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American Diabetes Association (ADA): Annual Scientific Sessions
Insulin glargine passes cancer test in ORIGIN
CHICAGO – Regular insulin glargine use does not increase the risk of cancer, including pancreatic cancer, in patients with prediabetes or type 2 diabetes and high cardiovascular risk, according to a substudy of the prospective randomized ORIGIN trial.
The unadjusted rate of any cancer was 1.32 per 100 person-years in patients receiving insulin glargine (Lantus) or standard care. Cancer death rates per 100 person-years were similar, at 0.51 and 0.54, respectively.
"Daily exposure to glargine for a median of 6.2 years had a neutral effect on cancer events, including any cancers, new or recurrent cancers, cancer-related mortality, and various subtypes of cancer," Dr. Louise Bordeleau said at the annual scientific sessions of the American Diabetes Association.
Previous results from the pivotal ORIGIN (Outcome Reduction with Initial Glargine Intervention) trial, a double-blind, randomized trial with a 2-by-2 factorial design, showed no effect of insulin glargine on the primary endpoints of heart attack or stroke among the 12,537 patients (N. Engl. J. Med. 2012;367:319-28).
The new data are reassuring, particularly the absence of any spike in pancreatic cancer, session cochair Dr. Bessie Young, with the University of Washington in Seattle, said in an interview. Retrospective analyses of claims databases have linked insulin use to incidence cancers and metformin to reduced cancer risk. The ADA also recently called for an independent review of clinical data on incretin therapies used to lower glucose levels, because of safety concerns the drugs may increase the risk of pancreatic cancer and pancreatitis in type 2 diabetes.
In the current analysis, 82% patients had a prior diagnosis of diabetes, 35% were women, and the median insulin dose in those allocated to glargine insulin was 0.31 U/kg at 1 year and 0.40 U/kg at 6 years. Their mean age was 63.5 years.
In all, 953 patients (7.6%) were diagnosed with cancer, said Dr. Bordeleau, of the department of oncology at McMaster University, Hamilton, Ont.
Patients with new diabetes were more likely to develop cancer (8.5% vs. 5.9%; P = .0001). Metformin exposure and dose did not impact the risk of any cancer events or specific cancers, although both exposure and dose increased over the study period, she said. Metformin use was reported in 27.6% of those with cancer and 27.4% without, a nonsignificant difference.
Patients who experienced cancer versus those who did not were significantly more likely to be older (mean age, 66.1 vs. 63.3 years), current smokers (15% vs. 12%), or ex-smokers (54% vs. 46%); and were more likely to drink alcohol more than twice a week (30.2% vs. 22.1%) and have a prior cardiovascular event (64.3% vs. 58.4%).
In exploratory analyses, postrandomization hemoglobin A1c, glucose-lowering therapies, and weight had no effect on cancer risk, Dr. Bordeleau said.
ORIGIN was funded by Sanofi. Dr. Bordeleau reported having no financial disclosures.
CHICAGO – Regular insulin glargine use does not increase the risk of cancer, including pancreatic cancer, in patients with prediabetes or type 2 diabetes and high cardiovascular risk, according to a substudy of the prospective randomized ORIGIN trial.
The unadjusted rate of any cancer was 1.32 per 100 person-years in patients receiving insulin glargine (Lantus) or standard care. Cancer death rates per 100 person-years were similar, at 0.51 and 0.54, respectively.
"Daily exposure to glargine for a median of 6.2 years had a neutral effect on cancer events, including any cancers, new or recurrent cancers, cancer-related mortality, and various subtypes of cancer," Dr. Louise Bordeleau said at the annual scientific sessions of the American Diabetes Association.
Previous results from the pivotal ORIGIN (Outcome Reduction with Initial Glargine Intervention) trial, a double-blind, randomized trial with a 2-by-2 factorial design, showed no effect of insulin glargine on the primary endpoints of heart attack or stroke among the 12,537 patients (N. Engl. J. Med. 2012;367:319-28).
The new data are reassuring, particularly the absence of any spike in pancreatic cancer, session cochair Dr. Bessie Young, with the University of Washington in Seattle, said in an interview. Retrospective analyses of claims databases have linked insulin use to incidence cancers and metformin to reduced cancer risk. The ADA also recently called for an independent review of clinical data on incretin therapies used to lower glucose levels, because of safety concerns the drugs may increase the risk of pancreatic cancer and pancreatitis in type 2 diabetes.
In the current analysis, 82% patients had a prior diagnosis of diabetes, 35% were women, and the median insulin dose in those allocated to glargine insulin was 0.31 U/kg at 1 year and 0.40 U/kg at 6 years. Their mean age was 63.5 years.
In all, 953 patients (7.6%) were diagnosed with cancer, said Dr. Bordeleau, of the department of oncology at McMaster University, Hamilton, Ont.
Patients with new diabetes were more likely to develop cancer (8.5% vs. 5.9%; P = .0001). Metformin exposure and dose did not impact the risk of any cancer events or specific cancers, although both exposure and dose increased over the study period, she said. Metformin use was reported in 27.6% of those with cancer and 27.4% without, a nonsignificant difference.
Patients who experienced cancer versus those who did not were significantly more likely to be older (mean age, 66.1 vs. 63.3 years), current smokers (15% vs. 12%), or ex-smokers (54% vs. 46%); and were more likely to drink alcohol more than twice a week (30.2% vs. 22.1%) and have a prior cardiovascular event (64.3% vs. 58.4%).
In exploratory analyses, postrandomization hemoglobin A1c, glucose-lowering therapies, and weight had no effect on cancer risk, Dr. Bordeleau said.
ORIGIN was funded by Sanofi. Dr. Bordeleau reported having no financial disclosures.
CHICAGO – Regular insulin glargine use does not increase the risk of cancer, including pancreatic cancer, in patients with prediabetes or type 2 diabetes and high cardiovascular risk, according to a substudy of the prospective randomized ORIGIN trial.
The unadjusted rate of any cancer was 1.32 per 100 person-years in patients receiving insulin glargine (Lantus) or standard care. Cancer death rates per 100 person-years were similar, at 0.51 and 0.54, respectively.
"Daily exposure to glargine for a median of 6.2 years had a neutral effect on cancer events, including any cancers, new or recurrent cancers, cancer-related mortality, and various subtypes of cancer," Dr. Louise Bordeleau said at the annual scientific sessions of the American Diabetes Association.
Previous results from the pivotal ORIGIN (Outcome Reduction with Initial Glargine Intervention) trial, a double-blind, randomized trial with a 2-by-2 factorial design, showed no effect of insulin glargine on the primary endpoints of heart attack or stroke among the 12,537 patients (N. Engl. J. Med. 2012;367:319-28).
The new data are reassuring, particularly the absence of any spike in pancreatic cancer, session cochair Dr. Bessie Young, with the University of Washington in Seattle, said in an interview. Retrospective analyses of claims databases have linked insulin use to incidence cancers and metformin to reduced cancer risk. The ADA also recently called for an independent review of clinical data on incretin therapies used to lower glucose levels, because of safety concerns the drugs may increase the risk of pancreatic cancer and pancreatitis in type 2 diabetes.
In the current analysis, 82% patients had a prior diagnosis of diabetes, 35% were women, and the median insulin dose in those allocated to glargine insulin was 0.31 U/kg at 1 year and 0.40 U/kg at 6 years. Their mean age was 63.5 years.
In all, 953 patients (7.6%) were diagnosed with cancer, said Dr. Bordeleau, of the department of oncology at McMaster University, Hamilton, Ont.
Patients with new diabetes were more likely to develop cancer (8.5% vs. 5.9%; P = .0001). Metformin exposure and dose did not impact the risk of any cancer events or specific cancers, although both exposure and dose increased over the study period, she said. Metformin use was reported in 27.6% of those with cancer and 27.4% without, a nonsignificant difference.
Patients who experienced cancer versus those who did not were significantly more likely to be older (mean age, 66.1 vs. 63.3 years), current smokers (15% vs. 12%), or ex-smokers (54% vs. 46%); and were more likely to drink alcohol more than twice a week (30.2% vs. 22.1%) and have a prior cardiovascular event (64.3% vs. 58.4%).
In exploratory analyses, postrandomization hemoglobin A1c, glucose-lowering therapies, and weight had no effect on cancer risk, Dr. Bordeleau said.
ORIGIN was funded by Sanofi. Dr. Bordeleau reported having no financial disclosures.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Major finding: The unadjusted rate of any cancer was 1.32 per 100 person-years in patients receiving insulin glargine or standard care. Cancer death rates per 100 person-years were similar at 0.51 and 0.54, respectively.
Data source: Cancer substudy of the double-blind, randomized, 2-by-2 factorial design ORIGIN trial in 12,537 persons with prediabetes or type 2 diabetes at high cardiovascular risk.
Disclosures: ORIGIN was funded by Sanofi. Dr. Bordeleau reported having no financial disclosures.
ACCORD: Insulin dose not implicated in excess CV deaths
CHICAGO – Insulin dose does not appear to be the culprit behind the excess cardiovascular deaths observed among type 2 diabetes in the pivotal ACCORD trial, according to a new analysis involving 10,163 patients.
In an unadjusted hazard model, an increase in daily insulin dose by 1 U/kg of body weight was associated with a significant 1.8- to 3.4-fold increased risk of cardiovascular death.
After adjustment for a series of baseline and on-treatment covariates in four subsequent models, however, no association between insulin dose and CV death was found, Dr. Elias Siraj reported at the annual scientific sessions of the American Diabetes Association.
Several post hoc analyses of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) data have so far failed to explain why aggressively driving down hemoglobin A1c levels below 6% did not cut cardiovascular events, but instead raised CV mortality by 35% and all-cause mortality by 22% (N. Engl. J. Med. 2008;358;2545-59).
Some theorized that the low HbA1c levels achieved with intensive treatment might be the cause, but a recent analysis reported that a higher average HbA1c in ACCORD was actually associated with a greater risk of death, particularly in the intensive treatment arm (Diabetes Care 2010;33:983-90).
Based on the study protocol, the investigators anticipated that within the intensive treatment arm, patients with higher HbA1c would be on a higher dose of insulin, and thus, began zeroing in on insulin dose as a potential cause, explained Dr. Siraj, director of the diabetes program, endocrinology section, Temple University, Philadelphia.
Data were analyzed for 10,163 patients with updated average daily dosage of total, basal, and prandial insulin, expressed as U/kg of body weight, and follow-up data for cardiovascular (CV) mortality and insulin dose with a mean follow-up of 5 years. As previously reported, all three insulin doses were higher in the intensive treatment arm than the standard arm in which HbA1c was targeted to 7%-7.9%.
In the unadjusted Cox proportional model, insulin exposure significantly increased the risk for CV mortality for total insulin (hazard ratio, 1.83), basal insulin (HR, 2.29), and bolus insulin (HR, 3.36; all P less than .0001).
Adjusted analyses
After adjustment, however, for 14 baseline characteristics including HbA1c, age, history of cardiovascular disease, HDL cholesterol, diabetic complications, serum creatinine, and urinary albumin-to-creatinine ratio, the hazard ratios dropped and the statistical significance was lost for total (HR, 1.21; P = .17), basal (HR, 1.3; P = .20), and bolus (HR, 1.65; P = .11) insulin, Dr. Siraj said during the presidential oral session.
Adding assignment to a blood pressure and lipid trial, severe hypoglycemia and weight change to model 2 did little to budge the hazard ratios (total HR, 1.21; P = .19), (basal HR, 1.29; P = .22) and (bolus HR, 1.63; P = .13).
