Sherry Boschert

SAN FRANCISCO — Although three recent major trials found that the potential harms of intensive glycemic control in patients with diabetes generally outweigh potential benefits, substudies of the data may help identify patients who could benefit from intensive therapy.

“There is some hope, which is that improvement in picking individuals for intensive glycemic control may be the right approach,” Dr. Peter D. Reaven said at a meeting sponsored by the American Diabetes Association.

The substudies and other recent analyses suggest that clinicians should avoid aggressive glycemic management (that is, trying to get hemoglobin A_1c values down to 6.5% or lower) in patients who are older and who have a longer duration of diabetes, more extensive calcified coronary atherosclerosis, or a higher burden of comorbidities, said Dr. Reaven, professor of clinical medicine at the University of Arizona, Phoenix.

Cardiovascular outcomes did not differ significantly between the intensive-control and usual-control groups in the three major recent studies—the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial (N. Engl. J. Med. 2008;358:2545–59); the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial (N. Engl. J. Med. 2008;358:2560–72), and the VADT (Veterans Affairs Diabetes Trial) (N. Engl. J. Med. 2009;360:129–39).

The ACCORD trial stopped early because of increased mortality in the intensive-control group. In the VADT, intensive glycemic control was associated with a tripled risk for hypoglycemia, which was a strong predictor of cardiovascular death.

However, a subanalysis within the ACCORD trial of prespecified subgroups found less risk of mortality in the intensive-control group if patients entered the study with no history of a prior cardiovascular event or if they entered the study with a hemoglobin A_1c (HbA_1c) level below 8%, he noted.

In the VADT, in which Dr. Reaven participated, a subanalysis found that patients with a shorter duration of diabetes in the intensive-control group appeared to have improved cardiovascular outcomes, compared with the usual-control group.

Patients in the intensive group who had diabetes for 15 years or less showed a 26% reduction in cardiovascular risk, compared with the usual-care group, but intensive glycemic control appeared to become harmful in patients who had longer durations of diabetes.

A separate meta-analysis found a significant 10% reduction in cardiovascular events with intensive glycemic control when data from the ACCORD trial, ADVANCE trial, VADT, and the UKPDS (United Kingdom Prospective Diabetes Study) (Lancet 1998:352:837–53) were combined.

Mortality rates did not differ significantly among treatment groups in this meta-analysis (Diabetologia 2009;52:2288–98), which was “somewhat reassuring,” though heterogeneity in the individual study results leaves uncertainty about the safety of intensive glycemic control, Dr. Reaven said.

A substudy by Dr. Reaven and associates of 301 patients in the VADT who had baseline CT scans to measure coronary artery calcium in the assessment of coronary atherosclerosis found that intensive glycemic control significantly reduced the risk of cardiovascular events if patients entered the study with lower levels of calcium in their coronary arteries. In the intensive-control group, the risk for cardiovascular events was nearly 10-fold higher in patients with higher coronary artery calcium levels at baseline (an Agatston score of 100 or greater), compared with patients who had lower scores (Diabetes 2009;58:2642–8).

Disclosures: Dr. Reaven has been a board member or adviser for AstraZeneca Pharmaceuticals and Bristol-Myers Squibb Co., a stockholder in Pfizer Inc. and Merck & Co., a speaker for Merck, and a consultant to Takeda Pharmaceutical Co. He has received research support from Amylin Pharmaceuticals Inc. and Takeda.

SAN FRANCISCO — Although three recent major trials found that the potential harms of intensive glycemic control in patients with diabetes generally outweigh potential benefits, substudies of the data may help identify patients who could benefit from intensive therapy.

“There is some hope, which is that improvement in picking individuals for intensive glycemic control may be the right approach,” Dr. Peter D. Reaven said at a meeting sponsored by the American Diabetes Association.

The substudies and other recent analyses suggest that clinicians should avoid aggressive glycemic management (that is, trying to get hemoglobin A_1c values down to 6.5% or lower) in patients who are older and who have a longer duration of diabetes, more extensive calcified coronary atherosclerosis, or a higher burden of comorbidities, said Dr. Reaven, professor of clinical medicine at the University of Arizona, Phoenix.

Cardiovascular outcomes did not differ significantly between the intensive-control and usual-control groups in the three major recent studies—the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial (N. Engl. J. Med. 2008;358:2545–59); the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial (N. Engl. J. Med. 2008;358:2560–72), and the VADT (Veterans Affairs Diabetes Trial) (N. Engl. J. Med. 2009;360:129–39).

The ACCORD trial stopped early because of increased mortality in the intensive-control group. In the VADT, intensive glycemic control was associated with a tripled risk for hypoglycemia, which was a strong predictor of cardiovascular death.

However, a subanalysis within the ACCORD trial of prespecified subgroups found less risk of mortality in the intensive-control group if patients entered the study with no history of a prior cardiovascular event or if they entered the study with a hemoglobin A_1c (HbA_1c) level below 8%, he noted.

In the VADT, in which Dr. Reaven participated, a subanalysis found that patients with a shorter duration of diabetes in the intensive-control group appeared to have improved cardiovascular outcomes, compared with the usual-control group.

Patients in the intensive group who had diabetes for 15 years or less showed a 26% reduction in cardiovascular risk, compared with the usual-care group, but intensive glycemic control appeared to become harmful in patients who had longer durations of diabetes.

A separate meta-analysis found a significant 10% reduction in cardiovascular events with intensive glycemic control when data from the ACCORD trial, ADVANCE trial, VADT, and the UKPDS (United Kingdom Prospective Diabetes Study) (Lancet 1998:352:837–53) were combined.

Mortality rates did not differ significantly among treatment groups in this meta-analysis (Diabetologia 2009;52:2288–98), which was “somewhat reassuring,” though heterogeneity in the individual study results leaves uncertainty about the safety of intensive glycemic control, Dr. Reaven said.

A substudy by Dr. Reaven and associates of 301 patients in the VADT who had baseline CT scans to measure coronary artery calcium in the assessment of coronary atherosclerosis found that intensive glycemic control significantly reduced the risk of cardiovascular events if patients entered the study with lower levels of calcium in their coronary arteries. In the intensive-control group, the risk for cardiovascular events was nearly 10-fold higher in patients with higher coronary artery calcium levels at baseline (an Agatston score of 100 or greater), compared with patients who had lower scores (Diabetes 2009;58:2642–8).

Disclosures: Dr. Reaven has been a board member or adviser for AstraZeneca Pharmaceuticals and Bristol-Myers Squibb Co., a stockholder in Pfizer Inc. and Merck & Co., a speaker for Merck, and a consultant to Takeda Pharmaceutical Co. He has received research support from Amylin Pharmaceuticals Inc. and Takeda.

SAN FRANCISCO — Although three recent major trials found that the potential harms of intensive glycemic control in patients with diabetes generally outweigh potential benefits, substudies of the data may help identify patients who could benefit from intensive therapy.

“There is some hope, which is that improvement in picking individuals for intensive glycemic control may be the right approach,” Dr. Peter D. Reaven said at a meeting sponsored by the American Diabetes Association.

The substudies and other recent analyses suggest that clinicians should avoid aggressive glycemic management (that is, trying to get hemoglobin A_1c values down to 6.5% or lower) in patients who are older and who have a longer duration of diabetes, more extensive calcified coronary atherosclerosis, or a higher burden of comorbidities, said Dr. Reaven, professor of clinical medicine at the University of Arizona, Phoenix.

Cardiovascular outcomes did not differ significantly between the intensive-control and usual-control groups in the three major recent studies—the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial (N. Engl. J. Med. 2008;358:2545–59); the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial (N. Engl. J. Med. 2008;358:2560–72), and the VADT (Veterans Affairs Diabetes Trial) (N. Engl. J. Med. 2009;360:129–39).

The ACCORD trial stopped early because of increased mortality in the intensive-control group. In the VADT, intensive glycemic control was associated with a tripled risk for hypoglycemia, which was a strong predictor of cardiovascular death.

However, a subanalysis within the ACCORD trial of prespecified subgroups found less risk of mortality in the intensive-control group if patients entered the study with no history of a prior cardiovascular event or if they entered the study with a hemoglobin A_1c (HbA_1c) level below 8%, he noted.

In the VADT, in which Dr. Reaven participated, a subanalysis found that patients with a shorter duration of diabetes in the intensive-control group appeared to have improved cardiovascular outcomes, compared with the usual-control group.

Patients in the intensive group who had diabetes for 15 years or less showed a 26% reduction in cardiovascular risk, compared with the usual-care group, but intensive glycemic control appeared to become harmful in patients who had longer durations of diabetes.

A separate meta-analysis found a significant 10% reduction in cardiovascular events with intensive glycemic control when data from the ACCORD trial, ADVANCE trial, VADT, and the UKPDS (United Kingdom Prospective Diabetes Study) (Lancet 1998:352:837–53) were combined.

Mortality rates did not differ significantly among treatment groups in this meta-analysis (Diabetologia 2009;52:2288–98), which was “somewhat reassuring,” though heterogeneity in the individual study results leaves uncertainty about the safety of intensive glycemic control, Dr. Reaven said.

A substudy by Dr. Reaven and associates of 301 patients in the VADT who had baseline CT scans to measure coronary artery calcium in the assessment of coronary atherosclerosis found that intensive glycemic control significantly reduced the risk of cardiovascular events if patients entered the study with lower levels of calcium in their coronary arteries. In the intensive-control group, the risk for cardiovascular events was nearly 10-fold higher in patients with higher coronary artery calcium levels at baseline (an Agatston score of 100 or greater), compared with patients who had lower scores (Diabetes 2009;58:2642–8).

Disclosures: Dr. Reaven has been a board member or adviser for AstraZeneca Pharmaceuticals and Bristol-Myers Squibb Co., a stockholder in Pfizer Inc. and Merck & Co., a speaker for Merck, and a consultant to Takeda Pharmaceutical Co. He has received research support from Amylin Pharmaceuticals Inc. and Takeda.

SAN FRANCISCO — The presence and severity of obstructive sleep apnea was associated with worse glucose control in a study of 60 patients with type 2 diabetes.

Polysomnography and hemoglobin A_1c tests showed that participants with no obstructive sleep apnea (OSA) had an average HbA_1c level of 5.7%. HbA_1c levels averaged 7.2% in participants with mild OSA, 7.7% in those with moderate OSA, and 9.4% in those with severe OSA, Dr. Esra Tasali reported.

“These effect sizes are comparable to some medications we use to treat A_1c levels,” she said, suggesting that “treatment of obstructive sleep apnea may improve glucose control as much as widely used pharmacologic agents.”

The linear trend for poorer glucose control with increasingly severe OSA was highly significant after adjustment of the data for the effects of age, gender, race, body mass index, level of exercise, duration of diabetes, number of diabetes medications being taken, and total sleep time, she said at a meeting sponsored by the American Diabetes Association.

Previous studies have shown a high prevalence of OSA in people with type 2 diabetes, and that in nondiabetics OSA is linked with alterations in glucose metabolism and reduced insulin sensitivity. The current study is the first to show the relation between OSA severity and glycemic control in diabetes patients (Am. J. Respir. Crit. Care Med. 2010;181:507–13).

Overall, 77% (46 of 60) of the study cohort had OSA. Three previous studies of diabetic populations found OSA prevalences of 58%, 71%, and 86%, said Dr. Tasali of the University of Chicago.

Six trials of treating OSA in patients with type 2 diabetes using continuous positive airway pressure (CPAP) produced conflicting results, with some showing improvements in HbA_1c levels, insulin sensitivity, or glucose levels, some showing no change, and others with split results. The only randomized clinical trial among them found no effect of CPAP therapy on HbA_1c or insulin sensitivity. All the studies were small (ranging from 9 to 44 patients), she noted.

Studies by Dr. Tasali and associates on healthy subjects suggest that sleep interruption or deprivation similar to that which occurs with OSA may increase the risk for developing type 2 diabetes. Depriving healthy subjects of short-wave sleep for 3 nights significantly decreased insulin sensitivity and glucose tolerance and elevated cardiac sympathetic nervous activity.

“Sleep duration and quality are potentially modifiable risk factors and therefore might have important clinical implications for the prevention and treatment of diabetes and obesity,” she said.

Dr. Tasali said she had no conflicts of interest to disclose.

SAN FRANCISCO — The presence and severity of obstructive sleep apnea was associated with worse glucose control in a study of 60 patients with type 2 diabetes.

Polysomnography and hemoglobin A_1c tests showed that participants with no obstructive sleep apnea (OSA) had an average HbA_1c level of 5.7%. HbA_1c levels averaged 7.2% in participants with mild OSA, 7.7% in those with moderate OSA, and 9.4% in those with severe OSA, Dr. Esra Tasali reported.

“These effect sizes are comparable to some medications we use to treat A_1c levels,” she said, suggesting that “treatment of obstructive sleep apnea may improve glucose control as much as widely used pharmacologic agents.”

The linear trend for poorer glucose control with increasingly severe OSA was highly significant after adjustment of the data for the effects of age, gender, race, body mass index, level of exercise, duration of diabetes, number of diabetes medications being taken, and total sleep time, she said at a meeting sponsored by the American Diabetes Association.

Previous studies have shown a high prevalence of OSA in people with type 2 diabetes, and that in nondiabetics OSA is linked with alterations in glucose metabolism and reduced insulin sensitivity. The current study is the first to show the relation between OSA severity and glycemic control in diabetes patients (Am. J. Respir. Crit. Care Med. 2010;181:507–13).

Overall, 77% (46 of 60) of the study cohort had OSA. Three previous studies of diabetic populations found OSA prevalences of 58%, 71%, and 86%, said Dr. Tasali of the University of Chicago.

Six trials of treating OSA in patients with type 2 diabetes using continuous positive airway pressure (CPAP) produced conflicting results, with some showing improvements in HbA_1c levels, insulin sensitivity, or glucose levels, some showing no change, and others with split results. The only randomized clinical trial among them found no effect of CPAP therapy on HbA_1c or insulin sensitivity. All the studies were small (ranging from 9 to 44 patients), she noted.

Studies by Dr. Tasali and associates on healthy subjects suggest that sleep interruption or deprivation similar to that which occurs with OSA may increase the risk for developing type 2 diabetes. Depriving healthy subjects of short-wave sleep for 3 nights significantly decreased insulin sensitivity and glucose tolerance and elevated cardiac sympathetic nervous activity.

“Sleep duration and quality are potentially modifiable risk factors and therefore might have important clinical implications for the prevention and treatment of diabetes and obesity,” she said.

Dr. Tasali said she had no conflicts of interest to disclose.

SAN FRANCISCO — The presence and severity of obstructive sleep apnea was associated with worse glucose control in a study of 60 patients with type 2 diabetes.

