. However, 23% of those with moderate to severe scores had mothers who smoked, and 50% were exposed to smoke in a car on a regular basis.

"On our measures of environmental tobacco smoke exposure, children with greater exposure had significantly higher symptom severity scores than children who weren’t exposed," Dr. Johnson said. "This relationship was particularly striking for the younger children aged 4-10 years old."

Physicians who see children with bladder dysfunction should ask parents about smoke exposure, she advised – not only because of its effect on the current problems, but because of its proven dangers as the child grows up.

"Tobacco smoke contains chemicals that are known bladder irritants in both children and adults, and European studies have shown a strong relationship between adult bladder cancer and childhood tobacco smoke exposure.

The discussion of a child’s urinary symptoms provides a very good opportunity to speak to parents about smoking cessation, she added.

"It’s a teachable moment," that can have a long-lasting positive impact on both the child and the parent. "Unlike other risky behaviors, which affect only the person who engages in them, smoking poses substantial health risks to those not involved in the process," she said.

Dr. Johnson said she had had no relevant financial disclosures.

ATLANTA – Children who are exposed to secondhand tobacco smoke have an increased risk of urinary urgency, frequency, and incontinence, prospective data from a small study have shown.

Among children with these bladder symptoms, 28% were exposed to tobacco smoke on a daily basis – 13% higher than the overall child exposure rate in New Jersey, Dr. Kelly Johnson said at the annual meeting of the American Urological Association.

In addition to irritating a child’s bladder, childhood exposure to tobacco smoke is directly linked to the development of bladder cancer as an adult, she said in a press briefing.

Dr. Johnson, chief urology resident at the Robert Wood Johnson University Hospital, New Brunswick, N.J., presented prospective data on 45 children, aged 4-17 years, who presented with irritative bladder symptoms – frequency, urgency, and incontinence.

She used the Harvard Children’s Health and the Children’s Neurotoxicant Exposure studies to classify tobacco smoke exposure. The patients’ symptom severity was scored with the Dysfunctional Voiding Scoring System and classified as very mild, mild, Drmoderate, or severe.

About half of the group (21) had very mild or mild symptoms, while the remainder had symptoms scored as moderate or severe.

None of the children with mild scores were exposed to secondhand smoke on a daily basis, and none had mothers who smoked. However, 23% of those with moderate to severe scores had mothers who smoked, and 50% were exposed to smoke in a car on a regular basis.

"On our measures of environmental tobacco smoke exposure, children with greater exposure had significantly higher symptom severity scores than children who weren’t exposed," Dr. Johnson said. "This relationship was particularly striking for the younger children aged 4-10 years old."

Physicians who see children with bladder dysfunction should ask parents about smoke exposure, she advised – not only because of its effect on the current problems, but because of its proven dangers as the child grows up.

"Tobacco smoke contains chemicals that are known bladder irritants in both children and adults, and European studies have shown a strong relationship between adult bladder cancer and childhood tobacco smoke exposure.

The discussion of a child’s urinary symptoms provides a very good opportunity to speak to parents about smoking cessation, she added.

"It’s a teachable moment," that can have a long-lasting positive impact on both the child and the parent. "Unlike other risky behaviors, which affect only the person who engages in them, smoking poses substantial health risks to those not involved in the process," she said.

Dr. Johnson said she had had no relevant financial disclosures.

ATLANTA – Children who are exposed to secondhand tobacco smoke have an increased risk of urinary urgency, frequency, and incontinence, prospective data from a small study have shown.

Among children with these bladder symptoms, 28% were exposed to tobacco smoke on a daily basis – 13% higher than the overall child exposure rate in New Jersey, Dr. Kelly Johnson said at the annual meeting of the American Urological Association.

In addition to irritating a child’s bladder, childhood exposure to tobacco smoke is directly linked to the development of bladder cancer as an adult, she said in a press briefing.

Dr. Johnson, chief urology resident at the Robert Wood Johnson University Hospital, New Brunswick, N.J., presented prospective data on 45 children, aged 4-17 years, who presented with irritative bladder symptoms – frequency, urgency, and incontinence.

She used the Harvard Children’s Health and the Children’s Neurotoxicant Exposure studies to classify tobacco smoke exposure. The patients’ symptom severity was scored with the Dysfunctional Voiding Scoring System and classified as very mild, mild, Drmoderate, or severe.

About half of the group (21) had very mild or mild symptoms, while the remainder had symptoms scored as moderate or severe.

None of the children with mild scores were exposed to secondhand smoke on a daily basis, and none had mothers who smoked. However, 23% of those with moderate to severe scores had mothers who smoked, and 50% were exposed to smoke in a car on a regular basis.

"On our measures of environmental tobacco smoke exposure, children with greater exposure had significantly higher symptom severity scores than children who weren’t exposed," Dr. Johnson said. "This relationship was particularly striking for the younger children aged 4-10 years old."

Physicians who see children with bladder dysfunction should ask parents about smoke exposure, she advised – not only because of its effect on the current problems, but because of its proven dangers as the child grows up.

"Tobacco smoke contains chemicals that are known bladder irritants in both children and adults, and European studies have shown a strong relationship between adult bladder cancer and childhood tobacco smoke exposure.

The discussion of a child’s urinary symptoms provides a very good opportunity to speak to parents about smoking cessation, she added.

"It’s a teachable moment," that can have a long-lasting positive impact on both the child and the parent. "Unlike other risky behaviors, which affect only the person who engages in them, smoking poses substantial health risks to those not involved in the process," she said.

Dr. Johnson said she had had no relevant financial disclosures.