American Diabetes Association (ADA): Annual Scientific Sessions 2011

SAN DIEGO – Intravenous exenatide appeared to be as effective and safe as IV insulin to treat hyperglycemia patients in the cardiac ICU, but caused nausea in a fifth of patients in a small study.

The prospective, open-label study included 40 adults admitted to the cardiac ICU primarily for cardiac reasons who were treated with IV exenatide for fasting blood glucose levels of 140-400 mg/dL. They were compared with two historical control groups: 39 patients who were admitted to a cardiac ICU in 2009-2010 and treated with IV insulin for blood glucose levels greater than 180 mg/dL, and 94 patients in the cardiac ICU before 2009 who were treated under prior protocols for stricter glycemic control that started insulin for blood glucose levels greater than 140 mg/dL.

The exenatide and recent control groups aimed to maintain glucose levels at 100-140 mg/dL. The pre-2009 control group aimed to maintain glucose levels at 90-119 mg/dL.

Mean glucose levels at admission to the cardiac ICU were 199 mg/dL in the exenatide group, significantly lower than mean levels at admission of 240 mg/dL in the recent control group and 218 mg/dL in the pre-2009 control group.

Exenatide was infused at a fixed dose of 0.05 mcg/min for a 30-minute bolus, then 0.025 mcg/min continuously for 24-48 hours.

It took a mean of 3.9 hours for patients in the exenatide group to achieve a first glucose value of 140 mg/dL or lower, significantly faster than the 9.3 hours required in the recent control group and similar to the 3.5 hours required in the pre-2009 control group, Dr. Steven P. Marso and his associates reported at the annual scientific sessions of the American Diabetes Association.

Mean steady state glucose values were 139 mg/dL in the exenatide group, 147 mg/dL in the recent control group, and 115 mg/dL in the pre-2009 control group, said Dr. Marso of St. Luke’s Cardiovascular Consultants, Kansas City, Mo.

Eight patients developed exenatide-related nausea, and six of these discontinued the drug.

The exenatide group had a lower rate of hypoglycemic events and severe hypoglycemic episodes than the other groups, though the differences were not statistically significant.

Blood glucose levels below 70 mg/dL were seen in 0.9% of 668 measurements in the exenatide group, 1.2% of 745 measurements in the recent control group, and 1.6% of 1,651 measurements in the pre-2009 control group. No patients on exenatide developed severe hypoglycemia (blood glucose less than 50 mg/dL), but this was seen in 0.3% of measurements in the recent control group and in 0.06% in the pre-2009 control group.

The findings show that it’s feasible to treat hyperglycemia in the cardiac ICU with fixed-dose IV exenatide and that results are comparable to those with IV insulin without the risk for severe hypoglycemia, Dr. Marso said. The disadvantage of IV exenatide is the risk for treatment-limited nausea.

He cautioned, however, that this is a small, nonrandomized, proof-of-concept study with no active control group and no long-term clinical follow-up.

A significantly greater proportion of patients in the exenatide group had diabetes (75%), compared with patients in the recent control group (67%).

The study included two historical control groups because recommendations for glycemic control in the ICU setting have changed in recent years. Initial clinical trials showed clinical benefit from intensive glucose control for patients with hyperglycemia in the ICU, but later studies reported higher risks for severe hypoglycemia and death with intensive glucose control in these patients, Dr. Marso said. Updated consensus guidelines subsequently called for less tight glycemic control.

A 2009 consensus statement on inpatient glycemic control from the American Diabetes Association and American Association of Clinical Endocrinologists calls for insulin therapy to be initiated in critically ill patients when blood glucose values drop below 180 mg/dL. Glucose should be maintained between 140-180 mg/dL, and targets less than 100 mg/dL are not recommended (Endocr. Pract. 2009;15:353-69).

The statement says that IV insulin is the preferred treatment and that noninsulin antihyperglycemic agents are not appropriate in most hospitalized patients who require therapy for hyperglycemia. But the potential risks with insulin therapy prompted the current study of IV exenatide.

The study excluded patients who were dependent on a ventilator, unconscious on sedation, who had type 1 diabetes, were pregnant, were post-orthotopic heart transplant, had a creatinine clearance less than 30 mL/min, had a history of pancreatitis, or who were being treated with insulin monotherapy other than long-acting basal insulin (glargine or detemir).

The study was funded by Amylin Pharmaceuticals, which markets exenatide with Lilly. Dr. Marso has been a consultant to, or received research support from, Amylin, Abbott Vascular, The Medicines Company, Novo Nordisk, Volcano, Boston Scientific, and Terumo Medical.

SAN DIEGO – Intravenous exenatide appeared to be as effective and safe as IV insulin to treat hyperglycemia patients in the cardiac ICU, but caused nausea in a fifth of patients in a small study.

The prospective, open-label study included 40 adults admitted to the cardiac ICU primarily for cardiac reasons who were treated with IV exenatide for fasting blood glucose levels of 140-400 mg/dL. They were compared with two historical control groups: 39 patients who were admitted to a cardiac ICU in 2009-2010 and treated with IV insulin for blood glucose levels greater than 180 mg/dL, and 94 patients in the cardiac ICU before 2009 who were treated under prior protocols for stricter glycemic control that started insulin for blood glucose levels greater than 140 mg/dL.

The exenatide and recent control groups aimed to maintain glucose levels at 100-140 mg/dL. The pre-2009 control group aimed to maintain glucose levels at 90-119 mg/dL.

Mean glucose levels at admission to the cardiac ICU were 199 mg/dL in the exenatide group, significantly lower than mean levels at admission of 240 mg/dL in the recent control group and 218 mg/dL in the pre-2009 control group.

Exenatide was infused at a fixed dose of 0.05 mcg/min for a 30-minute bolus, then 0.025 mcg/min continuously for 24-48 hours.

It took a mean of 3.9 hours for patients in the exenatide group to achieve a first glucose value of 140 mg/dL or lower, significantly faster than the 9.3 hours required in the recent control group and similar to the 3.5 hours required in the pre-2009 control group, Dr. Steven P. Marso and his associates reported at the annual scientific sessions of the American Diabetes Association.

Mean steady state glucose values were 139 mg/dL in the exenatide group, 147 mg/dL in the recent control group, and 115 mg/dL in the pre-2009 control group, said Dr. Marso of St. Luke’s Cardiovascular Consultants, Kansas City, Mo.

Eight patients developed exenatide-related nausea, and six of these discontinued the drug.

The exenatide group had a lower rate of hypoglycemic events and severe hypoglycemic episodes than the other groups, though the differences were not statistically significant.

Blood glucose levels below 70 mg/dL were seen in 0.9% of 668 measurements in the exenatide group, 1.2% of 745 measurements in the recent control group, and 1.6% of 1,651 measurements in the pre-2009 control group. No patients on exenatide developed severe hypoglycemia (blood glucose less than 50 mg/dL), but this was seen in 0.3% of measurements in the recent control group and in 0.06% in the pre-2009 control group.

The findings show that it’s feasible to treat hyperglycemia in the cardiac ICU with fixed-dose IV exenatide and that results are comparable to those with IV insulin without the risk for severe hypoglycemia, Dr. Marso said. The disadvantage of IV exenatide is the risk for treatment-limited nausea.

He cautioned, however, that this is a small, nonrandomized, proof-of-concept study with no active control group and no long-term clinical follow-up.

A significantly greater proportion of patients in the exenatide group had diabetes (75%), compared with patients in the recent control group (67%).

The study included two historical control groups because recommendations for glycemic control in the ICU setting have changed in recent years. Initial clinical trials showed clinical benefit from intensive glucose control for patients with hyperglycemia in the ICU, but later studies reported higher risks for severe hypoglycemia and death with intensive glucose control in these patients, Dr. Marso said. Updated consensus guidelines subsequently called for less tight glycemic control.

A 2009 consensus statement on inpatient glycemic control from the American Diabetes Association and American Association of Clinical Endocrinologists calls for insulin therapy to be initiated in critically ill patients when blood glucose values drop below 180 mg/dL. Glucose should be maintained between 140-180 mg/dL, and targets less than 100 mg/dL are not recommended (Endocr. Pract. 2009;15:353-69).

The statement says that IV insulin is the preferred treatment and that noninsulin antihyperglycemic agents are not appropriate in most hospitalized patients who require therapy for hyperglycemia. But the potential risks with insulin therapy prompted the current study of IV exenatide.

The study excluded patients who were dependent on a ventilator, unconscious on sedation, who had type 1 diabetes, were pregnant, were post-orthotopic heart transplant, had a creatinine clearance less than 30 mL/min, had a history of pancreatitis, or who were being treated with insulin monotherapy other than long-acting basal insulin (glargine or detemir).

The study was funded by Amylin Pharmaceuticals, which markets exenatide with Lilly. Dr. Marso has been a consultant to, or received research support from, Amylin, Abbott Vascular, The Medicines Company, Novo Nordisk, Volcano, Boston Scientific, and Terumo Medical.

SAN DIEGO – Intravenous exenatide appeared to be as effective and safe as IV insulin to treat hyperglycemia patients in the cardiac ICU, but caused nausea in a fifth of patients in a small study.

The prospective, open-label study included 40 adults admitted to the cardiac ICU primarily for cardiac reasons who were treated with IV exenatide for fasting blood glucose levels of 140-400 mg/dL. They were compared with two historical control groups: 39 patients who were admitted to a cardiac ICU in 2009-2010 and treated with IV insulin for blood glucose levels greater than 180 mg/dL, and 94 patients in the cardiac ICU before 2009 who were treated under prior protocols for stricter glycemic control that started insulin for blood glucose levels greater than 140 mg/dL.

The exenatide and recent control groups aimed to maintain glucose levels at 100-140 mg/dL. The pre-2009 control group aimed to maintain glucose levels at 90-119 mg/dL.

Mean glucose levels at admission to the cardiac ICU were 199 mg/dL in the exenatide group, significantly lower than mean levels at admission of 240 mg/dL in the recent control group and 218 mg/dL in the pre-2009 control group.

Exenatide was infused at a fixed dose of 0.05 mcg/min for a 30-minute bolus, then 0.025 mcg/min continuously for 24-48 hours.

It took a mean of 3.9 hours for patients in the exenatide group to achieve a first glucose value of 140 mg/dL or lower, significantly faster than the 9.3 hours required in the recent control group and similar to the 3.5 hours required in the pre-2009 control group, Dr. Steven P. Marso and his associates reported at the annual scientific sessions of the American Diabetes Association.

Mean steady state glucose values were 139 mg/dL in the exenatide group, 147 mg/dL in the recent control group, and 115 mg/dL in the pre-2009 control group, said Dr. Marso of St. Luke’s Cardiovascular Consultants, Kansas City, Mo.

Eight patients developed exenatide-related nausea, and six of these discontinued the drug.

The exenatide group had a lower rate of hypoglycemic events and severe hypoglycemic episodes than the other groups, though the differences were not statistically significant.

Blood glucose levels below 70 mg/dL were seen in 0.9% of 668 measurements in the exenatide group, 1.2% of 745 measurements in the recent control group, and 1.6% of 1,651 measurements in the pre-2009 control group. No patients on exenatide developed severe hypoglycemia (blood glucose less than 50 mg/dL), but this was seen in 0.3% of measurements in the recent control group and in 0.06% in the pre-2009 control group.

The findings show that it’s feasible to treat hyperglycemia in the cardiac ICU with fixed-dose IV exenatide and that results are comparable to those with IV insulin without the risk for severe hypoglycemia, Dr. Marso said. The disadvantage of IV exenatide is the risk for treatment-limited nausea.

He cautioned, however, that this is a small, nonrandomized, proof-of-concept study with no active control group and no long-term clinical follow-up.

A significantly greater proportion of patients in the exenatide group had diabetes (75%), compared with patients in the recent control group (67%).

The study included two historical control groups because recommendations for glycemic control in the ICU setting have changed in recent years. Initial clinical trials showed clinical benefit from intensive glucose control for patients with hyperglycemia in the ICU, but later studies reported higher risks for severe hypoglycemia and death with intensive glucose control in these patients, Dr. Marso said. Updated consensus guidelines subsequently called for less tight glycemic control.

A 2009 consensus statement on inpatient glycemic control from the American Diabetes Association and American Association of Clinical Endocrinologists calls for insulin therapy to be initiated in critically ill patients when blood glucose values drop below 180 mg/dL. Glucose should be maintained between 140-180 mg/dL, and targets less than 100 mg/dL are not recommended (Endocr. Pract. 2009;15:353-69).

The statement says that IV insulin is the preferred treatment and that noninsulin antihyperglycemic agents are not appropriate in most hospitalized patients who require therapy for hyperglycemia. But the potential risks with insulin therapy prompted the current study of IV exenatide.

The study excluded patients who were dependent on a ventilator, unconscious on sedation, who had type 1 diabetes, were pregnant, were post-orthotopic heart transplant, had a creatinine clearance less than 30 mL/min, had a history of pancreatitis, or who were being treated with insulin monotherapy other than long-acting basal insulin (glargine or detemir).

The study was funded by Amylin Pharmaceuticals, which markets exenatide with Lilly. Dr. Marso has been a consultant to, or received research support from, Amylin, Abbott Vascular, The Medicines Company, Novo Nordisk, Volcano, Boston Scientific, and Terumo Medical.

SAN DIEGO – Validated measures of cardiovascular risk and comorbidity at baseline helped predict response to intensive glucose control in a post hoc analysis of patients who participated in the Veterans Affairs Diabetes Trial.

In the overall VADT, in which 1,791 military veterans with suboptimally controlled type 2 diabetes were randomized to receive either intensive or standard glucose control, intensive therapy had no significant impact on the rates of major cardiovascular events at a median follow-up of 5.6 years (N. Engl. J. Med. 2009;360:129-39). However, a subgroup analysis of 301 trial participants showed that intensive glucose lowering did significantly reduce cardiovascular events among those with less-extensive calcified coronary atherosclerosis (Diabetes 2009;58:2642-8).

Because coronary artery calcification measurements are expensive, involve radiation exposure, and are not readily available everywhere, it would be advantageous to have alternative clinical indices for predicting which patients would be more likely to benefit from intensive glycemic therapy, said Dr. Nalurporn Chokrungvaranon, an endocrine fellow with the Phoenix VA Health Care System.

In the current post hoc analysis, patients were divided into upper, middle, and lower tertiles of scores on four different validated measures: the Framingham 10-year cardiovascular disease (CVD) Risk Score, the U.K. Prospective Diabetes Study score, the Charlson comorbidity index, and another measure for predicting 4-year mortality based on age, sex, self-reported comorbid conditions, and functional measures (JAMA 2006;295:801-8).

At baseline, the study patients had a mean age of 60 years and a mean hemoglobin A_1c level of 9.4%. Those in the upper tertiles for any of the four scales at baseline showed no benefit from intensive glycemic therapy, with hazard ratios ranging from 0.92 for the 4-year mortality score to 1.06 for the Framingham score.

However, there were differences at the lower and middle tertiles. For the Framingham score, patients in the middle tertile had significantly reduced risk of cardiovascular events with intensive therapy (hazard ratio, 0.66; P less than .05). She noted, however, that the lower tertile did not show that benefit (HR, 0.85).

Similarly, the middle tertile on the Charlson index also showed a significantly lower risk for CVD events (HR, 0.57; P less than .05), whereas the lowest tertile did not (HR, 0.99).

It’s not entirely clear why the lowest tertiles did not show benefit, but event rates were lower in that group, so it could be a power issue. Moreover, CVD events take longer to occur in those at lower risk, so it’s possible that differences would emerge if the study were carried out on a longer timeline, Dr. Chokrungvaranon commented.

