Kate Johnson

MONTREAL — Primary care patients with asthma face a significantly increased risk of developing depression, compared with the nonasthmatic population, according to the findings of a large, longitudinal study.

Furthermore, the combination of asthma and depression carries significantly increased mortality, reported Dr. Paul Walters of the Institute of Psychiatry, King's College, London.

Taken together, the findings suggest that it may be useful for family physicians to consider screening their asthmatic patients for depression, he said at the annual meeting of the North American Primary Care Research Group.

In a previous study, Dr. Walters and his colleagues found that asthma was the third-largest predictor of antidepressant prescriptions in the United Kingdom (Br. J. Psychiatry 2008; 193:235–9).

“We expected there to be a higher rate of antidepressant use with chronic illnesses, but we didn't expect to see this with asthma,” he said.

The current longitudinal cohort study, designed to explore the association between asthma and depression, identified 11,275 asthmatic patients with no history of depression and an equal number of control subjects, matched for age and sex from the United Kingdom's General Practice Research Database.

During a 10-year follow-up period, the incidence of depression was significantly higher in the group with asthma, compared with controls (22.4 versus 13.8 per 1,000 person-years); after adjustment for age, sex, chronic illness, and smoking, the odds ratio for depression among asthmatic patients remained elevated (1.5).

Looking next at the asthmatic patients only, the researchers noted those with comorbid depression had an elevated mortality ratio (1.87), compared with those with asthma alone. “So, if you've got asthma and you're depressed, then you're almost twice as likely to die than if you've just got asthma,” explained Dr. Walters.

He acknowledged that “we don't have any information on cause of death, so we're not able to say if it was due to asthma-related reasons or depression-related reasons or a combination of both.”

For clues as to why asthmatic patients face a higher risk for depression, the researchers explored the issue of disease severity, using medication use as a marker. Comparison of asthmatic patients who were depressed to those who were not depressed showed no significant differences in the use of medication overall, suggesting that disease severity was similar in both groups, he said.

The biggest difference between the groups was in their frequency of primary care visits (8.3 visits a year for depressed patients versus 5.3 for nondepressed patients). One possible explanation for this association may be that “if a patient goes to their [general practitioner] more often, they're more likely to get their depression diagnosed,” Dr. Walters said in an interview.

Another explanation, however, is that a patient's subjective experience of asthma symptoms might be quite different from objective medical assessments. “It could be that the objective measure of asthma, the peak flow rate, doesn't actually relate to how the person with asthma feels, so the depression comes because their asthma doesn't feel like it's getting better.”

Dr. Walters had no conflicts of interest to report.

MONTREAL — Primary care patients with asthma face a significantly increased risk of developing depression, compared with the nonasthmatic population, according to the findings of a large, longitudinal study.

Furthermore, the combination of asthma and depression carries significantly increased mortality, reported Dr. Paul Walters of the Institute of Psychiatry, King's College, London.

Taken together, the findings suggest that it may be useful for family physicians to consider screening their asthmatic patients for depression, he said at the annual meeting of the North American Primary Care Research Group.

In a previous study, Dr. Walters and his colleagues found that asthma was the third-largest predictor of antidepressant prescriptions in the United Kingdom (Br. J. Psychiatry 2008; 193:235–9).

“We expected there to be a higher rate of antidepressant use with chronic illnesses, but we didn't expect to see this with asthma,” he said.

The current longitudinal cohort study, designed to explore the association between asthma and depression, identified 11,275 asthmatic patients with no history of depression and an equal number of control subjects, matched for age and sex from the United Kingdom's General Practice Research Database.

During a 10-year follow-up period, the incidence of depression was significantly higher in the group with asthma, compared with controls (22.4 versus 13.8 per 1,000 person-years); after adjustment for age, sex, chronic illness, and smoking, the odds ratio for depression among asthmatic patients remained elevated (1.5).

Looking next at the asthmatic patients only, the researchers noted those with comorbid depression had an elevated mortality ratio (1.87), compared with those with asthma alone. “So, if you've got asthma and you're depressed, then you're almost twice as likely to die than if you've just got asthma,” explained Dr. Walters.

He acknowledged that “we don't have any information on cause of death, so we're not able to say if it was due to asthma-related reasons or depression-related reasons or a combination of both.”

For clues as to why asthmatic patients face a higher risk for depression, the researchers explored the issue of disease severity, using medication use as a marker. Comparison of asthmatic patients who were depressed to those who were not depressed showed no significant differences in the use of medication overall, suggesting that disease severity was similar in both groups, he said.

The biggest difference between the groups was in their frequency of primary care visits (8.3 visits a year for depressed patients versus 5.3 for nondepressed patients). One possible explanation for this association may be that “if a patient goes to their [general practitioner] more often, they're more likely to get their depression diagnosed,” Dr. Walters said in an interview.

Another explanation, however, is that a patient's subjective experience of asthma symptoms might be quite different from objective medical assessments. “It could be that the objective measure of asthma, the peak flow rate, doesn't actually relate to how the person with asthma feels, so the depression comes because their asthma doesn't feel like it's getting better.”

Dr. Walters had no conflicts of interest to report.

MONTREAL — Primary care patients with asthma face a significantly increased risk of developing depression, compared with the nonasthmatic population, according to the findings of a large, longitudinal study.

Furthermore, the combination of asthma and depression carries significantly increased mortality, reported Dr. Paul Walters of the Institute of Psychiatry, King's College, London.

Taken together, the findings suggest that it may be useful for family physicians to consider screening their asthmatic patients for depression, he said at the annual meeting of the North American Primary Care Research Group.

In a previous study, Dr. Walters and his colleagues found that asthma was the third-largest predictor of antidepressant prescriptions in the United Kingdom (Br. J. Psychiatry 2008; 193:235–9).

“We expected there to be a higher rate of antidepressant use with chronic illnesses, but we didn't expect to see this with asthma,” he said.

The current longitudinal cohort study, designed to explore the association between asthma and depression, identified 11,275 asthmatic patients with no history of depression and an equal number of control subjects, matched for age and sex from the United Kingdom's General Practice Research Database.

During a 10-year follow-up period, the incidence of depression was significantly higher in the group with asthma, compared with controls (22.4 versus 13.8 per 1,000 person-years); after adjustment for age, sex, chronic illness, and smoking, the odds ratio for depression among asthmatic patients remained elevated (1.5).

Looking next at the asthmatic patients only, the researchers noted those with comorbid depression had an elevated mortality ratio (1.87), compared with those with asthma alone. “So, if you've got asthma and you're depressed, then you're almost twice as likely to die than if you've just got asthma,” explained Dr. Walters.

He acknowledged that “we don't have any information on cause of death, so we're not able to say if it was due to asthma-related reasons or depression-related reasons or a combination of both.”

For clues as to why asthmatic patients face a higher risk for depression, the researchers explored the issue of disease severity, using medication use as a marker. Comparison of asthmatic patients who were depressed to those who were not depressed showed no significant differences in the use of medication overall, suggesting that disease severity was similar in both groups, he said.

The biggest difference between the groups was in their frequency of primary care visits (8.3 visits a year for depressed patients versus 5.3 for nondepressed patients). One possible explanation for this association may be that “if a patient goes to their [general practitioner] more often, they're more likely to get their depression diagnosed,” Dr. Walters said in an interview.

Another explanation, however, is that a patient's subjective experience of asthma symptoms might be quite different from objective medical assessments. “It could be that the objective measure of asthma, the peak flow rate, doesn't actually relate to how the person with asthma feels, so the depression comes because their asthma doesn't feel like it's getting better.”

Dr. Walters had no conflicts of interest to report.

MONTREAL — Insulin added to oral therapy in patients with long-standing type 2 diabetes is best initiated as a basal formulation and then intensified with prandial doses, according to the 3-year results of the Treat to Target in Type 2 Diabetes (4-T) trial.

“The results of our trial support current guidelines, which suggest that basal and prandial insulin regimens should be considered if adequate glycemic control is not achieved with initial regimens,” reported lead author Dr. Rury Holman of the diabetes trials unit at Oxford (England) University.

The findings were announced at the World Diabetes Congress, with simultaneous publication in the New England Journal of Medicine (2009;361:1736-47).

“We now have very clear evidence that the sequence of basal with added prandial gives you less weight gain and less hypoglycemia,” Dr. Holman said in an interview immediately following his presentation.

“The 4-T study supports the initiation of treatment with basal insulin, which is consistent with the concept that fasting hyperglycemia contributes more than postprandial hyperglycemia to glycated hemoglobin levels during periods of poor glycemic control,” Dr. Michael Roden of the German Diabetes Center and the Heinrich Heine University of Düsseldorf, Germany, said in an editorial in the same issue.

However, “it seems premature to recommend specific insulin regimens for patients with newly diagnosed disease.,” he said.

The 4-T multicenter, open-label trial included 708 patients who had inadequate glycemic control on dual oral metformin and sulfonylurea therapy. Mean patient age oas 61.7 years, wid mean disease duration ofwas 9 years.

They were randomized to one of three regimens in the first year: prandial insulin aspart (NovoRapid) three times daily, biphasic insulin aspart (NovoMix 30) twice daily, or basal detemir (Levemir) once or twice daily.

In the second year, sulfonylureas were replaced by a second insulin if hyperglycemia became unacceptable, which was the case in almost 90% of the patient population, Dr. Holman said.

For patients who had started on biphasic insulin, a midday prandial dose was added. Treatments converged for those who had started on either basal or prandial regimens, so that the basal group added prandial doses (10% of the daily basal dose with a minimum and maximum limit) and the prandial group added a basal dose (10 units at bedtime).

“The importance here is the temporal sequence—they are not identical,” Dr. Holman said. “So basal plus prandial was not the same as prandial plus basal …. Those who started with prandial had substantially more prandial than basal at the end, and those who started with the basal and then added prandial ended up with about 50/50.”

Preliminary results published after the first year of the study did not favor the basal insulin regimen, which was the least successful at bringing hemoglobin A_1c levels to 6.5% or less (N. Engl. J. Med. 2007;357:1716-30).

However, “the difference in outcomes from the first to the third year is startling,” Dr. Roden said in his editorial.

Final results showed that fewer than 45% of all patients achieved the HbA_1c target of 6.5% or less. In addition, significantly fewer patients on the biphasic regimen (31.9%), compared with the prandial (44.7%) and basal (43.2%) groups, reached the target.

The basal group gained significantly less weight (3.6 kg) than did the biphasic and prandial groups (5.7 and 6.4 kg, respectively), and the median number of hypoglycemic events per patient per year was lowest in the basal group (1.7), compared with the biphasic (3.0) and prandial groups (5.5).

“Median glycated hemoglobin levels converged after 1 year and remained stable in all groups, for an overall value at 3 years of 6.9%,” wrote the authors (7.1% for biphasic, 6.8% for prandial, and 6.9% for basal, with no significant differences).

The final mean reduction from baseline was 1.3% in the biphasic group, 1.4% in the prandial group, and 1.2% in the basal group.

“The overall message of the [final 4-T results] is that you need complex insulin regimens to obtain adequate glycemic control, Dr. Roden said in an interview.

The 4-T study was supported by Novo Nordisk A/S and Diabetes UK. Dr. Holman reported receiving grants, consulting fees, and lecture fees from pharmaceutical companies including Novartis and Novo Nordisk, and royalties from sale of the Unistik single-use safety lancet. Dr. Roden reported receiving consulting and lecture fees from several drug makers, including Novo Nordisk.

MONTREAL — Insulin added to oral therapy in patients with long-standing type 2 diabetes is best initiated as a basal formulation and then intensified with prandial doses, according to the 3-year results of the Treat to Target in Type 2 Diabetes (4-T) trial.

“The results of our trial support current guidelines, which suggest that basal and prandial insulin regimens should be considered if adequate glycemic control is not achieved with initial regimens,” reported lead author Dr. Rury Holman of the diabetes trials unit at Oxford (England) University.

The findings were announced at the World Diabetes Congress, with simultaneous publication in the New England Journal of Medicine (2009;361:1736-47).

“We now have very clear evidence that the sequence of basal with added prandial gives you less weight gain and less hypoglycemia,” Dr. Holman said in an interview immediately following his presentation.

“The 4-T study supports the initiation of treatment with basal insulin, which is consistent with the concept that fasting hyperglycemia contributes more than postprandial hyperglycemia to glycated hemoglobin levels during periods of poor glycemic control,” Dr. Michael Roden of the German Diabetes Center and the Heinrich Heine University of Düsseldorf, Germany, said in an editorial in the same issue.

However, “it seems premature to recommend specific insulin regimens for patients with newly diagnosed disease.,” he said.

The 4-T multicenter, open-label trial included 708 patients who had inadequate glycemic control on dual oral metformin and sulfonylurea therapy. Mean patient age oas 61.7 years, wid mean disease duration ofwas 9 years.

They were randomized to one of three regimens in the first year: prandial insulin aspart (NovoRapid) three times daily, biphasic insulin aspart (NovoMix 30) twice daily, or basal detemir (Levemir) once or twice daily.