There was a slight change after adjusting for updated average HbA1c in model 3, but again, the association between total (HR, 1.12; P = .45), basal (HR, 1.13; P = .56), and bolus (HR, 1.48; P = .23) insulin and CV death remained statistically nonsignificant, he said.
The same was true after adding glycemic treatment assignment in the fourth and final model (total HR, 0.99; P = .96), (basal HR, 0.94; P = .79), and (bolus HR, 1.23; P = .54).
"These results do not support the hypothesis that insulin dose is an independent risk factor for CV mortality in this population," Dr. Siraj concluded.
Why the question remains unanswered
Several audience members questioned the conclusion on a variety of fronts, including reverse causality, meaning that people who are sick require higher doses of insulin because they’re more insulin resistant, and if they’re sick to begin with, that’s the cause of the death. One attendee suggested that the data were overanalyzed in the models and called for the all-cause mortality data, while another went so far as to ask the investigators to release the entire ACCORD data set for others to analyze.
"I don’t think I said that we disproved a relationship, but that we didn’t see an association," Dr. Siraj responded. Acknowledging the limitations of a post hoc analysis, he mentioned that this is a routine way of looking into possible associations and that the result will contribute toward the debate, even though it may not give a definitive answer. While there are various ways of choosing models to adjust for covariates, the modeling approach they followed was reasonable, as it took away the potential role of baseline covariates as well as on-treatment factors, he added.
ADA chief scientific and medical officer Robert Ratner argued during the discussion of the results that the analysis failed to control for the very critical factor of insulin adherence.
"I am personally convinced, on the basis of zero data, and I have to emphasize that this is my speculation, that these people who are having sudden death are probably not taking their medication on a regular basis," Dr. Ratner said in an interview. "The protocol drives them to higher doses, so whenever they do take their medication, they have a higher risk of problems."
Session comoderator Marjorie Cypress, Ph.D., ADA health care and education president-elect and an adult nurse practitioner with Albuquerque Health Partners, agreed with Dr. Ratner’s concern.
"I’m a clinician, and if you start seeing [HbA1c numbers] going higher and higher, you do need to question adherence," she said. "I always question adherence with insulin."
As for whether mining the ACCORD data will ever reveal the cause of the excess deaths, Dr. Cypress said, "You keep doing post hoc analysis, and I guess at some point, there may be some tie-in."
Not so says Dr. Ratner.
"We’re never going to know," he said. "We can’t know because you can’t correlate hypoglycemia unless you have CGM [continuous glucose monitoring] for the entire length of study and you trust that it’s accurate."
In a later interview, Dr. Siraj said that the ACCORD study group will look into the adherence data and see whether it affects the association between insulin dose and CV mortality. And, the ACCORD leadership will decide the appropriateness of public release of the entire data set and its timing.
ACCORD was supported by grants from the National Heart, Lung, and Blood Institute. Dr. Siraj reported honoraria for speaking and/or consulting for Boehringer Ingelheim, Sanofi, and Merck and for serving as an advisory board member for Corcept.
CHICAGO – Insulin dose does not appear to be the culprit behind the excess cardiovascular deaths observed among type 2 diabetes in the pivotal ACCORD trial, according to a new analysis involving 10,163 patients.
In an unadjusted hazard model, an increase in daily insulin dose by 1 U/kg of body weight was associated with a significant 1.8- to 3.4-fold increased risk of cardiovascular death.
After adjustment for a series of baseline and on-treatment covariates in four subsequent models, however, no association between insulin dose and CV death was found, Dr. Elias Siraj reported at the annual scientific sessions of the American Diabetes Association.
Several post hoc analyses of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) data have so far failed to explain why aggressively driving down hemoglobin A1c levels below 6% did not cut cardiovascular events, but instead raised CV mortality by 35% and all-cause mortality by 22% (N. Engl. J. Med. 2008;358;2545-59).
Some theorized that the low HbA1c levels achieved with intensive treatment might be the cause, but a recent analysis reported that a higher average HbA1c in ACCORD was actually associated with a greater risk of death, particularly in the intensive treatment arm (Diabetes Care 2010;33:983-90).
Based on the study protocol, the investigators anticipated that within the intensive treatment arm, patients with higher HbA1c would be on a higher dose of insulin, and thus, began zeroing in on insulin dose as a potential cause, explained Dr. Siraj, director of the diabetes program, endocrinology section, Temple University, Philadelphia.
Data were analyzed for 10,163 patients with updated average daily dosage of total, basal, and prandial insulin, expressed as U/kg of body weight, and follow-up data for cardiovascular (CV) mortality and insulin dose with a mean follow-up of 5 years. As previously reported, all three insulin doses were higher in the intensive treatment arm than the standard arm in which HbA1c was targeted to 7%-7.9%.
In the unadjusted Cox proportional model, insulin exposure significantly increased the risk for CV mortality for total insulin (hazard ratio, 1.83), basal insulin (HR, 2.29), and bolus insulin (HR, 3.36; all P less than .0001).
Adjusted analyses
After adjustment, however, for 14 baseline characteristics including HbA1c, age, history of cardiovascular disease, HDL cholesterol, diabetic complications, serum creatinine, and urinary albumin-to-creatinine ratio, the hazard ratios dropped and the statistical significance was lost for total (HR, 1.21; P = .17), basal (HR, 1.3; P = .20), and bolus (HR, 1.65; P = .11) insulin, Dr. Siraj said during the presidential oral session.
Adding assignment to a blood pressure and lipid trial, severe hypoglycemia and weight change to model 2 did little to budge the hazard ratios (total HR, 1.21; P = .19), (basal HR, 1.29; P = .22) and (bolus HR, 1.63; P = .13).
There was a slight change after adjusting for updated average HbA1c in model 3, but again, the association between total (HR, 1.12; P = .45), basal (HR, 1.13; P = .56), and bolus (HR, 1.48; P = .23) insulin and CV death remained statistically nonsignificant, he said.
The same was true after adding glycemic treatment assignment in the fourth and final model (total HR, 0.99; P = .96), (basal HR, 0.94; P = .79), and (bolus HR, 1.23; P = .54).
"These results do not support the hypothesis that insulin dose is an independent risk factor for CV mortality in this population," Dr. Siraj concluded.
Why the question remains unanswered
Several audience members questioned the conclusion on a variety of fronts, including reverse causality, meaning that people who are sick require higher doses of insulin because they’re more insulin resistant, and if they’re sick to begin with, that’s the cause of the death. One attendee suggested that the data were overanalyzed in the models and called for the all-cause mortality data, while another went so far as to ask the investigators to release the entire ACCORD data set for others to analyze.
"I don’t think I said that we disproved a relationship, but that we didn’t see an association," Dr. Siraj responded. Acknowledging the limitations of a post hoc analysis, he mentioned that this is a routine way of looking into possible associations and that the result will contribute toward the debate, even though it may not give a definitive answer. While there are various ways of choosing models to adjust for covariates, the modeling approach they followed was reasonable, as it took away the potential role of baseline covariates as well as on-treatment factors, he added.
ADA chief scientific and medical officer Robert Ratner argued during the discussion of the results that the analysis failed to control for the very critical factor of insulin adherence.
"I am personally convinced, on the basis of zero data, and I have to emphasize that this is my speculation, that these people who are having sudden death are probably not taking their medication on a regular basis," Dr. Ratner said in an interview. "The protocol drives them to higher doses, so whenever they do take their medication, they have a higher risk of problems."
Session comoderator Marjorie Cypress, Ph.D., ADA health care and education president-elect and an adult nurse practitioner with Albuquerque Health Partners, agreed with Dr. Ratner’s concern.
"I’m a clinician, and if you start seeing [HbA1c numbers] going higher and higher, you do need to question adherence," she said. "I always question adherence with insulin."
As for whether mining the ACCORD data will ever reveal the cause of the excess deaths, Dr. Cypress said, "You keep doing post hoc analysis, and I guess at some point, there may be some tie-in."
Not so says Dr. Ratner.
"We’re never going to know," he said. "We can’t know because you can’t correlate hypoglycemia unless you have CGM [continuous glucose monitoring] for the entire length of study and you trust that it’s accurate."
In a later interview, Dr. Siraj said that the ACCORD study group will look into the adherence data and see whether it affects the association between insulin dose and CV mortality. And, the ACCORD leadership will decide the appropriateness of public release of the entire data set and its timing.
ACCORD was supported by grants from the National Heart, Lung, and Blood Institute. Dr. Siraj reported honoraria for speaking and/or consulting for Boehringer Ingelheim, Sanofi, and Merck and for serving as an advisory board member for Corcept.
CHICAGO – Insulin dose does not appear to be the culprit behind the excess cardiovascular deaths observed among type 2 diabetes in the pivotal ACCORD trial, according to a new analysis involving 10,163 patients.
In an unadjusted hazard model, an increase in daily insulin dose by 1 U/kg of body weight was associated with a significant 1.8- to 3.4-fold increased risk of cardiovascular death.
After adjustment for a series of baseline and on-treatment covariates in four subsequent models, however, no association between insulin dose and CV death was found, Dr. Elias Siraj reported at the annual scientific sessions of the American Diabetes Association.
Several post hoc analyses of the ACCORD (Action to Control Cardiovascular Risk in Diabetes) data have so far failed to explain why aggressively driving down hemoglobin A1c levels below 6% did not cut cardiovascular events, but instead raised CV mortality by 35% and all-cause mortality by 22% (N. Engl. J. Med. 2008;358;2545-59).
Some theorized that the low HbA1c levels achieved with intensive treatment might be the cause, but a recent analysis reported that a higher average HbA1c in ACCORD was actually associated with a greater risk of death, particularly in the intensive treatment arm (Diabetes Care 2010;33:983-90).
Based on the study protocol, the investigators anticipated that within the intensive treatment arm, patients with higher HbA1c would be on a higher dose of insulin, and thus, began zeroing in on insulin dose as a potential cause, explained Dr. Siraj, director of the diabetes program, endocrinology section, Temple University, Philadelphia.
Data were analyzed for 10,163 patients with updated average daily dosage of total, basal, and prandial insulin, expressed as U/kg of body weight, and follow-up data for cardiovascular (CV) mortality and insulin dose with a mean follow-up of 5 years. As previously reported, all three insulin doses were higher in the intensive treatment arm than the standard arm in which HbA1c was targeted to 7%-7.9%.
In the unadjusted Cox proportional model, insulin exposure significantly increased the risk for CV mortality for total insulin (hazard ratio, 1.83), basal insulin (HR, 2.29), and bolus insulin (HR, 3.36; all P less than .0001).
Adjusted analyses
After adjustment, however, for 14 baseline characteristics including HbA1c, age, history of cardiovascular disease, HDL cholesterol, diabetic complications, serum creatinine, and urinary albumin-to-creatinine ratio, the hazard ratios dropped and the statistical significance was lost for total (HR, 1.21; P = .17), basal (HR, 1.3; P = .20), and bolus (HR, 1.65; P = .11) insulin, Dr. Siraj said during the presidential oral session.
Adding assignment to a blood pressure and lipid trial, severe hypoglycemia and weight change to model 2 did little to budge the hazard ratios (total HR, 1.21; P = .19), (basal HR, 1.29; P = .22) and (bolus HR, 1.63; P = .13).
There was a slight change after adjusting for updated average HbA1c in model 3, but again, the association between total (HR, 1.12; P = .45), basal (HR, 1.13; P = .56), and bolus (HR, 1.48; P = .23) insulin and CV death remained statistically nonsignificant, he said.