Indeed, for the 4-year mortality prediction score, the lowest tertile did show a significantly lower event rate (HR, 0.71; P less than .05). Adjustment for prior CVD did not change the results, she said.

"Cardiovascular scores and comorbidity indices may be useful tools to identify patients who should be considered for less aggressive treatment for diabetes. ... These results further support the notion that A_1c goals should be individualized and should not be one size fits all," she concluded.

This study was supported by the VA Cooperative Studies Program. Dr. Chokrungvaranon stated that she has no disclosures.

SAN DIEGO – Validated measures of cardiovascular risk and comorbidity at baseline helped predict response to intensive glucose control in a post hoc analysis of patients who participated in the Veterans Affairs Diabetes Trial.

In the overall VADT, in which 1,791 military veterans with suboptimally controlled type 2 diabetes were randomized to receive either intensive or standard glucose control, intensive therapy had no significant impact on the rates of major cardiovascular events at a median follow-up of 5.6 years (N. Engl. J. Med. 2009;360:129-39). However, a subgroup analysis of 301 trial participants showed that intensive glucose lowering did significantly reduce cardiovascular events among those with less-extensive calcified coronary atherosclerosis (Diabetes 2009;58:2642-8).

Because coronary artery calcification measurements are expensive, involve radiation exposure, and are not readily available everywhere, it would be advantageous to have alternative clinical indices for predicting which patients would be more likely to benefit from intensive glycemic therapy, said Dr. Nalurporn Chokrungvaranon, an endocrine fellow with the Phoenix VA Health Care System.

In the current post hoc analysis, patients were divided into upper, middle, and lower tertiles of scores on four different validated measures: the Framingham 10-year cardiovascular disease (CVD) Risk Score, the U.K. Prospective Diabetes Study score, the Charlson comorbidity index, and another measure for predicting 4-year mortality based on age, sex, self-reported comorbid conditions, and functional measures (JAMA 2006;295:801-8).

At baseline, the study patients had a mean age of 60 years and a mean hemoglobin A_1c level of 9.4%. Those in the upper tertiles for any of the four scales at baseline showed no benefit from intensive glycemic therapy, with hazard ratios ranging from 0.92 for the 4-year mortality score to 1.06 for the Framingham score.

However, there were differences at the lower and middle tertiles. For the Framingham score, patients in the middle tertile had significantly reduced risk of cardiovascular events with intensive therapy (hazard ratio, 0.66; P less than .05). She noted, however, that the lower tertile did not show that benefit (HR, 0.85).

Similarly, the middle tertile on the Charlson index also showed a significantly lower risk for CVD events (HR, 0.57; P less than .05), whereas the lowest tertile did not (HR, 0.99).

It’s not entirely clear why the lowest tertiles did not show benefit, but event rates were lower in that group, so it could be a power issue. Moreover, CVD events take longer to occur in those at lower risk, so it’s possible that differences would emerge if the study were carried out on a longer timeline, Dr. Chokrungvaranon commented.

Indeed, for the 4-year mortality prediction score, the lowest tertile did show a significantly lower event rate (HR, 0.71; P less than .05). Adjustment for prior CVD did not change the results, she said.

"Cardiovascular scores and comorbidity indices may be useful tools to identify patients who should be considered for less aggressive treatment for diabetes. ... These results further support the notion that A_1c goals should be individualized and should not be one size fits all," she concluded.

This study was supported by the VA Cooperative Studies Program. Dr. Chokrungvaranon stated that she has no disclosures.

SAN DIEGO – Validated measures of cardiovascular risk and comorbidity at baseline helped predict response to intensive glucose control in a post hoc analysis of patients who participated in the Veterans Affairs Diabetes Trial.

In the overall VADT, in which 1,791 military veterans with suboptimally controlled type 2 diabetes were randomized to receive either intensive or standard glucose control, intensive therapy had no significant impact on the rates of major cardiovascular events at a median follow-up of 5.6 years (N. Engl. J. Med. 2009;360:129-39). However, a subgroup analysis of 301 trial participants showed that intensive glucose lowering did significantly reduce cardiovascular events among those with less-extensive calcified coronary atherosclerosis (Diabetes 2009;58:2642-8).

Because coronary artery calcification measurements are expensive, involve radiation exposure, and are not readily available everywhere, it would be advantageous to have alternative clinical indices for predicting which patients would be more likely to benefit from intensive glycemic therapy, said Dr. Nalurporn Chokrungvaranon, an endocrine fellow with the Phoenix VA Health Care System.

In the current post hoc analysis, patients were divided into upper, middle, and lower tertiles of scores on four different validated measures: the Framingham 10-year cardiovascular disease (CVD) Risk Score, the U.K. Prospective Diabetes Study score, the Charlson comorbidity index, and another measure for predicting 4-year mortality based on age, sex, self-reported comorbid conditions, and functional measures (JAMA 2006;295:801-8).

At baseline, the study patients had a mean age of 60 years and a mean hemoglobin A_1c level of 9.4%. Those in the upper tertiles for any of the four scales at baseline showed no benefit from intensive glycemic therapy, with hazard ratios ranging from 0.92 for the 4-year mortality score to 1.06 for the Framingham score.

However, there were differences at the lower and middle tertiles. For the Framingham score, patients in the middle tertile had significantly reduced risk of cardiovascular events with intensive therapy (hazard ratio, 0.66; P less than .05). She noted, however, that the lower tertile did not show that benefit (HR, 0.85).

Similarly, the middle tertile on the Charlson index also showed a significantly lower risk for CVD events (HR, 0.57; P less than .05), whereas the lowest tertile did not (HR, 0.99).

It’s not entirely clear why the lowest tertiles did not show benefit, but event rates were lower in that group, so it could be a power issue. Moreover, CVD events take longer to occur in those at lower risk, so it’s possible that differences would emerge if the study were carried out on a longer timeline, Dr. Chokrungvaranon commented.

Indeed, for the 4-year mortality prediction score, the lowest tertile did show a significantly lower event rate (HR, 0.71; P less than .05). Adjustment for prior CVD did not change the results, she said.

"Cardiovascular scores and comorbidity indices may be useful tools to identify patients who should be considered for less aggressive treatment for diabetes. ... These results further support the notion that A_1c goals should be individualized and should not be one size fits all," she concluded.

This study was supported by the VA Cooperative Studies Program. Dr. Chokrungvaranon stated that she has no disclosures.

When a landmark trial was stopped early due to a higher death rate in patients randomized to intensive glycemic control, the key question was the medical equivalent of the murder-mystery line, "Who done it?" What caused the higher death rate with intensive control compared with standard glycemic targets?

The randomized controlled trial, Action to Control Cardiovascular Risk in Diabetes (ACCORD), involving 10,251 patients with diabetes who were at high risk for cardiovascular disease, showed a 22% higher all-cause mortality rate among the 5,128 patients whose treatment arm aimed for a hemoglobin A_1c level of less than 6% compared with patients whose target HbA_1c was in the range of 7%-7.9% (N. Engl. J. Med. 2008;358:2545-59).

Subsequent analyses showed that a rapid drop in glucose wasn’t the cause. Neither was a low HbA_1c level in and of itself. "It’s not a problem to get a lower A_1c if you’re trying to," explained Dr. Richard M. Bergenstal of the ACCORD study team.

Neither could weight gain or the use of thiazolidinediones or other medications explain the higher mortality risk with intensive glycemic control.

Episodes of severe hypoglycemia increased the risk for death in both the intensive- and standard-therapy groups, but the general consensus is that severe hypoglycemia did not explain the difference in death rates between those groups, according to Dr. Bergenstal, executive director of the International Diabetes Center at Park Nicollet Health Services, Minneapolis.

Mild hypoglycemia was also investigated as a possible factor in the higher death rates. To get a profile of the potential risk associated with mild hypoglycemia, the ACCORD researchers analyzed more than 9.4 million data points from self-monitored blood glucose tests recorded over an average 2-year period by 5,347 patients, approximately half of the ACCORD cohort, he said at the annual meeting of the American Diabetes Association in San Diego.

What they found was surprising. It wasn’t a high or low HbA_1c per se that was most associated with the increased mortality risk in the intensive control group, but unintended high or low blood sugars.

"The more you diverge from what you’re trying to achieve in glycemic targets, the higher the risk of mortality," Dr. Bergenstal said.

In Dr. Bergenstal’s opinion, this implies that clinicians should set a goal not only for HbA_1c levels but for blood glucose levels, and they should monitor and evaluate patients’ blood glucose profiles.

"If you’re not achieving the target you set, be careful, and think about whether you want to intensify further if you’re diverging from that," he suggested.

Of the patients with self-monitored blood glucose data, the 2,691 patients in the intensive control group tested their blood sugar levels a mean of 2.7 times per day, compared with 2 times per day for the 2,656 patients with data in the standard control group.

Those who tested more frequently tended to have lower HbA_1c levels. In the intensive control group, those who tested blood glucose once per day had a mean HbA_1c of 6.9% and those who tested five or more times per day had a mean HbA_1c of 6.5%. In the standard control group, those who tested blood glucose once per day had a mean HbA_1c of 7.8% and those who tested five or more times per day had a mean HbA_1c of 7.3%.

When the investigators analyzed the blood glucose monitoring data by 2-hour intervals, a profile emerged of rising blood sugar levels during the day and a significant drop in glucose levels overnight, in both the intensive and standard control groups.

"The more steep both of those trajectories are, the worse they did," Dr. Bergenstal said.

This indicates that medication approaches are needed to help smooth out this type of curve, he said.

A modal day profile of patients with one or more severe hypoglycemic reactions produced the same pattern but with more instability – a sharper curve of blood glucose values going up during the day, and a sharper curve down overnight. Among patients who died, the modal day profile featured even steeper increases in blood glucose values during the day and sharper drops overnight.

"I can’t say we’ve had the database open long enough to go back and say, ‘At 8 p.m. on March 22, what happened to this person?’ But we will, trust me. We will look even closer at these numbers over time," he said. "I think they’re already giving a sense that it’s probably not a good thing to be going up and down with such velocity."

Difficulties in Controlling Blood Glucose Values

Patients in the intensive-control group recorded three times as many low blood glucose levels as did patients in the standard-control group. That might lead one to think that excess hypoglycemia was the cause of excess mortality in the intensive group, but that wasn’t the case. In the intensive control group, patients who died had more high blood glucose readings than did patients who survived, but not more low blood glucose readings.

The point is that patients who died diverged from their targets, Dr. Bergenstal said. Investigators expected to see low glucose levels in the intensive control group. Patients who died had a lot of blood glucose readings of 200 mg/dL or 300 mg/dL.

Patients in the standard-control group recorded twice as many high blood sugar readings as did patients in the intensive-control group. Patients in the standard group who died were more likely to have high or low blood glucose values compared with patients who survived.

"Again, they diverged" from the goal. "We were trying to keep these people about in the middle," he said.

The findings imply that clinicians should relax the intensity of therapy, he added. The HbA_1c and self-monitored blood glucose values diverged significantly from targets, despite reasonably intensive efforts at control.

High HbA_1c levels were associated with both dangerously high glucose values and dangerously low glucose values. High levels were dangerous because of hyperglycemia but also because people who had some of the worst hypoglycemia had high HbA_1c levels, he said.

Severe hypoglycemia increased risk for death in both patient groups.

And mild to moderate hypoglycemia? "We want to minimize it, particularly in those patients for whom we relax our A_1c and self-monitored blood glucose targets, such as the frail elderly," Dr. Bergenstal advised. "Be very careful about even mild to moderate hypoglycemia in those individuals."

Characteristics of patients with self-monitored blood glucose data were similar to those without the data, so this sample was fairly representative of all patients in ACCORD, he said.

The investigators are working to distill the findings into a practical message about how to quantify stability or variability in self-monitored blood glucose levels.

Dr. Bergenstal holds stock in Merck. He has received research support from, or been an adviser or consultant to, many companies including Abbot Diabetes Care, Amylin Pharmaceuticals, Bayer Health Care, Biodel, Calibra Medical, Eli Lilly, Hygieia, Intuity Medical, Lifescan, MannKind Corp., Medtronic, Novo Nordisk, Pfizer, ResMed, Roche Diagnostics, Roche Pharmaceuticals, Sanofi-Aventis, Takeda Pharmaceutical Company, Valeritas, United Health Group/i3 Statprobe, Dexcom, and Intarcia Therapeutics.

The ACCORD trial was sponsored by Abbot Laboratories, Amylin Pharmaceuticals, AstraZeneca Pharmaceuticals, Bayer HealthCare, Closer Healthcare, GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Merck, Novartis Pharmaceuticals, Novo Nordisk, Omron Healthcare, Sanofi U.S., Takeda Pharmaceuticals, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Eye Institute, the National Institute on Aging, and the Centers for Disease Control and Prevention.

When a landmark trial was stopped early due to a higher death rate in patients randomized to intensive glycemic control, the key question was the medical equivalent of the murder-mystery line, "Who done it?" What caused the higher death rate with intensive control compared with standard glycemic targets?

The randomized controlled trial, Action to Control Cardiovascular Risk in Diabetes (ACCORD), involving 10,251 patients with diabetes who were at high risk for cardiovascular disease, showed a 22% higher all-cause mortality rate among the 5,128 patients whose treatment arm aimed for a hemoglobin A_1c level of less than 6% compared with patients whose target HbA_1c was in the range of 7%-7.9% (N. Engl. J. Med. 2008;358:2545-59).

Subsequent analyses showed that a rapid drop in glucose wasn’t the cause. Neither was a low HbA_1c level in and of itself. "It’s not a problem to get a lower A_1c if you’re trying to," explained Dr. Richard M. Bergenstal of the ACCORD study team.

Neither could weight gain or the use of thiazolidinediones or other medications explain the higher mortality risk with intensive glycemic control.

Episodes of severe hypoglycemia increased the risk for death in both the intensive- and standard-therapy groups, but the general consensus is that severe hypoglycemia did not explain the difference in death rates between those groups, according to Dr. Bergenstal, executive director of the International Diabetes Center at Park Nicollet Health Services, Minneapolis.

Mild hypoglycemia was also investigated as a possible factor in the higher death rates. To get a profile of the potential risk associated with mild hypoglycemia, the ACCORD researchers analyzed more than 9.4 million data points from self-monitored blood glucose tests recorded over an average 2-year period by 5,347 patients, approximately half of the ACCORD cohort, he said at the annual meeting of the American Diabetes Association in San Diego.

What they found was surprising. It wasn’t a high or low HbA_1c per se that was most associated with the increased mortality risk in the intensive control group, but unintended high or low blood sugars.

"The more you diverge from what you’re trying to achieve in glycemic targets, the higher the risk of mortality," Dr. Bergenstal said.

In Dr. Bergenstal’s opinion, this implies that clinicians should set a goal not only for HbA_1c levels but for blood glucose levels, and they should monitor and evaluate patients’ blood glucose profiles.

"If you’re not achieving the target you set, be careful, and think about whether you want to intensify further if you’re diverging from that," he suggested.

Of the patients with self-monitored blood glucose data, the 2,691 patients in the intensive control group tested their blood sugar levels a mean of 2.7 times per day, compared with 2 times per day for the 2,656 patients with data in the standard control group.

Those who tested more frequently tended to have lower HbA_1c levels. In the intensive control group, those who tested blood glucose once per day had a mean HbA_1c of 6.9% and those who tested five or more times per day had a mean HbA_1c of 6.5%. In the standard control group, those who tested blood glucose once per day had a mean HbA_1c of 7.8% and those who tested five or more times per day had a mean HbA_1c of 7.3%.