In the second year, sulfonylureas were replaced by a second insulin if hyperglycemia became unacceptable, which was the case in almost 90% of the patient population, Dr. Holman said.

For patients who had started on biphasic insulin, a midday prandial dose was added. Treatments converged for those who had started on either basal or prandial regimens, so that the basal group added prandial doses (10% of the daily basal dose with a minimum and maximum limit) and the prandial group added a basal dose (10 units at bedtime).

“The importance here is the temporal sequence—they are not identical,” Dr. Holman said. “So basal plus prandial was not the same as prandial plus basal …. Those who started with prandial had substantially more prandial than basal at the end, and those who started with the basal and then added prandial ended up with about 50/50.”

Preliminary results published after the first year of the study did not favor the basal insulin regimen, which was the least successful at bringing hemoglobin A_1c levels to 6.5% or less (N. Engl. J. Med. 2007;357:1716-30).

However, “the difference in outcomes from the first to the third year is startling,” Dr. Roden said in his editorial.

Final results showed that fewer than 45% of all patients achieved the HbA_1c target of 6.5% or less. In addition, significantly fewer patients on the biphasic regimen (31.9%), compared with the prandial (44.7%) and basal (43.2%) groups, reached the target.

The basal group gained significantly less weight (3.6 kg) than did the biphasic and prandial groups (5.7 and 6.4 kg, respectively), and the median number of hypoglycemic events per patient per year was lowest in the basal group (1.7), compared with the biphasic (3.0) and prandial groups (5.5).

“Median glycated hemoglobin levels converged after 1 year and remained stable in all groups, for an overall value at 3 years of 6.9%,” wrote the authors (7.1% for biphasic, 6.8% for prandial, and 6.9% for basal, with no significant differences).

The final mean reduction from baseline was 1.3% in the biphasic group, 1.4% in the prandial group, and 1.2% in the basal group.

“The overall message of the [final 4-T results] is that you need complex insulin regimens to obtain adequate glycemic control, Dr. Roden said in an interview.

The 4-T study was supported by Novo Nordisk A/S and Diabetes UK. Dr. Holman reported receiving grants, consulting fees, and lecture fees from pharmaceutical companies including Novartis and Novo Nordisk, and royalties from sale of the Unistik single-use safety lancet. Dr. Roden reported receiving consulting and lecture fees from several drug makers, including Novo Nordisk.

MONTREAL — Insulin added to oral therapy in patients with long-standing type 2 diabetes is best initiated as a basal formulation and then intensified with prandial doses, according to the 3-year results of the Treat to Target in Type 2 Diabetes (4-T) trial.

“The results of our trial support current guidelines, which suggest that basal and prandial insulin regimens should be considered if adequate glycemic control is not achieved with initial regimens,” reported lead author Dr. Rury Holman of the diabetes trials unit at Oxford (England) University.

The findings were announced at the World Diabetes Congress, with simultaneous publication in the New England Journal of Medicine (2009;361:1736-47).

“We now have very clear evidence that the sequence of basal with added prandial gives you less weight gain and less hypoglycemia,” Dr. Holman said in an interview immediately following his presentation.

“The 4-T study supports the initiation of treatment with basal insulin, which is consistent with the concept that fasting hyperglycemia contributes more than postprandial hyperglycemia to glycated hemoglobin levels during periods of poor glycemic control,” Dr. Michael Roden of the German Diabetes Center and the Heinrich Heine University of Düsseldorf, Germany, said in an editorial in the same issue.

However, “it seems premature to recommend specific insulin regimens for patients with newly diagnosed disease.,” he said.

The 4-T multicenter, open-label trial included 708 patients who had inadequate glycemic control on dual oral metformin and sulfonylurea therapy. Mean patient age oas 61.7 years, wid mean disease duration ofwas 9 years.

They were randomized to one of three regimens in the first year: prandial insulin aspart (NovoRapid) three times daily, biphasic insulin aspart (NovoMix 30) twice daily, or basal detemir (Levemir) once or twice daily.

In the second year, sulfonylureas were replaced by a second insulin if hyperglycemia became unacceptable, which was the case in almost 90% of the patient population, Dr. Holman said.

For patients who had started on biphasic insulin, a midday prandial dose was added. Treatments converged for those who had started on either basal or prandial regimens, so that the basal group added prandial doses (10% of the daily basal dose with a minimum and maximum limit) and the prandial group added a basal dose (10 units at bedtime).

“The importance here is the temporal sequence—they are not identical,” Dr. Holman said. “So basal plus prandial was not the same as prandial plus basal …. Those who started with prandial had substantially more prandial than basal at the end, and those who started with the basal and then added prandial ended up with about 50/50.”

Preliminary results published after the first year of the study did not favor the basal insulin regimen, which was the least successful at bringing hemoglobin A_1c levels to 6.5% or less (N. Engl. J. Med. 2007;357:1716-30).

However, “the difference in outcomes from the first to the third year is startling,” Dr. Roden said in his editorial.

Final results showed that fewer than 45% of all patients achieved the HbA_1c target of 6.5% or less. In addition, significantly fewer patients on the biphasic regimen (31.9%), compared with the prandial (44.7%) and basal (43.2%) groups, reached the target.

The basal group gained significantly less weight (3.6 kg) than did the biphasic and prandial groups (5.7 and 6.4 kg, respectively), and the median number of hypoglycemic events per patient per year was lowest in the basal group (1.7), compared with the biphasic (3.0) and prandial groups (5.5).

“Median glycated hemoglobin levels converged after 1 year and remained stable in all groups, for an overall value at 3 years of 6.9%,” wrote the authors (7.1% for biphasic, 6.8% for prandial, and 6.9% for basal, with no significant differences).

The final mean reduction from baseline was 1.3% in the biphasic group, 1.4% in the prandial group, and 1.2% in the basal group.

“The overall message of the [final 4-T results] is that you need complex insulin regimens to obtain adequate glycemic control, Dr. Roden said in an interview.

The 4-T study was supported by Novo Nordisk A/S and Diabetes UK. Dr. Holman reported receiving grants, consulting fees, and lecture fees from pharmaceutical companies including Novartis and Novo Nordisk, and royalties from sale of the Unistik single-use safety lancet. Dr. Roden reported receiving consulting and lecture fees from several drug makers, including Novo Nordisk.

MONTREAL — Insulin added to oral therapy in patients with longstanding type 2 diabetes is best initiated as a basal formulation and then intensified with prandial doses, according to the 3-year results of the Treat to Target in Type 2 Diabetes (4-T) trial.

“The results of our trial support current guidelines, which suggest that basal and prandial insulin regimens should be considered if adequate glycemic control is not achieved with initial regimens,” reported lead author Rury Holman, MB, ChB, of the diabetes trials unit at Oxford (England) University.

The findings were announced at the World Diabetes Congress, with simultaneous publication in the New England Journal of Medicine (2009;361:1736-47).

“I think we now have very clear evidence that the sequence of basal with added prandial gives you less weight gain and less hypoglycemia,” said Dr. Holman in an interview immediately following his presentation. “It's a no-brainer that that is the way we should now initiate treatment for these patients.”

“The 4-T study supports the initiation of treatment with basal insulin, which is consistent with the concept that fasting hyperglycemia contributes more than postprandial hyperglycemia to glycated hemoglobin levels during periods of poor glycemic control,” commented Dr. Michael Roden from the German Diabetes Center and the Heinrich Heine University of Düsseldorf, Germany, in an editorial published in the same issue.

However, he suggested “it seems premature to recommend specific insulin regimens for patients with newly diagnosed disease.”

The 4-T multicenter, open-label trial included 708 patients who had inadequate glycemic control on dual oral metformin and sulfonylurea therapy. The patients were a mean age of 61.7 years, with a mean disease duration of 9 years.

They were randomized to one of three supplemental insulin regimens in the first year: prandial insulin aspart (NovoRapid) three times daily, biphasic insulin aspart (NovoMix 30) twice daily, or basal detemir (Levemir) once daily, or twice if needed.

In the second year, sulfonylureas were replaced by a second insulin if hyperglycemia became unacceptable, which was the case in almost 90% of the patient population, said Dr. Holman.

For such patients who had started on biphasic insulin, a midday prandial dose was added. For those who had started on either basal or prandial regimens, their treatments converged, so that the basal group added prandial doses (10% of the daily basal dose with a minimum and maximum limit) and the prandial group added a basal dose (10 units at bedtime).

“The importance here is the temporal sequence—they are not identical,” said Dr. Holman. “So basal plus prandial was not the same as prandial plus basal. They started at a different place and so the percentages were different. So those who started with prandial had substantially more prandial than basal at the end, and those who started with the basal and then added prandial ended up with about 50/50.”

Preliminary results published after the first year of the study did not favor the basal insulin regimen, which was the least successful at bringing hemoglobin A_1c levels to 6.5% or less (N. Engl. J. Med. 2007;357:1716-30). “The addition of biphasic or prandial insulin aspart reduced levels more than the addition of basal insulin detemir but was associated with greater risks of hypoglycemia and weight gain,” the authors concluded at that time.

However, “the difference in outcomes from the first to the third year is startling,” Dr. Roden remarked in his editorial.

Final results showed that fewer than 45% of all patients achieved the HbA_1c target of 6.5% or less. In addition, significantly fewer patients on the biphasic regimen (31.9%) compared to the prandial (44.7%) and basal (43.2%) groups, reached the target.

Furthermore, the basal group gained significantly less weight (3.6 kg) than did the biphasic and prandial groups (5.7 and 6.4 kg, respectively), and the median number of hypoglycemic events per patient per year was lowest in the basal group (1.7), compared to the biphasic (3.0) and prandial groups (5.5).

“Median glycated hemoglobin levels converged after 1 year and remained stable in all groups, for an overall value at 3 years of 6.9%,” wrote the authors (7.1% for biphasic, 6.8% for prandial, and 6.9% for basal, with no significant differences). The final mean reduction from baseline was 1.3% in the biphasic group, 1.4% in the prandial group, and 1.2% in the basal group.

In an interview, Dr. Matthew Riddell commented that the 4-T results confirm the current guidelines from the American Diabetes Association and the European Association for the Study of Diabetes. “It shows that if you use insulin systematically it doesn't really matter which way you start. You can get to the same glucose level, but there are other important differences in treatments. The 4-T gives us a clue that maybe the mealtime insulin treatments shouldn't be the mainstay,” said the professor of medicine at Oregon Health and Science University in Portland.

“The overall message of the [final 4-T results] is that you need complex insulin regimens to obtain adequate glycemic control, which is still not reached in a substantial number of subjects,” Dr. Roden said in an interview.

The 4-T study was supported by Novo Nordisk A/S and Diabetes UK.

Dr. Holman reported receiving grants and consulting fees from pharmaceutical companies that included Novartis and Novo Nordisk, lecture fees from pharmaceutical companies, and royalties from sale of the Unistik single-use safety lancet. Dr. Roden reported receiving consulting and lecture fees from several drug makers, including Novo Nordisk. Dr. Riddle reported paid lecturing from and advisory board work with several drug companies.

MONTREAL — Insulin added to oral therapy in patients with longstanding type 2 diabetes is best initiated as a basal formulation and then intensified with prandial doses, according to the 3-year results of the Treat to Target in Type 2 Diabetes (4-T) trial.

“The results of our trial support current guidelines, which suggest that basal and prandial insulin regimens should be considered if adequate glycemic control is not achieved with initial regimens,” reported lead author Rury Holman, MB, ChB, of the diabetes trials unit at Oxford (England) University.

The findings were announced at the World Diabetes Congress, with simultaneous publication in the New England Journal of Medicine (2009;361:1736-47).

“I think we now have very clear evidence that the sequence of basal with added prandial gives you less weight gain and less hypoglycemia,” said Dr. Holman in an interview immediately following his presentation. “It's a no-brainer that that is the way we should now initiate treatment for these patients.”

“The 4-T study supports the initiation of treatment with basal insulin, which is consistent with the concept that fasting hyperglycemia contributes more than postprandial hyperglycemia to glycated hemoglobin levels during periods of poor glycemic control,” commented Dr. Michael Roden from the German Diabetes Center and the Heinrich Heine University of Düsseldorf, Germany, in an editorial published in the same issue.

However, he suggested “it seems premature to recommend specific insulin regimens for patients with newly diagnosed disease.”

The 4-T multicenter, open-label trial included 708 patients who had inadequate glycemic control on dual oral metformin and sulfonylurea therapy. The patients were a mean age of 61.7 years, with a mean disease duration of 9 years.

They were randomized to one of three supplemental insulin regimens in the first year: prandial insulin aspart (NovoRapid) three times daily, biphasic insulin aspart (NovoMix 30) twice daily, or basal detemir (Levemir) once daily, or twice if needed.

In the second year, sulfonylureas were replaced by a second insulin if hyperglycemia became unacceptable, which was the case in almost 90% of the patient population, said Dr. Holman.