Polysomnography and hemoglobin A_1c tests showed that participants with no obstructive sleep apnea (OSA) had an average HbA_1c level of 5.7%. HbA_1c levels averaged 7.2% in participants with mild OSA, 7.7% in those with moderate OSA, and 9.4% in those with severe OSA, Dr. Esra Tasali reported.

“These effect sizes are comparable to some medications we use to treat A_1c levels,” she said, suggesting that “treatment of obstructive sleep apnea may improve glucose control as much as widely used pharmacologic agents.”

The linear trend for poorer glucose control with increasingly severe OSA was highly significant after adjustment of the data for the effects of age, gender, race, body mass index, level of exercise, duration of diabetes, number of diabetes medications being taken, and total sleep time, she said at a meeting sponsored by the American Diabetes Association.

Previous studies have shown a high prevalence of OSA in people with type 2 diabetes, and that in nondiabetics OSA is linked with alterations in glucose metabolism and reduced insulin sensitivity. The current study is the first to show the relation between OSA severity and glycemic control in diabetes patients (Am. J. Respir. Crit. Care Med. 2010;181:507–13).

Overall, 77% (46 of 60) of the study cohort had OSA. Three previous studies of diabetic populations found OSA prevalences of 58%, 71%, and 86%, said Dr. Tasali of the University of Chicago.

Six trials of treating OSA in patients with type 2 diabetes using continuous positive airway pressure (CPAP) produced conflicting results, with some showing improvements in HbA_1c levels, insulin sensitivity, or glucose levels, some showing no change, and others with split results. The only randomized clinical trial among them found no effect of CPAP therapy on HbA_1c or insulin sensitivity. All the studies were small (ranging from 9 to 44 patients), she noted.

Studies by Dr. Tasali and associates on healthy subjects suggest that sleep interruption or deprivation similar to that which occurs with OSA may increase the risk for developing type 2 diabetes. Depriving healthy subjects of short-wave sleep for 3 nights significantly decreased insulin sensitivity and glucose tolerance and elevated cardiac sympathetic nervous activity.

“Sleep duration and quality are potentially modifiable risk factors and therefore might have important clinical implications for the prevention and treatment of diabetes and obesity,” she said.

Dr. Tasali said she had no conflicts of interest to disclose.

Major Finding: A significantly greater proportion of patients on 1.8 mg/day of liraglutide (39%) achieved an HbA_1c level below 7% with no weight gain and no confirmed hypoglycemia by the end of the 26- to 52-week studies, compared with those on twice-daily injections of the GLP-1 agonist exenatide (24%) or patients treated with glargine (15%), a sulfonylurea (8%), placebo (8%), or a thiazolidinedione (6%).

Data Source: A secondary analysis that combined data from the more than 3,900 patients in the LEAD studies to compare the effectiveness of various therapies.

Disclosures: Novo Nordisk Inc., which markets liraglutide, sponsored the LEAD trials. Dr. Buse has been a consultant for or received research support from Novo Nordisk as well as Amylin Pharmaceuticals Inc. and Eli Lilly & Co., which together are marketing the long-acting version of Amylin's exenatide.

SAN FRANCISCO — The once-daily drug liraglutide may work better than other diabetes medications to help patients reach a combination of goals, a secondary analysis of data from pivotal liraglutide studies suggests.

The Food and Drug Administration approved liraglutide (Victoza) in January for adults with type 2 diabetes who fail first-line drug therapy, based on data from the pivotal Liraglutide Effect and Action in Diabetes (LEAD) studies. Liraglutide is an injectable human glucagonlike peptide–1 (GLP-1) analogue.

The LEAD trials were “truly heroic” in their number, breadth, and head-to-head comparisons with existing diabetes medications, and in most of those trials liraglutide was more effective at lowering hemoglobin A_1c levels, Dr. John B. Buse said at a meeting sponsored by the American Diabetes Association.

He reported on an analysis that combined data from the more than 3,900 patients in the LEAD studies to compare the effectiveness of various therapies at achieving a composite end point known among diabetologists as a “Zindex” (because the idea was first proposed by Dr. Bernard Zinman, professor of medicine at the University of Toronto).

The analysis assessed the proportion of patients achieving the Zindex of an HbA_1c level below 7% with no weight gain and no confirmed hypoglycemia by the end of the 26- to 52-week studies. A significantly greater proportion of patients on 1.8 mg/day of liraglutide (39%) achieved this Zindex, compared with those on twice-daily injections of the GLP-1 agonist exenatide (24%) or patients treated with glargine (15%), a sulfonylurea (8%), placebo (8%), or a thiazolidinedione (6%).

“An A_1c less than 7% without weight gain or hypoglycemia is something that's of substantial interest to patients and clinicians,” said Dr. Buse, chief of endocrinology and director of the diabetes care center at the University of North Carolina at Chapel Hill.

A second analysis compared the data with a second composite of three goals identified as standards of care by the American Diabetes Association in 2008: an HbA_1c less than 7%, no weight gain, and a systolic blood pressure less than 130 mm Hg. The GLP-1 therapies have modest effects on BP and lipids, with potentially greater changes in BP on long-acting GLP-1 agonists, Dr. Buse noted.

Significantly more patients on 1.8 mg/day of liraglutide (25%) achieved this composite than did patients on exenatide (14%), a sulfonylurea (7%), glargine or placebo (5% each), or a thiazolidinedione (3%).

Major Finding: A significantly greater proportion of patients on 1.8 mg/day of liraglutide (39%) achieved an HbA_1c level below 7% with no weight gain and no confirmed hypoglycemia by the end of the 26- to 52-week studies, compared with those on twice-daily injections of the GLP-1 agonist exenatide (24%) or patients treated with glargine (15%), a sulfonylurea (8%), placebo (8%), or a thiazolidinedione (6%).

Data Source: A secondary analysis that combined data from the more than 3,900 patients in the LEAD studies to compare the effectiveness of various therapies.

Disclosures: Novo Nordisk Inc., which markets liraglutide, sponsored the LEAD trials. Dr. Buse has been a consultant for or received research support from Novo Nordisk as well as Amylin Pharmaceuticals Inc. and Eli Lilly & Co., which together are marketing the long-acting version of Amylin's exenatide.

SAN FRANCISCO — The once-daily drug liraglutide may work better than other diabetes medications to help patients reach a combination of goals, a secondary analysis of data from pivotal liraglutide studies suggests.

The Food and Drug Administration approved liraglutide (Victoza) in January for adults with type 2 diabetes who fail first-line drug therapy, based on data from the pivotal Liraglutide Effect and Action in Diabetes (LEAD) studies. Liraglutide is an injectable human glucagonlike peptide–1 (GLP-1) analogue.

The LEAD trials were “truly heroic” in their number, breadth, and head-to-head comparisons with existing diabetes medications, and in most of those trials liraglutide was more effective at lowering hemoglobin A_1c levels, Dr. John B. Buse said at a meeting sponsored by the American Diabetes Association.

He reported on an analysis that combined data from the more than 3,900 patients in the LEAD studies to compare the effectiveness of various therapies at achieving a composite end point known among diabetologists as a “Zindex” (because the idea was first proposed by Dr. Bernard Zinman, professor of medicine at the University of Toronto).

The analysis assessed the proportion of patients achieving the Zindex of an HbA_1c level below 7% with no weight gain and no confirmed hypoglycemia by the end of the 26- to 52-week studies. A significantly greater proportion of patients on 1.8 mg/day of liraglutide (39%) achieved this Zindex, compared with those on twice-daily injections of the GLP-1 agonist exenatide (24%) or patients treated with glargine (15%), a sulfonylurea (8%), placebo (8%), or a thiazolidinedione (6%).

“An A_1c less than 7% without weight gain or hypoglycemia is something that's of substantial interest to patients and clinicians,” said Dr. Buse, chief of endocrinology and director of the diabetes care center at the University of North Carolina at Chapel Hill.

A second analysis compared the data with a second composite of three goals identified as standards of care by the American Diabetes Association in 2008: an HbA_1c less than 7%, no weight gain, and a systolic blood pressure less than 130 mm Hg. The GLP-1 therapies have modest effects on BP and lipids, with potentially greater changes in BP on long-acting GLP-1 agonists, Dr. Buse noted.

Significantly more patients on 1.8 mg/day of liraglutide (25%) achieved this composite than did patients on exenatide (14%), a sulfonylurea (7%), glargine or placebo (5% each), or a thiazolidinedione (3%).

Major Finding: A significantly greater proportion of patients on 1.8 mg/day of liraglutide (39%) achieved an HbA_1c level below 7% with no weight gain and no confirmed hypoglycemia by the end of the 26- to 52-week studies, compared with those on twice-daily injections of the GLP-1 agonist exenatide (24%) or patients treated with glargine (15%), a sulfonylurea (8%), placebo (8%), or a thiazolidinedione (6%).

Data Source: A secondary analysis that combined data from the more than 3,900 patients in the LEAD studies to compare the effectiveness of various therapies.

Disclosures: Novo Nordisk Inc., which markets liraglutide, sponsored the LEAD trials. Dr. Buse has been a consultant for or received research support from Novo Nordisk as well as Amylin Pharmaceuticals Inc. and Eli Lilly & Co., which together are marketing the long-acting version of Amylin's exenatide.

SAN FRANCISCO — The once-daily drug liraglutide may work better than other diabetes medications to help patients reach a combination of goals, a secondary analysis of data from pivotal liraglutide studies suggests.

The Food and Drug Administration approved liraglutide (Victoza) in January for adults with type 2 diabetes who fail first-line drug therapy, based on data from the pivotal Liraglutide Effect and Action in Diabetes (LEAD) studies. Liraglutide is an injectable human glucagonlike peptide–1 (GLP-1) analogue.

The LEAD trials were “truly heroic” in their number, breadth, and head-to-head comparisons with existing diabetes medications, and in most of those trials liraglutide was more effective at lowering hemoglobin A_1c levels, Dr. John B. Buse said at a meeting sponsored by the American Diabetes Association.

He reported on an analysis that combined data from the more than 3,900 patients in the LEAD studies to compare the effectiveness of various therapies at achieving a composite end point known among diabetologists as a “Zindex” (because the idea was first proposed by Dr. Bernard Zinman, professor of medicine at the University of Toronto).

The analysis assessed the proportion of patients achieving the Zindex of an HbA_1c level below 7% with no weight gain and no confirmed hypoglycemia by the end of the 26- to 52-week studies. A significantly greater proportion of patients on 1.8 mg/day of liraglutide (39%) achieved this Zindex, compared with those on twice-daily injections of the GLP-1 agonist exenatide (24%) or patients treated with glargine (15%), a sulfonylurea (8%), placebo (8%), or a thiazolidinedione (6%).

“An A_1c less than 7% without weight gain or hypoglycemia is something that's of substantial interest to patients and clinicians,” said Dr. Buse, chief of endocrinology and director of the diabetes care center at the University of North Carolina at Chapel Hill.

A second analysis compared the data with a second composite of three goals identified as standards of care by the American Diabetes Association in 2008: an HbA_1c less than 7%, no weight gain, and a systolic blood pressure less than 130 mm Hg. The GLP-1 therapies have modest effects on BP and lipids, with potentially greater changes in BP on long-acting GLP-1 agonists, Dr. Buse noted.

Significantly more patients on 1.8 mg/day of liraglutide (25%) achieved this composite than did patients on exenatide (14%), a sulfonylurea (7%), glargine or placebo (5% each), or a thiazolidinedione (3%).

SAN FRANCISCO — Although three recent major trials found that the potential harms of intensive glycemic control in patients with diabetes generally outweigh potential benefits, substudies of the data may help identify patients who could benefit from intensive therapy.

“There is some hope, which is that improvement in picking individuals for intensive glycemic control may be the right approach,” Dr. Peter D. Reaven said at a meeting sponsored by the American Diabetes Association.

The substudies and other recent analyses suggest that clinicians should avoid aggressive glycemic management (that is, trying to get hemoglobin A_1c values down to 6.5% or lower) in patients who are older and who have a longer duration of diabetes, more extensive calcified coronary atherosclerosis, or a higher burden of comorbidities, said Dr. Reaven, professor of clinical medicine at the University of Arizona, Phoenix.

“I think there probably are groups that do better with glycemic control being intensified, and others that don't,” he said.

Cardiovascular outcomes did not differ significantly between the intensive-control and usual-control groups in the three major recent studies—the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial (N. Engl. J. Med. 2008;358:2545–59); the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial (N. Engl. J. Med. 2008;358:2560–72), and the VADT (Veterans Affairs Diabetes Trial) (N. Engl. J. Med. 2009;360:129–39). The ACCORD trial stopped early because of increased mortality in the intensive-control group. In the VADT, intensive glycemic control was associated with a tripled risk for hypoglycemia, which was a strong predictor of cardiovascular death.

However, a subanalysis within the ACCORD trial of prespecified subgroups found less risk of mortality in the intensive-control group if patients entered the study with no history of a prior cardiovascular event or if they entered the study with a hemoglobin A_1c (HbA_1c) level below 8%, he noted.

In the VADT, in which Dr. Reaven participated, a subanalysis found that patients with a shorter duration of diabetes in the intensive-control group appeared to have improved cardiovascular outcomes, compared with the usual-control group. Patients in the intensive group who had diabetes for 15 years or less showed a 26% reduction in cardiovascular risk, compared with the usual-care group, but intensive glycemic control appeared to become harmful in patients who had longer durations of diabetes.

A separate meta-analysis found a significant 10% reduction in cardiovascular events with intensive glycemic control when data from the ACCORD trial, ADVANCE trial, VADT, and the UKPDS (United Kingdom Prospective Diabetes Study) (Lancet 1998:352:837–53) were combined. Mortality rates did not differ significantly among treatment groups in this meta-analysis (Diabetologia 2009;52:2288–98), which was “somewhat reassuring,” though heterogeneity in the individual study results leaves uncertainty about the safety of intensive glycemic control, Dr. Reaven said.

A substudy by Dr. Reaven and associates of 301 patients in the VADT who had baseline CT scans to measure coronary artery calcium in the assessment of coronary atherosclerosis found that intensive glycemic control significantly reduced the risk of cardiovascular events if patients entered the study with lower levels of calcium in their coronary arteries. In the intensive-control group, the risk for cardiovascular events was nearly 10-fold higher in patients with higher coronary artery calcium levels at baseline (an Agatston score of 100 or greater), compared with patients who had lower scores (Diabetes 2009;58:2642–8).

“Your vascular status may influence how you do with intensive glycemic control,” he said. Nearly 60% of VADT participants had higher levels of coronary artery calcium, he estimated, and the ACCORD and ADVANCE cohorts had a high prevalence of cardiovascular disease, which may help explain why the studies overall did not report cardiovascular benefits from tight glycemic control.

“If we can confirm the subset analysis of the VADT, perhaps some imaging method may be reasonable to try to assess vascular risk” when considering intensive glycemic therapy, Dr. Reaven said.