When the investigators analyzed the blood glucose monitoring data by 2-hour intervals, a profile emerged of rising blood sugar levels during the day and a significant drop in glucose levels overnight, in both the intensive and standard control groups.

"The more steep both of those trajectories are, the worse they did," Dr. Bergenstal said.

This indicates that medication approaches are needed to help smooth out this type of curve, he said.

A modal day profile of patients with one or more severe hypoglycemic reactions produced the same pattern but with more instability – a sharper curve of blood glucose values going up during the day, and a sharper curve down overnight. Among patients who died, the modal day profile featured even steeper increases in blood glucose values during the day and sharper drops overnight.

"I can’t say we’ve had the database open long enough to go back and say, ‘At 8 p.m. on March 22, what happened to this person?’ But we will, trust me. We will look even closer at these numbers over time," he said. "I think they’re already giving a sense that it’s probably not a good thing to be going up and down with such velocity."

Difficulties in Controlling Blood Glucose Values

Patients in the intensive-control group recorded three times as many low blood glucose levels as did patients in the standard-control group. That might lead one to think that excess hypoglycemia was the cause of excess mortality in the intensive group, but that wasn’t the case. In the intensive control group, patients who died had more high blood glucose readings than did patients who survived, but not more low blood glucose readings.

The point is that patients who died diverged from their targets, Dr. Bergenstal said. Investigators expected to see low glucose levels in the intensive control group. Patients who died had a lot of blood glucose readings of 200 mg/dL or 300 mg/dL.

Patients in the standard-control group recorded twice as many high blood sugar readings as did patients in the intensive-control group. Patients in the standard group who died were more likely to have high or low blood glucose values compared with patients who survived.

"Again, they diverged" from the goal. "We were trying to keep these people about in the middle," he said.

The findings imply that clinicians should relax the intensity of therapy, he added. The HbA_1c and self-monitored blood glucose values diverged significantly from targets, despite reasonably intensive efforts at control.

High HbA_1c levels were associated with both dangerously high glucose values and dangerously low glucose values. High levels were dangerous because of hyperglycemia but also because people who had some of the worst hypoglycemia had high HbA_1c levels, he said.

Severe hypoglycemia increased risk for death in both patient groups.

And mild to moderate hypoglycemia? "We want to minimize it, particularly in those patients for whom we relax our A_1c and self-monitored blood glucose targets, such as the frail elderly," Dr. Bergenstal advised. "Be very careful about even mild to moderate hypoglycemia in those individuals."

Characteristics of patients with self-monitored blood glucose data were similar to those without the data, so this sample was fairly representative of all patients in ACCORD, he said.

The investigators are working to distill the findings into a practical message about how to quantify stability or variability in self-monitored blood glucose levels.

Dr. Bergenstal holds stock in Merck. He has received research support from, or been an adviser or consultant to, many companies including Abbot Diabetes Care, Amylin Pharmaceuticals, Bayer Health Care, Biodel, Calibra Medical, Eli Lilly, Hygieia, Intuity Medical, Lifescan, MannKind Corp., Medtronic, Novo Nordisk, Pfizer, ResMed, Roche Diagnostics, Roche Pharmaceuticals, Sanofi-Aventis, Takeda Pharmaceutical Company, Valeritas, United Health Group/i3 Statprobe, Dexcom, and Intarcia Therapeutics.

The ACCORD trial was sponsored by Abbot Laboratories, Amylin Pharmaceuticals, AstraZeneca Pharmaceuticals, Bayer HealthCare, Closer Healthcare, GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Merck, Novartis Pharmaceuticals, Novo Nordisk, Omron Healthcare, Sanofi U.S., Takeda Pharmaceuticals, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Eye Institute, the National Institute on Aging, and the Centers for Disease Control and Prevention.

When a landmark trial was stopped early due to a higher death rate in patients randomized to intensive glycemic control, the key question was the medical equivalent of the murder-mystery line, "Who done it?" What caused the higher death rate with intensive control compared with standard glycemic targets?

The randomized controlled trial, Action to Control Cardiovascular Risk in Diabetes (ACCORD), involving 10,251 patients with diabetes who were at high risk for cardiovascular disease, showed a 22% higher all-cause mortality rate among the 5,128 patients whose treatment arm aimed for a hemoglobin A_1c level of less than 6% compared with patients whose target HbA_1c was in the range of 7%-7.9% (N. Engl. J. Med. 2008;358:2545-59).

Subsequent analyses showed that a rapid drop in glucose wasn’t the cause. Neither was a low HbA_1c level in and of itself. "It’s not a problem to get a lower A_1c if you’re trying to," explained Dr. Richard M. Bergenstal of the ACCORD study team.

Neither could weight gain or the use of thiazolidinediones or other medications explain the higher mortality risk with intensive glycemic control.

Episodes of severe hypoglycemia increased the risk for death in both the intensive- and standard-therapy groups, but the general consensus is that severe hypoglycemia did not explain the difference in death rates between those groups, according to Dr. Bergenstal, executive director of the International Diabetes Center at Park Nicollet Health Services, Minneapolis.

Mild hypoglycemia was also investigated as a possible factor in the higher death rates. To get a profile of the potential risk associated with mild hypoglycemia, the ACCORD researchers analyzed more than 9.4 million data points from self-monitored blood glucose tests recorded over an average 2-year period by 5,347 patients, approximately half of the ACCORD cohort, he said at the annual meeting of the American Diabetes Association in San Diego.

What they found was surprising. It wasn’t a high or low HbA_1c per se that was most associated with the increased mortality risk in the intensive control group, but unintended high or low blood sugars.

"The more you diverge from what you’re trying to achieve in glycemic targets, the higher the risk of mortality," Dr. Bergenstal said.

In Dr. Bergenstal’s opinion, this implies that clinicians should set a goal not only for HbA_1c levels but for blood glucose levels, and they should monitor and evaluate patients’ blood glucose profiles.

"If you’re not achieving the target you set, be careful, and think about whether you want to intensify further if you’re diverging from that," he suggested.

Of the patients with self-monitored blood glucose data, the 2,691 patients in the intensive control group tested their blood sugar levels a mean of 2.7 times per day, compared with 2 times per day for the 2,656 patients with data in the standard control group.

Those who tested more frequently tended to have lower HbA_1c levels. In the intensive control group, those who tested blood glucose once per day had a mean HbA_1c of 6.9% and those who tested five or more times per day had a mean HbA_1c of 6.5%. In the standard control group, those who tested blood glucose once per day had a mean HbA_1c of 7.8% and those who tested five or more times per day had a mean HbA_1c of 7.3%.

When the investigators analyzed the blood glucose monitoring data by 2-hour intervals, a profile emerged of rising blood sugar levels during the day and a significant drop in glucose levels overnight, in both the intensive and standard control groups.

"The more steep both of those trajectories are, the worse they did," Dr. Bergenstal said.

This indicates that medication approaches are needed to help smooth out this type of curve, he said.

A modal day profile of patients with one or more severe hypoglycemic reactions produced the same pattern but with more instability – a sharper curve of blood glucose values going up during the day, and a sharper curve down overnight. Among patients who died, the modal day profile featured even steeper increases in blood glucose values during the day and sharper drops overnight.

"I can’t say we’ve had the database open long enough to go back and say, ‘At 8 p.m. on March 22, what happened to this person?’ But we will, trust me. We will look even closer at these numbers over time," he said. "I think they’re already giving a sense that it’s probably not a good thing to be going up and down with such velocity."

Difficulties in Controlling Blood Glucose Values

Patients in the intensive-control group recorded three times as many low blood glucose levels as did patients in the standard-control group. That might lead one to think that excess hypoglycemia was the cause of excess mortality in the intensive group, but that wasn’t the case. In the intensive control group, patients who died had more high blood glucose readings than did patients who survived, but not more low blood glucose readings.

The point is that patients who died diverged from their targets, Dr. Bergenstal said. Investigators expected to see low glucose levels in the intensive control group. Patients who died had a lot of blood glucose readings of 200 mg/dL or 300 mg/dL.

Patients in the standard-control group recorded twice as many high blood sugar readings as did patients in the intensive-control group. Patients in the standard group who died were more likely to have high or low blood glucose values compared with patients who survived.

"Again, they diverged" from the goal. "We were trying to keep these people about in the middle," he said.

The findings imply that clinicians should relax the intensity of therapy, he added. The HbA_1c and self-monitored blood glucose values diverged significantly from targets, despite reasonably intensive efforts at control.

High HbA_1c levels were associated with both dangerously high glucose values and dangerously low glucose values. High levels were dangerous because of hyperglycemia but also because people who had some of the worst hypoglycemia had high HbA_1c levels, he said.

Severe hypoglycemia increased risk for death in both patient groups.

And mild to moderate hypoglycemia? "We want to minimize it, particularly in those patients for whom we relax our A_1c and self-monitored blood glucose targets, such as the frail elderly," Dr. Bergenstal advised. "Be very careful about even mild to moderate hypoglycemia in those individuals."

Characteristics of patients with self-monitored blood glucose data were similar to those without the data, so this sample was fairly representative of all patients in ACCORD, he said.

The investigators are working to distill the findings into a practical message about how to quantify stability or variability in self-monitored blood glucose levels.

Dr. Bergenstal holds stock in Merck. He has received research support from, or been an adviser or consultant to, many companies including Abbot Diabetes Care, Amylin Pharmaceuticals, Bayer Health Care, Biodel, Calibra Medical, Eli Lilly, Hygieia, Intuity Medical, Lifescan, MannKind Corp., Medtronic, Novo Nordisk, Pfizer, ResMed, Roche Diagnostics, Roche Pharmaceuticals, Sanofi-Aventis, Takeda Pharmaceutical Company, Valeritas, United Health Group/i3 Statprobe, Dexcom, and Intarcia Therapeutics.

The ACCORD trial was sponsored by Abbot Laboratories, Amylin Pharmaceuticals, AstraZeneca Pharmaceuticals, Bayer HealthCare, Closer Healthcare, GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Merck, Novartis Pharmaceuticals, Novo Nordisk, Omron Healthcare, Sanofi U.S., Takeda Pharmaceuticals, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Eye Institute, the National Institute on Aging, and the Centers for Disease Control and Prevention.

SAN DIEGO – The "low glucose suspend" insulin pump feature reduced the risk of hypoglycemia without any severe hyperglycemia or diabetic ketoacidosis in a German study of 21 children with type 1 diabetes.

Medtronic’s sensor-augmented insulin pump, the Paradigm Veo system, comprises an insulin pump, a continuous glucose monitor, and a component that first issues a "pre-alarm" if the sensor detects a reading below a preset level. If there is no response on the part of the patient and the glucose level continues to drop to a second preset level, the pump then alerts again and stops the basal insulin infusion for 2 hours or until there is a response. At 2 hours, the basal infusion resumes. If the glucose level is still too low at 4 hours after resumption, the cycle begins again.

The patient can interrupt the low glucose suspend (LGS) feature at any time, said Dr. Thomas Danne, head of the diabetes center for children and adolescents at the Kinderkrankenhaus auf der Bult in Hanover, Germany.

The Veo system is sold in 45 countries, including Canada, South Africa, Australia, and countries in Europe and Central and South America. It is not currently available in the United States. The U.S. Food and Drug Administration recently issued a guidance for manufacturers that are developing LGS systems, specifying the types of testing that must take place to address safety issues, including a concern that the device might overcorrect the hypoglycemia, resulting in hyperglycemia and/or diabetic ketoacidosis (DKA).

The Medtronic-sponsored study, conducted in three German pediatric diabetes centers, initially enrolled 24 patients aged 1-21 years (mean, 10.8 years) who had type 1 diabetes and had been on insulin pump therapy for an average of 3.6 years. Their mean baseline hemoglobin A_1c was 7.8%. After patients wore the Veo without the LGS and pre-alerts for 2 weeks, those features were then turned on for the subsequent 6 weeks. The hypoglycemia alert was set at 75 mg/dL, and the LGS alert at 70 mg/dL. Complete data were available for 21 of the children.

A total of 1,298 alerts occurred, of which 853 (66%) were shorter than 5 minutes because the patients reacted immediately and there was no automatic interruption of insulin delivery. The frequency of alerts was 2.56 per patient per day, of which 78% occurred during the day (6:00 a.m.–10:00 p.m.). However, because the patients were far less likely to respond to the alarms while sleeping, the frequency of insulin delivery disruptions was far more common during the night (92 vs. 17, or 0.175 vs. 0.032 per patient per day), said Dr. Danne.

During the time of the LGS suspension, glucose levels rose an average of 35 mg/dL per hour, totaling 68.4 mg/dL per hour for the entire 120-minute period. The mean blood glucose level during the 6-week LGS period was 148 mg/dL, which was nearly identical to the 145 mg/dL recorded during the initial 2-week phase without the LGS. Standard deviations were 56 mg/dL and 55 mg/dL, respectively, and the time spent with hyperglycemia (defined as greater than 140 mg/dL) also was not significantly different (639 vs. 651 minutes). There were no cases of DKA during either time period, Dr. Danne reported.

But hypoglycemia rates did differ significantly. The amount of time spent with blood glucose levels less than 70 mg/dL was 58 minutes per day with the LGS, compared with 101 minutes without, a highly statistically significant difference (P = .002). Excursions of hypoglycemia below 40 mg/dL were also much lower with the LGS (0.13 vs. 0.28 per patient per day; P = .005) during both the daytime and overnight hours. The LGS cut the amount of time spent with blood glucose levels lower than both 70 mg/dL and 40 mg/dL by about 50%.

On a 7-point satisfaction survey, patients’ responses ranged from a high of 6.3 for "information on the Veo was valuable," to a low of 4.1 for "LGS prevented severe hypoglycemic episodes." The latter score was brought down by two very-well-controlled patients who didn’t feel that their risk for severe low blood glucose was high to begin with, Dr. Danne explained.

Dr. Danne received funding from Medtronic to conduct this trial.

SAN DIEGO – The "low glucose suspend" insulin pump feature reduced the risk of hypoglycemia without any severe hyperglycemia or diabetic ketoacidosis in a German study of 21 children with type 1 diabetes.

Medtronic’s sensor-augmented insulin pump, the Paradigm Veo system, comprises an insulin pump, a continuous glucose monitor, and a component that first issues a "pre-alarm" if the sensor detects a reading below a preset level. If there is no response on the part of the patient and the glucose level continues to drop to a second preset level, the pump then alerts again and stops the basal insulin infusion for 2 hours or until there is a response. At 2 hours, the basal infusion resumes. If the glucose level is still too low at 4 hours after resumption, the cycle begins again.

The patient can interrupt the low glucose suspend (LGS) feature at any time, said Dr. Thomas Danne, head of the diabetes center for children and adolescents at the Kinderkrankenhaus auf der Bult in Hanover, Germany.

The Veo system is sold in 45 countries, including Canada, South Africa, Australia, and countries in Europe and Central and South America. It is not currently available in the United States. The U.S. Food and Drug Administration recently issued a guidance for manufacturers that are developing LGS systems, specifying the types of testing that must take place to address safety issues, including a concern that the device might overcorrect the hypoglycemia, resulting in hyperglycemia and/or diabetic ketoacidosis (DKA).