For such patients who had started on biphasic insulin, a midday prandial dose was added. For those who had started on either basal or prandial regimens, their treatments converged, so that the basal group added prandial doses (10% of the daily basal dose with a minimum and maximum limit) and the prandial group added a basal dose (10 units at bedtime).

“The importance here is the temporal sequence—they are not identical,” said Dr. Holman. “So basal plus prandial was not the same as prandial plus basal. They started at a different place and so the percentages were different. So those who started with prandial had substantially more prandial than basal at the end, and those who started with the basal and then added prandial ended up with about 50/50.”

Preliminary results published after the first year of the study did not favor the basal insulin regimen, which was the least successful at bringing hemoglobin A_1c levels to 6.5% or less (N. Engl. J. Med. 2007;357:1716-30). “The addition of biphasic or prandial insulin aspart reduced levels more than the addition of basal insulin detemir but was associated with greater risks of hypoglycemia and weight gain,” the authors concluded at that time.

However, “the difference in outcomes from the first to the third year is startling,” Dr. Roden remarked in his editorial.

Final results showed that fewer than 45% of all patients achieved the HbA_1c target of 6.5% or less. In addition, significantly fewer patients on the biphasic regimen (31.9%) compared to the prandial (44.7%) and basal (43.2%) groups, reached the target.

Furthermore, the basal group gained significantly less weight (3.6 kg) than did the biphasic and prandial groups (5.7 and 6.4 kg, respectively), and the median number of hypoglycemic events per patient per year was lowest in the basal group (1.7), compared to the biphasic (3.0) and prandial groups (5.5).

“Median glycated hemoglobin levels converged after 1 year and remained stable in all groups, for an overall value at 3 years of 6.9%,” wrote the authors (7.1% for biphasic, 6.8% for prandial, and 6.9% for basal, with no significant differences). The final mean reduction from baseline was 1.3% in the biphasic group, 1.4% in the prandial group, and 1.2% in the basal group.

In an interview, Dr. Matthew Riddell commented that the 4-T results confirm the current guidelines from the American Diabetes Association and the European Association for the Study of Diabetes. “It shows that if you use insulin systematically it doesn't really matter which way you start. You can get to the same glucose level, but there are other important differences in treatments. The 4-T gives us a clue that maybe the mealtime insulin treatments shouldn't be the mainstay,” said the professor of medicine at Oregon Health and Science University in Portland.

“The overall message of the [final 4-T results] is that you need complex insulin regimens to obtain adequate glycemic control, which is still not reached in a substantial number of subjects,” Dr. Roden said in an interview.

The 4-T study was supported by Novo Nordisk A/S and Diabetes UK.

Dr. Holman reported receiving grants and consulting fees from pharmaceutical companies that included Novartis and Novo Nordisk, lecture fees from pharmaceutical companies, and royalties from sale of the Unistik single-use safety lancet. Dr. Roden reported receiving consulting and lecture fees from several drug makers, including Novo Nordisk. Dr. Riddle reported paid lecturing from and advisory board work with several drug companies.

MONTREAL — Insulin added to oral therapy in patients with longstanding type 2 diabetes is best initiated as a basal formulation and then intensified with prandial doses, according to the 3-year results of the Treat to Target in Type 2 Diabetes (4-T) trial.

“The results of our trial support current guidelines, which suggest that basal and prandial insulin regimens should be considered if adequate glycemic control is not achieved with initial regimens,” reported lead author Rury Holman, MB, ChB, of the diabetes trials unit at Oxford (England) University.

The findings were announced at the World Diabetes Congress, with simultaneous publication in the New England Journal of Medicine (2009;361:1736-47).

“I think we now have very clear evidence that the sequence of basal with added prandial gives you less weight gain and less hypoglycemia,” said Dr. Holman in an interview immediately following his presentation. “It's a no-brainer that that is the way we should now initiate treatment for these patients.”

“The 4-T study supports the initiation of treatment with basal insulin, which is consistent with the concept that fasting hyperglycemia contributes more than postprandial hyperglycemia to glycated hemoglobin levels during periods of poor glycemic control,” commented Dr. Michael Roden from the German Diabetes Center and the Heinrich Heine University of Düsseldorf, Germany, in an editorial published in the same issue.

However, he suggested “it seems premature to recommend specific insulin regimens for patients with newly diagnosed disease.”

The 4-T multicenter, open-label trial included 708 patients who had inadequate glycemic control on dual oral metformin and sulfonylurea therapy. The patients were a mean age of 61.7 years, with a mean disease duration of 9 years.

They were randomized to one of three supplemental insulin regimens in the first year: prandial insulin aspart (NovoRapid) three times daily, biphasic insulin aspart (NovoMix 30) twice daily, or basal detemir (Levemir) once daily, or twice if needed.

In the second year, sulfonylureas were replaced by a second insulin if hyperglycemia became unacceptable, which was the case in almost 90% of the patient population, said Dr. Holman.

For such patients who had started on biphasic insulin, a midday prandial dose was added. For those who had started on either basal or prandial regimens, their treatments converged, so that the basal group added prandial doses (10% of the daily basal dose with a minimum and maximum limit) and the prandial group added a basal dose (10 units at bedtime).

“The importance here is the temporal sequence—they are not identical,” said Dr. Holman. “So basal plus prandial was not the same as prandial plus basal. They started at a different place and so the percentages were different. So those who started with prandial had substantially more prandial than basal at the end, and those who started with the basal and then added prandial ended up with about 50/50.”

Preliminary results published after the first year of the study did not favor the basal insulin regimen, which was the least successful at bringing hemoglobin A_1c levels to 6.5% or less (N. Engl. J. Med. 2007;357:1716-30). “The addition of biphasic or prandial insulin aspart reduced levels more than the addition of basal insulin detemir but was associated with greater risks of hypoglycemia and weight gain,” the authors concluded at that time.

However, “the difference in outcomes from the first to the third year is startling,” Dr. Roden remarked in his editorial.

Final results showed that fewer than 45% of all patients achieved the HbA_1c target of 6.5% or less. In addition, significantly fewer patients on the biphasic regimen (31.9%) compared to the prandial (44.7%) and basal (43.2%) groups, reached the target.

Furthermore, the basal group gained significantly less weight (3.6 kg) than did the biphasic and prandial groups (5.7 and 6.4 kg, respectively), and the median number of hypoglycemic events per patient per year was lowest in the basal group (1.7), compared to the biphasic (3.0) and prandial groups (5.5).

“Median glycated hemoglobin levels converged after 1 year and remained stable in all groups, for an overall value at 3 years of 6.9%,” wrote the authors (7.1% for biphasic, 6.8% for prandial, and 6.9% for basal, with no significant differences). The final mean reduction from baseline was 1.3% in the biphasic group, 1.4% in the prandial group, and 1.2% in the basal group.

In an interview, Dr. Matthew Riddell commented that the 4-T results confirm the current guidelines from the American Diabetes Association and the European Association for the Study of Diabetes. “It shows that if you use insulin systematically it doesn't really matter which way you start. You can get to the same glucose level, but there are other important differences in treatments. The 4-T gives us a clue that maybe the mealtime insulin treatments shouldn't be the mainstay,” said the professor of medicine at Oregon Health and Science University in Portland.

“The overall message of the [final 4-T results] is that you need complex insulin regimens to obtain adequate glycemic control, which is still not reached in a substantial number of subjects,” Dr. Roden said in an interview.

The 4-T study was supported by Novo Nordisk A/S and Diabetes UK.

Dr. Holman reported receiving grants and consulting fees from pharmaceutical companies that included Novartis and Novo Nordisk, lecture fees from pharmaceutical companies, and royalties from sale of the Unistik single-use safety lancet. Dr. Roden reported receiving consulting and lecture fees from several drug makers, including Novo Nordisk. Dr. Riddle reported paid lecturing from and advisory board work with several drug companies.

MONTREAL — The focus of lifestyle interventions for type 2 diabetes should be on combining weight loss diets with exercise, according to new research.

Weight loss is similar for either high-carbohydrate (HC) or a high-protein (HP) diets—with the addition of exercise fueling the benefits of either diet, reported Thomas Wycherley at the World Diabetes Congress.

The study, which was partially funded by the Pork Cooperative Research Centre in Australia, showed a nonsignificant trend toward better outcomes in patients on an HP rather than HC diet—an observation that makes sense for certain patients, remarked Dr. Jim Mann, an endocrinologist who was not connected to the study.

“I think there is a reasonable body of evidence that a high-protein diet may have some benefits [over a high-carbohydrate diet] for some people with the metabolic syndrome because these people tend towards a lot of high-glycemic carbohydrates, which is not good,” Dr. Mann, a professor of human nutrition and medicine at Edgar National Centre for Diabetes Research in Dunedin, New Zealand, said in an interview.

Previous research has indicated that there is some evidence that during weight loss, consumption of a high-protein diet may potentiate the impact of resistance exercise, compared with a high-carbohydrate diet, Mr. Wycherley said.

His study compared HC and HP weight-loss diets, with and without a resistance training program, over 12 weeks in 83 men and women with type 2 diabetes, 59 of whom completed the study. The groups had similar dropout rates.

The subjects were a mean age of 56 years, with a mean baseline body mass index of 35. The diets were equally energy restrictive (6 MJ/day for women and 7 MJ/day for men) and equal in fat content (about 25%), said Mr. Wycherley, a research assistant at the University of Adelaide (Australia). The HC diet had 55% carbohydrate and 20% protein, with the goal of providing 0.8 g/kg per day of protein. The HP diet contained 40% carbohydrate and 35% protein with the goal of providing 1.2 g/kg per day of protein. Both diets consisted mainly of whole foods, with dairy, animal, and vegetable sources of protein, and whole grains rather than processed carbohydrates.

Overall, there was a mean weight loss of about 10 kg (10%) across all four groups. Subjects in the HC and HP groups lost a mean of 8.6 and 9.0 kg, respectively. However, for those who also attended exercise sessions three times a week, the weight loss was greater (10.5 kg for HC and exercise, and 13.8 kg for HP and exercise).

All treatment groups had similar improvements in traditional cardiovascular disease risk markers, with a 10% drop in both systolic and diastolic blood pressure, and drops of 0.47 mmol/L in triglycerides, 0.67 mmol/L in total cholesterol, and 0.37 mmol/L in LDL cholesterol.

Glycemic control also showed similar improvements in all groups, with a mean drop of 2.1 mmol/L in fasting glucose, 4.7 mU/L in serum insulin, and 1.25% in hemoglobin A_1c.

“This really does reiterate the importance of achieving dietary weight loss in this patient group,” Mr. Wycherley said.

Recent research has shown similar results of exercise and high-protein versus high-carbohydrate diets in nondiabetic subjects, he said, but until now this has not been studied in patients with diabetes.

“In response to the diabetes and obesity epidemic, we're seeing an increase in the prevalence of alternative diets such as high-protein diets. This has raised some conjecture in the literature regarding the optimal dietary composition to deliver the most therapeutic benefits to this patient group—in particular surrounding the carbohydrate to protein ratio,” he said.

Mr. Wycherley did not declare any relevant conflicts of interest.

MONTREAL — The focus of lifestyle interventions for type 2 diabetes should be on combining weight loss diets with exercise, according to new research.

Weight loss is similar for either high-carbohydrate (HC) or a high-protein (HP) diets—with the addition of exercise fueling the benefits of either diet, reported Thomas Wycherley at the World Diabetes Congress.

The study, which was partially funded by the Pork Cooperative Research Centre in Australia, showed a nonsignificant trend toward better outcomes in patients on an HP rather than HC diet—an observation that makes sense for certain patients, remarked Dr. Jim Mann, an endocrinologist who was not connected to the study.

“I think there is a reasonable body of evidence that a high-protein diet may have some benefits [over a high-carbohydrate diet] for some people with the metabolic syndrome because these people tend towards a lot of high-glycemic carbohydrates, which is not good,” Dr. Mann, a professor of human nutrition and medicine at Edgar National Centre for Diabetes Research in Dunedin, New Zealand, said in an interview.

Previous research has indicated that there is some evidence that during weight loss, consumption of a high-protein diet may potentiate the impact of resistance exercise, compared with a high-carbohydrate diet, Mr. Wycherley said.

His study compared HC and HP weight-loss diets, with and without a resistance training program, over 12 weeks in 83 men and women with type 2 diabetes, 59 of whom completed the study. The groups had similar dropout rates.

The subjects were a mean age of 56 years, with a mean baseline body mass index of 35. The diets were equally energy restrictive (6 MJ/day for women and 7 MJ/day for men) and equal in fat content (about 25%), said Mr. Wycherley, a research assistant at the University of Adelaide (Australia). The HC diet had 55% carbohydrate and 20% protein, with the goal of providing 0.8 g/kg per day of protein. The HP diet contained 40% carbohydrate and 35% protein with the goal of providing 1.2 g/kg per day of protein. Both diets consisted mainly of whole foods, with dairy, animal, and vegetable sources of protein, and whole grains rather than processed carbohydrates.