A more clinician-friendly tool—the TIBI (Total Illness Burden Index)—was assessed in a separate longitudinal observational study of 2,613 patients with diabetes that was managed with intensive glycemic control in community practices. Cardiovascular risk was significantly reduced with intensive glycemic control in patients who had a lower baseline level of comorbidity (defined as a TIBI score of 12 or lower), but not in patients who had low TIBI scores and higher HbA_1c levels or in patients who had higher TIBI scores (Ann. Int. Med. 2009;151:854–60).

“Intensive glucose lowering may have a cardiovascular benefit that is most useful in certain subgroups and may be harmful in some individuals,” he said.

Dr. Reaven has financial relationships with AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., Pfizer Inc., Merck & Co., Takeda Pharmaceutical Co., and Amylin Pharmaceuticals Inc.

SAN FRANCISCO — Although three recent major trials found that the potential harms of intensive glycemic control in patients with diabetes generally outweigh potential benefits, substudies of the data may help identify patients who could benefit from intensive therapy.

“There is some hope, which is that improvement in picking individuals for intensive glycemic control may be the right approach,” Dr. Peter D. Reaven said at a meeting sponsored by the American Diabetes Association.

The substudies and other recent analyses suggest that clinicians should avoid aggressive glycemic management (that is, trying to get hemoglobin A_1c values down to 6.5% or lower) in patients who are older and who have a longer duration of diabetes, more extensive calcified coronary atherosclerosis, or a higher burden of comorbidities, said Dr. Reaven, professor of clinical medicine at the University of Arizona, Phoenix.

“I think there probably are groups that do better with glycemic control being intensified, and others that don't,” he said.

Cardiovascular outcomes did not differ significantly between the intensive-control and usual-control groups in the three major recent studies—the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial (N. Engl. J. Med. 2008;358:2545–59); the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial (N. Engl. J. Med. 2008;358:2560–72), and the VADT (Veterans Affairs Diabetes Trial) (N. Engl. J. Med. 2009;360:129–39). The ACCORD trial stopped early because of increased mortality in the intensive-control group. In the VADT, intensive glycemic control was associated with a tripled risk for hypoglycemia, which was a strong predictor of cardiovascular death.

However, a subanalysis within the ACCORD trial of prespecified subgroups found less risk of mortality in the intensive-control group if patients entered the study with no history of a prior cardiovascular event or if they entered the study with a hemoglobin A_1c (HbA_1c) level below 8%, he noted.

In the VADT, in which Dr. Reaven participated, a subanalysis found that patients with a shorter duration of diabetes in the intensive-control group appeared to have improved cardiovascular outcomes, compared with the usual-control group. Patients in the intensive group who had diabetes for 15 years or less showed a 26% reduction in cardiovascular risk, compared with the usual-care group, but intensive glycemic control appeared to become harmful in patients who had longer durations of diabetes.

A separate meta-analysis found a significant 10% reduction in cardiovascular events with intensive glycemic control when data from the ACCORD trial, ADVANCE trial, VADT, and the UKPDS (United Kingdom Prospective Diabetes Study) (Lancet 1998:352:837–53) were combined. Mortality rates did not differ significantly among treatment groups in this meta-analysis (Diabetologia 2009;52:2288–98), which was “somewhat reassuring,” though heterogeneity in the individual study results leaves uncertainty about the safety of intensive glycemic control, Dr. Reaven said.

A substudy by Dr. Reaven and associates of 301 patients in the VADT who had baseline CT scans to measure coronary artery calcium in the assessment of coronary atherosclerosis found that intensive glycemic control significantly reduced the risk of cardiovascular events if patients entered the study with lower levels of calcium in their coronary arteries. In the intensive-control group, the risk for cardiovascular events was nearly 10-fold higher in patients with higher coronary artery calcium levels at baseline (an Agatston score of 100 or greater), compared with patients who had lower scores (Diabetes 2009;58:2642–8).

“Your vascular status may influence how you do with intensive glycemic control,” he said. Nearly 60% of VADT participants had higher levels of coronary artery calcium, he estimated, and the ACCORD and ADVANCE cohorts had a high prevalence of cardiovascular disease, which may help explain why the studies overall did not report cardiovascular benefits from tight glycemic control.

“If we can confirm the subset analysis of the VADT, perhaps some imaging method may be reasonable to try to assess vascular risk” when considering intensive glycemic therapy, Dr. Reaven said.

A more clinician-friendly tool—the TIBI (Total Illness Burden Index)—was assessed in a separate longitudinal observational study of 2,613 patients with diabetes that was managed with intensive glycemic control in community practices. Cardiovascular risk was significantly reduced with intensive glycemic control in patients who had a lower baseline level of comorbidity (defined as a TIBI score of 12 or lower), but not in patients who had low TIBI scores and higher HbA_1c levels or in patients who had higher TIBI scores (Ann. Int. Med. 2009;151:854–60).

“Intensive glucose lowering may have a cardiovascular benefit that is most useful in certain subgroups and may be harmful in some individuals,” he said.

Dr. Reaven has financial relationships with AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., Pfizer Inc., Merck & Co., Takeda Pharmaceutical Co., and Amylin Pharmaceuticals Inc.

SAN FRANCISCO — Although three recent major trials found that the potential harms of intensive glycemic control in patients with diabetes generally outweigh potential benefits, substudies of the data may help identify patients who could benefit from intensive therapy.

“There is some hope, which is that improvement in picking individuals for intensive glycemic control may be the right approach,” Dr. Peter D. Reaven said at a meeting sponsored by the American Diabetes Association.

The substudies and other recent analyses suggest that clinicians should avoid aggressive glycemic management (that is, trying to get hemoglobin A_1c values down to 6.5% or lower) in patients who are older and who have a longer duration of diabetes, more extensive calcified coronary atherosclerosis, or a higher burden of comorbidities, said Dr. Reaven, professor of clinical medicine at the University of Arizona, Phoenix.

“I think there probably are groups that do better with glycemic control being intensified, and others that don't,” he said.

Cardiovascular outcomes did not differ significantly between the intensive-control and usual-control groups in the three major recent studies—the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial (N. Engl. J. Med. 2008;358:2545–59); the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial (N. Engl. J. Med. 2008;358:2560–72), and the VADT (Veterans Affairs Diabetes Trial) (N. Engl. J. Med. 2009;360:129–39). The ACCORD trial stopped early because of increased mortality in the intensive-control group. In the VADT, intensive glycemic control was associated with a tripled risk for hypoglycemia, which was a strong predictor of cardiovascular death.

However, a subanalysis within the ACCORD trial of prespecified subgroups found less risk of mortality in the intensive-control group if patients entered the study with no history of a prior cardiovascular event or if they entered the study with a hemoglobin A_1c (HbA_1c) level below 8%, he noted.

In the VADT, in which Dr. Reaven participated, a subanalysis found that patients with a shorter duration of diabetes in the intensive-control group appeared to have improved cardiovascular outcomes, compared with the usual-control group. Patients in the intensive group who had diabetes for 15 years or less showed a 26% reduction in cardiovascular risk, compared with the usual-care group, but intensive glycemic control appeared to become harmful in patients who had longer durations of diabetes.

A separate meta-analysis found a significant 10% reduction in cardiovascular events with intensive glycemic control when data from the ACCORD trial, ADVANCE trial, VADT, and the UKPDS (United Kingdom Prospective Diabetes Study) (Lancet 1998:352:837–53) were combined. Mortality rates did not differ significantly among treatment groups in this meta-analysis (Diabetologia 2009;52:2288–98), which was “somewhat reassuring,” though heterogeneity in the individual study results leaves uncertainty about the safety of intensive glycemic control, Dr. Reaven said.

A substudy by Dr. Reaven and associates of 301 patients in the VADT who had baseline CT scans to measure coronary artery calcium in the assessment of coronary atherosclerosis found that intensive glycemic control significantly reduced the risk of cardiovascular events if patients entered the study with lower levels of calcium in their coronary arteries. In the intensive-control group, the risk for cardiovascular events was nearly 10-fold higher in patients with higher coronary artery calcium levels at baseline (an Agatston score of 100 or greater), compared with patients who had lower scores (Diabetes 2009;58:2642–8).

“Your vascular status may influence how you do with intensive glycemic control,” he said. Nearly 60% of VADT participants had higher levels of coronary artery calcium, he estimated, and the ACCORD and ADVANCE cohorts had a high prevalence of cardiovascular disease, which may help explain why the studies overall did not report cardiovascular benefits from tight glycemic control.

“If we can confirm the subset analysis of the VADT, perhaps some imaging method may be reasonable to try to assess vascular risk” when considering intensive glycemic therapy, Dr. Reaven said.

A more clinician-friendly tool—the TIBI (Total Illness Burden Index)—was assessed in a separate longitudinal observational study of 2,613 patients with diabetes that was managed with intensive glycemic control in community practices. Cardiovascular risk was significantly reduced with intensive glycemic control in patients who had a lower baseline level of comorbidity (defined as a TIBI score of 12 or lower), but not in patients who had low TIBI scores and higher HbA_1c levels or in patients who had higher TIBI scores (Ann. Int. Med. 2009;151:854–60).

“Intensive glucose lowering may have a cardiovascular benefit that is most useful in certain subgroups and may be harmful in some individuals,” he said.

Dr. Reaven has financial relationships with AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., Pfizer Inc., Merck & Co., Takeda Pharmaceutical Co., and Amylin Pharmaceuticals Inc.

SAN FRANCISCO — Meeting the targets in consensus recommendations on inpatient glycemic control requires different protocols for different kinds of patients.

For hospitalized patients who are not critically ill, a protocol employing scheduled subcutaneous insulin therapy with basal, nutritional, and correctional components is effective, Dr. Mary T. Korytkowski said. For critically ill inpatients, intravenous insulin infusion protocols are better for achieving and maintaining glycemic control, she said at a meeting sponsored by the American Diabetes Association.

Many hospitals further subdivide the protocol for critically ill patients to have different glycemic targets for surgical and nonsurgical ICU patients, added Dr. Korytkowski, professor of medicine at the University of Pittsburgh's Center for Diabetes and Endocrinology.

A 2009 consensus statement from the American Association of Clinical Endocrinologists and the American Diabetes Association recommended maintaining glucose levels between 140 and 180 mg/dL in most critically ill patients, but added that glucose levels of 110-140 mg/dL may be appropriate in some, such as those in cardiothoracic intensive care.

“We don't have the data to prove that outside the surgical intensive care studies,” she said, “so many hospitals now have two protocols—one for their surgical patients, and one for nonsurgical patients.”

In noncritically ill inpatients, the consensus statement recommends targeting premeal glucose levels of 100-140 mg/dL and random glucose test results below 180 mg/dL (Endocr. Pract. 2009;15:353–69 and Diabetes Care 2009;32:1119–31).

Prolonged therapy with “sliding scale” insulin alone is not recommended, Dr. Korytkowski stressed. “This whole idea of putting patients on sliding scale insulin and continuing it for the duration of their hospitalization independent of what their blood sugar levels are needs to be stopped,” she said.

The 2009 consensus recommendations steered clinicians away from aiming for lower glucose levels of 80-110 mg/dL in hospitalized patients to reduce risk for complications related to uncontrolled hyperglycemia while also minimizing risk for sever hypoglycemia.

Institutions can choose from published protocols for managing inpatient glucose levels to meet consensus recommendations. For critically ill patients, it's better to initiate insulin infusions when glucose levels reach the lower end of the 140- to 180-mg/dL range rather than wait for levels to climb above 180 mg/dL, she said.

Her institution initiates insulin therapy by obtaining or estimating the patient's weight in kilograms, then calculating the total daily dose of insulin as 0.2-0.4 units/kg per day. Clinicians then choose the dosing schedule, usually giving 50%–60% of the total daily dose as basal insulin, with the remainder as premeal or nutritional bolus insulin divided up in three or four doses. Correction insulin is given when blood glucose levels exceed the goal range. “This is not a one-stop process,” Dr. Korytkowski said. Each day, the glucose levels are evaluated, and the insulin regimen is adjusted to avoid both hyper- and hypoglycemia.

The basal-bolus insulin protocol was shown to be safe when compared with sliding scale insulin in a prospective, randomized, controlled trial of 130 inpatients with type 2 diabetes, she noted (Diabetes Care 2007;30:2181–6).

Dr. Korytkowski also recommends monitoring glucose for at least 48 hours in all hospitalized patients who are starting glucocorticoid therapy or enteral or parenteral nutrition, because these are associated with increased risk for hyperglycemia. Prescribe insulin therapy as needed in these patients based on bedside blood glucose monitoring, and be proactive about adjusting insulin therapy especially during initiation and tapering of steroid therapy, she advised.

“One thing that's very important when patients go home and their steroid doses are tapered is that they need to know how to taper their insulin along with tapering their steroid, so they don't come back in 2-3 weeks in a hyperglycemic event,” she said.

Dr. Korytkowski and her associates published a glycemic management algorithm for patients receiving enteral nutrition that was shown to be safe in a prospective, randomized trial in 50 inpatients (Diabetes Care 2009;32:594–6).

Establishing a formal protocol for patients who enter the hospital on insulin pumps also can reduce confusion and treatment variability, she added. At her institution, patients who used insulin pumps before entering the hospital can continue to use them as inpatients provided that they have the mental and physical capacity to do so. Ideally, hospital staff who have experience in insulin pumps should be available if needed.

Dr. Korytkowski said she has no conflicts of interest to disclose.

A related video is at www.youtube.com/ElsGlobalMedicalNews

Glucose levels are evaluated daily, and the insulin regimen is adjusted to avoid hyper- and hypoglycemia.

Source DR. KORYTKOWSKI

SAN FRANCISCO — Meeting the targets in consensus recommendations on inpatient glycemic control requires different protocols for different kinds of patients.

For hospitalized patients who are not critically ill, a protocol employing scheduled subcutaneous insulin therapy with basal, nutritional, and correctional components is effective, Dr. Mary T. Korytkowski said. For critically ill inpatients, intravenous insulin infusion protocols are better for achieving and maintaining glycemic control, she said at a meeting sponsored by the American Diabetes Association.

Many hospitals further subdivide the protocol for critically ill patients to have different glycemic targets for surgical and nonsurgical ICU patients, added Dr. Korytkowski, professor of medicine at the University of Pittsburgh's Center for Diabetes and Endocrinology.

A 2009 consensus statement from the American Association of Clinical Endocrinologists and the American Diabetes Association recommended maintaining glucose levels between 140 and 180 mg/dL in most critically ill patients, but added that glucose levels of 110-140 mg/dL may be appropriate in some, such as those in cardiothoracic intensive care.

“We don't have the data to prove that outside the surgical intensive care studies,” she said, “so many hospitals now have two protocols—one for their surgical patients, and one for nonsurgical patients.”