The Medtronic-sponsored study, conducted in three German pediatric diabetes centers, initially enrolled 24 patients aged 1-21 years (mean, 10.8 years) who had type 1 diabetes and had been on insulin pump therapy for an average of 3.6 years. Their mean baseline hemoglobin A_1c was 7.8%. After patients wore the Veo without the LGS and pre-alerts for 2 weeks, those features were then turned on for the subsequent 6 weeks. The hypoglycemia alert was set at 75 mg/dL, and the LGS alert at 70 mg/dL. Complete data were available for 21 of the children.

A total of 1,298 alerts occurred, of which 853 (66%) were shorter than 5 minutes because the patients reacted immediately and there was no automatic interruption of insulin delivery. The frequency of alerts was 2.56 per patient per day, of which 78% occurred during the day (6:00 a.m.–10:00 p.m.). However, because the patients were far less likely to respond to the alarms while sleeping, the frequency of insulin delivery disruptions was far more common during the night (92 vs. 17, or 0.175 vs. 0.032 per patient per day), said Dr. Danne.

During the time of the LGS suspension, glucose levels rose an average of 35 mg/dL per hour, totaling 68.4 mg/dL per hour for the entire 120-minute period. The mean blood glucose level during the 6-week LGS period was 148 mg/dL, which was nearly identical to the 145 mg/dL recorded during the initial 2-week phase without the LGS. Standard deviations were 56 mg/dL and 55 mg/dL, respectively, and the time spent with hyperglycemia (defined as greater than 140 mg/dL) also was not significantly different (639 vs. 651 minutes). There were no cases of DKA during either time period, Dr. Danne reported.

But hypoglycemia rates did differ significantly. The amount of time spent with blood glucose levels less than 70 mg/dL was 58 minutes per day with the LGS, compared with 101 minutes without, a highly statistically significant difference (P = .002). Excursions of hypoglycemia below 40 mg/dL were also much lower with the LGS (0.13 vs. 0.28 per patient per day; P = .005) during both the daytime and overnight hours. The LGS cut the amount of time spent with blood glucose levels lower than both 70 mg/dL and 40 mg/dL by about 50%.

On a 7-point satisfaction survey, patients’ responses ranged from a high of 6.3 for "information on the Veo was valuable," to a low of 4.1 for "LGS prevented severe hypoglycemic episodes." The latter score was brought down by two very-well-controlled patients who didn’t feel that their risk for severe low blood glucose was high to begin with, Dr. Danne explained.

Dr. Danne received funding from Medtronic to conduct this trial.

SAN DIEGO – The "low glucose suspend" insulin pump feature reduced the risk of hypoglycemia without any severe hyperglycemia or diabetic ketoacidosis in a German study of 21 children with type 1 diabetes.

Medtronic’s sensor-augmented insulin pump, the Paradigm Veo system, comprises an insulin pump, a continuous glucose monitor, and a component that first issues a "pre-alarm" if the sensor detects a reading below a preset level. If there is no response on the part of the patient and the glucose level continues to drop to a second preset level, the pump then alerts again and stops the basal insulin infusion for 2 hours or until there is a response. At 2 hours, the basal infusion resumes. If the glucose level is still too low at 4 hours after resumption, the cycle begins again.

The patient can interrupt the low glucose suspend (LGS) feature at any time, said Dr. Thomas Danne, head of the diabetes center for children and adolescents at the Kinderkrankenhaus auf der Bult in Hanover, Germany.

The Veo system is sold in 45 countries, including Canada, South Africa, Australia, and countries in Europe and Central and South America. It is not currently available in the United States. The U.S. Food and Drug Administration recently issued a guidance for manufacturers that are developing LGS systems, specifying the types of testing that must take place to address safety issues, including a concern that the device might overcorrect the hypoglycemia, resulting in hyperglycemia and/or diabetic ketoacidosis (DKA).

The Medtronic-sponsored study, conducted in three German pediatric diabetes centers, initially enrolled 24 patients aged 1-21 years (mean, 10.8 years) who had type 1 diabetes and had been on insulin pump therapy for an average of 3.6 years. Their mean baseline hemoglobin A_1c was 7.8%. After patients wore the Veo without the LGS and pre-alerts for 2 weeks, those features were then turned on for the subsequent 6 weeks. The hypoglycemia alert was set at 75 mg/dL, and the LGS alert at 70 mg/dL. Complete data were available for 21 of the children.

A total of 1,298 alerts occurred, of which 853 (66%) were shorter than 5 minutes because the patients reacted immediately and there was no automatic interruption of insulin delivery. The frequency of alerts was 2.56 per patient per day, of which 78% occurred during the day (6:00 a.m.–10:00 p.m.). However, because the patients were far less likely to respond to the alarms while sleeping, the frequency of insulin delivery disruptions was far more common during the night (92 vs. 17, or 0.175 vs. 0.032 per patient per day), said Dr. Danne.

During the time of the LGS suspension, glucose levels rose an average of 35 mg/dL per hour, totaling 68.4 mg/dL per hour for the entire 120-minute period. The mean blood glucose level during the 6-week LGS period was 148 mg/dL, which was nearly identical to the 145 mg/dL recorded during the initial 2-week phase without the LGS. Standard deviations were 56 mg/dL and 55 mg/dL, respectively, and the time spent with hyperglycemia (defined as greater than 140 mg/dL) also was not significantly different (639 vs. 651 minutes). There were no cases of DKA during either time period, Dr. Danne reported.

But hypoglycemia rates did differ significantly. The amount of time spent with blood glucose levels less than 70 mg/dL was 58 minutes per day with the LGS, compared with 101 minutes without, a highly statistically significant difference (P = .002). Excursions of hypoglycemia below 40 mg/dL were also much lower with the LGS (0.13 vs. 0.28 per patient per day; P = .005) during both the daytime and overnight hours. The LGS cut the amount of time spent with blood glucose levels lower than both 70 mg/dL and 40 mg/dL by about 50%.

On a 7-point satisfaction survey, patients’ responses ranged from a high of 6.3 for "information on the Veo was valuable," to a low of 4.1 for "LGS prevented severe hypoglycemic episodes." The latter score was brought down by two very-well-controlled patients who didn’t feel that their risk for severe low blood glucose was high to begin with, Dr. Danne explained.

Dr. Danne received funding from Medtronic to conduct this trial.

SAN DIEGO – An updated version of the Yale Insulin Infusion Protocol for intensive care unit management of hyperglycemia provided effective and safe targeted blood glucose control in compliance with national guidelines among 115 patients in Yale’s medical ICU.

Yale–New Haven (Conn.) Hospital has used a standardized intravenous insulin infusion protocol (IIP) in its medical ICU since 2003. The initial glucose target was 100-140 mg/dL, based on a 2001 study demonstrating the benefits of glycemic control in that range among critically ill patients (N. Engl. J. Med. 2001;345:1359-67). In 2005, the target was further lowered to 90-120 mg/dL. Both of those protocols were validated and published, and are used in many U.S. hospitals, said Dr. Shilpa Shetty, an academic hospitalist at Griffin Hospital, Derby, Conn., an affiliate of Yale–New Haven Hospital.

A change was prompted in 2009, when the Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study demonstrated significantly increased mortality among ICU patients undergoing intensive insulin therapy (N. Engl. J. Med. 2009;360:1283-97). Following that, the American Association of Clinical Endocrinologists and the American Diabetes Association issued a joint consensus statement endorsing a less stringent blood glucose target of 140-180 mg/dL in critically ill patients (Endocr. Prac 2009;15:353-69).

Subsequently, the Yale Protocol was revised yet again to a target blood glucose range of 120-160 mg/dL. That range was chosen because the AACE/ADA consensus statement had said that there might be additional benefit in keeping patients at the lower end of the recommended 140-180 mg/dL range, and with prior validated protocols the median blood glucose values always ended up at the upper end of the target range.

"We expected to stay at the lower end of the AACE/ADA target, which we did," Dr. Shetty said in an interview.

In the current study, clinical responses to the first 115 drips using the latest revised protocol were tracked for validation at Yale–New Haven Hospital. Minimal inservicing was required, since the nurses were already fully trained in the previous protocols. The protocol was triggered when a registered nurse identified a patient with two blood glucose values above 180 mg/dL.

The responsible physician then placed the order for the drip. Insulin was delivered via infusion pumps in 0.5 units/hour increments, with bolus and initial infusion rates determined by a formula based on the patient’s blood glucose value. While on the infusion, the protocol specifies that the patients’ blood glucose be checked hourly until glucose levels stabilize – defined as three consecutive values in target range – at which point the checks could be done less frequently.

Data were collected during September 2009 through January 2010. The 115 consecutive insulin infusions included 17 patients who were placed on the drip more than once. The patients had a mean age of 62 years, with a mean body mass index of 31.8 kg/m². About half (51%) were male, 65% were white, 17% black, 13% Hispanic, and 5% Asian. Two-thirds (64%) had a prior diagnosis of diabetes, and 44% had been using insulin at home prior to entering the ICU.

Admitting diagnoses included acute respiratory failure in 29%, sepsis in 25%, and bacterial pneumonia in 11%. Mean length of ICU stay was 19.5 days, and hospital stay, 36.4 days. The mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score – a well-validated severity of illness scoring system that predicts mortality with a 0-71 scale – was 24 (higher numbers mean worse prognosis). In NICE-SUGAR, the mean APACHE score was 21, compared with 9 for the 2001 study that led to the original Yale Protocol, Dr. Shetty noted.

Starting at a mean pre-infusion blood glucose of 306.1 mg/dL, the infusion brought the blood glucose down to a mean of 155.9 mg/dL once the target of less than 160 mg/dL was reached, in a mean of 8.3 hours. During the infusion, the mean nadir glucose value was 92.5 mg/dL. Patients spent a mean of 95 hours on the infusion, with a mean infusion dose of 3.9 units per hour. Once the target was achieved, the protocol maintained 42% of subsequent blood glucose values within the target 120-160 mg/dL, and 76% were less than 180 mg/dL, she reported.

Hypoglycemia was rare. Of a total 8,272 recorded blood glucose readings, just 0.3% were less than 70 mg/dL, and 0.02% were below 40 mg/dL. No deleterious effects attributable to low blood sugar were noted. These low rates of hypoglycemia were comparable to prior Yale ICU protocols. The proportion of patients experiencing blood glucose values of 40 mg/dL or less was just 1.7%, compared with a mean 2.1% in seven previous insulin infusion studies, she noted.

The new Yale protocol was "readily accepted and easily implemented by the medical ICU nursing staff, and can be easily implemented by hospitals that are currently utilizing one of the original Yale protocols," Dr. Shetty concluded.

Dr. Shetty stated that she has no conflicts of interest.

SAN DIEGO – An updated version of the Yale Insulin Infusion Protocol for intensive care unit management of hyperglycemia provided effective and safe targeted blood glucose control in compliance with national guidelines among 115 patients in Yale’s medical ICU.

Yale–New Haven (Conn.) Hospital has used a standardized intravenous insulin infusion protocol (IIP) in its medical ICU since 2003. The initial glucose target was 100-140 mg/dL, based on a 2001 study demonstrating the benefits of glycemic control in that range among critically ill patients (N. Engl. J. Med. 2001;345:1359-67). In 2005, the target was further lowered to 90-120 mg/dL. Both of those protocols were validated and published, and are used in many U.S. hospitals, said Dr. Shilpa Shetty, an academic hospitalist at Griffin Hospital, Derby, Conn., an affiliate of Yale–New Haven Hospital.

A change was prompted in 2009, when the Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study demonstrated significantly increased mortality among ICU patients undergoing intensive insulin therapy (N. Engl. J. Med. 2009;360:1283-97). Following that, the American Association of Clinical Endocrinologists and the American Diabetes Association issued a joint consensus statement endorsing a less stringent blood glucose target of 140-180 mg/dL in critically ill patients (Endocr. Prac 2009;15:353-69).

Subsequently, the Yale Protocol was revised yet again to a target blood glucose range of 120-160 mg/dL. That range was chosen because the AACE/ADA consensus statement had said that there might be additional benefit in keeping patients at the lower end of the recommended 140-180 mg/dL range, and with prior validated protocols the median blood glucose values always ended up at the upper end of the target range.

"We expected to stay at the lower end of the AACE/ADA target, which we did," Dr. Shetty said in an interview.

In the current study, clinical responses to the first 115 drips using the latest revised protocol were tracked for validation at Yale–New Haven Hospital. Minimal inservicing was required, since the nurses were already fully trained in the previous protocols. The protocol was triggered when a registered nurse identified a patient with two blood glucose values above 180 mg/dL.

The responsible physician then placed the order for the drip. Insulin was delivered via infusion pumps in 0.5 units/hour increments, with bolus and initial infusion rates determined by a formula based on the patient’s blood glucose value. While on the infusion, the protocol specifies that the patients’ blood glucose be checked hourly until glucose levels stabilize – defined as three consecutive values in target range – at which point the checks could be done less frequently.

Data were collected during September 2009 through January 2010. The 115 consecutive insulin infusions included 17 patients who were placed on the drip more than once. The patients had a mean age of 62 years, with a mean body mass index of 31.8 kg/m². About half (51%) were male, 65% were white, 17% black, 13% Hispanic, and 5% Asian. Two-thirds (64%) had a prior diagnosis of diabetes, and 44% had been using insulin at home prior to entering the ICU.

Admitting diagnoses included acute respiratory failure in 29%, sepsis in 25%, and bacterial pneumonia in 11%. Mean length of ICU stay was 19.5 days, and hospital stay, 36.4 days. The mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score – a well-validated severity of illness scoring system that predicts mortality with a 0-71 scale – was 24 (higher numbers mean worse prognosis). In NICE-SUGAR, the mean APACHE score was 21, compared with 9 for the 2001 study that led to the original Yale Protocol, Dr. Shetty noted.

Starting at a mean pre-infusion blood glucose of 306.1 mg/dL, the infusion brought the blood glucose down to a mean of 155.9 mg/dL once the target of less than 160 mg/dL was reached, in a mean of 8.3 hours. During the infusion, the mean nadir glucose value was 92.5 mg/dL. Patients spent a mean of 95 hours on the infusion, with a mean infusion dose of 3.9 units per hour. Once the target was achieved, the protocol maintained 42% of subsequent blood glucose values within the target 120-160 mg/dL, and 76% were less than 180 mg/dL, she reported.

Hypoglycemia was rare. Of a total 8,272 recorded blood glucose readings, just 0.3% were less than 70 mg/dL, and 0.02% were below 40 mg/dL. No deleterious effects attributable to low blood sugar were noted. These low rates of hypoglycemia were comparable to prior Yale ICU protocols. The proportion of patients experiencing blood glucose values of 40 mg/dL or less was just 1.7%, compared with a mean 2.1% in seven previous insulin infusion studies, she noted.

The new Yale protocol was "readily accepted and easily implemented by the medical ICU nursing staff, and can be easily implemented by hospitals that are currently utilizing one of the original Yale protocols," Dr. Shetty concluded.

Dr. Shetty stated that she has no conflicts of interest.

SAN DIEGO – An updated version of the Yale Insulin Infusion Protocol for intensive care unit management of hyperglycemia provided effective and safe targeted blood glucose control in compliance with national guidelines among 115 patients in Yale’s medical ICU.

Yale–New Haven (Conn.) Hospital has used a standardized intravenous insulin infusion protocol (IIP) in its medical ICU since 2003. The initial glucose target was 100-140 mg/dL, based on a 2001 study demonstrating the benefits of glycemic control in that range among critically ill patients (N. Engl. J. Med. 2001;345:1359-67). In 2005, the target was further lowered to 90-120 mg/dL. Both of those protocols were validated and published, and are used in many U.S. hospitals, said Dr. Shilpa Shetty, an academic hospitalist at Griffin Hospital, Derby, Conn., an affiliate of Yale–New Haven Hospital.