Overall, there was a mean weight loss of about 10 kg (10%) across all four groups. Subjects in the HC and HP groups lost a mean of 8.6 and 9.0 kg, respectively. However, for those who also attended exercise sessions three times a week, the weight loss was greater (10.5 kg for HC and exercise, and 13.8 kg for HP and exercise).

All treatment groups had similar improvements in traditional cardiovascular disease risk markers, with a 10% drop in both systolic and diastolic blood pressure, and drops of 0.47 mmol/L in triglycerides, 0.67 mmol/L in total cholesterol, and 0.37 mmol/L in LDL cholesterol.

Glycemic control also showed similar improvements in all groups, with a mean drop of 2.1 mmol/L in fasting glucose, 4.7 mU/L in serum insulin, and 1.25% in hemoglobin A_1c.

“This really does reiterate the importance of achieving dietary weight loss in this patient group,” Mr. Wycherley said.

Recent research has shown similar results of exercise and high-protein versus high-carbohydrate diets in nondiabetic subjects, he said, but until now this has not been studied in patients with diabetes.

“In response to the diabetes and obesity epidemic, we're seeing an increase in the prevalence of alternative diets such as high-protein diets. This has raised some conjecture in the literature regarding the optimal dietary composition to deliver the most therapeutic benefits to this patient group—in particular surrounding the carbohydrate to protein ratio,” he said.

Mr. Wycherley did not declare any relevant conflicts of interest.

MONTREAL — The focus of lifestyle interventions for type 2 diabetes should be on combining weight loss diets with exercise, according to new research.

Weight loss is similar for either high-carbohydrate (HC) or a high-protein (HP) diets—with the addition of exercise fueling the benefits of either diet, reported Thomas Wycherley at the World Diabetes Congress.

The study, which was partially funded by the Pork Cooperative Research Centre in Australia, showed a nonsignificant trend toward better outcomes in patients on an HP rather than HC diet—an observation that makes sense for certain patients, remarked Dr. Jim Mann, an endocrinologist who was not connected to the study.

“I think there is a reasonable body of evidence that a high-protein diet may have some benefits [over a high-carbohydrate diet] for some people with the metabolic syndrome because these people tend towards a lot of high-glycemic carbohydrates, which is not good,” Dr. Mann, a professor of human nutrition and medicine at Edgar National Centre for Diabetes Research in Dunedin, New Zealand, said in an interview.

Previous research has indicated that there is some evidence that during weight loss, consumption of a high-protein diet may potentiate the impact of resistance exercise, compared with a high-carbohydrate diet, Mr. Wycherley said.

His study compared HC and HP weight-loss diets, with and without a resistance training program, over 12 weeks in 83 men and women with type 2 diabetes, 59 of whom completed the study. The groups had similar dropout rates.

The subjects were a mean age of 56 years, with a mean baseline body mass index of 35. The diets were equally energy restrictive (6 MJ/day for women and 7 MJ/day for men) and equal in fat content (about 25%), said Mr. Wycherley, a research assistant at the University of Adelaide (Australia). The HC diet had 55% carbohydrate and 20% protein, with the goal of providing 0.8 g/kg per day of protein. The HP diet contained 40% carbohydrate and 35% protein with the goal of providing 1.2 g/kg per day of protein. Both diets consisted mainly of whole foods, with dairy, animal, and vegetable sources of protein, and whole grains rather than processed carbohydrates.

Overall, there was a mean weight loss of about 10 kg (10%) across all four groups. Subjects in the HC and HP groups lost a mean of 8.6 and 9.0 kg, respectively. However, for those who also attended exercise sessions three times a week, the weight loss was greater (10.5 kg for HC and exercise, and 13.8 kg for HP and exercise).

All treatment groups had similar improvements in traditional cardiovascular disease risk markers, with a 10% drop in both systolic and diastolic blood pressure, and drops of 0.47 mmol/L in triglycerides, 0.67 mmol/L in total cholesterol, and 0.37 mmol/L in LDL cholesterol.

Glycemic control also showed similar improvements in all groups, with a mean drop of 2.1 mmol/L in fasting glucose, 4.7 mU/L in serum insulin, and 1.25% in hemoglobin A_1c.

“This really does reiterate the importance of achieving dietary weight loss in this patient group,” Mr. Wycherley said.

Recent research has shown similar results of exercise and high-protein versus high-carbohydrate diets in nondiabetic subjects, he said, but until now this has not been studied in patients with diabetes.

“In response to the diabetes and obesity epidemic, we're seeing an increase in the prevalence of alternative diets such as high-protein diets. This has raised some conjecture in the literature regarding the optimal dietary composition to deliver the most therapeutic benefits to this patient group—in particular surrounding the carbohydrate to protein ratio,” he said.

Mr. Wycherley did not declare any relevant conflicts of interest.

MONTREAL — A diet rich in pulses and nuts can improve glycemic control in type 2 diabetes patients to within ranges seen with pharmaceutical intervention, researchers reported at the World Diabetes Congress.

A meta-analysis of 41 trials of pulses, either alone or combined with low-glycemic or high-fiber diets, noted improved markers of long-term glycemic control (Diabetologia 2009;52:1479-95), reported Dr. John Sievenpiper of the risk factor modification center of St. Michael's Hospital, Toronto.

Another study, also conducted by his group, found that 75 g of mixed nuts daily for 3 months improved blood lipids and glycemic control in patients with type 2 diabetes, compared with a mixture of nuts and muffins, or muffins alone. “Whatever your favorite nut or form of nut, it's good to get it into your diet,” said Dr. Cyril Kendall of the University of Toronto's department of nutritional sciences.

Both researchers acknowledged long lists of industry relationships: serving on advisory boards for a number of food companies, as well as the International Nut Council, and the Canola and Flax Councils of Canada, and receiving consultant fees from Pulse Canada.

“These are very nice, confirmatory studies,” commented Dr. Jim Mann, an endocrinologist who was not connected to the analyses, but performed some of the first studies in the 1980s showing similar results.

“I believe implicitly that patients do respond to dietary advice. In fact, the degree of response for type 2 diabetes is quite often as great as it is for some of the medications, if people comply,” the professor of human nutrition and medicine at Edgar National Center for Diabetes Research in Dunedin, New Zealand, said in an interview. “Most physicians don't believe that people will adhere sufficiently to dietary advice to make a significant difference, and because physicians are not convinced, neither are their patients. It takes an enthusiastic physician to get an enthusiastic patient.”

Dietary pulses such as chickpeas, beans, lentils, and peas are characterized by a low glycemic index, high fiber content, high levels of amylose and resistant starches, and vegetable protein and various other antinutrients “which may act as enzyme inhibitors,” Dr. Sievenpiper said. “The effect is to decrease starch digestion and absorption and therefore postprandial glycemia.”

In his meta-analysis, “modest improvement in medium to long-term glycemic control was seen when [pulses] were given alone or in combination with dietary maneuvers to reduce the glycemic index in the diet.”

The analysis included 11 trials that examined consumption of pulses alone, which noted an overall decrease in standardized mean difference (SMD) of 0.71 in fasting blood glucose (FBG) and 0.62 in serum insulin. Similarly, 19 trials looking at consumption of pulses in low glycemic index diets noted an SMD decrease of 0.28 in glycosylated blood proteins—either hemoglobin A_1c or fructosamine. And in 11 trials examining pulses in high-fiber diets, there were SMD reductions in fasting blood glucose of 0.32 and in glycosylated blood protein of 0.27.

Based on these results, “we would expect about a 0.48% reduction in HbA_1c, and this level of benefit approaches that seen with acarbose, exceeds the [Food and Drug Administration] proposed clinically meaningful threshold of 0.3%, and lies at the lower limit of efficacy of what you might expect for oral agents,” Dr. Sievenpiper said.

The nut study randomized 117 patients with type 2 diabetes to consume either 75 g nuts, 38 g nuts and 1.5 bran muffins (150 kcal per muffin), or three muffins daily for 3 months. Nut portions included a mix of almonds, cashews, macadamias, pecans, pistachios, walnuts, and peanuts. All treatment portions were equivalent to 475 kcal/day and were designed to maintain rather than decrease body weight. The primary outcome of the study was change in HbA_1c and serum lipids.

The patients' baseline characteristics were similar across the groups. They ranged in age from 61 to 63 years, 75% were men, ethnic backgrounds were diverse, and body mass indexes ranged from 28.8 to 30.3 kg/m

All patients were being treated with oral hypoglycemic medication, and their mean HbA_1c level was 7.1%. Baseline lipid profiles were balanced across the groups, and the mean duration of diabetes was 7-8 years.

A total of 100 patients completed the study, with a similar dropout rate in each group.

An intention-to-treat analysis revealed that HbA_1c levels were significantly lower in the nuts-only group, compared with the nut-muffin combination group (6.88% versus 7.02%), although the latter was not significantly lower than the muffin-only group (7.06%), Dr. Kendall said. There was a significant dose response seen in LDL cholesterol level, which fell by 0.19 mmol/L in the full-nut group, compared with full-muffin group.

Weight change from baseline was not significant, although there was a trend toward more weight loss in the nuts-only group. This was particularly interesting, given that more daily calories were consumed in this group (2,072 kcal), compared with the muffin-only group (1,932 kcal), Dr. Kendall said.

Previous studies by Dr. Kendall and his colleagues, as well as other studies, have shown this same effect, he said. “What we've found is that nuts are not entirely digested and there's an excretion of about 15%-20% that are simply not absorbed and pass through the gastrointestinal tract.”

Previous unpublished work by his group has shown that nuts have favorable effects on postprandial glucose response to common carbohydrates such as white bread, potatoes, rice, and pasta. “You get a graded reduction in glycemic response depending on the dose of nuts,” Dr. Kendall said.

Dietary intake of pulses—such as chickpeas, beans, lentils, and peas—can help diabetic patients reduce postprandial glycemia.

Source © Tinka/Fotolia.com

MONTREAL — A diet rich in pulses and nuts can improve glycemic control in type 2 diabetes patients to within ranges seen with pharmaceutical intervention, researchers reported at the World Diabetes Congress.

A meta-analysis of 41 trials of pulses, either alone or combined with low-glycemic or high-fiber diets, noted improved markers of long-term glycemic control (Diabetologia 2009;52:1479-95), reported Dr. John Sievenpiper of the risk factor modification center of St. Michael's Hospital, Toronto.

Another study, also conducted by his group, found that 75 g of mixed nuts daily for 3 months improved blood lipids and glycemic control in patients with type 2 diabetes, compared with a mixture of nuts and muffins, or muffins alone. “Whatever your favorite nut or form of nut, it's good to get it into your diet,” said Dr. Cyril Kendall of the University of Toronto's department of nutritional sciences.

Both researchers acknowledged long lists of industry relationships: serving on advisory boards for a number of food companies, as well as the International Nut Council, and the Canola and Flax Councils of Canada, and receiving consultant fees from Pulse Canada.

“These are very nice, confirmatory studies,” commented Dr. Jim Mann, an endocrinologist who was not connected to the analyses, but performed some of the first studies in the 1980s showing similar results.

“I believe implicitly that patients do respond to dietary advice. In fact, the degree of response for type 2 diabetes is quite often as great as it is for some of the medications, if people comply,” the professor of human nutrition and medicine at Edgar National Center for Diabetes Research in Dunedin, New Zealand, said in an interview. “Most physicians don't believe that people will adhere sufficiently to dietary advice to make a significant difference, and because physicians are not convinced, neither are their patients. It takes an enthusiastic physician to get an enthusiastic patient.”

Dietary pulses such as chickpeas, beans, lentils, and peas are characterized by a low glycemic index, high fiber content, high levels of amylose and resistant starches, and vegetable protein and various other antinutrients “which may act as enzyme inhibitors,” Dr. Sievenpiper said. “The effect is to decrease starch digestion and absorption and therefore postprandial glycemia.”

In his meta-analysis, “modest improvement in medium to long-term glycemic control was seen when [pulses] were given alone or in combination with dietary maneuvers to reduce the glycemic index in the diet.”

The analysis included 11 trials that examined consumption of pulses alone, which noted an overall decrease in standardized mean difference (SMD) of 0.71 in fasting blood glucose (FBG) and 0.62 in serum insulin. Similarly, 19 trials looking at consumption of pulses in low glycemic index diets noted an SMD decrease of 0.28 in glycosylated blood proteins—either hemoglobin A_1c or fructosamine. And in 11 trials examining pulses in high-fiber diets, there were SMD reductions in fasting blood glucose of 0.32 and in glycosylated blood protein of 0.27.

Based on these results, “we would expect about a 0.48% reduction in HbA_1c, and this level of benefit approaches that seen with acarbose, exceeds the [Food and Drug Administration] proposed clinically meaningful threshold of 0.3%, and lies at the lower limit of efficacy of what you might expect for oral agents,” Dr. Sievenpiper said.