The same was true after adding glycemic treatment assignment in the fourth and final model (total HR, 0.99; P = .96), (basal HR, 0.94; P = .79), and (bolus HR, 1.23; P = .54).
"These results do not support the hypothesis that insulin dose is an independent risk factor for CV mortality in this population," Dr. Siraj concluded.
Why the question remains unanswered
Several audience members questioned the conclusion on a variety of fronts, including reverse causality, meaning that people who are sick require higher doses of insulin because they’re more insulin resistant, and if they’re sick to begin with, that’s the cause of the death. One attendee suggested that the data were overanalyzed in the models and called for the all-cause mortality data, while another went so far as to ask the investigators to release the entire ACCORD data set for others to analyze.
"I don’t think I said that we disproved a relationship, but that we didn’t see an association," Dr. Siraj responded. Acknowledging the limitations of a post hoc analysis, he mentioned that this is a routine way of looking into possible associations and that the result will contribute toward the debate, even though it may not give a definitive answer. While there are various ways of choosing models to adjust for covariates, the modeling approach they followed was reasonable, as it took away the potential role of baseline covariates as well as on-treatment factors, he added.
ADA chief scientific and medical officer Robert Ratner argued during the discussion of the results that the analysis failed to control for the very critical factor of insulin adherence.
"I am personally convinced, on the basis of zero data, and I have to emphasize that this is my speculation, that these people who are having sudden death are probably not taking their medication on a regular basis," Dr. Ratner said in an interview. "The protocol drives them to higher doses, so whenever they do take their medication, they have a higher risk of problems."
Session comoderator Marjorie Cypress, Ph.D., ADA health care and education president-elect and an adult nurse practitioner with Albuquerque Health Partners, agreed with Dr. Ratner’s concern.
"I’m a clinician, and if you start seeing [HbA1c numbers] going higher and higher, you do need to question adherence," she said. "I always question adherence with insulin."
As for whether mining the ACCORD data will ever reveal the cause of the excess deaths, Dr. Cypress said, "You keep doing post hoc analysis, and I guess at some point, there may be some tie-in."
Not so says Dr. Ratner.
"We’re never going to know," he said. "We can’t know because you can’t correlate hypoglycemia unless you have CGM [continuous glucose monitoring] for the entire length of study and you trust that it’s accurate."
In a later interview, Dr. Siraj said that the ACCORD study group will look into the adherence data and see whether it affects the association between insulin dose and CV mortality. And, the ACCORD leadership will decide the appropriateness of public release of the entire data set and its timing.
ACCORD was supported by grants from the National Heart, Lung, and Blood Institute. Dr. Siraj reported honoraria for speaking and/or consulting for Boehringer Ingelheim, Sanofi, and Merck and for serving as an advisory board member for Corcept.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Major finding: In the fourth, fully adjusted model, no significant association was observed between CV death and total insulin (HR, 0.99), basal insulin (HR, 0.94), or bolus insulin (HR, 1.23).
Data source: Post hoc analysis of 10,163 patients with type 2 diabetes in the randomized ACCORD trial.
Disclosures: ACCORD was supported by grants from the National Heart, Lung, and Blood Institute. Dr. Siraj reported honoraria for speaking and/or consulting for Boehringer Ingelheim, Sanofi and Merck and for serving as an advisory board member for Corcept.
Weight loss, exercise didn't affect heart outcomes in Look AHEAD
CHICAGO – A decade of diet and exercise had no effect on cardiovascular morbidity and mortality in overweight and obese adults with type 2 diabetes, according to a randomized, federally funded study that was stopped 2 years early due to futility.
"However, there are many reasons why, I would argue, that you should be encouraging patients with diabetes to lose weight," said Rena R. Wing, Ph.D., the trial’s chair. The results showed that the participants who were in the diet and exercise group, "are less likely to have kidney disease, have less incidence of depression, lower hospital costs, and less medication costs, so there are still many advantages to intense lifestyle interventions," Dr. Wing said during the presentation of the findings at the annual scientific sessions of the American Diabetes Association.
The results also showed that the participants were able to maintain a modest weight loss during a 10-year period.
The Look AHEAD (Action for Health in Diabetes) trial aimed to fill a gap in existing data about whether intensive lifestyle intervention would decrease cardiovascular morbidity and mortality of patients with type 2 diabetes in the long term.
Researchers recruited more than 5,100 patients and randomized them to the intensive lifestyle intervention program, which decreased calorie intake and increased exercise, or to the control group, which provided diabetes support and education. The goal of the intervention was achieving and maintaining weight loss of at least 7% through group and individual counseling.
The trial’s primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina. The trial was planned to have a greater than 80% probability of detecting an 18% difference in cardiovascular events between the two arms, assuming that two-sided alpha was 0.05, a primary outcome rate of 2% per year in the control group, and the planned maximum follow-up of 13.5 years.
But in September 2012, the trial was stopped at the request of its primary sponsors, based on a futility analysis. The median follow-up at the time was 9.6 years.
By then, 403 patients in the intervention group and 418 patients in the control group had met the trial’s primary outcome, with no statistically significant difference between the two groups (1.83 and 1.92 events per 100 person-years, respectively).
Why didn’t it work?
Researchers listed several possible explanations for the results. The study may have had insufficient power, although that wouldn’t explain the negative results, the authors wrote. It is also possible that a higher sustained weight loss was needed in the intervention group to reduce the risk of cardiovascular disease. Meanwhile, the educational sessions and increased use of statins in the control group may have lessened the difference between the two groups, the authors noted. And intensified medical management of cardiovascular risk factors for both groups may have made the relative benefit of the intensive lifestyle intervention more difficult to demonstrate, they added.
Earlier intervention during the course of diabetes may be needed, they added. The results were published online simultaneously with the presentation (N. Engl. J. Med. 2013 June 24 [doi:10.1056/NEJMoa1212914]).
In an editorial accompanying the published results, Dr. Hertzel C. Gerstein wrote that the inclusion of "the somewhat unreliable outcome of hospitalization for angina in the primary composite outcome may have added noise and further obscured any emerging signal" (N. Engl. J. Med. 2013 June 24 [doi:10.1056/NEJMe1306987]).
During the presentation, an audience member suggested that since the 1-year and 4-year findings of the trial were published and well publicized, the participants in the control group might have taken it upon themselves to take action and lose weight. The panel of investigators said that is also a possibility.
Dr. Peter H. Bennett, who is one of the trial’s investigators and was cochair of eligibility, said that stopping the trial "was a big mistake," and that it should have been carried on at least until the planned termination point. "They stopped this trial because they were projecting that if they carried on for 2 more years, the differences in the primary endpoint were unlikely to be statistically significant. But there are several problems. First, you prejudice the power to analyze any other events, and just as we’ve learned from natural history of diabetes-related mortality, it’s clear that you don’t see excess diabetes-related mortality until they’ve had at least 15 years of diabetes, and that’s just at the point that the trial was stopped," Dr. Bennett, scientist emeritus at the National Institutes of Health – one of the main funders of the trial – said in an interview.
"It is also possible that lifestyle interventions may have a real but modest effect on cardiovascular outcomes akin to that of glucose lowering (e.g., a 10%-15% reduction) that requires more than 10 years to become apparent. If so, this trial was clearly too small to detect such an effect," wrote Dr. Gerstein, an endocrinologist and professor at McMaster University and Hamilton Health Sciences, Hamilton, Ont.
A look at the data
The patients in the intervention group (2,570) and control group (2,575) had similar characteristics at baseline. They were between 45 and 75 years old, were mostly female (60%) and white (63%), and had a mean body mass index of 36.0. Fourteen percent had a history of cardiovascular disease, and the median duration of diabetes was 5 years. Less than 30% were on insulin.
Close to 96% of the patients stayed in the trial.
During months 1 and 6, the intervention group had weekly contact with staff members. The contact was gradually reduced in the following months to one on-site individual session per month, and one phone call or e-mail per month from 2 years onward. The patients’ medications were adjusted by their own physicians.
Patients in the control group had 3-4 meetings per year during years 1 through 4, and after that, they had one meeting per year. They received education on diet, exercise, and social support.
Weight loss was greater in the intervention group compared with the control group, with the greatest difference at 1 year (8.6% vs. 0.7%), but it remained significant through the end of the study (6.0% vs. 3.5%).
Specifically, the intervention group had an initial weight loss of 8.6%, followed by weight regain in the first 5 years, and then gradual weight loss, leading to average weight loss of 6%. The control group had a gradual but consistent weight loss, for an average of 3.5% at the end of the trial.
One audience member suggested that some of the weight loss might have been due to aging. The authors said they are looking at those factors in their ongoing data analysis, which they’re planning to publish in the near future.
Meanwhile, the intervention group had significantly greater weight loss than did the control group throughout the trial. They had significantly greater improvements in fitness, hemoglobin A1c levels, systolic blood pressure, and HDL cholesterol (P less than .05 for all). The control group had significantly greater reductions in LDL cholesterol (P less than .05), although they also had a significantly greater use of medications, including insulin, statins, and antihypertensives, compared with the intervention group, the authors noted.
In the short-term (1-4 years), the intervention group saw improvements in cardiovascular risk factors, preservation of mobility, and improvements in fitness, obstructive sleep apnea, fatty liver disease, urinary incontinence, sexual function, and markers of inflammation.
The intervention also reduced the incidence of high-risk chronic kidney disease by 31%, and reduced the total costs and service utilization, especially related to hospitalization ($2,500 per participant), and medication ($2,500 per participant), the authors reported. Although the intervention didn’t affect neuropathy symptoms, it reduced the incidence of reported retinopathy by 14%, reduced the incidence of symptoms of mild or greater depression by 20%, and slowed age-related decline in reported physical function.
Program reduced burden of diabetes
"Even with no clear evidence of cardiovascular benefit, the Look AHEAD investigators have shown that attention to activity and diet can safely reduce the burden of diabetes and have reaffirmed the importance of lifestyle approach as one of the foundations of modern diabetes care," Dr. Gerstein wrote in his editorial, adding that the data show "intensive lifestyle interventions are unlikely to cause harm and may provide a modest benefit."
Interactions among subgroups – history of cardiovascular disease at baseline, and gender, race/ethnicity – showed nonsignificant interaction with cardiovascular disease history (P = .06).
Summarizing the study’s limitations, the authors said that it’s not clear whether changing the intervention groups’ dietary composition might have yielded different results. Their diet during the intervention was 1,200 to 1,800 kcal/day, with less than 30% of calories from fat, and less than 15% from protein. Authors added that the patients recruited successfully competed the fitness test at baseline, so the results can’t be generalized to all patients with type 2 diabetes.
Although the intervention has stopped, the trial continues as an observational study, said Dr. Wing. And some wonder if longer-term results would reveal new information.
"My prediction is that even after stopping the trial, as long as follow-up is carried on for several more years, you’ll see differences in total mortality," said Dr. Bennett, citing the results of UK Prospective Diabetes Study (UKPDS), which showed no difference in cardiovascular disease at 12 years, but a significant difference at 20 years. "So it does appear that intervention does have a lasting but delayed effect on that endpoint."
"I hope [the results] are not misinterpreted," Dr. Bennett continued. "There’s a danger given the lack of effect of the primary endpoint that the headlines will say weight loss is useless, and that’s a total misinterpretation in my view. There are multiple reasons to encourage weight loss. Other than the fact that it doesn’t appear to affect mortality up to this point, it seems to have benefit for all sorts of other things – people feel better, walk better, they develop advanced renal disease less frequently, their cholesterol and blood pressure are lower. I hope that message gets through rather than the negative one."