In noncritically ill inpatients, the consensus statement recommends targeting premeal glucose levels of 100-140 mg/dL and random glucose test results below 180 mg/dL (Endocr. Pract. 2009;15:353–69 and Diabetes Care 2009;32:1119–31).

Prolonged therapy with “sliding scale” insulin alone is not recommended, Dr. Korytkowski stressed. “This whole idea of putting patients on sliding scale insulin and continuing it for the duration of their hospitalization independent of what their blood sugar levels are needs to be stopped,” she said.

The 2009 consensus recommendations steered clinicians away from aiming for lower glucose levels of 80-110 mg/dL in hospitalized patients to reduce risk for complications related to uncontrolled hyperglycemia while also minimizing risk for sever hypoglycemia.

Institutions can choose from published protocols for managing inpatient glucose levels to meet consensus recommendations. For critically ill patients, it's better to initiate insulin infusions when glucose levels reach the lower end of the 140- to 180-mg/dL range rather than wait for levels to climb above 180 mg/dL, she said.

Her institution initiates insulin therapy by obtaining or estimating the patient's weight in kilograms, then calculating the total daily dose of insulin as 0.2-0.4 units/kg per day. Clinicians then choose the dosing schedule, usually giving 50%–60% of the total daily dose as basal insulin, with the remainder as premeal or nutritional bolus insulin divided up in three or four doses. Correction insulin is given when blood glucose levels exceed the goal range. “This is not a one-stop process,” Dr. Korytkowski said. Each day, the glucose levels are evaluated, and the insulin regimen is adjusted to avoid both hyper- and hypoglycemia.

The basal-bolus insulin protocol was shown to be safe when compared with sliding scale insulin in a prospective, randomized, controlled trial of 130 inpatients with type 2 diabetes, she noted (Diabetes Care 2007;30:2181–6).

Dr. Korytkowski also recommends monitoring glucose for at least 48 hours in all hospitalized patients who are starting glucocorticoid therapy or enteral or parenteral nutrition, because these are associated with increased risk for hyperglycemia. Prescribe insulin therapy as needed in these patients based on bedside blood glucose monitoring, and be proactive about adjusting insulin therapy especially during initiation and tapering of steroid therapy, she advised.

“One thing that's very important when patients go home and their steroid doses are tapered is that they need to know how to taper their insulin along with tapering their steroid, so they don't come back in 2-3 weeks in a hyperglycemic event,” she said.

Dr. Korytkowski and her associates published a glycemic management algorithm for patients receiving enteral nutrition that was shown to be safe in a prospective, randomized trial in 50 inpatients (Diabetes Care 2009;32:594–6).

Establishing a formal protocol for patients who enter the hospital on insulin pumps also can reduce confusion and treatment variability, she added. At her institution, patients who used insulin pumps before entering the hospital can continue to use them as inpatients provided that they have the mental and physical capacity to do so. Ideally, hospital staff who have experience in insulin pumps should be available if needed.

Dr. Korytkowski said she has no conflicts of interest to disclose.

A related video is at www.youtube.com/ElsGlobalMedicalNews

Glucose levels are evaluated daily, and the insulin regimen is adjusted to avoid hyper- and hypoglycemia.

Source DR. KORYTKOWSKI

SAN FRANCISCO — Meeting the targets in consensus recommendations on inpatient glycemic control requires different protocols for different kinds of patients.

For hospitalized patients who are not critically ill, a protocol employing scheduled subcutaneous insulin therapy with basal, nutritional, and correctional components is effective, Dr. Mary T. Korytkowski said. For critically ill inpatients, intravenous insulin infusion protocols are better for achieving and maintaining glycemic control, she said at a meeting sponsored by the American Diabetes Association.

Many hospitals further subdivide the protocol for critically ill patients to have different glycemic targets for surgical and nonsurgical ICU patients, added Dr. Korytkowski, professor of medicine at the University of Pittsburgh's Center for Diabetes and Endocrinology.

A 2009 consensus statement from the American Association of Clinical Endocrinologists and the American Diabetes Association recommended maintaining glucose levels between 140 and 180 mg/dL in most critically ill patients, but added that glucose levels of 110-140 mg/dL may be appropriate in some, such as those in cardiothoracic intensive care.

“We don't have the data to prove that outside the surgical intensive care studies,” she said, “so many hospitals now have two protocols—one for their surgical patients, and one for nonsurgical patients.”

In noncritically ill inpatients, the consensus statement recommends targeting premeal glucose levels of 100-140 mg/dL and random glucose test results below 180 mg/dL (Endocr. Pract. 2009;15:353–69 and Diabetes Care 2009;32:1119–31).

Prolonged therapy with “sliding scale” insulin alone is not recommended, Dr. Korytkowski stressed. “This whole idea of putting patients on sliding scale insulin and continuing it for the duration of their hospitalization independent of what their blood sugar levels are needs to be stopped,” she said.

The 2009 consensus recommendations steered clinicians away from aiming for lower glucose levels of 80-110 mg/dL in hospitalized patients to reduce risk for complications related to uncontrolled hyperglycemia while also minimizing risk for sever hypoglycemia.

Institutions can choose from published protocols for managing inpatient glucose levels to meet consensus recommendations. For critically ill patients, it's better to initiate insulin infusions when glucose levels reach the lower end of the 140- to 180-mg/dL range rather than wait for levels to climb above 180 mg/dL, she said.

Her institution initiates insulin therapy by obtaining or estimating the patient's weight in kilograms, then calculating the total daily dose of insulin as 0.2-0.4 units/kg per day. Clinicians then choose the dosing schedule, usually giving 50%–60% of the total daily dose as basal insulin, with the remainder as premeal or nutritional bolus insulin divided up in three or four doses. Correction insulin is given when blood glucose levels exceed the goal range. “This is not a one-stop process,” Dr. Korytkowski said. Each day, the glucose levels are evaluated, and the insulin regimen is adjusted to avoid both hyper- and hypoglycemia.

The basal-bolus insulin protocol was shown to be safe when compared with sliding scale insulin in a prospective, randomized, controlled trial of 130 inpatients with type 2 diabetes, she noted (Diabetes Care 2007;30:2181–6).

Dr. Korytkowski also recommends monitoring glucose for at least 48 hours in all hospitalized patients who are starting glucocorticoid therapy or enteral or parenteral nutrition, because these are associated with increased risk for hyperglycemia. Prescribe insulin therapy as needed in these patients based on bedside blood glucose monitoring, and be proactive about adjusting insulin therapy especially during initiation and tapering of steroid therapy, she advised.

“One thing that's very important when patients go home and their steroid doses are tapered is that they need to know how to taper their insulin along with tapering their steroid, so they don't come back in 2-3 weeks in a hyperglycemic event,” she said.

Dr. Korytkowski and her associates published a glycemic management algorithm for patients receiving enteral nutrition that was shown to be safe in a prospective, randomized trial in 50 inpatients (Diabetes Care 2009;32:594–6).

Establishing a formal protocol for patients who enter the hospital on insulin pumps also can reduce confusion and treatment variability, she added. At her institution, patients who used insulin pumps before entering the hospital can continue to use them as inpatients provided that they have the mental and physical capacity to do so. Ideally, hospital staff who have experience in insulin pumps should be available if needed.

Dr. Korytkowski said she has no conflicts of interest to disclose.

A related video is at www.youtube.com/ElsGlobalMedicalNews

Glucose levels are evaluated daily, and the insulin regimen is adjusted to avoid hyper- and hypoglycemia.

Source DR. KORYTKOWSKI

SAN FRANCISCO — Metformin, some oral contraceptives, and possibly statins used to treat polycystic ovary syndrome can decrease the associated cardiovascular risk, while other oral contraceptives increase cardiovascular risk, studies suggest.

Dr. Andrea Dunaif summarized the data on cardiometabolic risk in the treatment of polycystic ovary syndrome at a meeting sponsored by the American Diabetes Association.

“We treat women with PCOS with insulin sensitizing drugs, but we also frequently treat them to regulate their menstrual periods with oral contraceptives,” explained Dr. Dunaif, professor of endocrinology at Northwestern University, Chicago.

Previous evidence that estrogen therapy can increase triglyceride levels and that certain oral contraceptives can exacerbate insulin resistance raised concern that oral contraceptives may have adverse metabolic consequences in women with PCOS.

One study randomized 48 hirsute women with polycystic ovary syndrome to 6 months of treatment with a common oral contraceptive (Yasmin, or Yaz) containing 3 mg of drospirenone and 20 mcg of ethinyl estradiol or the same therapy plus either metformin 1,500 mg/day or cyproterone acetate (12.5 mg/day, 10 days per cycle), a progesterone used in other countries, but not in the United States (Fertil. Steril. 2009 Nov. 19 [doi:10.1016.j.fertnstert.2009.10.016]).

Insulin sensitivity improved in patients on Yasmin alone or Yasmin plus metformin but significantly worsened with Yasmin plus cyproterone acetate in the open-label trial, Dr. Dunaif explained at the meeting.

A separate open-label trial randomized 100 overweight women with PCOS to 6 months of oral therapy with 35 mcg of ethinyl estradiol and 2 mg of cyproterone acetate (a formulation known in Europe as Diane-35), a low-dose oral contraceptive regimen (20 mcg of ethinyl estradiol and 100 mcg of levonorgestrel) plus the antiandrogen drug spironolactone 50 mg b.i.d., or metformin 1 g b.i.d.

Each of the treatment arms showed similar, significant improvements in PCOS symptoms and menstrual cycle length.

Insulin resistance improved significantly in the metformin group, but insulin resistance and arterial stiffness worsened in the ethinyl estradiol/cyproterone acetate group (Diabetes Care 2007;30:471–8).

“Cyproterone acetate looks to be a bad actor in these studies,” Dr. Dunaif said.

Several studies of metformin therapy in women with PCOS have shown that the drug can improve risk factors for cardiovascular disease such as endothelial dysfunction, she noted.

Compared with placebo, 12 weeks of metformin significantly decreased arterial stiffness and improved endothelial function in 30 women with polycystic ovary syndrome in a randomized, double-blind crossover trial (J. Clin. Endocrinol. Metab. 2010;95:722–30).

Most recently, “statins are showing promise” in women with polycystic ovary syndrome by decreasing androgen levels and improving insulin sensitivity, Dr. Dunaif added.

One prospective trial randomized 136 women with polycystic ovary syndrome to treatment with simvastatin, metformin, or a combination of the two drugs for 3 months.

Improvements in insulin sensitivity were greater with simvastatin than with metformin or with the combination, while testosterone levels decreased significantly and comparably in all groups (J. Clin. Endocrinol. Metab. 2009;94:4938–45).

“This is something to look out for in the future, to see more data on the role of statins in the treatment of women with PCOS,” she said.

Polycystic ovary syndrome has been associated with multiple cardiometabolic risk factors, including increased risk for type 2 diabetes. Indirect evidence suggests that the relative risk for myocardial infarction may be increased sevenfold in women with PCOS, Dr. Dunaif said.

Dr. Dunaif has been a consultant for Bristol-Myers Squibb Co., which makes metformin.

SAN FRANCISCO — Metformin, some oral contraceptives, and possibly statins used to treat polycystic ovary syndrome can decrease the associated cardiovascular risk, while other oral contraceptives increase cardiovascular risk, studies suggest.

Dr. Andrea Dunaif summarized the data on cardiometabolic risk in the treatment of polycystic ovary syndrome at a meeting sponsored by the American Diabetes Association.

“We treat women with PCOS with insulin sensitizing drugs, but we also frequently treat them to regulate their menstrual periods with oral contraceptives,” explained Dr. Dunaif, professor of endocrinology at Northwestern University, Chicago.

Previous evidence that estrogen therapy can increase triglyceride levels and that certain oral contraceptives can exacerbate insulin resistance raised concern that oral contraceptives may have adverse metabolic consequences in women with PCOS.

One study randomized 48 hirsute women with polycystic ovary syndrome to 6 months of treatment with a common oral contraceptive (Yasmin, or Yaz) containing 3 mg of drospirenone and 20 mcg of ethinyl estradiol or the same therapy plus either metformin 1,500 mg/day or cyproterone acetate (12.5 mg/day, 10 days per cycle), a progesterone used in other countries, but not in the United States (Fertil. Steril. 2009 Nov. 19 [doi:10.1016.j.fertnstert.2009.10.016]).

Insulin sensitivity improved in patients on Yasmin alone or Yasmin plus metformin but significantly worsened with Yasmin plus cyproterone acetate in the open-label trial, Dr. Dunaif explained at the meeting.

A separate open-label trial randomized 100 overweight women with PCOS to 6 months of oral therapy with 35 mcg of ethinyl estradiol and 2 mg of cyproterone acetate (a formulation known in Europe as Diane-35), a low-dose oral contraceptive regimen (20 mcg of ethinyl estradiol and 100 mcg of levonorgestrel) plus the antiandrogen drug spironolactone 50 mg b.i.d., or metformin 1 g b.i.d.

Each of the treatment arms showed similar, significant improvements in PCOS symptoms and menstrual cycle length.

Insulin resistance improved significantly in the metformin group, but insulin resistance and arterial stiffness worsened in the ethinyl estradiol/cyproterone acetate group (Diabetes Care 2007;30:471–8).

“Cyproterone acetate looks to be a bad actor in these studies,” Dr. Dunaif said.

Several studies of metformin therapy in women with PCOS have shown that the drug can improve risk factors for cardiovascular disease such as endothelial dysfunction, she noted.

Compared with placebo, 12 weeks of metformin significantly decreased arterial stiffness and improved endothelial function in 30 women with polycystic ovary syndrome in a randomized, double-blind crossover trial (J. Clin. Endocrinol. Metab. 2010;95:722–30).

Most recently, “statins are showing promise” in women with polycystic ovary syndrome by decreasing androgen levels and improving insulin sensitivity, Dr. Dunaif added.

One prospective trial randomized 136 women with polycystic ovary syndrome to treatment with simvastatin, metformin, or a combination of the two drugs for 3 months.

Improvements in insulin sensitivity were greater with simvastatin than with metformin or with the combination, while testosterone levels decreased significantly and comparably in all groups (J. Clin. Endocrinol. Metab. 2009;94:4938–45).

“This is something to look out for in the future, to see more data on the role of statins in the treatment of women with PCOS,” she said.

Polycystic ovary syndrome has been associated with multiple cardiometabolic risk factors, including increased risk for type 2 diabetes. Indirect evidence suggests that the relative risk for myocardial infarction may be increased sevenfold in women with PCOS, Dr. Dunaif said.

Dr. Dunaif has been a consultant for Bristol-Myers Squibb Co., which makes metformin.

SAN FRANCISCO — Metformin, some oral contraceptives, and possibly statins used to treat polycystic ovary syndrome can decrease the associated cardiovascular risk, while other oral contraceptives increase cardiovascular risk, studies suggest.

Dr. Andrea Dunaif summarized the data on cardiometabolic risk in the treatment of polycystic ovary syndrome at a meeting sponsored by the American Diabetes Association.