The nut study randomized 117 patients with type 2 diabetes to consume either 75 g nuts, 38 g nuts and 1.5 bran muffins (150 kcal per muffin), or three muffins daily for 3 months. Nut portions included a mix of almonds, cashews, macadamias, pecans, pistachios, walnuts, and peanuts. All treatment portions were equivalent to 475 kcal/day and were designed to maintain rather than decrease body weight. The primary outcome of the study was change in HbA_1c and serum lipids.

The patients' baseline characteristics were similar across the groups. They ranged in age from 61 to 63 years, 75% were men, ethnic backgrounds were diverse, and body mass indexes ranged from 28.8 to 30.3 kg/m

All patients were being treated with oral hypoglycemic medication, and their mean HbA_1c level was 7.1%. Baseline lipid profiles were balanced across the groups, and the mean duration of diabetes was 7-8 years.

A total of 100 patients completed the study, with a similar dropout rate in each group.

An intention-to-treat analysis revealed that HbA_1c levels were significantly lower in the nuts-only group, compared with the nut-muffin combination group (6.88% versus 7.02%), although the latter was not significantly lower than the muffin-only group (7.06%), Dr. Kendall said. There was a significant dose response seen in LDL cholesterol level, which fell by 0.19 mmol/L in the full-nut group, compared with full-muffin group.

Weight change from baseline was not significant, although there was a trend toward more weight loss in the nuts-only group. This was particularly interesting, given that more daily calories were consumed in this group (2,072 kcal), compared with the muffin-only group (1,932 kcal), Dr. Kendall said.

Previous studies by Dr. Kendall and his colleagues, as well as other studies, have shown this same effect, he said. “What we've found is that nuts are not entirely digested and there's an excretion of about 15%-20% that are simply not absorbed and pass through the gastrointestinal tract.”

Previous unpublished work by his group has shown that nuts have favorable effects on postprandial glucose response to common carbohydrates such as white bread, potatoes, rice, and pasta. “You get a graded reduction in glycemic response depending on the dose of nuts,” Dr. Kendall said.

Dietary intake of pulses—such as chickpeas, beans, lentils, and peas—can help diabetic patients reduce postprandial glycemia.

Source © Tinka/Fotolia.com

MONTREAL — A diet rich in pulses and nuts can improve glycemic control in type 2 diabetes patients to within ranges seen with pharmaceutical intervention, researchers reported at the World Diabetes Congress.

A meta-analysis of 41 trials of pulses, either alone or combined with low-glycemic or high-fiber diets, noted improved markers of long-term glycemic control (Diabetologia 2009;52:1479-95), reported Dr. John Sievenpiper of the risk factor modification center of St. Michael's Hospital, Toronto.

Another study, also conducted by his group, found that 75 g of mixed nuts daily for 3 months improved blood lipids and glycemic control in patients with type 2 diabetes, compared with a mixture of nuts and muffins, or muffins alone. “Whatever your favorite nut or form of nut, it's good to get it into your diet,” said Dr. Cyril Kendall of the University of Toronto's department of nutritional sciences.

Both researchers acknowledged long lists of industry relationships: serving on advisory boards for a number of food companies, as well as the International Nut Council, and the Canola and Flax Councils of Canada, and receiving consultant fees from Pulse Canada.

“These are very nice, confirmatory studies,” commented Dr. Jim Mann, an endocrinologist who was not connected to the analyses, but performed some of the first studies in the 1980s showing similar results.

“I believe implicitly that patients do respond to dietary advice. In fact, the degree of response for type 2 diabetes is quite often as great as it is for some of the medications, if people comply,” the professor of human nutrition and medicine at Edgar National Center for Diabetes Research in Dunedin, New Zealand, said in an interview. “Most physicians don't believe that people will adhere sufficiently to dietary advice to make a significant difference, and because physicians are not convinced, neither are their patients. It takes an enthusiastic physician to get an enthusiastic patient.”

Dietary pulses such as chickpeas, beans, lentils, and peas are characterized by a low glycemic index, high fiber content, high levels of amylose and resistant starches, and vegetable protein and various other antinutrients “which may act as enzyme inhibitors,” Dr. Sievenpiper said. “The effect is to decrease starch digestion and absorption and therefore postprandial glycemia.”

In his meta-analysis, “modest improvement in medium to long-term glycemic control was seen when [pulses] were given alone or in combination with dietary maneuvers to reduce the glycemic index in the diet.”

The analysis included 11 trials that examined consumption of pulses alone, which noted an overall decrease in standardized mean difference (SMD) of 0.71 in fasting blood glucose (FBG) and 0.62 in serum insulin. Similarly, 19 trials looking at consumption of pulses in low glycemic index diets noted an SMD decrease of 0.28 in glycosylated blood proteins—either hemoglobin A_1c or fructosamine. And in 11 trials examining pulses in high-fiber diets, there were SMD reductions in fasting blood glucose of 0.32 and in glycosylated blood protein of 0.27.

Based on these results, “we would expect about a 0.48% reduction in HbA_1c, and this level of benefit approaches that seen with acarbose, exceeds the [Food and Drug Administration] proposed clinically meaningful threshold of 0.3%, and lies at the lower limit of efficacy of what you might expect for oral agents,” Dr. Sievenpiper said.

The nut study randomized 117 patients with type 2 diabetes to consume either 75 g nuts, 38 g nuts and 1.5 bran muffins (150 kcal per muffin), or three muffins daily for 3 months. Nut portions included a mix of almonds, cashews, macadamias, pecans, pistachios, walnuts, and peanuts. All treatment portions were equivalent to 475 kcal/day and were designed to maintain rather than decrease body weight. The primary outcome of the study was change in HbA_1c and serum lipids.

The patients' baseline characteristics were similar across the groups. They ranged in age from 61 to 63 years, 75% were men, ethnic backgrounds were diverse, and body mass indexes ranged from 28.8 to 30.3 kg/m

All patients were being treated with oral hypoglycemic medication, and their mean HbA_1c level was 7.1%. Baseline lipid profiles were balanced across the groups, and the mean duration of diabetes was 7-8 years.

A total of 100 patients completed the study, with a similar dropout rate in each group.

An intention-to-treat analysis revealed that HbA_1c levels were significantly lower in the nuts-only group, compared with the nut-muffin combination group (6.88% versus 7.02%), although the latter was not significantly lower than the muffin-only group (7.06%), Dr. Kendall said. There was a significant dose response seen in LDL cholesterol level, which fell by 0.19 mmol/L in the full-nut group, compared with full-muffin group.

Weight change from baseline was not significant, although there was a trend toward more weight loss in the nuts-only group. This was particularly interesting, given that more daily calories were consumed in this group (2,072 kcal), compared with the muffin-only group (1,932 kcal), Dr. Kendall said.

Previous studies by Dr. Kendall and his colleagues, as well as other studies, have shown this same effect, he said. “What we've found is that nuts are not entirely digested and there's an excretion of about 15%-20% that are simply not absorbed and pass through the gastrointestinal tract.”

Previous unpublished work by his group has shown that nuts have favorable effects on postprandial glucose response to common carbohydrates such as white bread, potatoes, rice, and pasta. “You get a graded reduction in glycemic response depending on the dose of nuts,” Dr. Kendall said.

Dietary intake of pulses—such as chickpeas, beans, lentils, and peas—can help diabetic patients reduce postprandial glycemia.

Source © Tinka/Fotolia.com

MONTREAL — Better identification of risk, but lack of explanation for it, continues to frustrate investigators as they search for reasons for the excess mortality associated with intensive glycemic control in the ACCORD trial.

However, complex interactions between baseline characteristics, postrandomization characteristics, and treatment strategy are still being explored.

In the latest set of analyses, “neither rapid reduction of blood glucose nor the achievement of near normal hemoglobin A_1c levels led to an excess risk of all-cause or CV death with the intensive strategy,” said Dr. Matthew Riddle, who presented an update on the Action to Control Cardiovascular Risk in Diabetes trial at the World Diabetes Congress.

“We haven't been able to find either baseline characteristics or obvious events during the course of treatment that strongly predicted which group was at risk for cardiovascular death,” he said in an interview.

ACCORD compared intensive versus standard glycemic control in 10,251 adults from 77 sites. The hypothesis was that lowering HbA_1c levels below 6% would reduce cardiovascular events compared with levels of 7.0%-7.9%. However, the intensive arm of the trial was stopped early when it showed a 22% increase in all-cause mortality compared with standard treatment. There were 257 deaths in the intensive treatment arm, compared with 203 in the standard treatment arm.

Several previous analyses of the data have revealed baseline characteristics such as high HbA_1c (8.5% or more), self-reported neuropathy, and aspirin use as predictors for increased mortality risk with intensive treatment, said Dr. Riddle, professor of medicine at Oregon Health and Science University in Portland.

It could be hypothesized that a high HbA_1c is a surrogate for relative severity of metabolic control, neuropathy is a surrogate for established and significant microvascular disease, and aspirin use may be a surrogate for cardiovascular disease, he suggested.

However, this still does not explain the excess risk seen with intensive versus standard treatment. “We still do not know the mechanisms involved in this unfavorable finding,” he said.

An epidemiologic analysis of the whole study population showed every 1% increase in average HbA_1c above normal was associated with a 20% increased risk of all-cause mortality, CV mortality, MI, and stroke. Further investigation into the interaction between this finding and treatment strategy suggests patients who were unable to lower HbA_1c levels with intensive treatment were at greatest risk for all-cause and cardiovascular mortality. “This supports a lot of people's intuitive idea that the further along in the course of diabetes patients are, the higher their risks from any kind of intensive intervention, and thus the more cautious the approach should be,” he said in an interview.

“When should we stop being aggressive?” Dr. Rury Holman of the Diabetes Trials Unit at the University of Oxford (England) asked during the question period. “What is it that tells us that we're not winning, and if we continue to be aggressive the patient will fall into this high-risk category?”

“I can't speak for ACCORD as a whole,” answered Dr. Riddle, “but my own opinion is that I think we know within the first 6 months of attempting an intervention whether that person is going to succeed. If they are struggling with it for any reason, whether it's a physiologic reason, a medication-adherence reason, or any recurrent illness reason, I believe that would be a reason to back off.”

The investigators are still working on several other hypotheses for the excess risk seen with intensive treatment, including hypoglycemia, “although we've been unable to find a direct relationship,” he said. In addition, “weight gain remains on the table as a serious possibility, and certainly, possible unfavorable effects of high doses of the medications,”

Dr. Riddle has received lecture fees or research grants from Sanofi-Aventis, Amylin, Eli Lilly & Co., and GlaxoSmithKline; and has done advisory board work with Amylin, Eli Lilly, Sanofi-Aventis, and Valeritas Inc.

MONTREAL — Better identification of risk, but lack of explanation for it, continues to frustrate investigators as they search for reasons for the excess mortality associated with intensive glycemic control in the ACCORD trial.

However, complex interactions between baseline characteristics, postrandomization characteristics, and treatment strategy are still being explored.

In the latest set of analyses, “neither rapid reduction of blood glucose nor the achievement of near normal hemoglobin A_1c levels led to an excess risk of all-cause or CV death with the intensive strategy,” said Dr. Matthew Riddle, who presented an update on the Action to Control Cardiovascular Risk in Diabetes trial at the World Diabetes Congress.

“We haven't been able to find either baseline characteristics or obvious events during the course of treatment that strongly predicted which group was at risk for cardiovascular death,” he said in an interview.

ACCORD compared intensive versus standard glycemic control in 10,251 adults from 77 sites. The hypothesis was that lowering HbA_1c levels below 6% would reduce cardiovascular events compared with levels of 7.0%-7.9%. However, the intensive arm of the trial was stopped early when it showed a 22% increase in all-cause mortality compared with standard treatment. There were 257 deaths in the intensive treatment arm, compared with 203 in the standard treatment arm.

Several previous analyses of the data have revealed baseline characteristics such as high HbA_1c (8.5% or more), self-reported neuropathy, and aspirin use as predictors for increased mortality risk with intensive treatment, said Dr. Riddle, professor of medicine at Oregon Health and Science University in Portland.

It could be hypothesized that a high HbA_1c is a surrogate for relative severity of metabolic control, neuropathy is a surrogate for established and significant microvascular disease, and aspirin use may be a surrogate for cardiovascular disease, he suggested.

However, this still does not explain the excess risk seen with intensive versus standard treatment. “We still do not know the mechanisms involved in this unfavorable finding,” he said.

An epidemiologic analysis of the whole study population showed every 1% increase in average HbA_1c above normal was associated with a 20% increased risk of all-cause mortality, CV mortality, MI, and stroke. Further investigation into the interaction between this finding and treatment strategy suggests patients who were unable to lower HbA_1c levels with intensive treatment were at greatest risk for all-cause and cardiovascular mortality. “This supports a lot of people's intuitive idea that the further along in the course of diabetes patients are, the higher their risks from any kind of intensive intervention, and thus the more cautious the approach should be,” he said in an interview.

“When should we stop being aggressive?” Dr. Rury Holman of the Diabetes Trials Unit at the University of Oxford (England) asked during the question period. “What is it that tells us that we're not winning, and if we continue to be aggressive the patient will fall into this high-risk category?”