Dr. Wing, Dr. Bennett, and Dr. Gerstein had no disclosures relevant to the trial. The trial was supported by the National Institutes of Health, other Department of Health and Human Services agencies, and several companies including FedEx, Johnson & Johnson, Nestle Healthcare Nutrition, and Abbott Nutrition.
On Twitter @NaseemSMiller
I think the trial has a good message: that lifestyle can work, that intervention can work, that education can work, but it's not the only solution. For many people with diabetes, we must use medication. And, in many people with coronary disease, we must use medications. But to call it a failed trial is ridiculous, in my mind. If I can delay complications by 4 or 5 years, then we did well, we saved money, and we improved somebody's life.
We saw a 6% reduction in weight over 10 years. This is awesome and has never been shown before. Actually 3.5% reduction in weight [over 10 years] hasn't been shown before. I think that if you read the study, a lot of good stuff came out of it.
I will tell my patients how well the lifestyle management works. But I still will tell them that lifestyle is important, but many times, it needs to come in combination with medication.
My issue is that the trial was cut [short]. They saw that other aspects improved, and they should have continued to see what it means. It's like anything; we want fast solution to long-term tissues. Maybe we need to see a population study over 25 or 30 years.
Dr. Yehuda Handelsman is the medical director and principal investigator of Metabolic Institute of America, and president-elect of the American College of Endocrinology. He is on the advisory board for Clinical Endocrinology News.
I think the trial has a good message: that lifestyle can work, that intervention can work, that education can work, but it's not the only solution. For many people with diabetes, we must use medication. And, in many people with coronary disease, we must use medications. But to call it a failed trial is ridiculous, in my mind. If I can delay complications by 4 or 5 years, then we did well, we saved money, and we improved somebody's life.
We saw a 6% reduction in weight over 10 years. This is awesome and has never been shown before. Actually 3.5% reduction in weight [over 10 years] hasn't been shown before. I think that if you read the study, a lot of good stuff came out of it.
I will tell my patients how well the lifestyle management works. But I still will tell them that lifestyle is important, but many times, it needs to come in combination with medication.
My issue is that the trial was cut [short]. They saw that other aspects improved, and they should have continued to see what it means. It's like anything; we want fast solution to long-term tissues. Maybe we need to see a population study over 25 or 30 years.
Dr. Yehuda Handelsman is the medical director and principal investigator of Metabolic Institute of America, and president-elect of the American College of Endocrinology. He is on the advisory board for Clinical Endocrinology News.
I think the trial has a good message: that lifestyle can work, that intervention can work, that education can work, but it's not the only solution. For many people with diabetes, we must use medication. And, in many people with coronary disease, we must use medications. But to call it a failed trial is ridiculous, in my mind. If I can delay complications by 4 or 5 years, then we did well, we saved money, and we improved somebody's life.
We saw a 6% reduction in weight over 10 years. This is awesome and has never been shown before. Actually 3.5% reduction in weight [over 10 years] hasn't been shown before. I think that if you read the study, a lot of good stuff came out of it.
I will tell my patients how well the lifestyle management works. But I still will tell them that lifestyle is important, but many times, it needs to come in combination with medication.
My issue is that the trial was cut [short]. They saw that other aspects improved, and they should have continued to see what it means. It's like anything; we want fast solution to long-term tissues. Maybe we need to see a population study over 25 or 30 years.
Dr. Yehuda Handelsman is the medical director and principal investigator of Metabolic Institute of America, and president-elect of the American College of Endocrinology. He is on the advisory board for Clinical Endocrinology News.
CHICAGO – A decade of diet and exercise had no effect on cardiovascular morbidity and mortality in overweight and obese adults with type 2 diabetes, according to a randomized, federally funded study that was stopped 2 years early due to futility.
"However, there are many reasons why, I would argue, that you should be encouraging patients with diabetes to lose weight," said Rena R. Wing, Ph.D., the trial’s chair. The results showed that the participants who were in the diet and exercise group, "are less likely to have kidney disease, have less incidence of depression, lower hospital costs, and less medication costs, so there are still many advantages to intense lifestyle interventions," Dr. Wing said during the presentation of the findings at the annual scientific sessions of the American Diabetes Association.
The results also showed that the participants were able to maintain a modest weight loss during a 10-year period.
The Look AHEAD (Action for Health in Diabetes) trial aimed to fill a gap in existing data about whether intensive lifestyle intervention would decrease cardiovascular morbidity and mortality of patients with type 2 diabetes in the long term.
Researchers recruited more than 5,100 patients and randomized them to the intensive lifestyle intervention program, which decreased calorie intake and increased exercise, or to the control group, which provided diabetes support and education. The goal of the intervention was achieving and maintaining weight loss of at least 7% through group and individual counseling.
The trial’s primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina. The trial was planned to have a greater than 80% probability of detecting an 18% difference in cardiovascular events between the two arms, assuming that two-sided alpha was 0.05, a primary outcome rate of 2% per year in the control group, and the planned maximum follow-up of 13.5 years.
But in September 2012, the trial was stopped at the request of its primary sponsors, based on a futility analysis. The median follow-up at the time was 9.6 years.
By then, 403 patients in the intervention group and 418 patients in the control group had met the trial’s primary outcome, with no statistically significant difference between the two groups (1.83 and 1.92 events per 100 person-years, respectively).
Why didn’t it work?
Researchers listed several possible explanations for the results. The study may have had insufficient power, although that wouldn’t explain the negative results, the authors wrote. It is also possible that a higher sustained weight loss was needed in the intervention group to reduce the risk of cardiovascular disease. Meanwhile, the educational sessions and increased use of statins in the control group may have lessened the difference between the two groups, the authors noted. And intensified medical management of cardiovascular risk factors for both groups may have made the relative benefit of the intensive lifestyle intervention more difficult to demonstrate, they added.
Earlier intervention during the course of diabetes may be needed, they added. The results were published online simultaneously with the presentation (N. Engl. J. Med. 2013 June 24 [doi:10.1056/NEJMoa1212914]).
In an editorial accompanying the published results, Dr. Hertzel C. Gerstein wrote that the inclusion of "the somewhat unreliable outcome of hospitalization for angina in the primary composite outcome may have added noise and further obscured any emerging signal" (N. Engl. J. Med. 2013 June 24 [doi:10.1056/NEJMe1306987]).
During the presentation, an audience member suggested that since the 1-year and 4-year findings of the trial were published and well publicized, the participants in the control group might have taken it upon themselves to take action and lose weight. The panel of investigators said that is also a possibility.
Dr. Peter H. Bennett, who is one of the trial’s investigators and was cochair of eligibility, said that stopping the trial "was a big mistake," and that it should have been carried on at least until the planned termination point. "They stopped this trial because they were projecting that if they carried on for 2 more years, the differences in the primary endpoint were unlikely to be statistically significant. But there are several problems. First, you prejudice the power to analyze any other events, and just as we’ve learned from natural history of diabetes-related mortality, it’s clear that you don’t see excess diabetes-related mortality until they’ve had at least 15 years of diabetes, and that’s just at the point that the trial was stopped," Dr. Bennett, scientist emeritus at the National Institutes of Health – one of the main funders of the trial – said in an interview.
"It is also possible that lifestyle interventions may have a real but modest effect on cardiovascular outcomes akin to that of glucose lowering (e.g., a 10%-15% reduction) that requires more than 10 years to become apparent. If so, this trial was clearly too small to detect such an effect," wrote Dr. Gerstein, an endocrinologist and professor at McMaster University and Hamilton Health Sciences, Hamilton, Ont.
A look at the data
The patients in the intervention group (2,570) and control group (2,575) had similar characteristics at baseline. They were between 45 and 75 years old, were mostly female (60%) and white (63%), and had a mean body mass index of 36.0. Fourteen percent had a history of cardiovascular disease, and the median duration of diabetes was 5 years. Less than 30% were on insulin.
Close to 96% of the patients stayed in the trial.
During months 1 and 6, the intervention group had weekly contact with staff members. The contact was gradually reduced in the following months to one on-site individual session per month, and one phone call or e-mail per month from 2 years onward. The patients’ medications were adjusted by their own physicians.
Patients in the control group had 3-4 meetings per year during years 1 through 4, and after that, they had one meeting per year. They received education on diet, exercise, and social support.
Weight loss was greater in the intervention group compared with the control group, with the greatest difference at 1 year (8.6% vs. 0.7%), but it remained significant through the end of the study (6.0% vs. 3.5%).
Specifically, the intervention group had an initial weight loss of 8.6%, followed by weight regain in the first 5 years, and then gradual weight loss, leading to average weight loss of 6%. The control group had a gradual but consistent weight loss, for an average of 3.5% at the end of the trial.
One audience member suggested that some of the weight loss might have been due to aging. The authors said they are looking at those factors in their ongoing data analysis, which they’re planning to publish in the near future.
Meanwhile, the intervention group had significantly greater weight loss than did the control group throughout the trial. They had significantly greater improvements in fitness, hemoglobin A1c levels, systolic blood pressure, and HDL cholesterol (P less than .05 for all). The control group had significantly greater reductions in LDL cholesterol (P less than .05), although they also had a significantly greater use of medications, including insulin, statins, and antihypertensives, compared with the intervention group, the authors noted.
In the short-term (1-4 years), the intervention group saw improvements in cardiovascular risk factors, preservation of mobility, and improvements in fitness, obstructive sleep apnea, fatty liver disease, urinary incontinence, sexual function, and markers of inflammation.
The intervention also reduced the incidence of high-risk chronic kidney disease by 31%, and reduced the total costs and service utilization, especially related to hospitalization ($2,500 per participant), and medication ($2,500 per participant), the authors reported. Although the intervention didn’t affect neuropathy symptoms, it reduced the incidence of reported retinopathy by 14%, reduced the incidence of symptoms of mild or greater depression by 20%, and slowed age-related decline in reported physical function.
Program reduced burden of diabetes
"Even with no clear evidence of cardiovascular benefit, the Look AHEAD investigators have shown that attention to activity and diet can safely reduce the burden of diabetes and have reaffirmed the importance of lifestyle approach as one of the foundations of modern diabetes care," Dr. Gerstein wrote in his editorial, adding that the data show "intensive lifestyle interventions are unlikely to cause harm and may provide a modest benefit."
Interactions among subgroups – history of cardiovascular disease at baseline, and gender, race/ethnicity – showed nonsignificant interaction with cardiovascular disease history (P = .06).
Summarizing the study’s limitations, the authors said that it’s not clear whether changing the intervention groups’ dietary composition might have yielded different results. Their diet during the intervention was 1,200 to 1,800 kcal/day, with less than 30% of calories from fat, and less than 15% from protein. Authors added that the patients recruited successfully competed the fitness test at baseline, so the results can’t be generalized to all patients with type 2 diabetes.
Although the intervention has stopped, the trial continues as an observational study, said Dr. Wing. And some wonder if longer-term results would reveal new information.
"My prediction is that even after stopping the trial, as long as follow-up is carried on for several more years, you’ll see differences in total mortality," said Dr. Bennett, citing the results of UK Prospective Diabetes Study (UKPDS), which showed no difference in cardiovascular disease at 12 years, but a significant difference at 20 years. "So it does appear that intervention does have a lasting but delayed effect on that endpoint."