A change was prompted in 2009, when the Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study demonstrated significantly increased mortality among ICU patients undergoing intensive insulin therapy (N. Engl. J. Med. 2009;360:1283-97). Following that, the American Association of Clinical Endocrinologists and the American Diabetes Association issued a joint consensus statement endorsing a less stringent blood glucose target of 140-180 mg/dL in critically ill patients (Endocr. Prac 2009;15:353-69).

Subsequently, the Yale Protocol was revised yet again to a target blood glucose range of 120-160 mg/dL. That range was chosen because the AACE/ADA consensus statement had said that there might be additional benefit in keeping patients at the lower end of the recommended 140-180 mg/dL range, and with prior validated protocols the median blood glucose values always ended up at the upper end of the target range.

"We expected to stay at the lower end of the AACE/ADA target, which we did," Dr. Shetty said in an interview.

In the current study, clinical responses to the first 115 drips using the latest revised protocol were tracked for validation at Yale–New Haven Hospital. Minimal inservicing was required, since the nurses were already fully trained in the previous protocols. The protocol was triggered when a registered nurse identified a patient with two blood glucose values above 180 mg/dL.

The responsible physician then placed the order for the drip. Insulin was delivered via infusion pumps in 0.5 units/hour increments, with bolus and initial infusion rates determined by a formula based on the patient’s blood glucose value. While on the infusion, the protocol specifies that the patients’ blood glucose be checked hourly until glucose levels stabilize – defined as three consecutive values in target range – at which point the checks could be done less frequently.

Data were collected during September 2009 through January 2010. The 115 consecutive insulin infusions included 17 patients who were placed on the drip more than once. The patients had a mean age of 62 years, with a mean body mass index of 31.8 kg/m². About half (51%) were male, 65% were white, 17% black, 13% Hispanic, and 5% Asian. Two-thirds (64%) had a prior diagnosis of diabetes, and 44% had been using insulin at home prior to entering the ICU.

Admitting diagnoses included acute respiratory failure in 29%, sepsis in 25%, and bacterial pneumonia in 11%. Mean length of ICU stay was 19.5 days, and hospital stay, 36.4 days. The mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score – a well-validated severity of illness scoring system that predicts mortality with a 0-71 scale – was 24 (higher numbers mean worse prognosis). In NICE-SUGAR, the mean APACHE score was 21, compared with 9 for the 2001 study that led to the original Yale Protocol, Dr. Shetty noted.

Starting at a mean pre-infusion blood glucose of 306.1 mg/dL, the infusion brought the blood glucose down to a mean of 155.9 mg/dL once the target of less than 160 mg/dL was reached, in a mean of 8.3 hours. During the infusion, the mean nadir glucose value was 92.5 mg/dL. Patients spent a mean of 95 hours on the infusion, with a mean infusion dose of 3.9 units per hour. Once the target was achieved, the protocol maintained 42% of subsequent blood glucose values within the target 120-160 mg/dL, and 76% were less than 180 mg/dL, she reported.

Hypoglycemia was rare. Of a total 8,272 recorded blood glucose readings, just 0.3% were less than 70 mg/dL, and 0.02% were below 40 mg/dL. No deleterious effects attributable to low blood sugar were noted. These low rates of hypoglycemia were comparable to prior Yale ICU protocols. The proportion of patients experiencing blood glucose values of 40 mg/dL or less was just 1.7%, compared with a mean 2.1% in seven previous insulin infusion studies, she noted.

The new Yale protocol was "readily accepted and easily implemented by the medical ICU nursing staff, and can be easily implemented by hospitals that are currently utilizing one of the original Yale protocols," Dr. Shetty concluded.

Dr. Shetty stated that she has no conflicts of interest.

SAN DIEGO – More than one-third of type 1 diabetes cases from a large pediatric Medicaid population were misdiagnosed as having type 2 diabetes early in management, results from a 10-year analysis showed.

Such misclassification "may be associated with significantly increased risk of life-threatening but potentially preventable acute complications such as diabetic ketoacidosis," Dr. Avnish Tripathi said at the annual scientific sessions of the American Diabetes Association. "These findings have implications for primary health care of diabetes and reiterate the importance of performing laboratory tests such as autoantibody titers and C-peptide levels for establishing type 1 diabetes pathology earlier in the clinical management process."

The increasing prevalence of obesity "is changing the demographics and clinical manifestations of diabetes in children," said Dr. Tripathi, a doctoral candidate in the Arnold School of Public Health at the University of South Carolina, Columbia. "Then there are disease variations, such as double diabetes and ketosis-prone diabetes, which have further complicated the initial pediatric presentation of diabetes in terms of clear classification between type 1 and type 2 diabetes."

Misclassification can occur both ways, he continued. Since pediatric diabetes is traditionally assumed to be type 1, "it may be diagnosed as such even if characteristics point to type 2 diabetes. Because of increased awareness of type 2 diabetes in the pediatric population, type 1 diabetes in overweight or obese patients may be diagnosed as type 2 diabetes."

In an effort to characterize the rates of initial misclassification of type 1 diabetes as type 2 diabetes and to examine the impact of its clinical implications, Dr. Tripathi and his associates analyzed data from 4,070 subjects aged 17 years and younger enrolled in the South Carolina State Medicaid Program who had at least two initial service encounters with an ICD-9 diagnosis of type 2 diabetes between 1996 and 2006. They also evaluated ICD-9 codes for comorbid medical complications such as obesity and dyslipidemia, and for vascular and other complications such as diabetic ketoacidosis.

Of the 4,070 children and adolescents, more than half (57%) were female, 56% were non-Hispanic black, their median age was 8 years, and they were followed for a median of 7 years. Dr. Tripathi reported that 2,489 of the subjects (61%) maintained a diagnosis of type 2 diabetes over time while 39% were later reclassified as having type 1 (misclassification group).

Compared with their counterparts who maintained a diagnosis of type 2 diabetes over the follow-up period, a significantly higher proportion of youth in the misclassification group were treated with insulin (82% vs. 2%, respectively) and went on to develop dyslipidemia (P < 0.001) and hypertension (P = 0.0001).

After accounting for follow-up time and other variables, older age at diagnosis increased the risk of misclassification (odds ratio [OR] 1.66), while being obese or overweight decreased the risk of being in the misclassification group (OR 0.79).

Compared with those who maintained a diagnosis of type 2 diabetes, youth in the misclassification group had a 50-fold increased risk of at least one incidence of diabetic ketoacidosis (OR 49.5), nearly a fourfold increased risk of developing cumulative diabetic neuropathy (OR 3.75), a higher risk of cumulative renal complications (OR 1.27), and a lower risk of developing cardiac conditions (OR 0.81).

Dr. Tripathi also reported that older age was associated with increased risk of cumulative neuropathy (OR 1.79), renal complications (OR 1.17), and cardiovascular complications (OR 1.44).

He acknowledged certain limitations of the study, including ascertainment and information bias due to the use of administrative data, "but we tried to mitigate this by using more than one service encounter and use of concomitant medications to ascertain medical conditions. However, the direction of causality cannot be inferred from our results, and the results cannot be extrapolated to other regions and populations."

Dr. Tripathi said that he had no relevant financial disclosures.

SAN DIEGO – More than one-third of type 1 diabetes cases from a large pediatric Medicaid population were misdiagnosed as having type 2 diabetes early in management, results from a 10-year analysis showed.

Such misclassification "may be associated with significantly increased risk of life-threatening but potentially preventable acute complications such as diabetic ketoacidosis," Dr. Avnish Tripathi said at the annual scientific sessions of the American Diabetes Association. "These findings have implications for primary health care of diabetes and reiterate the importance of performing laboratory tests such as autoantibody titers and C-peptide levels for establishing type 1 diabetes pathology earlier in the clinical management process."

The increasing prevalence of obesity "is changing the demographics and clinical manifestations of diabetes in children," said Dr. Tripathi, a doctoral candidate in the Arnold School of Public Health at the University of South Carolina, Columbia. "Then there are disease variations, such as double diabetes and ketosis-prone diabetes, which have further complicated the initial pediatric presentation of diabetes in terms of clear classification between type 1 and type 2 diabetes."

Misclassification can occur both ways, he continued. Since pediatric diabetes is traditionally assumed to be type 1, "it may be diagnosed as such even if characteristics point to type 2 diabetes. Because of increased awareness of type 2 diabetes in the pediatric population, type 1 diabetes in overweight or obese patients may be diagnosed as type 2 diabetes."

In an effort to characterize the rates of initial misclassification of type 1 diabetes as type 2 diabetes and to examine the impact of its clinical implications, Dr. Tripathi and his associates analyzed data from 4,070 subjects aged 17 years and younger enrolled in the South Carolina State Medicaid Program who had at least two initial service encounters with an ICD-9 diagnosis of type 2 diabetes between 1996 and 2006. They also evaluated ICD-9 codes for comorbid medical complications such as obesity and dyslipidemia, and for vascular and other complications such as diabetic ketoacidosis.

Of the 4,070 children and adolescents, more than half (57%) were female, 56% were non-Hispanic black, their median age was 8 years, and they were followed for a median of 7 years. Dr. Tripathi reported that 2,489 of the subjects (61%) maintained a diagnosis of type 2 diabetes over time while 39% were later reclassified as having type 1 (misclassification group).

Compared with their counterparts who maintained a diagnosis of type 2 diabetes over the follow-up period, a significantly higher proportion of youth in the misclassification group were treated with insulin (82% vs. 2%, respectively) and went on to develop dyslipidemia (P < 0.001) and hypertension (P = 0.0001).

After accounting for follow-up time and other variables, older age at diagnosis increased the risk of misclassification (odds ratio [OR] 1.66), while being obese or overweight decreased the risk of being in the misclassification group (OR 0.79).

Compared with those who maintained a diagnosis of type 2 diabetes, youth in the misclassification group had a 50-fold increased risk of at least one incidence of diabetic ketoacidosis (OR 49.5), nearly a fourfold increased risk of developing cumulative diabetic neuropathy (OR 3.75), a higher risk of cumulative renal complications (OR 1.27), and a lower risk of developing cardiac conditions (OR 0.81).

Dr. Tripathi also reported that older age was associated with increased risk of cumulative neuropathy (OR 1.79), renal complications (OR 1.17), and cardiovascular complications (OR 1.44).

He acknowledged certain limitations of the study, including ascertainment and information bias due to the use of administrative data, "but we tried to mitigate this by using more than one service encounter and use of concomitant medications to ascertain medical conditions. However, the direction of causality cannot be inferred from our results, and the results cannot be extrapolated to other regions and populations."

Dr. Tripathi said that he had no relevant financial disclosures.

SAN DIEGO – More than one-third of type 1 diabetes cases from a large pediatric Medicaid population were misdiagnosed as having type 2 diabetes early in management, results from a 10-year analysis showed.

Such misclassification "may be associated with significantly increased risk of life-threatening but potentially preventable acute complications such as diabetic ketoacidosis," Dr. Avnish Tripathi said at the annual scientific sessions of the American Diabetes Association. "These findings have implications for primary health care of diabetes and reiterate the importance of performing laboratory tests such as autoantibody titers and C-peptide levels for establishing type 1 diabetes pathology earlier in the clinical management process."

The increasing prevalence of obesity "is changing the demographics and clinical manifestations of diabetes in children," said Dr. Tripathi, a doctoral candidate in the Arnold School of Public Health at the University of South Carolina, Columbia. "Then there are disease variations, such as double diabetes and ketosis-prone diabetes, which have further complicated the initial pediatric presentation of diabetes in terms of clear classification between type 1 and type 2 diabetes."

Misclassification can occur both ways, he continued. Since pediatric diabetes is traditionally assumed to be type 1, "it may be diagnosed as such even if characteristics point to type 2 diabetes. Because of increased awareness of type 2 diabetes in the pediatric population, type 1 diabetes in overweight or obese patients may be diagnosed as type 2 diabetes."

In an effort to characterize the rates of initial misclassification of type 1 diabetes as type 2 diabetes and to examine the impact of its clinical implications, Dr. Tripathi and his associates analyzed data from 4,070 subjects aged 17 years and younger enrolled in the South Carolina State Medicaid Program who had at least two initial service encounters with an ICD-9 diagnosis of type 2 diabetes between 1996 and 2006. They also evaluated ICD-9 codes for comorbid medical complications such as obesity and dyslipidemia, and for vascular and other complications such as diabetic ketoacidosis.

Of the 4,070 children and adolescents, more than half (57%) were female, 56% were non-Hispanic black, their median age was 8 years, and they were followed for a median of 7 years. Dr. Tripathi reported that 2,489 of the subjects (61%) maintained a diagnosis of type 2 diabetes over time while 39% were later reclassified as having type 1 (misclassification group).

Compared with their counterparts who maintained a diagnosis of type 2 diabetes over the follow-up period, a significantly higher proportion of youth in the misclassification group were treated with insulin (82% vs. 2%, respectively) and went on to develop dyslipidemia (P < 0.001) and hypertension (P = 0.0001).

After accounting for follow-up time and other variables, older age at diagnosis increased the risk of misclassification (odds ratio [OR] 1.66), while being obese or overweight decreased the risk of being in the misclassification group (OR 0.79).

Compared with those who maintained a diagnosis of type 2 diabetes, youth in the misclassification group had a 50-fold increased risk of at least one incidence of diabetic ketoacidosis (OR 49.5), nearly a fourfold increased risk of developing cumulative diabetic neuropathy (OR 3.75), a higher risk of cumulative renal complications (OR 1.27), and a lower risk of developing cardiac conditions (OR 0.81).

Dr. Tripathi also reported that older age was associated with increased risk of cumulative neuropathy (OR 1.79), renal complications (OR 1.17), and cardiovascular complications (OR 1.44).

He acknowledged certain limitations of the study, including ascertainment and information bias due to the use of administrative data, "but we tried to mitigate this by using more than one service encounter and use of concomitant medications to ascertain medical conditions. However, the direction of causality cannot be inferred from our results, and the results cannot be extrapolated to other regions and populations."

Dr. Tripathi said that he had no relevant financial disclosures.

SAN DIEGO – The investigational glucose-lowering agent dapagliflozin produced sustained glycemic efficacy and weight loss after 2 years in a phase III extension study of 624 patients with type 2 diabetes.

Genital and urinary tract infections were increased during the initial 52 weeks and through the 2-year extension. New data on cancers showed no overall excess, but there were increases in certain types of cancers, Dr. Michael A. Nauck reported in a late-breaking poster presentation at the annual scientific sessions of the American Diabetes Association.

Bristol-Myers Squibb and AstraZeneca’s dapagliflozin is a selective SGLT2 inhibitor that reduces hyperglycemia independently of insulin by promoting urinary glucose excretion. In the initial 52-week double-blind trial presented last fall at the meeting of the European Association for the Study of Diabetes, a total of 814 patients with type 2 diabetes who were inadequately controlled on metformin alone were randomized to up to 10 mg/day of dapagliflozin or up to 20 mg/day of glipizide as add-on therapy to 2,000 mg/day of metformin.

In both groups, there were identical mean reductions in hemoglobin A_1c of 0.52 percentage points from a baseline mean of 7.72% (the primary end point of noninferiority). However, dapagliflozin was associated with a 3.2 kg mean weight loss, whereas the glipizide group gained an average of 1.4 kg. Hypoglycemia was also dramatically less with dapagliflozin than with glipizide, 3.5% vs. 40.8%, Dr. Nauck, head of the Diabetes Center, Bad Lauterberg, Germany, reported at EASD.