“We treat women with PCOS with insulin sensitizing drugs, but we also frequently treat them to regulate their menstrual periods with oral contraceptives,” explained Dr. Dunaif, professor of endocrinology at Northwestern University, Chicago.

Previous evidence that estrogen therapy can increase triglyceride levels and that certain oral contraceptives can exacerbate insulin resistance raised concern that oral contraceptives may have adverse metabolic consequences in women with PCOS.

One study randomized 48 hirsute women with polycystic ovary syndrome to 6 months of treatment with a common oral contraceptive (Yasmin, or Yaz) containing 3 mg of drospirenone and 20 mcg of ethinyl estradiol or the same therapy plus either metformin 1,500 mg/day or cyproterone acetate (12.5 mg/day, 10 days per cycle), a progesterone used in other countries, but not in the United States (Fertil. Steril. 2009 Nov. 19 [doi:10.1016.j.fertnstert.2009.10.016]).

Insulin sensitivity improved in patients on Yasmin alone or Yasmin plus metformin but significantly worsened with Yasmin plus cyproterone acetate in the open-label trial, Dr. Dunaif explained at the meeting.

A separate open-label trial randomized 100 overweight women with PCOS to 6 months of oral therapy with 35 mcg of ethinyl estradiol and 2 mg of cyproterone acetate (a formulation known in Europe as Diane-35), a low-dose oral contraceptive regimen (20 mcg of ethinyl estradiol and 100 mcg of levonorgestrel) plus the antiandrogen drug spironolactone 50 mg b.i.d., or metformin 1 g b.i.d.

Each of the treatment arms showed similar, significant improvements in PCOS symptoms and menstrual cycle length.

Insulin resistance improved significantly in the metformin group, but insulin resistance and arterial stiffness worsened in the ethinyl estradiol/cyproterone acetate group (Diabetes Care 2007;30:471–8).

“Cyproterone acetate looks to be a bad actor in these studies,” Dr. Dunaif said.

Several studies of metformin therapy in women with PCOS have shown that the drug can improve risk factors for cardiovascular disease such as endothelial dysfunction, she noted.

Compared with placebo, 12 weeks of metformin significantly decreased arterial stiffness and improved endothelial function in 30 women with polycystic ovary syndrome in a randomized, double-blind crossover trial (J. Clin. Endocrinol. Metab. 2010;95:722–30).

Most recently, “statins are showing promise” in women with polycystic ovary syndrome by decreasing androgen levels and improving insulin sensitivity, Dr. Dunaif added.

One prospective trial randomized 136 women with polycystic ovary syndrome to treatment with simvastatin, metformin, or a combination of the two drugs for 3 months.

Improvements in insulin sensitivity were greater with simvastatin than with metformin or with the combination, while testosterone levels decreased significantly and comparably in all groups (J. Clin. Endocrinol. Metab. 2009;94:4938–45).

“This is something to look out for in the future, to see more data on the role of statins in the treatment of women with PCOS,” she said.

Polycystic ovary syndrome has been associated with multiple cardiometabolic risk factors, including increased risk for type 2 diabetes. Indirect evidence suggests that the relative risk for myocardial infarction may be increased sevenfold in women with PCOS, Dr. Dunaif said.

Dr. Dunaif has been a consultant for Bristol-Myers Squibb Co., which makes metformin.

SAN FRANCISCO — Metformin, some oral contraceptives, and possibly statins used to treat polycystic ovary syndrome can decrease the associated cardiovascular risk, while other oral contraceptives increase cardiovascular risk, studies suggest.

Dr. Andrea Dunaif summarized the data on cardiometabolic risk in the treatment of polycystic ovary syndrome (PCOS) at a meeting sponsored by the American Diabetes Association.

“We treat women with PCOS with insulin sensitizing drugs, but we also frequently treat them to regulate their menstrual periods with oral contraceptives,” explained Dr. Dunaif, professor of endocrinology at Northwestern University, Chicago.

Previous evidence that estrogen therapy can increase triglyceride levels and that certain oral contraceptives can exacerbate insulin resistance raised concern that oral contraceptives may have adverse metabolic consequences in women with PCOS.

One study randomized 48 hirsute women with PCOS to 6 months of treatment with a common oral contraceptive (Yasmin, or Yaz) containing 3 mg of drospirenone and 20 mcg of ethinyl estradiol or the same therapy plus either metformin 1,500 mg/day or cyproterone acetate (12.5 mg/day, 10 days per cycle), a progesterone that is not used in the United States but is used in other countries (Fertil. Steril. 2009 Nov. 19 [doi: 10.1016.j.fertnstert.2009.10.016]).

Insulin sensitivity improved in patients on Yasmin alone or Yasmin plus metformin but significantly worsened with Yasmin plus cyproterone acetate in the open-label trial, Dr. Dunaif said.

A separate open-label trial randomized 100 overweight women with PCOS to 6 months of oral therapy with 35 mcg of ethinyl estradiol and 2 mg of cyproterone acetate (a formulation known in Europe as Diane-35), a low-dose oral contraceptive regimen (20 mcg of ethinyl estradiol and 100 mcg of levonorgestrel) plus the antiandrogen drug spironolactone 50 mg b.i.d., or metformin 1 g b.i.d.

Each of the treatment arms showed similar, significant improvements in PCOS symptoms and menstrual cycle length.

Insulin resistance improved significantly in the metformin group, but insulin resistance and arterial stiffness worsened in the ethinyl estradiol/cyproterone acetate group (Diabetes Care 2007;30:471-8).

“Cyproterone acetate looks to be a bad actor in these studies,” Dr. Dunaif said.

Several studies of metformin therapy in women with PCOS have shown that the drug can improve risk factors for cardiovascular disease such as endothelial dysfunction, she noted.

Compared with placebo, 12 weeks of metformin significantly decreased arterial stiffness and improved endothelial function in 30 women with PCOS in a randomized, double-blind crossover trial (J. Clin. Endocrinol. Metab. 2010;95: 722-30).

Most recently, “statins are showing promise” in women with PCOS by decreasing androgen levels and improving insulin sensitivity, Dr. Dunaif added.

One prospective trial randomized 136 women with PCOS to treatment with simvastatin, metformin, or a combination of the two drugs for a period of 3 months.

Improvements in insulin sensitivity were greater with simvastatin than with metformin or with the combination, while testosterone levels decreased significantly and comparably in all groups (J. Clin. Endocrinol. Metab. 2009; 94:4938-45).

“This is something to look out for in the future, to see more data on the role of statins in the treatment of women with PCOS,” she said.

PCOS has been associated with multiple cardiometabolic risk factors including increased risk for type 2 diabetes. Indirect evidence suggests that the relative risk for MI may be increased sevenfold in women with PCOS, Dr. Dunaif said.

Disclosures: Dr. Dunaif has been a consultant for Bristol-Myers Squibb Co., which makes metformin.

SAN FRANCISCO — Metformin, some oral contraceptives, and possibly statins used to treat polycystic ovary syndrome can decrease the associated cardiovascular risk, while other oral contraceptives increase cardiovascular risk, studies suggest.

Dr. Andrea Dunaif summarized the data on cardiometabolic risk in the treatment of polycystic ovary syndrome (PCOS) at a meeting sponsored by the American Diabetes Association.

“We treat women with PCOS with insulin sensitizing drugs, but we also frequently treat them to regulate their menstrual periods with oral contraceptives,” explained Dr. Dunaif, professor of endocrinology at Northwestern University, Chicago.

Previous evidence that estrogen therapy can increase triglyceride levels and that certain oral contraceptives can exacerbate insulin resistance raised concern that oral contraceptives may have adverse metabolic consequences in women with PCOS.

One study randomized 48 hirsute women with PCOS to 6 months of treatment with a common oral contraceptive (Yasmin, or Yaz) containing 3 mg of drospirenone and 20 mcg of ethinyl estradiol or the same therapy plus either metformin 1,500 mg/day or cyproterone acetate (12.5 mg/day, 10 days per cycle), a progesterone that is not used in the United States but is used in other countries (Fertil. Steril. 2009 Nov. 19 [doi: 10.1016.j.fertnstert.2009.10.016]).

Insulin sensitivity improved in patients on Yasmin alone or Yasmin plus metformin but significantly worsened with Yasmin plus cyproterone acetate in the open-label trial, Dr. Dunaif said.

A separate open-label trial randomized 100 overweight women with PCOS to 6 months of oral therapy with 35 mcg of ethinyl estradiol and 2 mg of cyproterone acetate (a formulation known in Europe as Diane-35), a low-dose oral contraceptive regimen (20 mcg of ethinyl estradiol and 100 mcg of levonorgestrel) plus the antiandrogen drug spironolactone 50 mg b.i.d., or metformin 1 g b.i.d.

Each of the treatment arms showed similar, significant improvements in PCOS symptoms and menstrual cycle length.

Insulin resistance improved significantly in the metformin group, but insulin resistance and arterial stiffness worsened in the ethinyl estradiol/cyproterone acetate group (Diabetes Care 2007;30:471-8).

“Cyproterone acetate looks to be a bad actor in these studies,” Dr. Dunaif said.

Several studies of metformin therapy in women with PCOS have shown that the drug can improve risk factors for cardiovascular disease such as endothelial dysfunction, she noted.

Compared with placebo, 12 weeks of metformin significantly decreased arterial stiffness and improved endothelial function in 30 women with PCOS in a randomized, double-blind crossover trial (J. Clin. Endocrinol. Metab. 2010;95: 722-30).

Most recently, “statins are showing promise” in women with PCOS by decreasing androgen levels and improving insulin sensitivity, Dr. Dunaif added.

One prospective trial randomized 136 women with PCOS to treatment with simvastatin, metformin, or a combination of the two drugs for a period of 3 months.

Improvements in insulin sensitivity were greater with simvastatin than with metformin or with the combination, while testosterone levels decreased significantly and comparably in all groups (J. Clin. Endocrinol. Metab. 2009; 94:4938-45).

“This is something to look out for in the future, to see more data on the role of statins in the treatment of women with PCOS,” she said.

PCOS has been associated with multiple cardiometabolic risk factors including increased risk for type 2 diabetes. Indirect evidence suggests that the relative risk for MI may be increased sevenfold in women with PCOS, Dr. Dunaif said.

Disclosures: Dr. Dunaif has been a consultant for Bristol-Myers Squibb Co., which makes metformin.

SAN FRANCISCO — Metformin, some oral contraceptives, and possibly statins used to treat polycystic ovary syndrome can decrease the associated cardiovascular risk, while other oral contraceptives increase cardiovascular risk, studies suggest.

Dr. Andrea Dunaif summarized the data on cardiometabolic risk in the treatment of polycystic ovary syndrome (PCOS) at a meeting sponsored by the American Diabetes Association.

“We treat women with PCOS with insulin sensitizing drugs, but we also frequently treat them to regulate their menstrual periods with oral contraceptives,” explained Dr. Dunaif, professor of endocrinology at Northwestern University, Chicago.

Previous evidence that estrogen therapy can increase triglyceride levels and that certain oral contraceptives can exacerbate insulin resistance raised concern that oral contraceptives may have adverse metabolic consequences in women with PCOS.

One study randomized 48 hirsute women with PCOS to 6 months of treatment with a common oral contraceptive (Yasmin, or Yaz) containing 3 mg of drospirenone and 20 mcg of ethinyl estradiol or the same therapy plus either metformin 1,500 mg/day or cyproterone acetate (12.5 mg/day, 10 days per cycle), a progesterone that is not used in the United States but is used in other countries (Fertil. Steril. 2009 Nov. 19 [doi: 10.1016.j.fertnstert.2009.10.016]).

Insulin sensitivity improved in patients on Yasmin alone or Yasmin plus metformin but significantly worsened with Yasmin plus cyproterone acetate in the open-label trial, Dr. Dunaif said.

A separate open-label trial randomized 100 overweight women with PCOS to 6 months of oral therapy with 35 mcg of ethinyl estradiol and 2 mg of cyproterone acetate (a formulation known in Europe as Diane-35), a low-dose oral contraceptive regimen (20 mcg of ethinyl estradiol and 100 mcg of levonorgestrel) plus the antiandrogen drug spironolactone 50 mg b.i.d., or metformin 1 g b.i.d.

Each of the treatment arms showed similar, significant improvements in PCOS symptoms and menstrual cycle length.

Insulin resistance improved significantly in the metformin group, but insulin resistance and arterial stiffness worsened in the ethinyl estradiol/cyproterone acetate group (Diabetes Care 2007;30:471-8).

“Cyproterone acetate looks to be a bad actor in these studies,” Dr. Dunaif said.

Several studies of metformin therapy in women with PCOS have shown that the drug can improve risk factors for cardiovascular disease such as endothelial dysfunction, she noted.

Compared with placebo, 12 weeks of metformin significantly decreased arterial stiffness and improved endothelial function in 30 women with PCOS in a randomized, double-blind crossover trial (J. Clin. Endocrinol. Metab. 2010;95: 722-30).

Most recently, “statins are showing promise” in women with PCOS by decreasing androgen levels and improving insulin sensitivity, Dr. Dunaif added.

One prospective trial randomized 136 women with PCOS to treatment with simvastatin, metformin, or a combination of the two drugs for a period of 3 months.

Improvements in insulin sensitivity were greater with simvastatin than with metformin or with the combination, while testosterone levels decreased significantly and comparably in all groups (J. Clin. Endocrinol. Metab. 2009; 94:4938-45).

“This is something to look out for in the future, to see more data on the role of statins in the treatment of women with PCOS,” she said.

PCOS has been associated with multiple cardiometabolic risk factors including increased risk for type 2 diabetes. Indirect evidence suggests that the relative risk for MI may be increased sevenfold in women with PCOS, Dr. Dunaif said.

Disclosures: Dr. Dunaif has been a consultant for Bristol-Myers Squibb Co., which makes metformin.

SAN FRANCISCO — Lack of attention to biological differences between males and females may be hurting both sexes in the treatment of health problems.

Research in the past decade has begun to delve into sex differences in depression, pain perception, sleep, stroke, multiple sclerosis, drug responses, and more, speakers said at a meeting sponsored by the Institute of Medicine on sex differences and their implications for translational neuroscience research.

“The advances in molecular biology and in brain imaging make it clear that there's a biological basis to the sex differences,” said Rae Silver, Ph.D., who codirected the workshop and is a professor of natural and physical sciences at Barnard College and Columbia University, both in New York.

When researchers don't examine differences between males and females—in basic science on cell biology all the way up to human clinical trials—the resulting lack of data may lead to flawed conclusions. For example, data showing that only 20% of studies on heart disease have included women help to explain why the disease and its treatments are less well understood in women than in men, several speakers noted.

On the other hand, an investigational drug that may have been effective in treating chronic pain in men—but not women—was abandoned after the drug failed in a clinical trial that included both sexes but did not analyze differences in response by sex, another speaker said.