"I hope [the results] are not misinterpreted," Dr. Bennett continued. "There’s a danger given the lack of effect of the primary endpoint that the headlines will say weight loss is useless, and that’s a total misinterpretation in my view. There are multiple reasons to encourage weight loss. Other than the fact that it doesn’t appear to affect mortality up to this point, it seems to have benefit for all sorts of other things – people feel better, walk better, they develop advanced renal disease less frequently, their cholesterol and blood pressure are lower. I hope that message gets through rather than the negative one."
Dr. Wing, Dr. Bennett, and Dr. Gerstein had no disclosures relevant to the trial. The trial was supported by the National Institutes of Health, other Department of Health and Human Services agencies, and several companies including FedEx, Johnson & Johnson, Nestle Healthcare Nutrition, and Abbott Nutrition.
On Twitter @NaseemSMiller
CHICAGO – A decade of diet and exercise had no effect on cardiovascular morbidity and mortality in overweight and obese adults with type 2 diabetes, according to a randomized, federally funded study that was stopped 2 years early due to futility.
"However, there are many reasons why, I would argue, that you should be encouraging patients with diabetes to lose weight," said Rena R. Wing, Ph.D., the trial’s chair. The results showed that the participants who were in the diet and exercise group, "are less likely to have kidney disease, have less incidence of depression, lower hospital costs, and less medication costs, so there are still many advantages to intense lifestyle interventions," Dr. Wing said during the presentation of the findings at the annual scientific sessions of the American Diabetes Association.
The results also showed that the participants were able to maintain a modest weight loss during a 10-year period.
The Look AHEAD (Action for Health in Diabetes) trial aimed to fill a gap in existing data about whether intensive lifestyle intervention would decrease cardiovascular morbidity and mortality of patients with type 2 diabetes in the long term.
Researchers recruited more than 5,100 patients and randomized them to the intensive lifestyle intervention program, which decreased calorie intake and increased exercise, or to the control group, which provided diabetes support and education. The goal of the intervention was achieving and maintaining weight loss of at least 7% through group and individual counseling.
The trial’s primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina. The trial was planned to have a greater than 80% probability of detecting an 18% difference in cardiovascular events between the two arms, assuming that two-sided alpha was 0.05, a primary outcome rate of 2% per year in the control group, and the planned maximum follow-up of 13.5 years.
But in September 2012, the trial was stopped at the request of its primary sponsors, based on a futility analysis. The median follow-up at the time was 9.6 years.
By then, 403 patients in the intervention group and 418 patients in the control group had met the trial’s primary outcome, with no statistically significant difference between the two groups (1.83 and 1.92 events per 100 person-years, respectively).
Why didn’t it work?
Researchers listed several possible explanations for the results. The study may have had insufficient power, although that wouldn’t explain the negative results, the authors wrote. It is also possible that a higher sustained weight loss was needed in the intervention group to reduce the risk of cardiovascular disease. Meanwhile, the educational sessions and increased use of statins in the control group may have lessened the difference between the two groups, the authors noted. And intensified medical management of cardiovascular risk factors for both groups may have made the relative benefit of the intensive lifestyle intervention more difficult to demonstrate, they added.
Earlier intervention during the course of diabetes may be needed, they added. The results were published online simultaneously with the presentation (N. Engl. J. Med. 2013 June 24 [doi:10.1056/NEJMoa1212914]).
In an editorial accompanying the published results, Dr. Hertzel C. Gerstein wrote that the inclusion of "the somewhat unreliable outcome of hospitalization for angina in the primary composite outcome may have added noise and further obscured any emerging signal" (N. Engl. J. Med. 2013 June 24 [doi:10.1056/NEJMe1306987]).
During the presentation, an audience member suggested that since the 1-year and 4-year findings of the trial were published and well publicized, the participants in the control group might have taken it upon themselves to take action and lose weight. The panel of investigators said that is also a possibility.
Dr. Peter H. Bennett, who is one of the trial’s investigators and was cochair of eligibility, said that stopping the trial "was a big mistake," and that it should have been carried on at least until the planned termination point. "They stopped this trial because they were projecting that if they carried on for 2 more years, the differences in the primary endpoint were unlikely to be statistically significant. But there are several problems. First, you prejudice the power to analyze any other events, and just as we’ve learned from natural history of diabetes-related mortality, it’s clear that you don’t see excess diabetes-related mortality until they’ve had at least 15 years of diabetes, and that’s just at the point that the trial was stopped," Dr. Bennett, scientist emeritus at the National Institutes of Health – one of the main funders of the trial – said in an interview.
"It is also possible that lifestyle interventions may have a real but modest effect on cardiovascular outcomes akin to that of glucose lowering (e.g., a 10%-15% reduction) that requires more than 10 years to become apparent. If so, this trial was clearly too small to detect such an effect," wrote Dr. Gerstein, an endocrinologist and professor at McMaster University and Hamilton Health Sciences, Hamilton, Ont.
A look at the data
The patients in the intervention group (2,570) and control group (2,575) had similar characteristics at baseline. They were between 45 and 75 years old, were mostly female (60%) and white (63%), and had a mean body mass index of 36.0. Fourteen percent had a history of cardiovascular disease, and the median duration of diabetes was 5 years. Less than 30% were on insulin.
Close to 96% of the patients stayed in the trial.
During months 1 and 6, the intervention group had weekly contact with staff members. The contact was gradually reduced in the following months to one on-site individual session per month, and one phone call or e-mail per month from 2 years onward. The patients’ medications were adjusted by their own physicians.
Patients in the control group had 3-4 meetings per year during years 1 through 4, and after that, they had one meeting per year. They received education on diet, exercise, and social support.
Weight loss was greater in the intervention group compared with the control group, with the greatest difference at 1 year (8.6% vs. 0.7%), but it remained significant through the end of the study (6.0% vs. 3.5%).
Specifically, the intervention group had an initial weight loss of 8.6%, followed by weight regain in the first 5 years, and then gradual weight loss, leading to average weight loss of 6%. The control group had a gradual but consistent weight loss, for an average of 3.5% at the end of the trial.
One audience member suggested that some of the weight loss might have been due to aging. The authors said they are looking at those factors in their ongoing data analysis, which they’re planning to publish in the near future.
Meanwhile, the intervention group had significantly greater weight loss than did the control group throughout the trial. They had significantly greater improvements in fitness, hemoglobin A1c levels, systolic blood pressure, and HDL cholesterol (P less than .05 for all). The control group had significantly greater reductions in LDL cholesterol (P less than .05), although they also had a significantly greater use of medications, including insulin, statins, and antihypertensives, compared with the intervention group, the authors noted.
In the short-term (1-4 years), the intervention group saw improvements in cardiovascular risk factors, preservation of mobility, and improvements in fitness, obstructive sleep apnea, fatty liver disease, urinary incontinence, sexual function, and markers of inflammation.
The intervention also reduced the incidence of high-risk chronic kidney disease by 31%, and reduced the total costs and service utilization, especially related to hospitalization ($2,500 per participant), and medication ($2,500 per participant), the authors reported. Although the intervention didn’t affect neuropathy symptoms, it reduced the incidence of reported retinopathy by 14%, reduced the incidence of symptoms of mild or greater depression by 20%, and slowed age-related decline in reported physical function.
Program reduced burden of diabetes
"Even with no clear evidence of cardiovascular benefit, the Look AHEAD investigators have shown that attention to activity and diet can safely reduce the burden of diabetes and have reaffirmed the importance of lifestyle approach as one of the foundations of modern diabetes care," Dr. Gerstein wrote in his editorial, adding that the data show "intensive lifestyle interventions are unlikely to cause harm and may provide a modest benefit."
Interactions among subgroups – history of cardiovascular disease at baseline, and gender, race/ethnicity – showed nonsignificant interaction with cardiovascular disease history (P = .06).
Summarizing the study’s limitations, the authors said that it’s not clear whether changing the intervention groups’ dietary composition might have yielded different results. Their diet during the intervention was 1,200 to 1,800 kcal/day, with less than 30% of calories from fat, and less than 15% from protein. Authors added that the patients recruited successfully competed the fitness test at baseline, so the results can’t be generalized to all patients with type 2 diabetes.
Although the intervention has stopped, the trial continues as an observational study, said Dr. Wing. And some wonder if longer-term results would reveal new information.
"My prediction is that even after stopping the trial, as long as follow-up is carried on for several more years, you’ll see differences in total mortality," said Dr. Bennett, citing the results of UK Prospective Diabetes Study (UKPDS), which showed no difference in cardiovascular disease at 12 years, but a significant difference at 20 years. "So it does appear that intervention does have a lasting but delayed effect on that endpoint."
"I hope [the results] are not misinterpreted," Dr. Bennett continued. "There’s a danger given the lack of effect of the primary endpoint that the headlines will say weight loss is useless, and that’s a total misinterpretation in my view. There are multiple reasons to encourage weight loss. Other than the fact that it doesn’t appear to affect mortality up to this point, it seems to have benefit for all sorts of other things – people feel better, walk better, they develop advanced renal disease less frequently, their cholesterol and blood pressure are lower. I hope that message gets through rather than the negative one."
Dr. Wing, Dr. Bennett, and Dr. Gerstein had no disclosures relevant to the trial. The trial was supported by the National Institutes of Health, other Department of Health and Human Services agencies, and several companies including FedEx, Johnson & Johnson, Nestle Healthcare Nutrition, and Abbott Nutrition.
On Twitter @NaseemSMiller
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Major finding: A total of 403 patients in the intervention group and 418 patients in the control group had met the trial’s primary outcome, with no statistically significant difference between the two groups (1.83 and 1.92 events per 100 person-years, respectively).
Data source: Look AHEAD, a study that randomized 5,100 U.S. overweight or obese patients with type 2 diabetes to an intensive weight-loss and physical activity intervention or diabetes support and education.
Disclosures: Dr. Wing, Dr. Bennett, and Dr. Gerstein had no disclosures relevant to the trial.
Low-carb, high-fat diet may not be best for gestational diabetes
CHICAGO – Women with gestational diabetes on a conventional low-carbohydrate, high-fat diet were more insulin resistant, and their infants had slightly higher rates of adiposity, than did with women who consumed a diet high in complex carbohydrates and low in fat, according to a randomized pilot study of 11 women.
Both diets controlled maternal glucose and weight. "So, they’re both okay, except that tissue data and fasting levels imply that higher fat content is exacerbating insulin resistance during pregnancy," Teri L. Hernandez, Ph.D., said in an interview after presenting her findings at the annual scientific sessions of the American Diabetes Association.
It’s too soon to tell if and when the findings will have implications on practice. "It’s a good study," said Dr. Assiamira Ferrara, senior research scientist at Kaiser Permanente, Oakland, Calif., who was a moderator and not involved in the study. "But we need a bigger sample size and more feasibility studies on whether women will adhere to the diet" before we try this outside of a research environment.
The conventional diet recommended to women who have gestational diabetes (GDM) has mainly focused on carbohydrate (CHO) restriction. But Dr. Hernandez and her colleagues said that the restrictions result in greater fat intake, which in turn could promote insulin resistance and increase fetal adiposity. Meanwhile, owing to patient noncompliance and a lack of controlled designs, evidence remains confounded, she reported.
In a recent unpublished systematic review of prospective, randomized, controlled trials of diet interventions in women with GDM, Dr. Hernandez and her colleagues found that women tolerated higher complex carb/low glycemic index diets and that diets higher in unrefined carbs effectively blunted postprandial glycemia, reduced the need for insulin therapy, and improved insulin sensitivity, hemoglobin A1c, and systolic blood pressure.