“I can't speak for ACCORD as a whole,” answered Dr. Riddle, “but my own opinion is that I think we know within the first 6 months of attempting an intervention whether that person is going to succeed. If they are struggling with it for any reason, whether it's a physiologic reason, a medication-adherence reason, or any recurrent illness reason, I believe that would be a reason to back off.”

The investigators are still working on several other hypotheses for the excess risk seen with intensive treatment, including hypoglycemia, “although we've been unable to find a direct relationship,” he said. In addition, “weight gain remains on the table as a serious possibility, and certainly, possible unfavorable effects of high doses of the medications,”

Dr. Riddle has received lecture fees or research grants from Sanofi-Aventis, Amylin, Eli Lilly & Co., and GlaxoSmithKline; and has done advisory board work with Amylin, Eli Lilly, Sanofi-Aventis, and Valeritas Inc.

MONTREAL — Better identification of risk, but lack of explanation for it, continues to frustrate investigators as they search for reasons for the excess mortality associated with intensive glycemic control in the ACCORD trial.

However, complex interactions between baseline characteristics, postrandomization characteristics, and treatment strategy are still being explored.

In the latest set of analyses, “neither rapid reduction of blood glucose nor the achievement of near normal hemoglobin A_1c levels led to an excess risk of all-cause or CV death with the intensive strategy,” said Dr. Matthew Riddle, who presented an update on the Action to Control Cardiovascular Risk in Diabetes trial at the World Diabetes Congress.

“We haven't been able to find either baseline characteristics or obvious events during the course of treatment that strongly predicted which group was at risk for cardiovascular death,” he said in an interview.

ACCORD compared intensive versus standard glycemic control in 10,251 adults from 77 sites. The hypothesis was that lowering HbA_1c levels below 6% would reduce cardiovascular events compared with levels of 7.0%-7.9%. However, the intensive arm of the trial was stopped early when it showed a 22% increase in all-cause mortality compared with standard treatment. There were 257 deaths in the intensive treatment arm, compared with 203 in the standard treatment arm.

Several previous analyses of the data have revealed baseline characteristics such as high HbA_1c (8.5% or more), self-reported neuropathy, and aspirin use as predictors for increased mortality risk with intensive treatment, said Dr. Riddle, professor of medicine at Oregon Health and Science University in Portland.

It could be hypothesized that a high HbA_1c is a surrogate for relative severity of metabolic control, neuropathy is a surrogate for established and significant microvascular disease, and aspirin use may be a surrogate for cardiovascular disease, he suggested.

However, this still does not explain the excess risk seen with intensive versus standard treatment. “We still do not know the mechanisms involved in this unfavorable finding,” he said.

An epidemiologic analysis of the whole study population showed every 1% increase in average HbA_1c above normal was associated with a 20% increased risk of all-cause mortality, CV mortality, MI, and stroke. Further investigation into the interaction between this finding and treatment strategy suggests patients who were unable to lower HbA_1c levels with intensive treatment were at greatest risk for all-cause and cardiovascular mortality. “This supports a lot of people's intuitive idea that the further along in the course of diabetes patients are, the higher their risks from any kind of intensive intervention, and thus the more cautious the approach should be,” he said in an interview.

“When should we stop being aggressive?” Dr. Rury Holman of the Diabetes Trials Unit at the University of Oxford (England) asked during the question period. “What is it that tells us that we're not winning, and if we continue to be aggressive the patient will fall into this high-risk category?”

“I can't speak for ACCORD as a whole,” answered Dr. Riddle, “but my own opinion is that I think we know within the first 6 months of attempting an intervention whether that person is going to succeed. If they are struggling with it for any reason, whether it's a physiologic reason, a medication-adherence reason, or any recurrent illness reason, I believe that would be a reason to back off.”

The investigators are still working on several other hypotheses for the excess risk seen with intensive treatment, including hypoglycemia, “although we've been unable to find a direct relationship,” he said. In addition, “weight gain remains on the table as a serious possibility, and certainly, possible unfavorable effects of high doses of the medications,”

Dr. Riddle has received lecture fees or research grants from Sanofi-Aventis, Amylin, Eli Lilly & Co., and GlaxoSmithKline; and has done advisory board work with Amylin, Eli Lilly, Sanofi-Aventis, and Valeritas Inc.

Women with metabolic syndrome have an increased risk of developing symptomatic peripheral artery disease, compared with healthy women, according to a new analysis of the Women's Health Study.

“In this generally low-risk population of women, the excess risk associated with [metabolic syndrome] may be mediated through heightened inflammation and/or endothelial activation,” reported Dr. Aruna Pradhan of Brigham and Women's Hospital, Boston, and colleagues.

The prospective cohort study included a subgroup of 27,111 women, aged at least 45 years, who were enrolled in the Women's Health Study and followed for a median of 13 years (Circulation 2009 Sept. 8 [doi:10.1161/circulationaha.109.863092]).

About one-quarter of the study population (6,920) had metabolic syndrome, defined according to the ATP (Adult Treatment Panel) III guidelines as the presence of three or more of the following traits: a waist circumference of 88 cm or more; a triglyceride level of 150 mg/dL or greater; HDL cholesterol levels lower than 50 mg/dL; a blood pressure of at least 130/85 mm Hg; and abnormal glucose metabolism as identified by a fasting blood glucose level of at least 100 mg/dL.

Incident symptomatic peripheral artery disease (PAD), defined as intermittent claudication and/or peripheral artery surgery inclusive of catheter-based interventions, occurred in 114 women, 70 of them with metabolic syndrome and 44 without.

The hazard ratio for PAD with metabolic syndrome, compared with PAD without metabolic syndrome, was 1.62 on univariate analysis, and 1.48 after adjustment for patient age and smoking status.

Even among women who did not have metabolic syndrome, the risk for PAD increased with the number of metabolic syndrome traits. Compared with women who did not have any traits, those who had one or two traits had a 2.5-fold increased risk of PAD.

The hazard ratios for PAD were 0.98 with elevated body mass index, 1.39 for elevated triglycerides, 1.50 for hypertension, 1.60 for low HDL cholesterol, and 2.05 for dysglycemia, reported the authors.

By comparison, the hazard ratio associated with current smoking was 12.7.

“Smoking was by far the strongest risk in this population,” the researchers wrote. “This study underscores the importance of abstinence from smoking for the prevention of PAD.”

Women with metabolic syndrome have an increased risk of developing symptomatic peripheral artery disease, compared with healthy women, according to a new analysis of the Women's Health Study.

“In this generally low-risk population of women, the excess risk associated with [metabolic syndrome] may be mediated through heightened inflammation and/or endothelial activation,” reported Dr. Aruna Pradhan of Brigham and Women's Hospital, Boston, and colleagues.

The prospective cohort study included a subgroup of 27,111 women, aged at least 45 years, who were enrolled in the Women's Health Study and followed for a median of 13 years (Circulation 2009 Sept. 8 [doi:10.1161/circulationaha.109.863092]).

About one-quarter of the study population (6,920) had metabolic syndrome, defined according to the ATP (Adult Treatment Panel) III guidelines as the presence of three or more of the following traits: a waist circumference of 88 cm or more; a triglyceride level of 150 mg/dL or greater; HDL cholesterol levels lower than 50 mg/dL; a blood pressure of at least 130/85 mm Hg; and abnormal glucose metabolism as identified by a fasting blood glucose level of at least 100 mg/dL.

Incident symptomatic peripheral artery disease (PAD), defined as intermittent claudication and/or peripheral artery surgery inclusive of catheter-based interventions, occurred in 114 women, 70 of them with metabolic syndrome and 44 without.

The hazard ratio for PAD with metabolic syndrome, compared with PAD without metabolic syndrome, was 1.62 on univariate analysis, and 1.48 after adjustment for patient age and smoking status.

Even among women who did not have metabolic syndrome, the risk for PAD increased with the number of metabolic syndrome traits. Compared with women who did not have any traits, those who had one or two traits had a 2.5-fold increased risk of PAD.

The hazard ratios for PAD were 0.98 with elevated body mass index, 1.39 for elevated triglycerides, 1.50 for hypertension, 1.60 for low HDL cholesterol, and 2.05 for dysglycemia, reported the authors.

By comparison, the hazard ratio associated with current smoking was 12.7.

“Smoking was by far the strongest risk in this population,” the researchers wrote. “This study underscores the importance of abstinence from smoking for the prevention of PAD.”

Women with metabolic syndrome have an increased risk of developing symptomatic peripheral artery disease, compared with healthy women, according to a new analysis of the Women's Health Study.

“In this generally low-risk population of women, the excess risk associated with [metabolic syndrome] may be mediated through heightened inflammation and/or endothelial activation,” reported Dr. Aruna Pradhan of Brigham and Women's Hospital, Boston, and colleagues.

The prospective cohort study included a subgroup of 27,111 women, aged at least 45 years, who were enrolled in the Women's Health Study and followed for a median of 13 years (Circulation 2009 Sept. 8 [doi:10.1161/circulationaha.109.863092]).

About one-quarter of the study population (6,920) had metabolic syndrome, defined according to the ATP (Adult Treatment Panel) III guidelines as the presence of three or more of the following traits: a waist circumference of 88 cm or more; a triglyceride level of 150 mg/dL or greater; HDL cholesterol levels lower than 50 mg/dL; a blood pressure of at least 130/85 mm Hg; and abnormal glucose metabolism as identified by a fasting blood glucose level of at least 100 mg/dL.

Incident symptomatic peripheral artery disease (PAD), defined as intermittent claudication and/or peripheral artery surgery inclusive of catheter-based interventions, occurred in 114 women, 70 of them with metabolic syndrome and 44 without.

The hazard ratio for PAD with metabolic syndrome, compared with PAD without metabolic syndrome, was 1.62 on univariate analysis, and 1.48 after adjustment for patient age and smoking status.

Even among women who did not have metabolic syndrome, the risk for PAD increased with the number of metabolic syndrome traits. Compared with women who did not have any traits, those who had one or two traits had a 2.5-fold increased risk of PAD.

The hazard ratios for PAD were 0.98 with elevated body mass index, 1.39 for elevated triglycerides, 1.50 for hypertension, 1.60 for low HDL cholesterol, and 2.05 for dysglycemia, reported the authors.

By comparison, the hazard ratio associated with current smoking was 12.7.

“Smoking was by far the strongest risk in this population,” the researchers wrote. “This study underscores the importance of abstinence from smoking for the prevention of PAD.”

MONTREAL — A diet rich in pulses and nuts can improve glycemic control in type 2 diabetes patients to within ranges seen with pharmaceutical intervention, researchers reported at the World Diabetes Congress.

A meta-analysis of 41 trials of pulses, either alone or combined with low glycemic or high fiber diets, noted improved markers of long-term glycemic control (Diabetologia 2009;52:1479–95), reported Dr. John Sievenpiper of St. Michael's Hospital's risk factor modification center, Toronto.

Another study, also conducted by his group, found that 75 g of mixed nuts daily for 3 months improved blood lipids and glycemic control in patients with type 2 diabetes, compared with a mixture of nuts and muffins, or muffins alone. “Whatever your favorite nut or form of nut, it's good to get it into your diet,” said Dr. Cyril Kendall of the University of Toronto's department of nutritional sciences.

Both researchers acknowledged long lists of industry relationships: serving on advisory boards for a number of food companies, as well as the International Nut Council, and the Canola and Flax Councils of Canada, and receiving consultant fees from Pulse Canada.

Dietary pulses such as chickpeas, beans, lentils, and peas are characterized by a low glycemic index, high fiber content, high levels of amylose and resistant starches, and vegetable protein, and various other antinutrients “which may act as enzyme inhibitors,” said Dr. Sievenpiper. “The effect is to decrease starch digestion and absorption and therefore postprandial glycemia.”

His meta-analysis included 11 trials that examined consumption of pulses alone, which noted an overall decrease in standardized mean difference (SMD) of 0.71 in fasting blood glucose (FBG) and 0.62 in serum insulin. Similarly, 19 trials looking at consumption of pulses in low glycemic index (GI) diets noted an SMD decrease of 0.28 in glycosylated blood proteins (GP)—either hemoglobin A_1c or fructosamine. And in 11 trials examining pulses in high-fiber diets, there were SMD reductions in fasting blood glucose of 0.32 and in GP of 0.27.

Based on these results, “We would expect about a 0.48% reduction in HbA_1c, and this level of benefit approaches that seen with acarbose, exceeds the [Food and Drug Administration] proposed clinically meaningful threshold of 0.3%, and lies at the lower limit of efficacy of what you might expect for oral agents,” Dr. Sievenpiper said.

The nut study randomized 117 patients with type 2 diabetes to consume either 75 g nuts, 38 g nuts and 1.5 bran muffins (150 kcal per muffin), or three muffins daily for 3 months. Nut portions included a mix of almonds, cashews, macadamias, pecans, pistachios, walnuts, and peanuts. All treatment portions were equivalent to 475 kcal/day and were designed to maintain rather than decrease body weight.

The primary outcome of the study was change in HbA_1c and serum lipids.