The IOM convened the workshop to follow up on its 2001 report, “Exploring the Biological Contributions to Human Health: Does Sex Matter?” which recommended that sex differences be studied “from womb to tomb” (across the lifespan), across species, and at the cellular level, and that all human diseases affecting both sexes be monitored for sex differences and similarities.

The progress reports at the workshop showed how much remains to be done, and generated lively debate about what the IOM, the National Institutes of Health, and the Food and Drug Administration could do to promote greater attention to sex differences in research and drug development.

Currently, only NIH-funded studies must include some attention to sex differences, and this requirement does not apply to studies funded by industry or other sources.

The NIH and the FDA created an online course on sex differences that offers continuing medical education credits to researchers and clinicians, said Dr. Vivian W. Pinn, director of the NIH Office of Research on Women's Health. The course provides a basic scientific understanding of the major physiological differences between the sexes, the influences these differences have on illness and health outcomes, and the implications for policy, medical research, and health care. It can be found at http://sexandgendercourse.od.nih.gov

Sex differences in disease susceptibility should be studied whenever there are differences between the sexes in anatomy, in physiology, in the incidence or age of onset of disease, in the symptoms or diagnosis of disease, or in the severity, progression, and outcome of disease, argued Kathryn Sandberg, Ph.D.

“There's growing interest because it's become clear that, in stroke, not only is there a sex difference in incidence, but also a sex difference in symptoms,” according to Dr. Sandberg, director of the center for the study of sex differences in health, aging, and disease at Georgetown University in Washington.

A recent study reported sex differences in types of acute ischemic stroke. Men are significantly more likely than women to have lacunar (39% vs. 29%) or atherosclerotic strokes (19% vs. 13%), whereas women are significantly more likely to have cardioembolic strokes than men (30% vs. 23%), she noted (Women's Health 2010;6:51–7).

“That's just screaming at you that there's a mechanism that has to be studied,” Dr. Sandberg said.

Other speakers emphasized the need for more research on sex differences in major depression, which is twice as common in females as in males, and in multiple sclerosis, which is two to four times more common in females than in males.

Because multiple sclerosis relapses in 80% of women during pregnancy, and findings from animal tests have suggested that estriol protects against multiple sclerosis, a clinical trial is underway of estriol treatment in women with the disease, said Dr. Rhonda Voskuhl, professor of neurology at the University of California, Los Angeles.

Similarly, animal test data showed a protective effect of testosterone in men, and a pilot study of testosterone gel in men with multiple sclerosis showed markers of improvement.

“I'm now primed to do a clinical trial in men,” she added.

The problem is that both of these are generic drugs, so it will be difficult to find the $5-$25 million needed for phase II/III clinical trials. “It's a shame to drop estradiol and testosterone merely because nobody can make money on it. If you're a patient, you'd rather take estriol, which has been given to hundreds of thousands of people, instead of compound x, y, or z” with unknown side effects, she said.

In the growing field of sleep medicine, “We still lack some basic understandings about sex differences and their consequences for disease,” added Roseanne Armitage, Ph.D., professor of psychiatry at the University of Michigan in Ann Arbor.

Jeanne Duffy, Ph.D., director of the Chronobiology Core at Brigham and Women's Hospital, Boston, described profound differences between the sexes in subjective and objective measures of sleep quality. For example, women are more likely to subjectively report not having good sleep even when objective measures would suggest they slept better than men. “We don't understand these differences,” she said.

In other sleep research, men report better daytime functioning after getting less than 7 hours of sleep, though objective measures suggest they're functioning no better than women on the same amount of sleep, said Rachel Manber, Ph.D., director of the Sleep Medicine Clinic at Stanford (Calif.) University.

On a preclinical level, a review of studies in rodents found that 87% either used only male rodents, didn't specify sex, or didn't examine sex differences in the few studies that included males and females, Jeffrey S. Mogil, Ph.D., said (Pain 2005;117:1–5).

There's an assumption among scientists that data from female mice are more variable and thus are harder to work with, but research by Dr. Mogil and his associates found that this is not true. If anything, data are more variable from male mice, although not significantly more so than data from females, said Dr. Mogil, professor of psychology at the center for research on pain at McGill University in Montreal.

Moreover, a once-radical hypothesis has been proved to be true—that males and females have qualitatively different pain processing mechanisms that are genetically and neurochemically distinct from males, Dr. Mogil's mice studies have shown.

All of that could explain why more than 100 promising studies in mice suggesting that dextromethorphan (a common ingredient in cough syrup) potentiates the analgesic effects of morphine resulted in a failed clinical trial in humans of the drug combination, Dr. Mogil said. The mice studies undoubtedly focused on males, and later studies by Dr. Mogil showed that dextromethorphan boosts morphine's effects in males but not in females. The pharmaceutical company that sponsored the human trial and later abandoned the drug combination had not analyzed sex differences.

“That was an example of a flaw in the NIH policy. They included women but didn't do anything with them” in the analysis of results, Dr. Mogil said.

At the basic science level, it's now understood that the three main causes of sex differences are activational and organizational effects of testicular and ovarian hormones and direct sex chromosome effects, Arthur P. Arnold, Ph.D., said.

The differences between these have clinical implications, yet in almost no cases have these “big three” causes of sex differences been studied systematically and comprehensively in preclinical studies, said Dr. Arnold, professor and chair of physiological sciences at the University of California, Los Angeles.

In a discussion at the end of the workshop, more than one participant suggested adopting some kind of mandate to push harder for inclusion of sex differences—perhaps, for instance, requiring that basic scientists or clinicians who do not plan to include female subjects in studies at least provide a rationale for that decision.

Other attendees pushed back against the idea of a mandate, however, and argued instead that making money available for sex difference research would stimulate the desired work.

Dr. Pinn said she'd take back to the NIH the idea of educating program officers who handle grant decisions about sex differences, in hopes of developing some of them into advocates or champions of sex differences research.

She added, “We may think of doing a small pilot program to look at incorporating sex differences in basic research.”

Neuroendocrinologist Jon Levine, Ph.D., argued that scientists and physicians need earlier education on sex differences. “Our brightest and best are going into graduate and medical school programs that don't recognize that there are sex differences in brain function” and other areas, said Dr. Levine, professor of neurobiology and physiology at Northwestern University, Chicago. “At my own institution, there is one day's class within one course on sex differences in brain function and disease. That has to change.”

Disclosures: The speakers included in this article reported having no relevant conflicts of interest.

SAN FRANCISCO — Lack of attention to biological differences between males and females may be hurting both sexes in the treatment of health problems.

Research in the past decade has begun to delve into sex differences in depression, pain perception, sleep, stroke, multiple sclerosis, drug responses, and more, speakers said at a meeting sponsored by the Institute of Medicine on sex differences and their implications for translational neuroscience research.

“The advances in molecular biology and in brain imaging make it clear that there's a biological basis to the sex differences,” said Rae Silver, Ph.D., who codirected the workshop and is a professor of natural and physical sciences at Barnard College and Columbia University, both in New York.

When researchers don't examine differences between males and females—in basic science on cell biology all the way up to human clinical trials—the resulting lack of data may lead to flawed conclusions. For example, data showing that only 20% of studies on heart disease have included women help to explain why the disease and its treatments are less well understood in women than in men, several speakers noted.

On the other hand, an investigational drug that may have been effective in treating chronic pain in men—but not women—was abandoned after the drug failed in a clinical trial that included both sexes but did not analyze differences in response by sex, another speaker said.

The IOM convened the workshop to follow up on its 2001 report, “Exploring the Biological Contributions to Human Health: Does Sex Matter?” which recommended that sex differences be studied “from womb to tomb” (across the lifespan), across species, and at the cellular level, and that all human diseases affecting both sexes be monitored for sex differences and similarities.

The progress reports at the workshop showed how much remains to be done, and generated lively debate about what the IOM, the National Institutes of Health, and the Food and Drug Administration could do to promote greater attention to sex differences in research and drug development.

Currently, only NIH-funded studies must include some attention to sex differences, and this requirement does not apply to studies funded by industry or other sources.

The NIH and the FDA created an online course on sex differences that offers continuing medical education credits to researchers and clinicians, said Dr. Vivian W. Pinn, director of the NIH Office of Research on Women's Health. The course provides a basic scientific understanding of the major physiological differences between the sexes, the influences these differences have on illness and health outcomes, and the implications for policy, medical research, and health care. It can be found at http://sexandgendercourse.od.nih.gov

Sex differences in disease susceptibility should be studied whenever there are differences between the sexes in anatomy, in physiology, in the incidence or age of onset of disease, in the symptoms or diagnosis of disease, or in the severity, progression, and outcome of disease, argued Kathryn Sandberg, Ph.D.

“There's growing interest because it's become clear that, in stroke, not only is there a sex difference in incidence, but also a sex difference in symptoms,” according to Dr. Sandberg, director of the center for the study of sex differences in health, aging, and disease at Georgetown University in Washington.

A recent study reported sex differences in types of acute ischemic stroke. Men are significantly more likely than women to have lacunar (39% vs. 29%) or atherosclerotic strokes (19% vs. 13%), whereas women are significantly more likely to have cardioembolic strokes than men (30% vs. 23%), she noted (Women's Health 2010;6:51–7).

“That's just screaming at you that there's a mechanism that has to be studied,” Dr. Sandberg said.

Other speakers emphasized the need for more research on sex differences in major depression, which is twice as common in females as in males, and in multiple sclerosis, which is two to four times more common in females than in males.

Because multiple sclerosis relapses in 80% of women during pregnancy, and findings from animal tests have suggested that estriol protects against multiple sclerosis, a clinical trial is underway of estriol treatment in women with the disease, said Dr. Rhonda Voskuhl, professor of neurology at the University of California, Los Angeles.

Similarly, animal test data showed a protective effect of testosterone in men, and a pilot study of testosterone gel in men with multiple sclerosis showed markers of improvement.

“I'm now primed to do a clinical trial in men,” she added.

The problem is that both of these are generic drugs, so it will be difficult to find the $5-$25 million needed for phase II/III clinical trials. “It's a shame to drop estradiol and testosterone merely because nobody can make money on it. If you're a patient, you'd rather take estriol, which has been given to hundreds of thousands of people, instead of compound x, y, or z” with unknown side effects, she said.

In the growing field of sleep medicine, “We still lack some basic understandings about sex differences and their consequences for disease,” added Roseanne Armitage, Ph.D., professor of psychiatry at the University of Michigan in Ann Arbor.

Jeanne Duffy, Ph.D., director of the Chronobiology Core at Brigham and Women's Hospital, Boston, described profound differences between the sexes in subjective and objective measures of sleep quality. For example, women are more likely to subjectively report not having good sleep even when objective measures would suggest they slept better than men. “We don't understand these differences,” she said.

In other sleep research, men report better daytime functioning after getting less than 7 hours of sleep, though objective measures suggest they're functioning no better than women on the same amount of sleep, said Rachel Manber, Ph.D., director of the Sleep Medicine Clinic at Stanford (Calif.) University.

On a preclinical level, a review of studies in rodents found that 87% either used only male rodents, didn't specify sex, or didn't examine sex differences in the few studies that included males and females, Jeffrey S. Mogil, Ph.D., said (Pain 2005;117:1–5).

There's an assumption among scientists that data from female mice are more variable and thus are harder to work with, but research by Dr. Mogil and his associates found that this is not true. If anything, data are more variable from male mice, although not significantly more so than data from females, said Dr. Mogil, professor of psychology at the center for research on pain at McGill University in Montreal.

Moreover, a once-radical hypothesis has been proved to be true—that males and females have qualitatively different pain processing mechanisms that are genetically and neurochemically distinct from males, Dr. Mogil's mice studies have shown.

All of that could explain why more than 100 promising studies in mice suggesting that dextromethorphan (a common ingredient in cough syrup) potentiates the analgesic effects of morphine resulted in a failed clinical trial in humans of the drug combination, Dr. Mogil said. The mice studies undoubtedly focused on males, and later studies by Dr. Mogil showed that dextromethorphan boosts morphine's effects in males but not in females. The pharmaceutical company that sponsored the human trial and later abandoned the drug combination had not analyzed sex differences.

“That was an example of a flaw in the NIH policy. They included women but didn't do anything with them” in the analysis of results, Dr. Mogil said.

At the basic science level, it's now understood that the three main causes of sex differences are activational and organizational effects of testicular and ovarian hormones and direct sex chromosome effects, Arthur P. Arnold, Ph.D., said.

The differences between these have clinical implications, yet in almost no cases have these “big three” causes of sex differences been studied systematically and comprehensively in preclinical studies, said Dr. Arnold, professor and chair of physiological sciences at the University of California, Los Angeles.

In a discussion at the end of the workshop, more than one participant suggested adopting some kind of mandate to push harder for inclusion of sex differences—perhaps, for instance, requiring that basic scientists or clinicians who do not plan to include female subjects in studies at least provide a rationale for that decision.

Other attendees pushed back against the idea of a mandate, however, and argued instead that making money available for sex difference research would stimulate the desired work.

Dr. Pinn said she'd take back to the NIH the idea of educating program officers who handle grant decisions about sex differences, in hopes of developing some of them into advocates or champions of sex differences research.

She added, “We may think of doing a small pilot program to look at incorporating sex differences in basic research.”

Neuroendocrinologist Jon Levine, Ph.D., argued that scientists and physicians need earlier education on sex differences. “Our brightest and best are going into graduate and medical school programs that don't recognize that there are sex differences in brain function” and other areas, said Dr. Levine, professor of neurobiology and physiology at Northwestern University, Chicago. “At my own institution, there is one day's class within one course on sex differences in brain function and disease. That has to change.”

Disclosures: The speakers included in this article reported having no relevant conflicts of interest.

SAN FRANCISCO — Lack of attention to biological differences between males and females may be hurting both sexes in the treatment of health problems.

Research in the past decade has begun to delve into sex differences in depression, pain perception, sleep, stroke, multiple sclerosis, drug responses, and more, speakers said at a meeting sponsored by the Institute of Medicine on sex differences and their implications for translational neuroscience research.

“The advances in molecular biology and in brain imaging make it clear that there's a biological basis to the sex differences,” said Rae Silver, Ph.D., who codirected the workshop and is a professor of natural and physical sciences at Barnard College and Columbia University, both in New York.

When researchers don't examine differences between males and females—in basic science on cell biology all the way up to human clinical trials—the resulting lack of data may lead to flawed conclusions. For example, data showing that only 20% of studies on heart disease have included women help to explain why the disease and its treatments are less well understood in women than in men, several speakers noted.

On the other hand, an investigational drug that may have been effective in treating chronic pain in men—but not women—was abandoned after the drug failed in a clinical trial that included both sexes but did not analyze differences in response by sex, another speaker said.