Dr. Hernandez of the departments of medicine and nursing at University of Colorado at Denver in Aurora, said that she has a larger number women in her ongoing study, but the findings so far "lend evidence to the idea that women can tolerate more carb than we thought.
"These women are worried about their baby’s outcome, and they’re afraid their babies are going to be born too big, so they become very fearful of carbohydrates. What this says is that they can actually have toast and other carbs in their diet and still have a great outcome, and it could even help improve their insulin resistance," she said in an interview.
Researchers randomized five women to the conventional low-carb/high-fat diet, and 6 women to the high-carb/low-fat diet.
The low-carb/high fat diet comprised 40% CHO, 45% fat, and 15% protein; the high-carb/low fat diet contained 60% CHO, 25% fat, and 15% protein. Simple sugars made up about 18% or less of total daily calories.
The subjects were rather healthy women with mild gestational diabetes, were highly compliant, and were closely matched, with a mean body mass index of 33.5 kg/m2, and were 29-30 years old. They were provided with all the meals.
During the study period, weight gain was similar in both groups, and their glycemic profiles were below target.
However, the high-carb/low-fat diet group had lower fasting glucose and fasting insulin at 6 and 7 weeks, compared with the low-carb/high-fat diet group (P = .007 and .06, respectively)
Results also showed that the postprandial free fatty acids were significantly higher in the low-carb/high-fat diet group (P = .037). And, at week 37, fasting glucose, insulin, and maternal insulin resistance (HOMA-IR) were significantly higher in the low-carb/high-fat diet, compared with the low-fat/high-carb diet (P = .007, .06, and .02, respectively).
Meanwhile, infant adiposity was slightly higher in the infants of the low-carb/high-fat groups, compared with the high-carb/low-fat group (14% v. 11%). And, regardless of diet, higher fasting insulin and HOMA-IR at 37 weeks were associated with greater infant adiposity (P less than .05).
Dr. Hernandez said that both diets are doing a good job, and thus far, there haven’t been any adverse outcomes because of either diet.
Dr. Hernandez had no disclosures. Dr. Ferrara is an employee of Takeda Global Research and Development and has received research support from Takeda Pharmaceutical.
On Twitter @NaseemSMiller
CHICAGO – Women with gestational diabetes on a conventional low-carbohydrate, high-fat diet were more insulin resistant, and their infants had slightly higher rates of adiposity, than did with women who consumed a diet high in complex carbohydrates and low in fat, according to a randomized pilot study of 11 women.
Both diets controlled maternal glucose and weight. "So, they’re both okay, except that tissue data and fasting levels imply that higher fat content is exacerbating insulin resistance during pregnancy," Teri L. Hernandez, Ph.D., said in an interview after presenting her findings at the annual scientific sessions of the American Diabetes Association.
It’s too soon to tell if and when the findings will have implications on practice. "It’s a good study," said Dr. Assiamira Ferrara, senior research scientist at Kaiser Permanente, Oakland, Calif., who was a moderator and not involved in the study. "But we need a bigger sample size and more feasibility studies on whether women will adhere to the diet" before we try this outside of a research environment.
The conventional diet recommended to women who have gestational diabetes (GDM) has mainly focused on carbohydrate (CHO) restriction. But Dr. Hernandez and her colleagues said that the restrictions result in greater fat intake, which in turn could promote insulin resistance and increase fetal adiposity. Meanwhile, owing to patient noncompliance and a lack of controlled designs, evidence remains confounded, she reported.
In a recent unpublished systematic review of prospective, randomized, controlled trials of diet interventions in women with GDM, Dr. Hernandez and her colleagues found that women tolerated higher complex carb/low glycemic index diets and that diets higher in unrefined carbs effectively blunted postprandial glycemia, reduced the need for insulin therapy, and improved insulin sensitivity, hemoglobin A1c, and systolic blood pressure.
Dr. Hernandez of the departments of medicine and nursing at University of Colorado at Denver in Aurora, said that she has a larger number women in her ongoing study, but the findings so far "lend evidence to the idea that women can tolerate more carb than we thought.
"These women are worried about their baby’s outcome, and they’re afraid their babies are going to be born too big, so they become very fearful of carbohydrates. What this says is that they can actually have toast and other carbs in their diet and still have a great outcome, and it could even help improve their insulin resistance," she said in an interview.
Researchers randomized five women to the conventional low-carb/high-fat diet, and 6 women to the high-carb/low-fat diet.
The low-carb/high fat diet comprised 40% CHO, 45% fat, and 15% protein; the high-carb/low fat diet contained 60% CHO, 25% fat, and 15% protein. Simple sugars made up about 18% or less of total daily calories.
The subjects were rather healthy women with mild gestational diabetes, were highly compliant, and were closely matched, with a mean body mass index of 33.5 kg/m2, and were 29-30 years old. They were provided with all the meals.
During the study period, weight gain was similar in both groups, and their glycemic profiles were below target.
However, the high-carb/low-fat diet group had lower fasting glucose and fasting insulin at 6 and 7 weeks, compared with the low-carb/high-fat diet group (P = .007 and .06, respectively)
Results also showed that the postprandial free fatty acids were significantly higher in the low-carb/high-fat diet group (P = .037). And, at week 37, fasting glucose, insulin, and maternal insulin resistance (HOMA-IR) were significantly higher in the low-carb/high-fat diet, compared with the low-fat/high-carb diet (P = .007, .06, and .02, respectively).
Meanwhile, infant adiposity was slightly higher in the infants of the low-carb/high-fat groups, compared with the high-carb/low-fat group (14% v. 11%). And, regardless of diet, higher fasting insulin and HOMA-IR at 37 weeks were associated with greater infant adiposity (P less than .05).
Dr. Hernandez said that both diets are doing a good job, and thus far, there haven’t been any adverse outcomes because of either diet.
Dr. Hernandez had no disclosures. Dr. Ferrara is an employee of Takeda Global Research and Development and has received research support from Takeda Pharmaceutical.
On Twitter @NaseemSMiller
CHICAGO – Women with gestational diabetes on a conventional low-carbohydrate, high-fat diet were more insulin resistant, and their infants had slightly higher rates of adiposity, than did with women who consumed a diet high in complex carbohydrates and low in fat, according to a randomized pilot study of 11 women.
Both diets controlled maternal glucose and weight. "So, they’re both okay, except that tissue data and fasting levels imply that higher fat content is exacerbating insulin resistance during pregnancy," Teri L. Hernandez, Ph.D., said in an interview after presenting her findings at the annual scientific sessions of the American Diabetes Association.
It’s too soon to tell if and when the findings will have implications on practice. "It’s a good study," said Dr. Assiamira Ferrara, senior research scientist at Kaiser Permanente, Oakland, Calif., who was a moderator and not involved in the study. "But we need a bigger sample size and more feasibility studies on whether women will adhere to the diet" before we try this outside of a research environment.
The conventional diet recommended to women who have gestational diabetes (GDM) has mainly focused on carbohydrate (CHO) restriction. But Dr. Hernandez and her colleagues said that the restrictions result in greater fat intake, which in turn could promote insulin resistance and increase fetal adiposity. Meanwhile, owing to patient noncompliance and a lack of controlled designs, evidence remains confounded, she reported.
In a recent unpublished systematic review of prospective, randomized, controlled trials of diet interventions in women with GDM, Dr. Hernandez and her colleagues found that women tolerated higher complex carb/low glycemic index diets and that diets higher in unrefined carbs effectively blunted postprandial glycemia, reduced the need for insulin therapy, and improved insulin sensitivity, hemoglobin A1c, and systolic blood pressure.
Dr. Hernandez of the departments of medicine and nursing at University of Colorado at Denver in Aurora, said that she has a larger number women in her ongoing study, but the findings so far "lend evidence to the idea that women can tolerate more carb than we thought.
"These women are worried about their baby’s outcome, and they’re afraid their babies are going to be born too big, so they become very fearful of carbohydrates. What this says is that they can actually have toast and other carbs in their diet and still have a great outcome, and it could even help improve their insulin resistance," she said in an interview.
Researchers randomized five women to the conventional low-carb/high-fat diet, and 6 women to the high-carb/low-fat diet.
The low-carb/high fat diet comprised 40% CHO, 45% fat, and 15% protein; the high-carb/low fat diet contained 60% CHO, 25% fat, and 15% protein. Simple sugars made up about 18% or less of total daily calories.
The subjects were rather healthy women with mild gestational diabetes, were highly compliant, and were closely matched, with a mean body mass index of 33.5 kg/m2, and were 29-30 years old. They were provided with all the meals.
During the study period, weight gain was similar in both groups, and their glycemic profiles were below target.
However, the high-carb/low-fat diet group had lower fasting glucose and fasting insulin at 6 and 7 weeks, compared with the low-carb/high-fat diet group (P = .007 and .06, respectively)
Results also showed that the postprandial free fatty acids were significantly higher in the low-carb/high-fat diet group (P = .037). And, at week 37, fasting glucose, insulin, and maternal insulin resistance (HOMA-IR) were significantly higher in the low-carb/high-fat diet, compared with the low-fat/high-carb diet (P = .007, .06, and .02, respectively).
Meanwhile, infant adiposity was slightly higher in the infants of the low-carb/high-fat groups, compared with the high-carb/low-fat group (14% v. 11%). And, regardless of diet, higher fasting insulin and HOMA-IR at 37 weeks were associated with greater infant adiposity (P less than .05).
Dr. Hernandez said that both diets are doing a good job, and thus far, there haven’t been any adverse outcomes because of either diet.
Dr. Hernandez had no disclosures. Dr. Ferrara is an employee of Takeda Global Research and Development and has received research support from Takeda Pharmaceutical.
On Twitter @NaseemSMiller
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Major finding: At week 37, fasting glucose, insulin, and maternal insulin resistance (HOMA-IR) were significantly higher in the low carb/high fat diet, compared with the low fat/high carb diet.
Data source: Randomized pilot study of 11 women with mild gestational diabetes.
Disclosures: Dr. Hernandez had no disclosures. Dr. Ferrara is an employee of Takeda Global Research and Development and has received research support from Takeda Pharmaceutical.
Novel food insulin index algorithm improved glycemic control
CHICAGO – A novel food insulin index algorithm appears to be a safe and useful tool for estimating the mealtime insulin dose in type 1 diabetic patients, without the need for counting carbohydrates, according to Dr. Stephen Colagiuri.
Application of the food insulin index algorithm to common protein-containing foods produced lower postprandial blood glucose levels without significantly increasing the risk of hypoglycemia in a small, triple-randomized crossover comparison study, he reported at the annual scientific sessions of the American Diabetes Association.
Similar in concept to the glycemic index, the food insulin index (FII) is an algorithm for ranking foods based on their insulin demand relative to a reference food. When compared with carbohydrate counting in a prior study involving 28 patients with type 1 diabetes using insulin pump therapy, the algorithm significantly improved the percentage of time within the normal blood glucose range without a significant difference in the incidence of hypoglycemia (Diabetes Care 2011;34:2146-51).
The aim of the current study was to compare carbohydrate counting with the FII algorithm for estimating insulin dosage on postprandial glycemia in adults with type 1 diabetes consuming six single foods. The six foods – low-fat strawberry yogurt, salted peanuts, baked beans, poached eggs, beef steak, and battered fish fillets – were chosen to represent a cross-section of common protein-containing foods with at least a twofold difference between their carbohydrate content per serving and estimated food insulin demand (FID), explained Dr. Colagiuri, professor of metabolic health, University of Sydney (Australia).