The patients' baseline characteristics were similar across the groups. They ranged in age from 61 to 63 years, 75% were male, ethnic backgrounds were diverse, and body mass index ranged from 28.8 to 30.3.

All patients were being treated with oral hypoglycemic medication, and their mean HbA_1c level was 7.1%. The mean duration of diabetes was 7–8 years. One hundred patients completed the study, with a similar dropout rate in each group.

An intention-to-treat analysis revealed that HbA_1c levels were significantly lower in the nuts-only group, compared with the nut-muffin combination group (6.88% versus 7.02%), although the latter was not significantly lower than the muffin-only group (7.06%), said Dr. Kendall.

There was a significant dose response seen in LDL cholesterol, which fell by 0.19 mmol/L in the full-nut group, compared with full-muffin group.

Previous studies have shown that “nuts are not entirely digested and there's an excretion of about 15%–20% that are simply not absorbed and pass through the gastrointestinal tract,” Dr. Kendall said.

MONTREAL — A diet rich in pulses and nuts can improve glycemic control in type 2 diabetes patients to within ranges seen with pharmaceutical intervention, researchers reported at the World Diabetes Congress.

A meta-analysis of 41 trials of pulses, either alone or combined with low glycemic or high fiber diets, noted improved markers of long-term glycemic control (Diabetologia 2009;52:1479–95), reported Dr. John Sievenpiper of St. Michael's Hospital's risk factor modification center, Toronto.

Another study, also conducted by his group, found that 75 g of mixed nuts daily for 3 months improved blood lipids and glycemic control in patients with type 2 diabetes, compared with a mixture of nuts and muffins, or muffins alone. “Whatever your favorite nut or form of nut, it's good to get it into your diet,” said Dr. Cyril Kendall of the University of Toronto's department of nutritional sciences.

Both researchers acknowledged long lists of industry relationships: serving on advisory boards for a number of food companies, as well as the International Nut Council, and the Canola and Flax Councils of Canada, and receiving consultant fees from Pulse Canada.

Dietary pulses such as chickpeas, beans, lentils, and peas are characterized by a low glycemic index, high fiber content, high levels of amylose and resistant starches, and vegetable protein, and various other antinutrients “which may act as enzyme inhibitors,” said Dr. Sievenpiper. “The effect is to decrease starch digestion and absorption and therefore postprandial glycemia.”

His meta-analysis included 11 trials that examined consumption of pulses alone, which noted an overall decrease in standardized mean difference (SMD) of 0.71 in fasting blood glucose (FBG) and 0.62 in serum insulin. Similarly, 19 trials looking at consumption of pulses in low glycemic index (GI) diets noted an SMD decrease of 0.28 in glycosylated blood proteins (GP)—either hemoglobin A_1c or fructosamine. And in 11 trials examining pulses in high-fiber diets, there were SMD reductions in fasting blood glucose of 0.32 and in GP of 0.27.

Based on these results, “We would expect about a 0.48% reduction in HbA_1c, and this level of benefit approaches that seen with acarbose, exceeds the [Food and Drug Administration] proposed clinically meaningful threshold of 0.3%, and lies at the lower limit of efficacy of what you might expect for oral agents,” Dr. Sievenpiper said.

The nut study randomized 117 patients with type 2 diabetes to consume either 75 g nuts, 38 g nuts and 1.5 bran muffins (150 kcal per muffin), or three muffins daily for 3 months. Nut portions included a mix of almonds, cashews, macadamias, pecans, pistachios, walnuts, and peanuts. All treatment portions were equivalent to 475 kcal/day and were designed to maintain rather than decrease body weight.

The primary outcome of the study was change in HbA_1c and serum lipids.

The patients' baseline characteristics were similar across the groups. They ranged in age from 61 to 63 years, 75% were male, ethnic backgrounds were diverse, and body mass index ranged from 28.8 to 30.3.

All patients were being treated with oral hypoglycemic medication, and their mean HbA_1c level was 7.1%. The mean duration of diabetes was 7–8 years. One hundred patients completed the study, with a similar dropout rate in each group.

An intention-to-treat analysis revealed that HbA_1c levels were significantly lower in the nuts-only group, compared with the nut-muffin combination group (6.88% versus 7.02%), although the latter was not significantly lower than the muffin-only group (7.06%), said Dr. Kendall.

There was a significant dose response seen in LDL cholesterol, which fell by 0.19 mmol/L in the full-nut group, compared with full-muffin group.

Previous studies have shown that “nuts are not entirely digested and there's an excretion of about 15%–20% that are simply not absorbed and pass through the gastrointestinal tract,” Dr. Kendall said.

MONTREAL — A diet rich in pulses and nuts can improve glycemic control in type 2 diabetes patients to within ranges seen with pharmaceutical intervention, researchers reported at the World Diabetes Congress.

A meta-analysis of 41 trials of pulses, either alone or combined with low glycemic or high fiber diets, noted improved markers of long-term glycemic control (Diabetologia 2009;52:1479–95), reported Dr. John Sievenpiper of St. Michael's Hospital's risk factor modification center, Toronto.

Another study, also conducted by his group, found that 75 g of mixed nuts daily for 3 months improved blood lipids and glycemic control in patients with type 2 diabetes, compared with a mixture of nuts and muffins, or muffins alone. “Whatever your favorite nut or form of nut, it's good to get it into your diet,” said Dr. Cyril Kendall of the University of Toronto's department of nutritional sciences.

Both researchers acknowledged long lists of industry relationships: serving on advisory boards for a number of food companies, as well as the International Nut Council, and the Canola and Flax Councils of Canada, and receiving consultant fees from Pulse Canada.

Dietary pulses such as chickpeas, beans, lentils, and peas are characterized by a low glycemic index, high fiber content, high levels of amylose and resistant starches, and vegetable protein, and various other antinutrients “which may act as enzyme inhibitors,” said Dr. Sievenpiper. “The effect is to decrease starch digestion and absorption and therefore postprandial glycemia.”

His meta-analysis included 11 trials that examined consumption of pulses alone, which noted an overall decrease in standardized mean difference (SMD) of 0.71 in fasting blood glucose (FBG) and 0.62 in serum insulin. Similarly, 19 trials looking at consumption of pulses in low glycemic index (GI) diets noted an SMD decrease of 0.28 in glycosylated blood proteins (GP)—either hemoglobin A_1c or fructosamine. And in 11 trials examining pulses in high-fiber diets, there were SMD reductions in fasting blood glucose of 0.32 and in GP of 0.27.

Based on these results, “We would expect about a 0.48% reduction in HbA_1c, and this level of benefit approaches that seen with acarbose, exceeds the [Food and Drug Administration] proposed clinically meaningful threshold of 0.3%, and lies at the lower limit of efficacy of what you might expect for oral agents,” Dr. Sievenpiper said.

The nut study randomized 117 patients with type 2 diabetes to consume either 75 g nuts, 38 g nuts and 1.5 bran muffins (150 kcal per muffin), or three muffins daily for 3 months. Nut portions included a mix of almonds, cashews, macadamias, pecans, pistachios, walnuts, and peanuts. All treatment portions were equivalent to 475 kcal/day and were designed to maintain rather than decrease body weight.

The primary outcome of the study was change in HbA_1c and serum lipids.

The patients' baseline characteristics were similar across the groups. They ranged in age from 61 to 63 years, 75% were male, ethnic backgrounds were diverse, and body mass index ranged from 28.8 to 30.3.

All patients were being treated with oral hypoglycemic medication, and their mean HbA_1c level was 7.1%. The mean duration of diabetes was 7–8 years. One hundred patients completed the study, with a similar dropout rate in each group.

An intention-to-treat analysis revealed that HbA_1c levels were significantly lower in the nuts-only group, compared with the nut-muffin combination group (6.88% versus 7.02%), although the latter was not significantly lower than the muffin-only group (7.06%), said Dr. Kendall.

There was a significant dose response seen in LDL cholesterol, which fell by 0.19 mmol/L in the full-nut group, compared with full-muffin group.

Previous studies have shown that “nuts are not entirely digested and there's an excretion of about 15%–20% that are simply not absorbed and pass through the gastrointestinal tract,” Dr. Kendall said.

MONTREAL — The presence of bone marrow lesions in pain-free knees may be a marker for an increased risk of future osteoarthritis among people who participate in vigorous activity. However, it's not known whether a modified exercise program could reduce this risk, said Dr. Anita Wluka at the World Congress on Osteoarthritis.

“It's possible that we should be changing our recommendations from weight-bearing to non–weight-bearing physical activity in this group, but this warrants further investigation,” said Dr. Wluka of Monash University in Clayton, Victoria, Australia.

Dr. Wluka's findings were based on a subgroup analysis of people participating in the longitudinal Melbourne Collaborative Cohort (MCC) study, established in 1990 to assess the role of diet and lifestyle in the risk for cancer and diabetes. The original cohort included 41,500 people (aged 40-69 years). In 2002, the investigators expanded the outcomes of interest to include cardiovascular disease and metabolic syndrome.

In a subanalysis, her group identified 271 individuals (aged 50-79 years) who had no knee disease or pain at baseline and results from two magnetic resonance imaging scans taken 2 years apart. Both cartilage volume and defects, as well as the presence of bone marrow lesions (BMLs), were assessed on MRI.

Degree of participation in vigorous physical activity was recorded when subjects first entered the larger MCC study (1990-1994), and again around the time of the first MRI (2004).

Overall, the worsening of cartilage loss and defects was similar among all subjects from the first to the second MRI, regardless of their level of exercise, she said.

“These were not people who ran marathons. These were people who jogged, or danced, or played tennis for more than 20 minutes—enough to raise a sweat or become short of breath.”

However, when the cohort was divided according to the presence (37 subjects) or absence (234 subjects) of BMLs on MRI, the risk of medical knee cartilage defects and volume loss was much more pronounced among exercisers, compared with nonexercisers (odds ratio, 3.4).

“This study identifies a subgroup—those with BML—who are more likely to have adverse outcomes with exercise,” she concluded. “It may be that the biomechanical properties of bones with BML are altered, and this alters the ability of cartilage to withstand normal or abnormal loading related to physical activity.”

Dr. Wluka said her group chose to look at BMLs because they have been associated with pain and progression in patients with symptomatic OA. Even in clinically asymptomatic populations, BMLs have been associated with an increased prevalence of cartilage defects and loss, she said.

“I'm not suggesting everyone go out and get an MRI to see if they have BMLs, but looking at why people have BMLs might be helpful, and there might be noninvasive ways of identifying them,” she said in an interview.

The congress was sponsored by the Osteoarthritis Research Society International.

Dr. Wluka said she had no conflicts of interest.

Patients with bone marrow lesions, as shown above on MRI, had adverse outcomes with exercise.

Source Courtesy Dr. Anita Wluka

MONTREAL — The presence of bone marrow lesions in pain-free knees may be a marker for an increased risk of future osteoarthritis among people who participate in vigorous activity. However, it's not known whether a modified exercise program could reduce this risk, said Dr. Anita Wluka at the World Congress on Osteoarthritis.

“It's possible that we should be changing our recommendations from weight-bearing to non–weight-bearing physical activity in this group, but this warrants further investigation,” said Dr. Wluka of Monash University in Clayton, Victoria, Australia.

Dr. Wluka's findings were based on a subgroup analysis of people participating in the longitudinal Melbourne Collaborative Cohort (MCC) study, established in 1990 to assess the role of diet and lifestyle in the risk for cancer and diabetes. The original cohort included 41,500 people (aged 40-69 years). In 2002, the investigators expanded the outcomes of interest to include cardiovascular disease and metabolic syndrome.

In a subanalysis, her group identified 271 individuals (aged 50-79 years) who had no knee disease or pain at baseline and results from two magnetic resonance imaging scans taken 2 years apart. Both cartilage volume and defects, as well as the presence of bone marrow lesions (BMLs), were assessed on MRI.

Degree of participation in vigorous physical activity was recorded when subjects first entered the larger MCC study (1990-1994), and again around the time of the first MRI (2004).

Overall, the worsening of cartilage loss and defects was similar among all subjects from the first to the second MRI, regardless of their level of exercise, she said.

“These were not people who ran marathons. These were people who jogged, or danced, or played tennis for more than 20 minutes—enough to raise a sweat or become short of breath.”

However, when the cohort was divided according to the presence (37 subjects) or absence (234 subjects) of BMLs on MRI, the risk of medical knee cartilage defects and volume loss was much more pronounced among exercisers, compared with nonexercisers (odds ratio, 3.4).

“This study identifies a subgroup—those with BML—who are more likely to have adverse outcomes with exercise,” she concluded. “It may be that the biomechanical properties of bones with BML are altered, and this alters the ability of cartilage to withstand normal or abnormal loading related to physical activity.”

Dr. Wluka said her group chose to look at BMLs because they have been associated with pain and progression in patients with symptomatic OA. Even in clinically asymptomatic populations, BMLs have been associated with an increased prevalence of cartilage defects and loss, she said.