The IOM convened the workshop to follow up on its 2001 report, “Exploring the Biological Contributions to Human Health: Does Sex Matter?” which recommended that sex differences be studied “from womb to tomb” (across the lifespan), across species, and at the cellular level, and that all human diseases affecting both sexes be monitored for sex differences and similarities.

The progress reports at the workshop showed how much remains to be done, and generated lively debate about what the IOM, the National Institutes of Health, and the Food and Drug Administration could do to promote greater attention to sex differences in research and drug development.

Currently, only NIH-funded studies must include some attention to sex differences, and this requirement does not apply to studies funded by industry or other sources.

The NIH and the FDA created an online course on sex differences that offers continuing medical education credits to researchers and clinicians, said Dr. Vivian W. Pinn, director of the NIH Office of Research on Women's Health. The course provides a basic scientific understanding of the major physiological differences between the sexes, the influences these differences have on illness and health outcomes, and the implications for policy, medical research, and health care. It can be found at http://sexandgendercourse.od.nih.gov

Sex differences in disease susceptibility should be studied whenever there are differences between the sexes in anatomy, in physiology, in the incidence or age of onset of disease, in the symptoms or diagnosis of disease, or in the severity, progression, and outcome of disease, argued Kathryn Sandberg, Ph.D.

“There's growing interest because it's become clear that, in stroke, not only is there a sex difference in incidence, but also a sex difference in symptoms,” according to Dr. Sandberg, director of the center for the study of sex differences in health, aging, and disease at Georgetown University in Washington.

A recent study reported sex differences in types of acute ischemic stroke. Men are significantly more likely than women to have lacunar (39% vs. 29%) or atherosclerotic strokes (19% vs. 13%), whereas women are significantly more likely to have cardioembolic strokes than men (30% vs. 23%), she noted (Women's Health 2010;6:51–7).

“That's just screaming at you that there's a mechanism that has to be studied,” Dr. Sandberg said.

Other speakers emphasized the need for more research on sex differences in major depression, which is twice as common in females as in males, and in multiple sclerosis, which is two to four times more common in females than in males.

Because multiple sclerosis relapses in 80% of women during pregnancy, and findings from animal tests have suggested that estriol protects against multiple sclerosis, a clinical trial is underway of estriol treatment in women with the disease, said Dr. Rhonda Voskuhl, professor of neurology at the University of California, Los Angeles.

Similarly, animal test data showed a protective effect of testosterone in men, and a pilot study of testosterone gel in men with multiple sclerosis showed markers of improvement.

“I'm now primed to do a clinical trial in men,” she added.

The problem is that both of these are generic drugs, so it will be difficult to find the $5-$25 million needed for phase II/III clinical trials. “It's a shame to drop estradiol and testosterone merely because nobody can make money on it. If you're a patient, you'd rather take estriol, which has been given to hundreds of thousands of people, instead of compound x, y, or z” with unknown side effects, she said.

In the growing field of sleep medicine, “We still lack some basic understandings about sex differences and their consequences for disease,” added Roseanne Armitage, Ph.D., professor of psychiatry at the University of Michigan in Ann Arbor.

Jeanne Duffy, Ph.D., director of the Chronobiology Core at Brigham and Women's Hospital, Boston, described profound differences between the sexes in subjective and objective measures of sleep quality. For example, women are more likely to subjectively report not having good sleep even when objective measures would suggest they slept better than men. “We don't understand these differences,” she said.

In other sleep research, men report better daytime functioning after getting less than 7 hours of sleep, though objective measures suggest they're functioning no better than women on the same amount of sleep, said Rachel Manber, Ph.D., director of the Sleep Medicine Clinic at Stanford (Calif.) University.

On a preclinical level, a review of studies in rodents found that 87% either used only male rodents, didn't specify sex, or didn't examine sex differences in the few studies that included males and females, Jeffrey S. Mogil, Ph.D., said (Pain 2005;117:1–5).

There's an assumption among scientists that data from female mice are more variable and thus are harder to work with, but research by Dr. Mogil and his associates found that this is not true. If anything, data are more variable from male mice, although not significantly more so than data from females, said Dr. Mogil, professor of psychology at the center for research on pain at McGill University in Montreal.

Moreover, a once-radical hypothesis has been proved to be true—that males and females have qualitatively different pain processing mechanisms that are genetically and neurochemically distinct from males, Dr. Mogil's mice studies have shown.

All of that could explain why more than 100 promising studies in mice suggesting that dextromethorphan (a common ingredient in cough syrup) potentiates the analgesic effects of morphine resulted in a failed clinical trial in humans of the drug combination, Dr. Mogil said. The mice studies undoubtedly focused on males, and later studies by Dr. Mogil showed that dextromethorphan boosts morphine's effects in males but not in females. The pharmaceutical company that sponsored the human trial and later abandoned the drug combination had not analyzed sex differences.

“That was an example of a flaw in the NIH policy. They included women but didn't do anything with them” in the analysis of results, Dr. Mogil said.

At the basic science level, it's now understood that the three main causes of sex differences are activational and organizational effects of testicular and ovarian hormones and direct sex chromosome effects, Arthur P. Arnold, Ph.D., said.

The differences between these have clinical implications, yet in almost no cases have these “big three” causes of sex differences been studied systematically and comprehensively in preclinical studies, said Dr. Arnold, professor and chair of physiological sciences at the University of California, Los Angeles.

In a discussion at the end of the workshop, more than one participant suggested adopting some kind of mandate to push harder for inclusion of sex differences—perhaps, for instance, requiring that basic scientists or clinicians who do not plan to include female subjects in studies at least provide a rationale for that decision.

Other attendees pushed back against the idea of a mandate, however, and argued instead that making money available for sex difference research would stimulate the desired work.

Dr. Pinn said she'd take back to the NIH the idea of educating program officers who handle grant decisions about sex differences, in hopes of developing some of them into advocates or champions of sex differences research.

She added, “We may think of doing a small pilot program to look at incorporating sex differences in basic research.”

Neuroendocrinologist Jon Levine, Ph.D., argued that scientists and physicians need earlier education on sex differences. “Our brightest and best are going into graduate and medical school programs that don't recognize that there are sex differences in brain function” and other areas, said Dr. Levine, professor of neurobiology and physiology at Northwestern University, Chicago. “At my own institution, there is one day's class within one course on sex differences in brain function and disease. That has to change.”

Disclosures: The speakers included in this article reported having no relevant conflicts of interest.

SAN FRANCISCO — The first update in recommendations for dietary intake of vitamin D since 1997 is expected in May and probably will include a conservative change from the status quo, according to one expert.

The Institute of Medicine's Food and Nutrition Board has been reviewing the literature, including consideration of associations between serum vitamin D levels and disease indicators.

“The grapevine says they are going to come in very conservative. They are going to require evidence from randomized, controlled trials, and those don't really exist today,” Dr. Neil Binkley said at a meeting sponsored by the American Diabetes Association.

The current Dietary Reference Intake (or Recommended Dietary Allowance) describes “adequate” intake as 200 IU/day for people up to age 50 years, 400 IU/day for those aged 51-70 years, and 600 IU/day for people older than 70 years.

Dr. Binkley of the University of Wisconsin in Madison expects the new intake recommendation for older adults to roughly double, from 400 IU/day to 800 or maybe 1,000 IU/day.

“This will be an evolution,” he said. “I think the next iteration coming out in May is going to be a step up, but it's probably not going to get us all the way there.”

Recent data suggest that much higher levels should be consumed daily to keep serum 25-hydroxyvitamin D levels (25[OH]D) in desired ranges, he explained. Generally, levels lower than 10 ng/mL indicate vitamin D deficiency, 10-30 ng/mL reflects vitamin D insufficiency, and a 25(OH)D level above 30 ng/mL is considered optimal.

Optimal levels may differ by bodily system, he noted. Serum 25(OH)D levels greater than 40 ng/mL may be best for bone health, whereas leg function appears to be better with levels above 38 ng/mL. But a level above 36 ng/mL has been associated with reduced risk for co-lorectal cancer, and levels of 36-40 ng/mL have been associated with lower risk for periodontal disease.

One study calculated that 2,600 IU/day of vitamin D supplementation would be needed to ensure that 97.5% of older women have 25(OH)D levels at or above desirable levels (J. Nutr. 2006;136:1123–6).

Other experts recommend that between 2,000 and 4,000 IU/day be consumed to reduce risks for cancer and autoimmune disease, Dr. Binkley said.

He aims for levels above 40 ng/mL in his patients to consistently hit targets above 30 ng/mL, he said.

As a general rule of thumb, for every 1,000 IU of supplemental vitamin D₃ ingested, circulating 25(OH)D goes up by roughly 6 ng/mL, he said. For a patient with a serum 25(OH)D level of 20 ng/mL, taking 2,000 IU/day of vitamin D₃ would boost serum levels to about 32 ng/mL, and more than 3,000 IU/day would be needed to reach 40 ng/mL.

People are unlikely to get adequate vitamin D from sunlight, and fortified foods contain roughly 40-100 IU per serving. “If we truly do need 1,000, 2,000 or 4,000 IU/day, that means you'd need to drink between 10 and 40 glasses of milk per day to get your vitamin D requirement” at current levels of food fortification, he said. “I'm hopeful that after the Institute of Medicine meets, food fortification will go up,” he added.

The American Academy of Pediatrics in 2008 recommended that children and adolescents get 400 IU/day of vitamin D, double the current Dietary Reference Intake. The National Osteoporosis Foundation recommends that people up to age 50 ingest 400-800 IU/day, and that adults aged 50 or older get 800-1,000 IU/day.

Observational studies suggest that low vitamin D levels are associated with increased risk for diabetes. Several studies found that children who received vitamin D supplementation had a lower risk for developing type 1 diabetes, and the Nurses Health Study found an association between low vitamin D status and higher risk for type 2 diabetes over 20 years of follow-up.

Two prospective studies with 36 patients each found no significant effect of vitamin D supplementation on diabetes risk, however, but these studies were too small, Dr. Binkley said.

A post hoc analysis of a randomized, controlled trial of 800 IU/day of vitamin D for fracture prevention in 3,314 women over age 70 found no protective effect against the development of type 2 diabetes, but compliance with vitamin D supplements in the trial was poor, he noted (Age Ageing 2009;38:606–9).

The Women's Health Study also found no significant reduction in risk for diabetes after a median 7-year follow-up in 33,951 women randomized to 1,000 mg/day of calcium plus 400 IU/day of vitamin D or placebo (Diabetes Care 2008;31:701–7). The vitamin D dose was too low, Dr. Binkley said, and the compliance rate was only around 60%.

“We need larger studies, with higher vitamin D doses,” he said.

Dr. Binkley said he has no conflicts of interest related to these topics.

The National Osteoporosis Foundation recommends that adults younger than 50 years ingest 400-800 IU/day of vitamin D. Those aged 50 years or older need 800-1,000 IU/day.

Source © Joss/Fotolia.com

SAN FRANCISCO — The first update in recommendations for dietary intake of vitamin D since 1997 is expected in May and probably will include a conservative change from the status quo, according to one expert.

The Institute of Medicine's Food and Nutrition Board has been reviewing the literature, including consideration of associations between serum vitamin D levels and disease indicators.

“The grapevine says they are going to come in very conservative. They are going to require evidence from randomized, controlled trials, and those don't really exist today,” Dr. Neil Binkley said at a meeting sponsored by the American Diabetes Association.

The current Dietary Reference Intake (or Recommended Dietary Allowance) describes “adequate” intake as 200 IU/day for people up to age 50 years, 400 IU/day for those aged 51-70 years, and 600 IU/day for people older than 70 years.

Dr. Binkley of the University of Wisconsin in Madison expects the new intake recommendation for older adults to roughly double, from 400 IU/day to 800 or maybe 1,000 IU/day.

“This will be an evolution,” he said. “I think the next iteration coming out in May is going to be a step up, but it's probably not going to get us all the way there.”

Recent data suggest that much higher levels should be consumed daily to keep serum 25-hydroxyvitamin D levels (25[OH]D) in desired ranges, he explained. Generally, levels lower than 10 ng/mL indicate vitamin D deficiency, 10-30 ng/mL reflects vitamin D insufficiency, and a 25(OH)D level above 30 ng/mL is considered optimal.

Optimal levels may differ by bodily system, he noted. Serum 25(OH)D levels greater than 40 ng/mL may be best for bone health, whereas leg function appears to be better with levels above 38 ng/mL. But a level above 36 ng/mL has been associated with reduced risk for co-lorectal cancer, and levels of 36-40 ng/mL have been associated with lower risk for periodontal disease.

One study calculated that 2,600 IU/day of vitamin D supplementation would be needed to ensure that 97.5% of older women have 25(OH)D levels at or above desirable levels (J. Nutr. 2006;136:1123–6).

Other experts recommend that between 2,000 and 4,000 IU/day be consumed to reduce risks for cancer and autoimmune disease, Dr. Binkley said.

He aims for levels above 40 ng/mL in his patients to consistently hit targets above 30 ng/mL, he said.

As a general rule of thumb, for every 1,000 IU of supplemental vitamin D₃ ingested, circulating 25(OH)D goes up by roughly 6 ng/mL, he said. For a patient with a serum 25(OH)D level of 20 ng/mL, taking 2,000 IU/day of vitamin D₃ would boost serum levels to about 32 ng/mL, and more than 3,000 IU/day would be needed to reach 40 ng/mL.

People are unlikely to get adequate vitamin D from sunlight, and fortified foods contain roughly 40-100 IU per serving. “If we truly do need 1,000, 2,000 or 4,000 IU/day, that means you'd need to drink between 10 and 40 glasses of milk per day to get your vitamin D requirement” at current levels of food fortification, he said. “I'm hopeful that after the Institute of Medicine meets, food fortification will go up,” he added.

The American Academy of Pediatrics in 2008 recommended that children and adolescents get 400 IU/day of vitamin D, double the current Dietary Reference Intake. The National Osteoporosis Foundation recommends that people up to age 50 ingest 400-800 IU/day, and that adults aged 50 or older get 800-1,000 IU/day.

Observational studies suggest that low vitamin D levels are associated with increased risk for diabetes. Several studies found that children who received vitamin D supplementation had a lower risk for developing type 1 diabetes, and the Nurses Health Study found an association between low vitamin D status and higher risk for type 2 diabetes over 20 years of follow-up.

Two prospective studies with 36 patients each found no significant effect of vitamin D supplementation on diabetes risk, however, but these studies were too small, Dr. Binkley said.

A post hoc analysis of a randomized, controlled trial of 800 IU/day of vitamin D for fracture prevention in 3,314 women over age 70 found no protective effect against the development of type 2 diabetes, but compliance with vitamin D supplements in the trial was poor, he noted (Age Ageing 2009;38:606–9).

The Women's Health Study also found no significant reduction in risk for diabetes after a median 7-year follow-up in 33,951 women randomized to 1,000 mg/day of calcium plus 400 IU/day of vitamin D or placebo (Diabetes Care 2008;31:701–7). The vitamin D dose was too low, Dr. Binkley said, and the compliance rate was only around 60%.