FID extends the FII concept by combining a food’s FII with the kilojoule in the portion size. Unlike the FII, which is a fixed value, FID changes as the food portion size changes, and can therefore be used to determine the mealtime insulin dose, similar to the calculation of the insulin to carbohydrate ratio, he said.
For example, if one consumes 200 g of low-fat strawberry yogurt, that’s 770 kJ for the portion size, which is multiplied by an FII of 84 for the yogurt and then divided by 1,000, resulting in an FID of 65.
Eleven adults with type 1 diabetes on insulin pump therapy consumed one of the six foods and were administered with an insulin dose determined by either the FID or carbohydrate counting. Postprandial glycemia was measured through capillary glucose samples at regular intervals over a 3-hour period.
The patients’ mean diabetes duration was 14.4 years, their mean insulin pump therapy duration was 3.6 years, and their mean hemoglobin A1c level was 7%. Their average body mass index was 24.6 kg/m2, and their mean age was 38.
Compared with carbohydrate counting, the FID significantly reduced mean blood glucose level (5.7 mmol/L vs. 6.5 mmol/L; P = .003), produced a smaller mean change in blood glucose level (–0.7 mmol/L vs. 0.1 mmol/L; P = .001) and trended toward a smaller peak change in blood glucose excursion (1.3 mmol/L vs. 1.8 mmol/L; P = .10), reported the investigators, led by Kirstine Bell, a diabetes educator and PhD candidate at the University of Sydney.
The risk of hypoglycemia over the 3-hour period was not significantly different, at 22 events with carbohydrate counting and 32 events with the FID (33% vs. 48%).
A study is planned to evaluate the FID in adolescents, and another is ongoing and is looking at the FID in everyday use among 36 adults with type 1 diabetes. Several resources, including an iPhone app, pictorial guides and a website have been developed to help support patients in using the FID, Ms. Bell said in an interview.
"It is essentially very similar to carbohydrate counting," she said. Just as patients would learn that a slice of bread has so many grams of carbohydrates, "they’d simply learn that a slice of bread has this much FID," she said. The FIDs are then added up and put into the patient’s pump, which is programmed to create an insulin-to-FID ratio, just as it does an insulin-to-carbohydrate ratio.
While the iPhone app doesn’t have the functionality yet to calculate an FID based on a food photo, patients can look up 130 commonly consumed foods in the United States that have been tested by the team and entered into their database. Patients can then input their serving size, and it will calculate the FID for them.
The authors reported no relevant financial disclosures.
CHICAGO – A novel food insulin index algorithm appears to be a safe and useful tool for estimating the mealtime insulin dose in type 1 diabetic patients, without the need for counting carbohydrates, according to Dr. Stephen Colagiuri.
Application of the food insulin index algorithm to common protein-containing foods produced lower postprandial blood glucose levels without significantly increasing the risk of hypoglycemia in a small, triple-randomized crossover comparison study, he reported at the annual scientific sessions of the American Diabetes Association.
Similar in concept to the glycemic index, the food insulin index (FII) is an algorithm for ranking foods based on their insulin demand relative to a reference food. When compared with carbohydrate counting in a prior study involving 28 patients with type 1 diabetes using insulin pump therapy, the algorithm significantly improved the percentage of time within the normal blood glucose range without a significant difference in the incidence of hypoglycemia (Diabetes Care 2011;34:2146-51).
The aim of the current study was to compare carbohydrate counting with the FII algorithm for estimating insulin dosage on postprandial glycemia in adults with type 1 diabetes consuming six single foods. The six foods – low-fat strawberry yogurt, salted peanuts, baked beans, poached eggs, beef steak, and battered fish fillets – were chosen to represent a cross-section of common protein-containing foods with at least a twofold difference between their carbohydrate content per serving and estimated food insulin demand (FID), explained Dr. Colagiuri, professor of metabolic health, University of Sydney (Australia).
FID extends the FII concept by combining a food’s FII with the kilojoule in the portion size. Unlike the FII, which is a fixed value, FID changes as the food portion size changes, and can therefore be used to determine the mealtime insulin dose, similar to the calculation of the insulin to carbohydrate ratio, he said.
For example, if one consumes 200 g of low-fat strawberry yogurt, that’s 770 kJ for the portion size, which is multiplied by an FII of 84 for the yogurt and then divided by 1,000, resulting in an FID of 65.
Eleven adults with type 1 diabetes on insulin pump therapy consumed one of the six foods and were administered with an insulin dose determined by either the FID or carbohydrate counting. Postprandial glycemia was measured through capillary glucose samples at regular intervals over a 3-hour period.
The patients’ mean diabetes duration was 14.4 years, their mean insulin pump therapy duration was 3.6 years, and their mean hemoglobin A1c level was 7%. Their average body mass index was 24.6 kg/m2, and their mean age was 38.
Compared with carbohydrate counting, the FID significantly reduced mean blood glucose level (5.7 mmol/L vs. 6.5 mmol/L; P = .003), produced a smaller mean change in blood glucose level (–0.7 mmol/L vs. 0.1 mmol/L; P = .001) and trended toward a smaller peak change in blood glucose excursion (1.3 mmol/L vs. 1.8 mmol/L; P = .10), reported the investigators, led by Kirstine Bell, a diabetes educator and PhD candidate at the University of Sydney.
The risk of hypoglycemia over the 3-hour period was not significantly different, at 22 events with carbohydrate counting and 32 events with the FID (33% vs. 48%).
A study is planned to evaluate the FID in adolescents, and another is ongoing and is looking at the FID in everyday use among 36 adults with type 1 diabetes. Several resources, including an iPhone app, pictorial guides and a website have been developed to help support patients in using the FID, Ms. Bell said in an interview.
"It is essentially very similar to carbohydrate counting," she said. Just as patients would learn that a slice of bread has so many grams of carbohydrates, "they’d simply learn that a slice of bread has this much FID," she said. The FIDs are then added up and put into the patient’s pump, which is programmed to create an insulin-to-FID ratio, just as it does an insulin-to-carbohydrate ratio.
While the iPhone app doesn’t have the functionality yet to calculate an FID based on a food photo, patients can look up 130 commonly consumed foods in the United States that have been tested by the team and entered into their database. Patients can then input their serving size, and it will calculate the FID for them.
The authors reported no relevant financial disclosures.
CHICAGO – A novel food insulin index algorithm appears to be a safe and useful tool for estimating the mealtime insulin dose in type 1 diabetic patients, without the need for counting carbohydrates, according to Dr. Stephen Colagiuri.
Application of the food insulin index algorithm to common protein-containing foods produced lower postprandial blood glucose levels without significantly increasing the risk of hypoglycemia in a small, triple-randomized crossover comparison study, he reported at the annual scientific sessions of the American Diabetes Association.
Similar in concept to the glycemic index, the food insulin index (FII) is an algorithm for ranking foods based on their insulin demand relative to a reference food. When compared with carbohydrate counting in a prior study involving 28 patients with type 1 diabetes using insulin pump therapy, the algorithm significantly improved the percentage of time within the normal blood glucose range without a significant difference in the incidence of hypoglycemia (Diabetes Care 2011;34:2146-51).
The aim of the current study was to compare carbohydrate counting with the FII algorithm for estimating insulin dosage on postprandial glycemia in adults with type 1 diabetes consuming six single foods. The six foods – low-fat strawberry yogurt, salted peanuts, baked beans, poached eggs, beef steak, and battered fish fillets – were chosen to represent a cross-section of common protein-containing foods with at least a twofold difference between their carbohydrate content per serving and estimated food insulin demand (FID), explained Dr. Colagiuri, professor of metabolic health, University of Sydney (Australia).
FID extends the FII concept by combining a food’s FII with the kilojoule in the portion size. Unlike the FII, which is a fixed value, FID changes as the food portion size changes, and can therefore be used to determine the mealtime insulin dose, similar to the calculation of the insulin to carbohydrate ratio, he said.
For example, if one consumes 200 g of low-fat strawberry yogurt, that’s 770 kJ for the portion size, which is multiplied by an FII of 84 for the yogurt and then divided by 1,000, resulting in an FID of 65.
Eleven adults with type 1 diabetes on insulin pump therapy consumed one of the six foods and were administered with an insulin dose determined by either the FID or carbohydrate counting. Postprandial glycemia was measured through capillary glucose samples at regular intervals over a 3-hour period.
The patients’ mean diabetes duration was 14.4 years, their mean insulin pump therapy duration was 3.6 years, and their mean hemoglobin A1c level was 7%. Their average body mass index was 24.6 kg/m2, and their mean age was 38.
Compared with carbohydrate counting, the FID significantly reduced mean blood glucose level (5.7 mmol/L vs. 6.5 mmol/L; P = .003), produced a smaller mean change in blood glucose level (–0.7 mmol/L vs. 0.1 mmol/L; P = .001) and trended toward a smaller peak change in blood glucose excursion (1.3 mmol/L vs. 1.8 mmol/L; P = .10), reported the investigators, led by Kirstine Bell, a diabetes educator and PhD candidate at the University of Sydney.
The risk of hypoglycemia over the 3-hour period was not significantly different, at 22 events with carbohydrate counting and 32 events with the FID (33% vs. 48%).
A study is planned to evaluate the FID in adolescents, and another is ongoing and is looking at the FID in everyday use among 36 adults with type 1 diabetes. Several resources, including an iPhone app, pictorial guides and a website have been developed to help support patients in using the FID, Ms. Bell said in an interview.
"It is essentially very similar to carbohydrate counting," she said. Just as patients would learn that a slice of bread has so many grams of carbohydrates, "they’d simply learn that a slice of bread has this much FID," she said. The FIDs are then added up and put into the patient’s pump, which is programmed to create an insulin-to-FID ratio, just as it does an insulin-to-carbohydrate ratio.
While the iPhone app doesn’t have the functionality yet to calculate an FID based on a food photo, patients can look up 130 commonly consumed foods in the United States that have been tested by the team and entered into their database. Patients can then input their serving size, and it will calculate the FID for them.
The authors reported no relevant financial disclosures.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Major finding: Compared with carbohydrate counting, the FID significantly reduced mean blood glucose level (5.7 mmol/L vs. 6.5 mmol/L; P = .003).
Data source: A triple-randomized crossover comparison trial in 11 adults with type 1 diabetes on insulin pump therapy.
Disclosures: The authors reported no relevant financial disclosures.
African ancestry linked to fasting glucose in people with no diabetes diagnosis
Results from a large, ongoing epidemiologic study demonstrated a positive association between African ancestry and fasting glucose in individuals without diagnosed diabetes.
"This association is not substantively diminished by accounting for body mass index or available socioeconomic status measures, suggesting that differences between African Americans and whites in diabetes risk might include genetic/biologically mediated differences in glucose homeostasis," Dr. James B. Meigs reported at the annual scientific sessions of the American Diabetes Association.
Dr. Meigs, who directs the Massachusetts General Hospital Clinical Research Program’s Disease Management Research Unit, presented findings from 1,545 individuals without diagnosed diabetes who are enrolled in the Boston Area Community Health (BACH) Pre-Diabetes Study, an ongoing, community-based, random-sample cohort study. During morning in-home interviews, the researchers collected data on body mass index and socioeconomic status, and took samples for analysis of fasting glucose and DNA for genotyping 63 markers that discriminate between European, African, and Native American ancestry.
To test the hypothesis that the degree of African ancestry is associated with fasting glucose levels in individuals without diagnosed diabetes independent of socioeconomic factors, the researchers used three different linear regression models predicting fasting glucose. Model 1 included terms for age, gender, percent African, and percent Native American ancestry. Model 2 added BMI as a measure, and model 3 added socioeconomic status as a measure (income, education, and occupation).