In the extension study, which was primarily aimed at assessing safety, patients continued to receive dapagliflozin (n = 315) or glipizide (n = 309) added to metformin. At the end of year 2, there was a 0.32 percentage point drop from baseline in HbA_1c with dapagliflozin, compared with just 0.14 with glipizide. Body weight loss was also sustained, at 3.70 kg, compared with a gain of 1.36 kg with glipizide. Just as at 1 year, hypoglycemia was significantly lower at 2 years with dapagliflozin, 4.2%, compared with 45.8% with glipizide.

On active questioning, the proportion of patients who reported signs, symptoms, and events suggestive of urinary tract infection was 13.5% for dapagliflozin, compared with 9.1% for glipizide. And for signs, symptoms, and events suggesting genital infections, the difference was 14.8% vs. 2.9%, respectively. The difference was even greater for the women, with 23.3% reporting genital infection, compared with 5.9% with glipizide. However, most infections occurred during the first year, were mild to moderate in intensity, and responded to standard care. There was one discontinuation in each arm because of a UTI and three in the dapagliflozin arm because of genital infection in the first year. There were no discontinuations from either type of infection during the second year, Dr. Nauck reported.

In all dapagliflozin studies to date, there have been no imbalances in malignant tumors. However, there were increases in two specific tumor types. Nine bladder cancers occurred among 5,478 patients on dapagliflozin and in one of 3,156 patients in control groups. A total of 6 of these 10 had hematuria at baseline and 5 were diagnosed within a year after the study start. Nine breast cancers have also occurred in 2,223 women on dapagliflozin and one in 1,053 women in control groups. All were diagnosed within a year after study start.

In preclinical studies, dapagliflozin was not shown to be genotoxic or carcinogenic and the agent has no known off-target pharmacology. The SGLT2 receptor is not expressed in the breast or in the bladder, Dr. Nauck noted.

These clinical and preclinical data have been shared with the Food and Drug Administration and other health authorities and were reviewed fully at the scheduled Endocrinologic and Metabolic Drugs Advisory Committee on July 19. In a 9-6 vote, the committee recommended against approval, citing concerns about bladder and breast cancer incidence among treated patients in the clinical trial, compared with controls.

Dr. Nauck said that patients who are at risk for more urinary tract and genital infections from diabetes plus glycosuria would need to be defined, and that dapagliflozin should be preferentially used in those at low risk. "Attempts to define strata for low and high risk are urgently needed, because generally, infection rates up to more than 20% are hardly acceptable. It should be noted that, as with all novel diabetes medications, clinical studies aiming at a reduction in diabetic complications have yet to be started and are not currently available."

As for the tumor findings, "a numerical excess was found in dapagliflozin vs. comparator-treated patients regarding bladder and breast cancer. These findings, based on the small numbers and short follow-up do not prove a causal relationship, but warrant further studies to finally assess any risk concerning the promotion of tumor growth. Also, a true benefit needs to be shown in large-scale studies assessing clinical outcomes, because one needs to judge the benefits and risks in relation to each other."

Both the initial 52-week study and the 2-year extension trial were funded by BMS and AstraZeneca.

Dr. Nauck has been member on advisory boards or has consulted with AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Hoffman La Roche, Menarini/Berlin-Chemie, Merck, Sharp & Dohme, Novo Nordisk, and Versatis. He has received grant support from and served on the speakers bureau of Eli Lilly, Menarini/Berlin-Chemie, Merck, Sharp & Dohme as well as serving on the speakers bureau of AstraZeneca, Boehringer Ingelheim, Hoffman La Roche, and Novo Nordisk.

SAN DIEGO – The investigational glucose-lowering agent dapagliflozin produced sustained glycemic efficacy and weight loss after 2 years in a phase III extension study of 624 patients with type 2 diabetes.

Genital and urinary tract infections were increased during the initial 52 weeks and through the 2-year extension. New data on cancers showed no overall excess, but there were increases in certain types of cancers, Dr. Michael A. Nauck reported in a late-breaking poster presentation at the annual scientific sessions of the American Diabetes Association.

Bristol-Myers Squibb and AstraZeneca’s dapagliflozin is a selective SGLT2 inhibitor that reduces hyperglycemia independently of insulin by promoting urinary glucose excretion. In the initial 52-week double-blind trial presented last fall at the meeting of the European Association for the Study of Diabetes, a total of 814 patients with type 2 diabetes who were inadequately controlled on metformin alone were randomized to up to 10 mg/day of dapagliflozin or up to 20 mg/day of glipizide as add-on therapy to 2,000 mg/day of metformin.

In both groups, there were identical mean reductions in hemoglobin A_1c of 0.52 percentage points from a baseline mean of 7.72% (the primary end point of noninferiority). However, dapagliflozin was associated with a 3.2 kg mean weight loss, whereas the glipizide group gained an average of 1.4 kg. Hypoglycemia was also dramatically less with dapagliflozin than with glipizide, 3.5% vs. 40.8%, Dr. Nauck, head of the Diabetes Center, Bad Lauterberg, Germany, reported at EASD.

In the extension study, which was primarily aimed at assessing safety, patients continued to receive dapagliflozin (n = 315) or glipizide (n = 309) added to metformin. At the end of year 2, there was a 0.32 percentage point drop from baseline in HbA_1c with dapagliflozin, compared with just 0.14 with glipizide. Body weight loss was also sustained, at 3.70 kg, compared with a gain of 1.36 kg with glipizide. Just as at 1 year, hypoglycemia was significantly lower at 2 years with dapagliflozin, 4.2%, compared with 45.8% with glipizide.

On active questioning, the proportion of patients who reported signs, symptoms, and events suggestive of urinary tract infection was 13.5% for dapagliflozin, compared with 9.1% for glipizide. And for signs, symptoms, and events suggesting genital infections, the difference was 14.8% vs. 2.9%, respectively. The difference was even greater for the women, with 23.3% reporting genital infection, compared with 5.9% with glipizide. However, most infections occurred during the first year, were mild to moderate in intensity, and responded to standard care. There was one discontinuation in each arm because of a UTI and three in the dapagliflozin arm because of genital infection in the first year. There were no discontinuations from either type of infection during the second year, Dr. Nauck reported.

In all dapagliflozin studies to date, there have been no imbalances in malignant tumors. However, there were increases in two specific tumor types. Nine bladder cancers occurred among 5,478 patients on dapagliflozin and in one of 3,156 patients in control groups. A total of 6 of these 10 had hematuria at baseline and 5 were diagnosed within a year after the study start. Nine breast cancers have also occurred in 2,223 women on dapagliflozin and one in 1,053 women in control groups. All were diagnosed within a year after study start.

In preclinical studies, dapagliflozin was not shown to be genotoxic or carcinogenic and the agent has no known off-target pharmacology. The SGLT2 receptor is not expressed in the breast or in the bladder, Dr. Nauck noted.

These clinical and preclinical data have been shared with the Food and Drug Administration and other health authorities and were reviewed fully at the scheduled Endocrinologic and Metabolic Drugs Advisory Committee on July 19. In a 9-6 vote, the committee recommended against approval, citing concerns about bladder and breast cancer incidence among treated patients in the clinical trial, compared with controls.

Dr. Nauck said that patients who are at risk for more urinary tract and genital infections from diabetes plus glycosuria would need to be defined, and that dapagliflozin should be preferentially used in those at low risk. "Attempts to define strata for low and high risk are urgently needed, because generally, infection rates up to more than 20% are hardly acceptable. It should be noted that, as with all novel diabetes medications, clinical studies aiming at a reduction in diabetic complications have yet to be started and are not currently available."

As for the tumor findings, "a numerical excess was found in dapagliflozin vs. comparator-treated patients regarding bladder and breast cancer. These findings, based on the small numbers and short follow-up do not prove a causal relationship, but warrant further studies to finally assess any risk concerning the promotion of tumor growth. Also, a true benefit needs to be shown in large-scale studies assessing clinical outcomes, because one needs to judge the benefits and risks in relation to each other."

Both the initial 52-week study and the 2-year extension trial were funded by BMS and AstraZeneca.

Dr. Nauck has been member on advisory boards or has consulted with AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Hoffman La Roche, Menarini/Berlin-Chemie, Merck, Sharp & Dohme, Novo Nordisk, and Versatis. He has received grant support from and served on the speakers bureau of Eli Lilly, Menarini/Berlin-Chemie, Merck, Sharp & Dohme as well as serving on the speakers bureau of AstraZeneca, Boehringer Ingelheim, Hoffman La Roche, and Novo Nordisk.

SAN DIEGO – The investigational glucose-lowering agent dapagliflozin produced sustained glycemic efficacy and weight loss after 2 years in a phase III extension study of 624 patients with type 2 diabetes.

Genital and urinary tract infections were increased during the initial 52 weeks and through the 2-year extension. New data on cancers showed no overall excess, but there were increases in certain types of cancers, Dr. Michael A. Nauck reported in a late-breaking poster presentation at the annual scientific sessions of the American Diabetes Association.

Bristol-Myers Squibb and AstraZeneca’s dapagliflozin is a selective SGLT2 inhibitor that reduces hyperglycemia independently of insulin by promoting urinary glucose excretion. In the initial 52-week double-blind trial presented last fall at the meeting of the European Association for the Study of Diabetes, a total of 814 patients with type 2 diabetes who were inadequately controlled on metformin alone were randomized to up to 10 mg/day of dapagliflozin or up to 20 mg/day of glipizide as add-on therapy to 2,000 mg/day of metformin.

In both groups, there were identical mean reductions in hemoglobin A_1c of 0.52 percentage points from a baseline mean of 7.72% (the primary end point of noninferiority). However, dapagliflozin was associated with a 3.2 kg mean weight loss, whereas the glipizide group gained an average of 1.4 kg. Hypoglycemia was also dramatically less with dapagliflozin than with glipizide, 3.5% vs. 40.8%, Dr. Nauck, head of the Diabetes Center, Bad Lauterberg, Germany, reported at EASD.

In the extension study, which was primarily aimed at assessing safety, patients continued to receive dapagliflozin (n = 315) or glipizide (n = 309) added to metformin. At the end of year 2, there was a 0.32 percentage point drop from baseline in HbA_1c with dapagliflozin, compared with just 0.14 with glipizide. Body weight loss was also sustained, at 3.70 kg, compared with a gain of 1.36 kg with glipizide. Just as at 1 year, hypoglycemia was significantly lower at 2 years with dapagliflozin, 4.2%, compared with 45.8% with glipizide.

On active questioning, the proportion of patients who reported signs, symptoms, and events suggestive of urinary tract infection was 13.5% for dapagliflozin, compared with 9.1% for glipizide. And for signs, symptoms, and events suggesting genital infections, the difference was 14.8% vs. 2.9%, respectively. The difference was even greater for the women, with 23.3% reporting genital infection, compared with 5.9% with glipizide. However, most infections occurred during the first year, were mild to moderate in intensity, and responded to standard care. There was one discontinuation in each arm because of a UTI and three in the dapagliflozin arm because of genital infection in the first year. There were no discontinuations from either type of infection during the second year, Dr. Nauck reported.

In all dapagliflozin studies to date, there have been no imbalances in malignant tumors. However, there were increases in two specific tumor types. Nine bladder cancers occurred among 5,478 patients on dapagliflozin and in one of 3,156 patients in control groups. A total of 6 of these 10 had hematuria at baseline and 5 were diagnosed within a year after the study start. Nine breast cancers have also occurred in 2,223 women on dapagliflozin and one in 1,053 women in control groups. All were diagnosed within a year after study start.

In preclinical studies, dapagliflozin was not shown to be genotoxic or carcinogenic and the agent has no known off-target pharmacology. The SGLT2 receptor is not expressed in the breast or in the bladder, Dr. Nauck noted.

These clinical and preclinical data have been shared with the Food and Drug Administration and other health authorities and were reviewed fully at the scheduled Endocrinologic and Metabolic Drugs Advisory Committee on July 19. In a 9-6 vote, the committee recommended against approval, citing concerns about bladder and breast cancer incidence among treated patients in the clinical trial, compared with controls.

Dr. Nauck said that patients who are at risk for more urinary tract and genital infections from diabetes plus glycosuria would need to be defined, and that dapagliflozin should be preferentially used in those at low risk. "Attempts to define strata for low and high risk are urgently needed, because generally, infection rates up to more than 20% are hardly acceptable. It should be noted that, as with all novel diabetes medications, clinical studies aiming at a reduction in diabetic complications have yet to be started and are not currently available."

As for the tumor findings, "a numerical excess was found in dapagliflozin vs. comparator-treated patients regarding bladder and breast cancer. These findings, based on the small numbers and short follow-up do not prove a causal relationship, but warrant further studies to finally assess any risk concerning the promotion of tumor growth. Also, a true benefit needs to be shown in large-scale studies assessing clinical outcomes, because one needs to judge the benefits and risks in relation to each other."

Both the initial 52-week study and the 2-year extension trial were funded by BMS and AstraZeneca.

Dr. Nauck has been member on advisory boards or has consulted with AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Hoffman La Roche, Menarini/Berlin-Chemie, Merck, Sharp & Dohme, Novo Nordisk, and Versatis. He has received grant support from and served on the speakers bureau of Eli Lilly, Menarini/Berlin-Chemie, Merck, Sharp & Dohme as well as serving on the speakers bureau of AstraZeneca, Boehringer Ingelheim, Hoffman La Roche, and Novo Nordisk.

SAN DIEGO – Treatment with the investigational device ITCA 650 delivering exenatide at 20 mcg/day and dose escalation to 60 mcg/day was well tolerated and led to significant reductions in HbA_1c and body weight in patients with type 2 diabetes, results from a phase II, 48-week extension study showed.

ITCA 650 is manufactured by Intarcia Therapeutics of Hayward, Calif., and is a matchstick-size, osmotic mini-pump using the DUROS technology that is placed subcutaneously, providing continuous and consistent delivery of exenatide (Byetta) at specified doses. The device is inserted during a 10- to 15-minute office procedure. ITCA 650 has been shown to be effective in lowering HbA_1c and having a favorable weight profile at 12 and 24 weeks, Dr. Julio Rosenstock said at the annual scientific sessions of the American Diabetes Association, where he presented the results of the 48-week extension of the study that demonstrated sustained effects.

"Therefore, this device has the potential for greater adherence using ITCA 650 devices that can deliver 6 or 12 months of treatment with a single placement," said Dr. Rosenstock, an endocrinologist who directs the Dallas Diabetes and Endocrine Center at Medical City and who served as the current study’s principal investigator. "It also may result in enhanced efficacy and a reduced side effect profile."

In a trial conducted at 50 sites, 155 patients treated with metformin who had baseline HbA_1c levels between 7% and 10% were enrolled in a 24-week study and were randomized to receive ITCA 650 at 20, 40, 60, or 80 mcg/day following initial 12 weeks of either ITCA 650 (20 or 40 mcg/day) or exenatide injections (10 mcg b.i.d. self-injection). At week 24, Dr. Rosenstock and his associates offered patients the option to continue treatment at their current dose for an additional 12 weeks. A total of 86 patients from 35 of the original 50 sites entered the extension study.