“I'm not suggesting everyone go out and get an MRI to see if they have BMLs, but looking at why people have BMLs might be helpful, and there might be noninvasive ways of identifying them,” she said in an interview.

The congress was sponsored by the Osteoarthritis Research Society International.

Dr. Wluka said she had no conflicts of interest.

Patients with bone marrow lesions, as shown above on MRI, had adverse outcomes with exercise.

Source Courtesy Dr. Anita Wluka

MONTREAL — The presence of bone marrow lesions in pain-free knees may be a marker for an increased risk of future osteoarthritis among people who participate in vigorous activity. However, it's not known whether a modified exercise program could reduce this risk, said Dr. Anita Wluka at the World Congress on Osteoarthritis.

“It's possible that we should be changing our recommendations from weight-bearing to non–weight-bearing physical activity in this group, but this warrants further investigation,” said Dr. Wluka of Monash University in Clayton, Victoria, Australia.

Dr. Wluka's findings were based on a subgroup analysis of people participating in the longitudinal Melbourne Collaborative Cohort (MCC) study, established in 1990 to assess the role of diet and lifestyle in the risk for cancer and diabetes. The original cohort included 41,500 people (aged 40-69 years). In 2002, the investigators expanded the outcomes of interest to include cardiovascular disease and metabolic syndrome.

In a subanalysis, her group identified 271 individuals (aged 50-79 years) who had no knee disease or pain at baseline and results from two magnetic resonance imaging scans taken 2 years apart. Both cartilage volume and defects, as well as the presence of bone marrow lesions (BMLs), were assessed on MRI.

Degree of participation in vigorous physical activity was recorded when subjects first entered the larger MCC study (1990-1994), and again around the time of the first MRI (2004).

Overall, the worsening of cartilage loss and defects was similar among all subjects from the first to the second MRI, regardless of their level of exercise, she said.

“These were not people who ran marathons. These were people who jogged, or danced, or played tennis for more than 20 minutes—enough to raise a sweat or become short of breath.”

However, when the cohort was divided according to the presence (37 subjects) or absence (234 subjects) of BMLs on MRI, the risk of medical knee cartilage defects and volume loss was much more pronounced among exercisers, compared with nonexercisers (odds ratio, 3.4).

“This study identifies a subgroup—those with BML—who are more likely to have adverse outcomes with exercise,” she concluded. “It may be that the biomechanical properties of bones with BML are altered, and this alters the ability of cartilage to withstand normal or abnormal loading related to physical activity.”

Dr. Wluka said her group chose to look at BMLs because they have been associated with pain and progression in patients with symptomatic OA. Even in clinically asymptomatic populations, BMLs have been associated with an increased prevalence of cartilage defects and loss, she said.

“I'm not suggesting everyone go out and get an MRI to see if they have BMLs, but looking at why people have BMLs might be helpful, and there might be noninvasive ways of identifying them,” she said in an interview.

The congress was sponsored by the Osteoarthritis Research Society International.

Dr. Wluka said she had no conflicts of interest.

Patients with bone marrow lesions, as shown above on MRI, had adverse outcomes with exercise.

Source Courtesy Dr. Anita Wluka

MONTREAL – Despite postmarketing concerns about the psychiatric side effects of varenicline for smoking cessation, the medication appears to be safe in patients who are depressed or at risk for depression, Jennifer B. McClure, Ph.D., reported at the annual meeting of the Society of Behavioral Medicine.

In a subanalysis of the Chronicle Offers Management to Patients With Advanced Signs and Symptoms of Heart Failure (COMPASS-HF) trial, 661 smokers with a baseline history of depression, or a risk of depression, were monitored for mood changes and compared with 516 nondepressed smokers during their 12-week course of varenicline (Chantix) combined with behavioral smoking-cessation counseling (J. Gen. Intern. Med. 2009;24:563-9).

“We think that physicians should continue to closely monitor patients who are using varenicline, particularly if they have a psychiatric history,” she said. Although people with a history of depression were more likely than nondepressed people to report side effects with the medication, “we didn't find an overall difference in their qualitative symptom experience, or treatment outcomes,” said Dr. McClure, who is affiliated with Group Health Center for Health Studies, Seattle.

The study, funded by the National Cancer Institute, was a collaborative effort between Group Health; Free & Clear Inc., Seattle; and SRI International, an independent, nonprofit, research and development organization in Menlo Park, Calif. Medication was provided by Pfizer Inc., maker of varenicline.

Varenicline was approved by the Food and Drug Administration about 3 years ago. It works by blocking nicotinic receptors and thus the rewarding effects of nicotine, while stimulating some dopamine release to provide relief from craving and withdrawal, Dr. McClure said.

Shortly after its release to market, the FDA raised concerns that varenicline might be associated with increased neuropsychiatric symptoms, including depressed mood, agitation, suicidal ideation, and behavior–particularly in people with a psychiatric history, she said.

“Unfortunately, due to the nature of the reports to the FDA, we are not able to determine if varenicline itself was the cause of the symptoms reported–it's possible they were due to nicotine withdrawal, substance use, the psychiatric conditions themselves, or some other factors. Unfortunately, subjects with a psychiatric history were excluded from the original efficacy trials.”

Research shows that between one- and two-thirds of smokers have a history of depression, and that smokers with a history of depression report more symptoms of nicotine withdrawal, have more negative affect after they quit, and have higher relapse rates, compared with nondepressed smokers, she added.

“But because varenicline does stimulate some release of dopamine, it's possible that it might ameliorate some of this negative effect and other side effects, and so prevent relapse.”

At baseline, the subjects in the study were screened for symptoms of depression. “We didn't do an in-depth clinical interview; we just looked for the hallmark symptoms by asking: 'Have you ever, for a 2-week period or more, felt down, depressed, or hopeless, or had little interest or pleasure in doing things?'” she said.

Depressed and nondepressed subjects had similar nonsmoking rates at 21 days (49% vs. 47%, respectively), and 3 months (45% vs. 43%, respectively). However, depressed patients were more likely to endorse depression, anxiety, tension, agitation, difficulty concentrating and sleeping, and confusion. Depressed patients also were more likely to report other known side effects of the medication. However, despite this, negative affect actually declined in both groups, Dr. McClure said. One case of suicidal ideation was reported in a subject with undisclosed, untreated bipolar disorder.

Additional research is necessary to tease out the safety and effectiveness of varenicline among psychologically vulnerable populations, she concluded.

Dr. McClure said she had no conflicts to disclose in connection with this study.

MONTREAL – Despite postmarketing concerns about the psychiatric side effects of varenicline for smoking cessation, the medication appears to be safe in patients who are depressed or at risk for depression, Jennifer B. McClure, Ph.D., reported at the annual meeting of the Society of Behavioral Medicine.

In a subanalysis of the Chronicle Offers Management to Patients With Advanced Signs and Symptoms of Heart Failure (COMPASS-HF) trial, 661 smokers with a baseline history of depression, or a risk of depression, were monitored for mood changes and compared with 516 nondepressed smokers during their 12-week course of varenicline (Chantix) combined with behavioral smoking-cessation counseling (J. Gen. Intern. Med. 2009;24:563-9).

“We think that physicians should continue to closely monitor patients who are using varenicline, particularly if they have a psychiatric history,” she said. Although people with a history of depression were more likely than nondepressed people to report side effects with the medication, “we didn't find an overall difference in their qualitative symptom experience, or treatment outcomes,” said Dr. McClure, who is affiliated with Group Health Center for Health Studies, Seattle.

The study, funded by the National Cancer Institute, was a collaborative effort between Group Health; Free & Clear Inc., Seattle; and SRI International, an independent, nonprofit, research and development organization in Menlo Park, Calif. Medication was provided by Pfizer Inc., maker of varenicline.

Varenicline was approved by the Food and Drug Administration about 3 years ago. It works by blocking nicotinic receptors and thus the rewarding effects of nicotine, while stimulating some dopamine release to provide relief from craving and withdrawal, Dr. McClure said.

Shortly after its release to market, the FDA raised concerns that varenicline might be associated with increased neuropsychiatric symptoms, including depressed mood, agitation, suicidal ideation, and behavior–particularly in people with a psychiatric history, she said.

“Unfortunately, due to the nature of the reports to the FDA, we are not able to determine if varenicline itself was the cause of the symptoms reported–it's possible they were due to nicotine withdrawal, substance use, the psychiatric conditions themselves, or some other factors. Unfortunately, subjects with a psychiatric history were excluded from the original efficacy trials.”

Research shows that between one- and two-thirds of smokers have a history of depression, and that smokers with a history of depression report more symptoms of nicotine withdrawal, have more negative affect after they quit, and have higher relapse rates, compared with nondepressed smokers, she added.

“But because varenicline does stimulate some release of dopamine, it's possible that it might ameliorate some of this negative effect and other side effects, and so prevent relapse.”

At baseline, the subjects in the study were screened for symptoms of depression. “We didn't do an in-depth clinical interview; we just looked for the hallmark symptoms by asking: 'Have you ever, for a 2-week period or more, felt down, depressed, or hopeless, or had little interest or pleasure in doing things?'” she said.

Depressed and nondepressed subjects had similar nonsmoking rates at 21 days (49% vs. 47%, respectively), and 3 months (45% vs. 43%, respectively). However, depressed patients were more likely to endorse depression, anxiety, tension, agitation, difficulty concentrating and sleeping, and confusion. Depressed patients also were more likely to report other known side effects of the medication. However, despite this, negative affect actually declined in both groups, Dr. McClure said. One case of suicidal ideation was reported in a subject with undisclosed, untreated bipolar disorder.

Additional research is necessary to tease out the safety and effectiveness of varenicline among psychologically vulnerable populations, she concluded.

Dr. McClure said she had no conflicts to disclose in connection with this study.

MONTREAL – Despite postmarketing concerns about the psychiatric side effects of varenicline for smoking cessation, the medication appears to be safe in patients who are depressed or at risk for depression, Jennifer B. McClure, Ph.D., reported at the annual meeting of the Society of Behavioral Medicine.

In a subanalysis of the Chronicle Offers Management to Patients With Advanced Signs and Symptoms of Heart Failure (COMPASS-HF) trial, 661 smokers with a baseline history of depression, or a risk of depression, were monitored for mood changes and compared with 516 nondepressed smokers during their 12-week course of varenicline (Chantix) combined with behavioral smoking-cessation counseling (J. Gen. Intern. Med. 2009;24:563-9).

“We think that physicians should continue to closely monitor patients who are using varenicline, particularly if they have a psychiatric history,” she said. Although people with a history of depression were more likely than nondepressed people to report side effects with the medication, “we didn't find an overall difference in their qualitative symptom experience, or treatment outcomes,” said Dr. McClure, who is affiliated with Group Health Center for Health Studies, Seattle.

The study, funded by the National Cancer Institute, was a collaborative effort between Group Health; Free & Clear Inc., Seattle; and SRI International, an independent, nonprofit, research and development organization in Menlo Park, Calif. Medication was provided by Pfizer Inc., maker of varenicline.

Varenicline was approved by the Food and Drug Administration about 3 years ago. It works by blocking nicotinic receptors and thus the rewarding effects of nicotine, while stimulating some dopamine release to provide relief from craving and withdrawal, Dr. McClure said.

Shortly after its release to market, the FDA raised concerns that varenicline might be associated with increased neuropsychiatric symptoms, including depressed mood, agitation, suicidal ideation, and behavior–particularly in people with a psychiatric history, she said.

“Unfortunately, due to the nature of the reports to the FDA, we are not able to determine if varenicline itself was the cause of the symptoms reported–it's possible they were due to nicotine withdrawal, substance use, the psychiatric conditions themselves, or some other factors. Unfortunately, subjects with a psychiatric history were excluded from the original efficacy trials.”

Research shows that between one- and two-thirds of smokers have a history of depression, and that smokers with a history of depression report more symptoms of nicotine withdrawal, have more negative affect after they quit, and have higher relapse rates, compared with nondepressed smokers, she added.

“But because varenicline does stimulate some release of dopamine, it's possible that it might ameliorate some of this negative effect and other side effects, and so prevent relapse.”

At baseline, the subjects in the study were screened for symptoms of depression. “We didn't do an in-depth clinical interview; we just looked for the hallmark symptoms by asking: 'Have you ever, for a 2-week period or more, felt down, depressed, or hopeless, or had little interest or pleasure in doing things?'” she said.

Depressed and nondepressed subjects had similar nonsmoking rates at 21 days (49% vs. 47%, respectively), and 3 months (45% vs. 43%, respectively). However, depressed patients were more likely to endorse depression, anxiety, tension, agitation, difficulty concentrating and sleeping, and confusion. Depressed patients also were more likely to report other known side effects of the medication. However, despite this, negative affect actually declined in both groups, Dr. McClure said. One case of suicidal ideation was reported in a subject with undisclosed, untreated bipolar disorder.

Additional research is necessary to tease out the safety and effectiveness of varenicline among psychologically vulnerable populations, she concluded.

Dr. McClure said she had no conflicts to disclose in connection with this study.