“We need larger studies, with higher vitamin D doses,” he said.

Dr. Binkley said he has no conflicts of interest related to these topics.

The National Osteoporosis Foundation recommends that adults younger than 50 years ingest 400-800 IU/day of vitamin D. Those aged 50 years or older need 800-1,000 IU/day.

Source © Joss/Fotolia.com

SAN FRANCISCO — The first update in recommendations for dietary intake of vitamin D since 1997 is expected in May and probably will include a conservative change from the status quo, according to one expert.

The Institute of Medicine's Food and Nutrition Board has been reviewing the literature, including consideration of associations between serum vitamin D levels and disease indicators.

“The grapevine says they are going to come in very conservative. They are going to require evidence from randomized, controlled trials, and those don't really exist today,” Dr. Neil Binkley said at a meeting sponsored by the American Diabetes Association.

The current Dietary Reference Intake (or Recommended Dietary Allowance) describes “adequate” intake as 200 IU/day for people up to age 50 years, 400 IU/day for those aged 51-70 years, and 600 IU/day for people older than 70 years.

Dr. Binkley of the University of Wisconsin in Madison expects the new intake recommendation for older adults to roughly double, from 400 IU/day to 800 or maybe 1,000 IU/day.

“This will be an evolution,” he said. “I think the next iteration coming out in May is going to be a step up, but it's probably not going to get us all the way there.”

Recent data suggest that much higher levels should be consumed daily to keep serum 25-hydroxyvitamin D levels (25[OH]D) in desired ranges, he explained. Generally, levels lower than 10 ng/mL indicate vitamin D deficiency, 10-30 ng/mL reflects vitamin D insufficiency, and a 25(OH)D level above 30 ng/mL is considered optimal.

Optimal levels may differ by bodily system, he noted. Serum 25(OH)D levels greater than 40 ng/mL may be best for bone health, whereas leg function appears to be better with levels above 38 ng/mL. But a level above 36 ng/mL has been associated with reduced risk for co-lorectal cancer, and levels of 36-40 ng/mL have been associated with lower risk for periodontal disease.

One study calculated that 2,600 IU/day of vitamin D supplementation would be needed to ensure that 97.5% of older women have 25(OH)D levels at or above desirable levels (J. Nutr. 2006;136:1123–6).

Other experts recommend that between 2,000 and 4,000 IU/day be consumed to reduce risks for cancer and autoimmune disease, Dr. Binkley said.

He aims for levels above 40 ng/mL in his patients to consistently hit targets above 30 ng/mL, he said.

As a general rule of thumb, for every 1,000 IU of supplemental vitamin D₃ ingested, circulating 25(OH)D goes up by roughly 6 ng/mL, he said. For a patient with a serum 25(OH)D level of 20 ng/mL, taking 2,000 IU/day of vitamin D₃ would boost serum levels to about 32 ng/mL, and more than 3,000 IU/day would be needed to reach 40 ng/mL.

People are unlikely to get adequate vitamin D from sunlight, and fortified foods contain roughly 40-100 IU per serving. “If we truly do need 1,000, 2,000 or 4,000 IU/day, that means you'd need to drink between 10 and 40 glasses of milk per day to get your vitamin D requirement” at current levels of food fortification, he said. “I'm hopeful that after the Institute of Medicine meets, food fortification will go up,” he added.

The American Academy of Pediatrics in 2008 recommended that children and adolescents get 400 IU/day of vitamin D, double the current Dietary Reference Intake. The National Osteoporosis Foundation recommends that people up to age 50 ingest 400-800 IU/day, and that adults aged 50 or older get 800-1,000 IU/day.

Observational studies suggest that low vitamin D levels are associated with increased risk for diabetes. Several studies found that children who received vitamin D supplementation had a lower risk for developing type 1 diabetes, and the Nurses Health Study found an association between low vitamin D status and higher risk for type 2 diabetes over 20 years of follow-up.

Two prospective studies with 36 patients each found no significant effect of vitamin D supplementation on diabetes risk, however, but these studies were too small, Dr. Binkley said.

A post hoc analysis of a randomized, controlled trial of 800 IU/day of vitamin D for fracture prevention in 3,314 women over age 70 found no protective effect against the development of type 2 diabetes, but compliance with vitamin D supplements in the trial was poor, he noted (Age Ageing 2009;38:606–9).

The Women's Health Study also found no significant reduction in risk for diabetes after a median 7-year follow-up in 33,951 women randomized to 1,000 mg/day of calcium plus 400 IU/day of vitamin D or placebo (Diabetes Care 2008;31:701–7). The vitamin D dose was too low, Dr. Binkley said, and the compliance rate was only around 60%.

“We need larger studies, with higher vitamin D doses,” he said.

Dr. Binkley said he has no conflicts of interest related to these topics.

The National Osteoporosis Foundation recommends that adults younger than 50 years ingest 400-800 IU/day of vitamin D. Those aged 50 years or older need 800-1,000 IU/day.

Source © Joss/Fotolia.com

Major Finding: A significantly greater proportion of patients on 1.8 mg/day of liraglutide (39%) achieved an HbA_1c level below 7% with no weight gain and no confirmed hypoglycemia by the end of the 26- to 52-week studies, compared with those on twice-daily injections of the GLP-1 agonist exenatide (24%) or patients treated with glargine (15%), a sulfonylurea (8%), placebo (8%), or a thiazolidinedione (6%).

Data Source: A secondary analysis that combined data from the more than 3,900 patients in the LEAD studies to compare the effectiveness of various therapies.

Disclosures: Dr. Buse has been a consultant for, or received research support from, Novo Nordisk Inc. (which markets liraglutide), and Amylin Pharmaceuticals Inc. and Eli Lilly & Co. (which together are marketing the long-acting version of Amylin's exenatide). He has held stock in Insulet Corp., which makes an insulin pump.

SAN FRANCISCO — The once-daily drug liraglutide may work better than other diabetes medications to help patients reach a combination of goals, a secondary analysis of data from pivotal liraglutide studies suggests.

The Food and Drug Administration approved the use of liraglutide (Victoza) in January for adults with type 2 diabetes who fail first-line drug therapy, based on data from the pivotal Liraglutide Effect and Action in Diabetes (LEAD) studies. Liraglutide is an injectable human glucagonlike peptide–1 (GLP-1) analogue.

The LEAD trials were “truly heroic” in their number, breadth, and head-to-head comparisons between existing diabetes medications, and in most of those trials liraglutide was found to be more effective at lowering hemoglobin A_1c levels, Dr. John B. Buse said at a meeting sponsored by the American Diabetes Association.

Dr. Buse reported on an analysis that combined data from the more than 3,900 patients in the LEAD studies to compare the effectiveness of various therapies at achieving a composite end point known among diabetologists as a “Zindex.” (The idea was first proposed by Dr. Bernard Zinman, who is professor of medicine at the University of Toronto.)

The analysis assessed the proportion of patients achieving the Zindex of an HbA_1c level below 7% with no weight gain and no confirmed hypoglycemia (minor or severe) by the end of the 26- to 52-week studies.

A significantly greater proportion of patients on 1.8 mg/day of liraglutide achieved this Zindex (39%), compared with those on twice-daily injections of the GLP-1 agonist exenatide (24%) or patients treated with glargine (15%), a sulfonylurea (8%), placebo (8%), or a thiazolidinedione (6%).

“An A_1c less than 7% without weight gain or hypoglycemia is something that's of substantial interest to patients and clinicians,” said Dr. Buse, chief of endocrinology and director of the diabetes care center at the University of North Carolina at Chapel Hill.

A second analysis compared the data with a second Zindex that combines three goals identified as standards of care by the American Diabetes Association in 2008: an HbA_1c less than 7%, no weight gain, and a systolic blood pressure less than 130 mm Hg. The GLP-1 therapies in general have modest effects on blood pressure and lipids, with potentially greater changes in blood pressure on long-acting GLP-1 agonists, Dr. Buse noted.

Again, a significantly greater proportion of patients on 1.8 mg/day of liraglutide (25%) achieved the second Zindex, compared with patients on exenatide (14%), a sulfonylurea (7%), glargine or placebo (5% each), or a thiazolidinedione (3%).

“This is of considerable interest, particularly in our pay-for-performance kind of world,” he said.

Major Finding: A significantly greater proportion of patients on 1.8 mg/day of liraglutide (39%) achieved an HbA_1c level below 7% with no weight gain and no confirmed hypoglycemia by the end of the 26- to 52-week studies, compared with those on twice-daily injections of the GLP-1 agonist exenatide (24%) or patients treated with glargine (15%), a sulfonylurea (8%), placebo (8%), or a thiazolidinedione (6%).

Data Source: A secondary analysis that combined data from the more than 3,900 patients in the LEAD studies to compare the effectiveness of various therapies.

Disclosures: Dr. Buse has been a consultant for, or received research support from, Novo Nordisk Inc. (which markets liraglutide), and Amylin Pharmaceuticals Inc. and Eli Lilly & Co. (which together are marketing the long-acting version of Amylin's exenatide). He has held stock in Insulet Corp., which makes an insulin pump.

SAN FRANCISCO — The once-daily drug liraglutide may work better than other diabetes medications to help patients reach a combination of goals, a secondary analysis of data from pivotal liraglutide studies suggests.

The Food and Drug Administration approved the use of liraglutide (Victoza) in January for adults with type 2 diabetes who fail first-line drug therapy, based on data from the pivotal Liraglutide Effect and Action in Diabetes (LEAD) studies. Liraglutide is an injectable human glucagonlike peptide–1 (GLP-1) analogue.

The LEAD trials were “truly heroic” in their number, breadth, and head-to-head comparisons between existing diabetes medications, and in most of those trials liraglutide was found to be more effective at lowering hemoglobin A_1c levels, Dr. John B. Buse said at a meeting sponsored by the American Diabetes Association.

Dr. Buse reported on an analysis that combined data from the more than 3,900 patients in the LEAD studies to compare the effectiveness of various therapies at achieving a composite end point known among diabetologists as a “Zindex.” (The idea was first proposed by Dr. Bernard Zinman, who is professor of medicine at the University of Toronto.)

The analysis assessed the proportion of patients achieving the Zindex of an HbA_1c level below 7% with no weight gain and no confirmed hypoglycemia (minor or severe) by the end of the 26- to 52-week studies.

A significantly greater proportion of patients on 1.8 mg/day of liraglutide achieved this Zindex (39%), compared with those on twice-daily injections of the GLP-1 agonist exenatide (24%) or patients treated with glargine (15%), a sulfonylurea (8%), placebo (8%), or a thiazolidinedione (6%).

“An A_1c less than 7% without weight gain or hypoglycemia is something that's of substantial interest to patients and clinicians,” said Dr. Buse, chief of endocrinology and director of the diabetes care center at the University of North Carolina at Chapel Hill.

A second analysis compared the data with a second Zindex that combines three goals identified as standards of care by the American Diabetes Association in 2008: an HbA_1c less than 7%, no weight gain, and a systolic blood pressure less than 130 mm Hg. The GLP-1 therapies in general have modest effects on blood pressure and lipids, with potentially greater changes in blood pressure on long-acting GLP-1 agonists, Dr. Buse noted.

Again, a significantly greater proportion of patients on 1.8 mg/day of liraglutide (25%) achieved the second Zindex, compared with patients on exenatide (14%), a sulfonylurea (7%), glargine or placebo (5% each), or a thiazolidinedione (3%).

“This is of considerable interest, particularly in our pay-for-performance kind of world,” he said.

Major Finding: A significantly greater proportion of patients on 1.8 mg/day of liraglutide (39%) achieved an HbA_1c level below 7% with no weight gain and no confirmed hypoglycemia by the end of the 26- to 52-week studies, compared with those on twice-daily injections of the GLP-1 agonist exenatide (24%) or patients treated with glargine (15%), a sulfonylurea (8%), placebo (8%), or a thiazolidinedione (6%).

Data Source: A secondary analysis that combined data from the more than 3,900 patients in the LEAD studies to compare the effectiveness of various therapies.

Disclosures: Dr. Buse has been a consultant for, or received research support from, Novo Nordisk Inc. (which markets liraglutide), and Amylin Pharmaceuticals Inc. and Eli Lilly & Co. (which together are marketing the long-acting version of Amylin's exenatide). He has held stock in Insulet Corp., which makes an insulin pump.

SAN FRANCISCO — The once-daily drug liraglutide may work better than other diabetes medications to help patients reach a combination of goals, a secondary analysis of data from pivotal liraglutide studies suggests.

The Food and Drug Administration approved the use of liraglutide (Victoza) in January for adults with type 2 diabetes who fail first-line drug therapy, based on data from the pivotal Liraglutide Effect and Action in Diabetes (LEAD) studies. Liraglutide is an injectable human glucagonlike peptide–1 (GLP-1) analogue.

The LEAD trials were “truly heroic” in their number, breadth, and head-to-head comparisons between existing diabetes medications, and in most of those trials liraglutide was found to be more effective at lowering hemoglobin A_1c levels, Dr. John B. Buse said at a meeting sponsored by the American Diabetes Association.

Dr. Buse reported on an analysis that combined data from the more than 3,900 patients in the LEAD studies to compare the effectiveness of various therapies at achieving a composite end point known among diabetologists as a “Zindex.” (The idea was first proposed by Dr. Bernard Zinman, who is professor of medicine at the University of Toronto.)

The analysis assessed the proportion of patients achieving the Zindex of an HbA_1c level below 7% with no weight gain and no confirmed hypoglycemia (minor or severe) by the end of the 26- to 52-week studies.

A significantly greater proportion of patients on 1.8 mg/day of liraglutide achieved this Zindex (39%), compared with those on twice-daily injections of the GLP-1 agonist exenatide (24%) or patients treated with glargine (15%), a sulfonylurea (8%), placebo (8%), or a thiazolidinedione (6%).

“An A_1c less than 7% without weight gain or hypoglycemia is something that's of substantial interest to patients and clinicians,” said Dr. Buse, chief of endocrinology and director of the diabetes care center at the University of North Carolina at Chapel Hill.

A second analysis compared the data with a second Zindex that combines three goals identified as standards of care by the American Diabetes Association in 2008: an HbA_1c less than 7%, no weight gain, and a systolic blood pressure less than 130 mm Hg. The GLP-1 therapies in general have modest effects on blood pressure and lipids, with potentially greater changes in blood pressure on long-acting GLP-1 agonists, Dr. Buse noted.

Again, a significantly greater proportion of patients on 1.8 mg/day of liraglutide (25%) achieved the second Zindex, compared with patients on exenatide (14%), a sulfonylurea (7%), glargine or placebo (5% each), or a thiazolidinedione (3%).

“This is of considerable interest, particularly in our pay-for-performance kind of world,” he said.