Dr. Rosenstock reported that continued reductions in HbA_1c and weight were observed across all ITCA 650 treatment arms at week 48, compared with week 24, with the greatest reductions seen in the 60 mcg/day and 80 mcg/day arms. Between baseline and week 48, the mean HbA_1c improved 1% in the 20 mcg/day arm (from 7.8% to 6.8%), 1% in the 40 mcg/day arm (from 7.8% to 6.8%), 1.5% in the 60 mcg/day arm (from 8.1% to 6.6%), and 1.4% in the 80 mcg/day arm (from 7.9% to 6.5%). Weight reductions were observed in all treatment arms (mean reductions of 6, 10.8, 7.7, and 7.9 pounds, respectively).

There were no treatment discontinuations between weeks 24 and 48 in the group initially treated with 20 mcg/day and then escalated to 60 mcg/day, Dr. Rosenstock said. The chief side effects in all of the dose groups were nausea (10.5%) and diarrhea (3.5%). Other reported side effects were related to the skin at the placement site and included irritation (7%), pain (7%), erythema (4.7%), pruritus (3.5%), and hematoma (3.5%).

"These results support further evaluation of ITCA 650 using longer duration subcutaneous devices for injection-free exenatide therapy in type 2 diabetes," Dr. Rosenstock said.

According to a prepared statement from Intarcia, a phase III study planned for 2011 will evaluate treatment regimens involving initial 12-week ITCA dosing at 20 mcg/day transitioning to 60 mcg/day thereafter using ITCA 650 devices of both 6- and 12-month duration.

Dr. Rosenstock disclosed that he has relationships with numerous pharmaceutical and device companies, including Intarcia Therapeutics, in the form of research support, advisory board roles, and consulting honorariums.

SAN DIEGO – Treatment with the investigational device ITCA 650 delivering exenatide at 20 mcg/day and dose escalation to 60 mcg/day was well tolerated and led to significant reductions in HbA_1c and body weight in patients with type 2 diabetes, results from a phase II, 48-week extension study showed.

ITCA 650 is manufactured by Intarcia Therapeutics of Hayward, Calif., and is a matchstick-size, osmotic mini-pump using the DUROS technology that is placed subcutaneously, providing continuous and consistent delivery of exenatide (Byetta) at specified doses. The device is inserted during a 10- to 15-minute office procedure. ITCA 650 has been shown to be effective in lowering HbA_1c and having a favorable weight profile at 12 and 24 weeks, Dr. Julio Rosenstock said at the annual scientific sessions of the American Diabetes Association, where he presented the results of the 48-week extension of the study that demonstrated sustained effects.

"Therefore, this device has the potential for greater adherence using ITCA 650 devices that can deliver 6 or 12 months of treatment with a single placement," said Dr. Rosenstock, an endocrinologist who directs the Dallas Diabetes and Endocrine Center at Medical City and who served as the current study’s principal investigator. "It also may result in enhanced efficacy and a reduced side effect profile."

In a trial conducted at 50 sites, 155 patients treated with metformin who had baseline HbA_1c levels between 7% and 10% were enrolled in a 24-week study and were randomized to receive ITCA 650 at 20, 40, 60, or 80 mcg/day following initial 12 weeks of either ITCA 650 (20 or 40 mcg/day) or exenatide injections (10 mcg b.i.d. self-injection). At week 24, Dr. Rosenstock and his associates offered patients the option to continue treatment at their current dose for an additional 12 weeks. A total of 86 patients from 35 of the original 50 sites entered the extension study.

Dr. Rosenstock reported that continued reductions in HbA_1c and weight were observed across all ITCA 650 treatment arms at week 48, compared with week 24, with the greatest reductions seen in the 60 mcg/day and 80 mcg/day arms. Between baseline and week 48, the mean HbA_1c improved 1% in the 20 mcg/day arm (from 7.8% to 6.8%), 1% in the 40 mcg/day arm (from 7.8% to 6.8%), 1.5% in the 60 mcg/day arm (from 8.1% to 6.6%), and 1.4% in the 80 mcg/day arm (from 7.9% to 6.5%). Weight reductions were observed in all treatment arms (mean reductions of 6, 10.8, 7.7, and 7.9 pounds, respectively).

There were no treatment discontinuations between weeks 24 and 48 in the group initially treated with 20 mcg/day and then escalated to 60 mcg/day, Dr. Rosenstock said. The chief side effects in all of the dose groups were nausea (10.5%) and diarrhea (3.5%). Other reported side effects were related to the skin at the placement site and included irritation (7%), pain (7%), erythema (4.7%), pruritus (3.5%), and hematoma (3.5%).

"These results support further evaluation of ITCA 650 using longer duration subcutaneous devices for injection-free exenatide therapy in type 2 diabetes," Dr. Rosenstock said.

According to a prepared statement from Intarcia, a phase III study planned for 2011 will evaluate treatment regimens involving initial 12-week ITCA dosing at 20 mcg/day transitioning to 60 mcg/day thereafter using ITCA 650 devices of both 6- and 12-month duration.

Dr. Rosenstock disclosed that he has relationships with numerous pharmaceutical and device companies, including Intarcia Therapeutics, in the form of research support, advisory board roles, and consulting honorariums.

SAN DIEGO – Treatment with the investigational device ITCA 650 delivering exenatide at 20 mcg/day and dose escalation to 60 mcg/day was well tolerated and led to significant reductions in HbA_1c and body weight in patients with type 2 diabetes, results from a phase II, 48-week extension study showed.

ITCA 650 is manufactured by Intarcia Therapeutics of Hayward, Calif., and is a matchstick-size, osmotic mini-pump using the DUROS technology that is placed subcutaneously, providing continuous and consistent delivery of exenatide (Byetta) at specified doses. The device is inserted during a 10- to 15-minute office procedure. ITCA 650 has been shown to be effective in lowering HbA_1c and having a favorable weight profile at 12 and 24 weeks, Dr. Julio Rosenstock said at the annual scientific sessions of the American Diabetes Association, where he presented the results of the 48-week extension of the study that demonstrated sustained effects.

"Therefore, this device has the potential for greater adherence using ITCA 650 devices that can deliver 6 or 12 months of treatment with a single placement," said Dr. Rosenstock, an endocrinologist who directs the Dallas Diabetes and Endocrine Center at Medical City and who served as the current study’s principal investigator. "It also may result in enhanced efficacy and a reduced side effect profile."

In a trial conducted at 50 sites, 155 patients treated with metformin who had baseline HbA_1c levels between 7% and 10% were enrolled in a 24-week study and were randomized to receive ITCA 650 at 20, 40, 60, or 80 mcg/day following initial 12 weeks of either ITCA 650 (20 or 40 mcg/day) or exenatide injections (10 mcg b.i.d. self-injection). At week 24, Dr. Rosenstock and his associates offered patients the option to continue treatment at their current dose for an additional 12 weeks. A total of 86 patients from 35 of the original 50 sites entered the extension study.

Dr. Rosenstock reported that continued reductions in HbA_1c and weight were observed across all ITCA 650 treatment arms at week 48, compared with week 24, with the greatest reductions seen in the 60 mcg/day and 80 mcg/day arms. Between baseline and week 48, the mean HbA_1c improved 1% in the 20 mcg/day arm (from 7.8% to 6.8%), 1% in the 40 mcg/day arm (from 7.8% to 6.8%), 1.5% in the 60 mcg/day arm (from 8.1% to 6.6%), and 1.4% in the 80 mcg/day arm (from 7.9% to 6.5%). Weight reductions were observed in all treatment arms (mean reductions of 6, 10.8, 7.7, and 7.9 pounds, respectively).

There were no treatment discontinuations between weeks 24 and 48 in the group initially treated with 20 mcg/day and then escalated to 60 mcg/day, Dr. Rosenstock said. The chief side effects in all of the dose groups were nausea (10.5%) and diarrhea (3.5%). Other reported side effects were related to the skin at the placement site and included irritation (7%), pain (7%), erythema (4.7%), pruritus (3.5%), and hematoma (3.5%).

"These results support further evaluation of ITCA 650 using longer duration subcutaneous devices for injection-free exenatide therapy in type 2 diabetes," Dr. Rosenstock said.

According to a prepared statement from Intarcia, a phase III study planned for 2011 will evaluate treatment regimens involving initial 12-week ITCA dosing at 20 mcg/day transitioning to 60 mcg/day thereafter using ITCA 650 devices of both 6- and 12-month duration.

Dr. Rosenstock disclosed that he has relationships with numerous pharmaceutical and device companies, including Intarcia Therapeutics, in the form of research support, advisory board roles, and consulting honorariums.

SAN DIEGO – Slightly more than half of veterans targeted for screening have unrecognized diabetes or prediabetes, results from a recent analysis showed.

However, screening such patients by measuring hemoglobin A_1c "would result in major misclassification – missing disease when it is present and, to a lesser extent, mislabeling normals as having disease," Sandra L. Jackson, M.P.H., said at the annual scientific sessions of the American Diabetes Association.

The findings are based on a study of 789 individuals from the Atlanta VA Medical Center that assessed the use of targeted screening to detect prediabetes and diabetes, and to compare HbA_1c testing with the oral glucose tolerance test (OGTT), said Ms. Jackson, a graduate student in the nutrition and health sciences doctoral program at Emory University, Atlanta.

Although screening to detect unrecognized diabetes and prediabetes is recommended, the best strategy for screening in patients in primary care settings is unknown. The upside of the OGTT, Ms. Jackson said, is that it’s established in clinical use, it can detect all patients with prediabetes, and the glucose measurement itself is accurate. However, "on the downside, it requires [fasting] and morning testing. It’s burdensome for patients and health care systems, and it has poor day-to-day reproducibility."

The upside of HbA_1c, she continued, is that it does not require a fast, "and it’s only a single blood draw, so it’s much more convenient, there’s less day-to-day variation, and there’s greater preanalytic stability. On the downside, measurement may be problematic as platforms vary, point-of-care testing can be unreliable, there’s a lack of agreement on cutoffs, and there may be racial and age disparities such that blacks and older persons may have higher HbA_1c independent of glucose."

The researchers defined hyperglycemia according to American Diabetes Association (ADA) criteria: prediabetes as a fasting OGTT of 100-125 mg/dL or a 2-hour OGTT of 149-199 mg/dL, and diabetes as a fasting OGTT of 126 mg/dL or greater or a 2-hour OGTT of 200 mg/dL or greater.

They categorized HbA_1c results according to three sets of diagnostic criteria: the International Expert Committee (IEC) (prediabetes 6.0%-6.4%, diabetes 6.5% or greater), ADA (prediabetes 5.7%-6.4%, diabetes 6.5% or greater), and Department of Veterans Affairs/Department of Defense (VA/DoD) (prediabetes 5.7%-6.9%, diabetes 7.0% or greater).

The mean age of the 789 study participants was 58 years, 95% were men, 74% were black, and their mean BMI was 30.5 kg/m².

Screening was offered to patients meeting National Institutes of Health guidelines for screening: without known diabetes, and with age greater than 45 years or a BMI of more than 25 with another risk factor.

Fully 10% of patients met criteria for diabetes based on the OGTT, which was a higher rate compared with the HbA_1c guidelines (6.7% by the IEC, 6.7% by the ADA, and 1.5% by the VA/DoD guidelines, respectively). "This would indicate that these cutoffs are insensitive compared with the OGTT for detecting diabetes," she said.

According to the OGTT, 42% had prediabetes: 27% had isolated impaired fasting glucose, 6% had isolated impaired glucose tolerance, and 9% had both.

In patients with diabetes by OGTT criteria, HbA_1c classification by IEC criteria labeled 32% correctly, 38% incorrectly as having prediabetes, and 29% incorrectly as being normal; ADA criteria labeled 32% correctly, 50% incorrectly as having prediabetes, and 18% incorrectly as being normal; and VA/DoD criteria labeled 12% correctly, 71% incorrectly as having prediabetes, and 18% incorrectly as being normal.

In patients with prediabetes by OGTT criteria, HbA_1c classification by IEC criteria labeled 36% correctly, 6% incorrectly as having diabetes, and 59% incorrectly as being normal; ADA criteria labeled 61% correctly, 6% incorrectly as having diabetes, and 33% incorrectly as being normal; and VA/DoD criteria labeled 66% correctly, 1% incorrectly as having diabetes, and 33% incorrectly as being normal.

The prevalence of diabetes increased in a stepwise fashion with increasing BMI, from 1.5% among those with a normal BMI (18.5-24.9) to 15% among those who met criteria for class III obesity (BMI more than 40). "For every 1 unit increase in BMI, we observed a 10% increase in the odds of having diabetes," she said.

Ms. Jackson also reported that with the IEC, ADA, and VA/DoD cutoffs for diabetes, screening with HbA_1c was specific but insensitive, with a false negative rate of 68% at the 6.5% cutoff and a false negative rate of 89% at the 7.0% cutoff.

"Many veterans – and probably many Americans – targeted by national guidelines have unrecognized diabetes and prediabetes, yet screening with HbA_1c would miss many," she said. "Given these findings, we should consider or develop alternative diabetes screening strategies that can be used opportunistically during outpatient visits, without fasting, but are more accurate."

The study was supported by a grant from the VA’s Health Services Research and Development Service. Ms. Jackson said that she had no relevant financial conflicts of interest.

SAN DIEGO – Slightly more than half of veterans targeted for screening have unrecognized diabetes or prediabetes, results from a recent analysis showed.

However, screening such patients by measuring hemoglobin A_1c "would result in major misclassification – missing disease when it is present and, to a lesser extent, mislabeling normals as having disease," Sandra L. Jackson, M.P.H., said at the annual scientific sessions of the American Diabetes Association.

The findings are based on a study of 789 individuals from the Atlanta VA Medical Center that assessed the use of targeted screening to detect prediabetes and diabetes, and to compare HbA_1c testing with the oral glucose tolerance test (OGTT), said Ms. Jackson, a graduate student in the nutrition and health sciences doctoral program at Emory University, Atlanta.

Although screening to detect unrecognized diabetes and prediabetes is recommended, the best strategy for screening in patients in primary care settings is unknown. The upside of the OGTT, Ms. Jackson said, is that it’s established in clinical use, it can detect all patients with prediabetes, and the glucose measurement itself is accurate. However, "on the downside, it requires [fasting] and morning testing. It’s burdensome for patients and health care systems, and it has poor day-to-day reproducibility."

The upside of HbA_1c, she continued, is that it does not require a fast, "and it’s only a single blood draw, so it’s much more convenient, there’s less day-to-day variation, and there’s greater preanalytic stability. On the downside, measurement may be problematic as platforms vary, point-of-care testing can be unreliable, there’s a lack of agreement on cutoffs, and there may be racial and age disparities such that blacks and older persons may have higher HbA_1c independent of glucose."

The researchers defined hyperglycemia according to American Diabetes Association (ADA) criteria: prediabetes as a fasting OGTT of 100-125 mg/dL or a 2-hour OGTT of 149-199 mg/dL, and diabetes as a fasting OGTT of 126 mg/dL or greater or a 2-hour OGTT of 200 mg/dL or greater.

They categorized HbA_1c results according to three sets of diagnostic criteria: the International Expert Committee (IEC) (prediabetes 6.0%-6.4%, diabetes 6.5% or greater), ADA (prediabetes 5.7%-6.4%, diabetes 6.5% or greater), and Department of Veterans Affairs/Department of Defense (VA/DoD) (prediabetes 5.7%-6.9%, diabetes 7.0% or greater).

The mean age of the 789 study participants was 58 years, 95% were men, 74% were black, and their mean BMI was 30.5 kg/m².

Screening was offered to patients meeting National Institutes of Health guidelines for screening: without known diabetes, and with age greater than 45 years or a BMI of more than 25 with another risk factor.

Fully 10% of patients met criteria for diabetes based on the OGTT, which was a higher rate compared with the HbA_1c guidelines (6.7% by the IEC, 6.7% by the ADA, and 1.5% by the VA/DoD guidelines, respectively). "This would indicate that these cutoffs are insensitive compared with the OGTT for detecting diabetes," she said.

According to the OGTT, 42% had prediabetes: 27% had isolated impaired fasting glucose, 6% had isolated impaired glucose tolerance, and 9% had both.

In patients with diabetes by OGTT criteria, HbA_1c classification by IEC criteria labeled 32% correctly, 38% incorrectly as having prediabetes, and 29% incorrectly as being normal; ADA criteria labeled 32% correctly, 50% incorrectly as having prediabetes, and 18% incorrectly as being normal; and VA/DoD criteria labeled 12% correctly, 71% incorrectly as having prediabetes, and 18% incorrectly as being normal.

In patients with prediabetes by OGTT criteria, HbA_1c classification by IEC criteria labeled 36% correctly, 6% incorrectly as having diabetes, and 59% incorrectly as being normal; ADA criteria labeled 61% correctly, 6% incorrectly as having diabetes, and 33% incorrectly as being normal; and VA/DoD criteria labeled 66% correctly, 1% incorrectly as having diabetes, and 33% incorrectly as being normal.

The prevalence of diabetes increased in a stepwise fashion with increasing BMI, from 1.5% among those with a normal BMI (18.5-24.9) to 15% among those who met criteria for class III obesity (BMI more than 40). "For every 1 unit increase in BMI, we observed a 10% increase in the odds of having diabetes," she said.

Ms. Jackson also reported that with the IEC, ADA, and VA/DoD cutoffs for diabetes, screening with HbA_1c was specific but insensitive, with a false negative rate of 68% at the 6.5% cutoff and a false negative rate of 89% at the 7.0% cutoff.

"Many veterans – and probably many Americans – targeted by national guidelines have unrecognized diabetes and prediabetes, yet screening with HbA_1c would miss many," she said. "Given these findings, we should consider or develop alternative diabetes screening strategies that can be used opportunistically during outpatient visits, without fasting, but are more accurate."

The study was supported by a grant from the VA’s Health Services Research and Development Service. Ms. Jackson said that she had no relevant financial conflicts of interest.

SAN DIEGO – Slightly more than half of veterans targeted for screening have unrecognized diabetes or prediabetes, results from a recent analysis showed.

However, screening such patients by measuring hemoglobin A_1c "would result in major misclassification – missing disease when it is present and, to a lesser extent, mislabeling normals as having disease," Sandra L. Jackson, M.P.H., said at the annual scientific sessions of the American Diabetes Association.

The findings are based on a study of 789 individuals from the Atlanta VA Medical Center that assessed the use of targeted screening to detect prediabetes and diabetes, and to compare HbA_1c testing with the oral glucose tolerance test (OGTT), said Ms. Jackson, a graduate student in the nutrition and health sciences doctoral program at Emory University, Atlanta.

Although screening to detect unrecognized diabetes and prediabetes is recommended, the best strategy for screening in patients in primary care settings is unknown. The upside of the OGTT, Ms. Jackson said, is that it’s established in clinical use, it can detect all patients with prediabetes, and the glucose measurement itself is accurate. However, "on the downside, it requires [fasting] and morning testing. It’s burdensome for patients and health care systems, and it has poor day-to-day reproducibility."

The upside of HbA_1c, she continued, is that it does not require a fast, "and it’s only a single blood draw, so it’s much more convenient, there’s less day-to-day variation, and there’s greater preanalytic stability. On the downside, measurement may be problematic as platforms vary, point-of-care testing can be unreliable, there’s a lack of agreement on cutoffs, and there may be racial and age disparities such that blacks and older persons may have higher HbA_1c independent of glucose."

The researchers defined hyperglycemia according to American Diabetes Association (ADA) criteria: prediabetes as a fasting OGTT of 100-125 mg/dL or a 2-hour OGTT of 149-199 mg/dL, and diabetes as a fasting OGTT of 126 mg/dL or greater or a 2-hour OGTT of 200 mg/dL or greater.

They categorized HbA_1c results according to three sets of diagnostic criteria: the International Expert Committee (IEC) (prediabetes 6.0%-6.4%, diabetes 6.5% or greater), ADA (prediabetes 5.7%-6.4%, diabetes 6.5% or greater), and Department of Veterans Affairs/Department of Defense (VA/DoD) (prediabetes 5.7%-6.9%, diabetes 7.0% or greater).

The mean age of the 789 study participants was 58 years, 95% were men, 74% were black, and their mean BMI was 30.5 kg/m².

Screening was offered to patients meeting National Institutes of Health guidelines for screening: without known diabetes, and with age greater than 45 years or a BMI of more than 25 with another risk factor.

Fully 10% of patients met criteria for diabetes based on the OGTT, which was a higher rate compared with the HbA_1c guidelines (6.7% by the IEC, 6.7% by the ADA, and 1.5% by the VA/DoD guidelines, respectively). "This would indicate that these cutoffs are insensitive compared with the OGTT for detecting diabetes," she said.

According to the OGTT, 42% had prediabetes: 27% had isolated impaired fasting glucose, 6% had isolated impaired glucose tolerance, and 9% had both.

In patients with diabetes by OGTT criteria, HbA_1c classification by IEC criteria labeled 32% correctly, 38% incorrectly as having prediabetes, and 29% incorrectly as being normal; ADA criteria labeled 32% correctly, 50% incorrectly as having prediabetes, and 18% incorrectly as being normal; and VA/DoD criteria labeled 12% correctly, 71% incorrectly as having prediabetes, and 18% incorrectly as being normal.

In patients with prediabetes by OGTT criteria, HbA_1c classification by IEC criteria labeled 36% correctly, 6% incorrectly as having diabetes, and 59% incorrectly as being normal; ADA criteria labeled 61% correctly, 6% incorrectly as having diabetes, and 33% incorrectly as being normal; and VA/DoD criteria labeled 66% correctly, 1% incorrectly as having diabetes, and 33% incorrectly as being normal.

The prevalence of diabetes increased in a stepwise fashion with increasing BMI, from 1.5% among those with a normal BMI (18.5-24.9) to 15% among those who met criteria for class III obesity (BMI more than 40). "For every 1 unit increase in BMI, we observed a 10% increase in the odds of having diabetes," she said.

Ms. Jackson also reported that with the IEC, ADA, and VA/DoD cutoffs for diabetes, screening with HbA_1c was specific but insensitive, with a false negative rate of 68% at the 6.5% cutoff and a false negative rate of 89% at the 7.0% cutoff.

"Many veterans – and probably many Americans – targeted by national guidelines have unrecognized diabetes and prediabetes, yet screening with HbA_1c would miss many," she said. "Given these findings, we should consider or develop alternative diabetes screening strategies that can be used opportunistically during outpatient visits, without fasting, but are more accurate."

The study was supported by a grant from the VA’s Health Services Research and Development Service. Ms. Jackson said that she had no relevant financial conflicts of interest.

SAN DIEGO – Obstructive sleep apnea in patients with type 2 diabetes predicted a three- to fourfold higher risk for diabetic peripheral neuropathy or sight-threatening retinopathy, separate analyses have found.

The results suggest that obstructive sleep apnea may play a role in the development of peripheral neuropathy and sight-threatening retinopathy in people with diabetes, Dr. Abd Tahrani and his associates reported at the annual scientific sessions of the American Diabetes Association. Ongoing studies are exploring the possible mechanisms involved.

Further research also is warranted on the possibility that treating obstructive sleep apnea might affect the development or progression of retinopathy or neuropathy, added Dr. Tahrani of the University of Birmingham (U.K.), where he is a research fellow for the U.K. National Institute for Health Research.

The prospective studies recruited random patients from a hospital-based, outpatient diabetes clinic in the United Kingdom. Individuals were excluded if they had a known respiratory disorder, including obstructive sleep apnea. Patients had a mean age of 59 years and a mean 11-year history of diabetes, and 48% were white.

Participants underwent one night of home-based multichannel respiratory monitoring, and were considered to have obstructive sleep apnea if they had an apnea-hypopnea index of at least 5 events per hour.

In 224 patients who also were assessed for sight-threatening retinopathy, 63% had obstructive sleep apnea and 38% had sight-threatening retinopathy. Patients with obstructive sleep apnea were significantly more likely to have sight-threatening retinopathy (48%) than were patients without obstructive sleep apnea (20%).

The study defined sight-threatening retinopathy as the presence of preproliferative or proliferative retinopathy, maculopathy, or the need for laser treatment.

After adjustment for a wide range of possible confounders, patients with obstructive sleep apnea were 3.6 times more likely to have sight-threatening retinopathy, 5 times more likely to have advanced diabetic retinopathy, and 4.4 times more likely to have maculopathy than were patients without obstructive sleep apnea.

In a separate study by the same investigators involving 231 patients who were assessed for both obstructive sleep apnea and peripheral neuropathy, 65% had obstructive sleep apnea and 45% had diabetic peripheral neuropathy. Patients with obstructive sleep apnea reported more neuropathic symptoms.

Among patients with obstructive sleep apnea, 60% had diabetic peripheral neuropathy, compared with 27% of patients without sleep apnea.

Obstructive sleep apnea conferred a significant threefold higher risk for peripheral neuropathy after adjustment for a wide variety of potentially confounding variables, Dr. Tahrani reported. The severity of peripheral neuropathy correlated with the severity of obstructive sleep apnea.

Obstructive sleep apnea was prevalent in 75% and 52% of white and South Asian patients, respectively. Likewise, diabetic peripheral neuropathy was more prevalent in whites (56% vs. 40%). Both differences were significant.

The lower prevalence of obstructive sleep apnea in the South Asian patients might be one reason for the lower prevalence of diabetic peripheral neuropathy, the investigators suggested.

Dr. Tahrani reported having no conflicts of interest.

SAN DIEGO – Obstructive sleep apnea in patients with type 2 diabetes predicted a three- to fourfold higher risk for diabetic peripheral neuropathy or sight-threatening retinopathy, separate analyses have found.

The results suggest that obstructive sleep apnea may play a role in the development of peripheral neuropathy and sight-threatening retinopathy in people with diabetes, Dr. Abd Tahrani and his associates reported at the annual scientific sessions of the American Diabetes Association. Ongoing studies are exploring the possible mechanisms involved.

Further research also is warranted on the possibility that treating obstructive sleep apnea might affect the development or progression of retinopathy or neuropathy, added Dr. Tahrani of the University of Birmingham (U.K.), where he is a research fellow for the U.K. National Institute for Health Research.

The prospective studies recruited random patients from a hospital-based, outpatient diabetes clinic in the United Kingdom. Individuals were excluded if they had a known respiratory disorder, including obstructive sleep apnea. Patients had a mean age of 59 years and a mean 11-year history of diabetes, and 48% were white.

Participants underwent one night of home-based multichannel respiratory monitoring, and were considered to have obstructive sleep apnea if they had an apnea-hypopnea index of at least 5 events per hour.

In 224 patients who also were assessed for sight-threatening retinopathy, 63% had obstructive sleep apnea and 38% had sight-threatening retinopathy. Patients with obstructive sleep apnea were significantly more likely to have sight-threatening retinopathy (48%) than were patients without obstructive sleep apnea (20%).

The study defined sight-threatening retinopathy as the presence of preproliferative or proliferative retinopathy, maculopathy, or the need for laser treatment.

After adjustment for a wide range of possible confounders, patients with obstructive sleep apnea were 3.6 times more likely to have sight-threatening retinopathy, 5 times more likely to have advanced diabetic retinopathy, and 4.4 times more likely to have maculopathy than were patients without obstructive sleep apnea.

In a separate study by the same investigators involving 231 patients who were assessed for both obstructive sleep apnea and peripheral neuropathy, 65% had obstructive sleep apnea and 45% had diabetic peripheral neuropathy. Patients with obstructive sleep apnea reported more neuropathic symptoms.

Among patients with obstructive sleep apnea, 60% had diabetic peripheral neuropathy, compared with 27% of patients without sleep apnea.

Obstructive sleep apnea conferred a significant threefold higher risk for peripheral neuropathy after adjustment for a wide variety of potentially confounding variables, Dr. Tahrani reported. The severity of peripheral neuropathy correlated with the severity of obstructive sleep apnea.

Obstructive sleep apnea was prevalent in 75% and 52% of white and South Asian patients, respectively. Likewise, diabetic peripheral neuropathy was more prevalent in whites (56% vs. 40%). Both differences were significant.

The lower prevalence of obstructive sleep apnea in the South Asian patients might be one reason for the lower prevalence of diabetic peripheral neuropathy, the investigators suggested.

Dr. Tahrani reported having no conflicts of interest.

SAN DIEGO – Obstructive sleep apnea in patients with type 2 diabetes predicted a three- to fourfold higher risk for diabetic peripheral neuropathy or sight-threatening retinopathy, separate analyses have found.

The results suggest that obstructive sleep apnea may play a role in the development of peripheral neuropathy and sight-threatening retinopathy in people with diabetes, Dr. Abd Tahrani and his associates reported at the annual scientific sessions of the American Diabetes Association. Ongoing studies are exploring the possible mechanisms involved.

Further research also is warranted on the possibility that treating obstructive sleep apnea might affect the development or progression of retinopathy or neuropathy, added Dr. Tahrani of the University of Birmingham (U.K.), where he is a research fellow for the U.K. National Institute for Health Research.

The prospective studies recruited random patients from a hospital-based, outpatient diabetes clinic in the United Kingdom. Individuals were excluded if they had a known respiratory disorder, including obstructive sleep apnea. Patients had a mean age of 59 years and a mean 11-year history of diabetes, and 48% were white.

Participants underwent one night of home-based multichannel respiratory monitoring, and were considered to have obstructive sleep apnea if they had an apnea-hypopnea index of at least 5 events per hour.

In 224 patients who also were assessed for sight-threatening retinopathy, 63% had obstructive sleep apnea and 38% had sight-threatening retinopathy. Patients with obstructive sleep apnea were significantly more likely to have sight-threatening retinopathy (48%) than were patients without obstructive sleep apnea (20%).

The study defined sight-threatening retinopathy as the presence of preproliferative or proliferative retinopathy, maculopathy, or the need for laser treatment.

After adjustment for a wide range of possible confounders, patients with obstructive sleep apnea were 3.6 times more likely to have sight-threatening retinopathy, 5 times more likely to have advanced diabetic retinopathy, and 4.4 times more likely to have maculopathy than were patients without obstructive sleep apnea.

In a separate study by the same investigators involving 231 patients who were assessed for both obstructive sleep apnea and peripheral neuropathy, 65% had obstructive sleep apnea and 45% had diabetic peripheral neuropathy. Patients with obstructive sleep apnea reported more neuropathic symptoms.

Among patients with obstructive sleep apnea, 60% had diabetic peripheral neuropathy, compared with 27% of patients without sleep apnea.

Obstructive sleep apnea conferred a significant threefold higher risk for peripheral neuropathy after adjustment for a wide variety of potentially confounding variables, Dr. Tahrani reported. The severity of peripheral neuropathy correlated with the severity of obstructive sleep apnea.

Obstructive sleep apnea was prevalent in 75% and 52% of white and South Asian patients, respectively. Likewise, diabetic peripheral neuropathy was more prevalent in whites (56% vs. 40%). Both differences were significant.

The lower prevalence of obstructive sleep apnea in the South Asian patients might be one reason for the lower prevalence of diabetic peripheral neuropathy, the investigators suggested.

Dr. Tahrani reported having no conflicts of interest.