Dr. Meigs, who is also an associate professor of medicine at Harvard Medical School in Boston, reported that the mean age- and gender-adjusted fasting glucose levels were 103 mg/dL in those with 100% African ancestry and 97 mg/dL in those with 100% European ancestry. When the researchers applied model 1, each 10% increase in percentage of African ancestry was associated with a fasting glucose increase of 0.53 mg/dL (P = .005). In model 2, adjustment for BMI weakened the association with fasting glucose (0.42 mg/dL; P = .02), while in model 3 additional adjustment for socioeconomic factors did not further diminish the association (0.46 mg/dL; P = .02).
Although the clinical application of genetics in diabetes is a long way off, a lot is being learned about the mechanisms underlying type 2 diabetes, Dr. Meigs said. "We’re looking for the differences between whites, who have been studied principally so far, and other ancestral groups, in terms of the specific mutations that alter levels of diabetes risk."
To accomplish this, the BACH Prediabetes Study is attempting to exhaust all other social and environmental factors, such as employment, insurance status, access to care, nutritional environment, and detailed neighborhood characteristics, he said.
BACH is supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Meigs said that he had no relevant financial disclosures to make.
Results from a large, ongoing epidemiologic study demonstrated a positive association between African ancestry and fasting glucose in individuals without diagnosed diabetes.
"This association is not substantively diminished by accounting for body mass index or available socioeconomic status measures, suggesting that differences between African Americans and whites in diabetes risk might include genetic/biologically mediated differences in glucose homeostasis," Dr. James B. Meigs reported at the annual scientific sessions of the American Diabetes Association.
Dr. Meigs, who directs the Massachusetts General Hospital Clinical Research Program’s Disease Management Research Unit, presented findings from 1,545 individuals without diagnosed diabetes who are enrolled in the Boston Area Community Health (BACH) Pre-Diabetes Study, an ongoing, community-based, random-sample cohort study. During morning in-home interviews, the researchers collected data on body mass index and socioeconomic status, and took samples for analysis of fasting glucose and DNA for genotyping 63 markers that discriminate between European, African, and Native American ancestry.
To test the hypothesis that the degree of African ancestry is associated with fasting glucose levels in individuals without diagnosed diabetes independent of socioeconomic factors, the researchers used three different linear regression models predicting fasting glucose. Model 1 included terms for age, gender, percent African, and percent Native American ancestry. Model 2 added BMI as a measure, and model 3 added socioeconomic status as a measure (income, education, and occupation).
Dr. Meigs, who is also an associate professor of medicine at Harvard Medical School in Boston, reported that the mean age- and gender-adjusted fasting glucose levels were 103 mg/dL in those with 100% African ancestry and 97 mg/dL in those with 100% European ancestry. When the researchers applied model 1, each 10% increase in percentage of African ancestry was associated with a fasting glucose increase of 0.53 mg/dL (P = .005). In model 2, adjustment for BMI weakened the association with fasting glucose (0.42 mg/dL; P = .02), while in model 3 additional adjustment for socioeconomic factors did not further diminish the association (0.46 mg/dL; P = .02).
Although the clinical application of genetics in diabetes is a long way off, a lot is being learned about the mechanisms underlying type 2 diabetes, Dr. Meigs said. "We’re looking for the differences between whites, who have been studied principally so far, and other ancestral groups, in terms of the specific mutations that alter levels of diabetes risk."
To accomplish this, the BACH Prediabetes Study is attempting to exhaust all other social and environmental factors, such as employment, insurance status, access to care, nutritional environment, and detailed neighborhood characteristics, he said.
BACH is supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Meigs said that he had no relevant financial disclosures to make.
Results from a large, ongoing epidemiologic study demonstrated a positive association between African ancestry and fasting glucose in individuals without diagnosed diabetes.
"This association is not substantively diminished by accounting for body mass index or available socioeconomic status measures, suggesting that differences between African Americans and whites in diabetes risk might include genetic/biologically mediated differences in glucose homeostasis," Dr. James B. Meigs reported at the annual scientific sessions of the American Diabetes Association.
Dr. Meigs, who directs the Massachusetts General Hospital Clinical Research Program’s Disease Management Research Unit, presented findings from 1,545 individuals without diagnosed diabetes who are enrolled in the Boston Area Community Health (BACH) Pre-Diabetes Study, an ongoing, community-based, random-sample cohort study. During morning in-home interviews, the researchers collected data on body mass index and socioeconomic status, and took samples for analysis of fasting glucose and DNA for genotyping 63 markers that discriminate between European, African, and Native American ancestry.
To test the hypothesis that the degree of African ancestry is associated with fasting glucose levels in individuals without diagnosed diabetes independent of socioeconomic factors, the researchers used three different linear regression models predicting fasting glucose. Model 1 included terms for age, gender, percent African, and percent Native American ancestry. Model 2 added BMI as a measure, and model 3 added socioeconomic status as a measure (income, education, and occupation).
Dr. Meigs, who is also an associate professor of medicine at Harvard Medical School in Boston, reported that the mean age- and gender-adjusted fasting glucose levels were 103 mg/dL in those with 100% African ancestry and 97 mg/dL in those with 100% European ancestry. When the researchers applied model 1, each 10% increase in percentage of African ancestry was associated with a fasting glucose increase of 0.53 mg/dL (P = .005). In model 2, adjustment for BMI weakened the association with fasting glucose (0.42 mg/dL; P = .02), while in model 3 additional adjustment for socioeconomic factors did not further diminish the association (0.46 mg/dL; P = .02).
Although the clinical application of genetics in diabetes is a long way off, a lot is being learned about the mechanisms underlying type 2 diabetes, Dr. Meigs said. "We’re looking for the differences between whites, who have been studied principally so far, and other ancestral groups, in terms of the specific mutations that alter levels of diabetes risk."
To accomplish this, the BACH Prediabetes Study is attempting to exhaust all other social and environmental factors, such as employment, insurance status, access to care, nutritional environment, and detailed neighborhood characteristics, he said.
BACH is supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Meigs said that he had no relevant financial disclosures to make.
FROM THE ADA ANNUAL SCIENTIFIC SESSIONS
Major finding: Each 10% increase in percentage of African ancestry was associated with a fasting glucose increase of 0.53 mg/dL (P = .005).
Data source: Findings from 1,545 individuals without diagnosed diabetes who are enrolled in the Boston Area Community Health (BACH) Pre-Diabetes Study.
Disclosures: BACH is supported by a grant from NIDDK. Dr. Meigs said that he had no relevant financial disclosures to make.
Three continuous glucose monitoring devices highly reliable
Current generation continuous glucose monitoring devices continue to improve in accuracy and performance, judging from the results from a comparative study
"Continuous glucose monitoring can improve glucose control when used as an adjunct to intermittent self-monitoring of blood glucose and is a critical component of bionic pancreas devices for automated glucose control," Dr. Steven J. Russell reported during the annual scientific sessions of the American Diabetes Association. "The effectiveness of continuous glucose monitoring in both applications is critically dependent on the accuracy and reliability of the data produced."
In a previous comparative trial with 2,360 reference values, Dr. Russell of the department of medicine at the Massachusetts General Hospital Diabetes Center in Boston and his associates compared three continuous glucose monitoring (CGM) devices: the FreeStyle Navigator (Abbott Diabetes Care; approved in March of 2008), the Seven Plus (DexCom; received premarket approval in November of 2010), and the Guardian (Medtronic; approved in July 2006), which were worn simultaneously by six subjects with type 1 diabetes (Diabetes Care 2013;36:251-9). The FreeStyle Navigator had the best overall accuracy, with an aggregate mean absolute relative difference (MARD) in plasma glucose, relative to venous levels, of all paired points of 11.8%. The Seven Plus and Guardian produced aggregate MARDs of all paired points of 16.5% and 20.3%, respectively.
For the current comparative study with 4,657 reference values, the researchers compared three CGM devices: the G4 Platinum (DexCom; approved in October of 2012), Enlite (Medtronic; not yet available in the United States), and the FreeStyle Navigator, which were worn simultaneously over a 2-day period by 23 volunteers participating in a trial of blood glucose control with a closed-loop artificial pancreas. Every 15 minutes, the researchers obtained venous glucose measurements and paired them in time with the CGM measurements.
Dr. Russell reported that the G4 Platinum and the FreeStyle Navigator had similar accuracy, with an aggregate MARD of 10.8% and 12.3%, respectively, while the aggregate MARD for the Enlite was 17.9%. Data reporting percentages, which the researchers described as a "measure of reliability," were 99.7% for the G4 Platinum, 99.7% for the FreeStyle Navigator, and 97.1% for the Enlite.
However, Dr. Russell noted, CGM calibration errors remain a problem, one that if not resolved will prevent closed-loop systems from use outside a controlled research setting. For example, when the Navigator calibrated at a time when blood glucose was rising sharply, it overestimated glucose for the rest of the day. On the other hand, calibration corrected low readings by the Navigator in another instance. Compared with the earlier comparison study, "the G4 Platinum accuracy is markedly improved over the Seven Plus, and slightly better than the Navigator, and markedly better than the Enlite." However, for all the sensors, "calibration remains an important and, I think, preventable source of error."
The study was supported by the National Institutes of Health, and several research foundations. Technical and material support came from DexCom, Tandem Diabetes, SweetSpot Diabetes, International Biomedical, Hospira, Abbott, Insulet, and Medtronic. Dr. Russell has received research support from Abbott, Dexcom, Insulet, International Biomedical, and Medtronic, and MiniMed.
Current generation continuous glucose monitoring devices continue to improve in accuracy and performance, judging from the results from a comparative study
"Continuous glucose monitoring can improve glucose control when used as an adjunct to intermittent self-monitoring of blood glucose and is a critical component of bionic pancreas devices for automated glucose control," Dr. Steven J. Russell reported during the annual scientific sessions of the American Diabetes Association. "The effectiveness of continuous glucose monitoring in both applications is critically dependent on the accuracy and reliability of the data produced."
In a previous comparative trial with 2,360 reference values, Dr. Russell of the department of medicine at the Massachusetts General Hospital Diabetes Center in Boston and his associates compared three continuous glucose monitoring (CGM) devices: the FreeStyle Navigator (Abbott Diabetes Care; approved in March of 2008), the Seven Plus (DexCom; received premarket approval in November of 2010), and the Guardian (Medtronic; approved in July 2006), which were worn simultaneously by six subjects with type 1 diabetes (Diabetes Care 2013;36:251-9). The FreeStyle Navigator had the best overall accuracy, with an aggregate mean absolute relative difference (MARD) in plasma glucose, relative to venous levels, of all paired points of 11.8%. The Seven Plus and Guardian produced aggregate MARDs of all paired points of 16.5% and 20.3%, respectively.
For the current comparative study with 4,657 reference values, the researchers compared three CGM devices: the G4 Platinum (DexCom; approved in October of 2012), Enlite (Medtronic; not yet available in the United States), and the FreeStyle Navigator, which were worn simultaneously over a 2-day period by 23 volunteers participating in a trial of blood glucose control with a closed-loop artificial pancreas. Every 15 minutes, the researchers obtained venous glucose measurements and paired them in time with the CGM measurements.
Dr. Russell reported that the G4 Platinum and the FreeStyle Navigator had similar accuracy, with an aggregate MARD of 10.8% and 12.3%, respectively, while the aggregate MARD for the Enlite was 17.9%. Data reporting percentages, which the researchers described as a "measure of reliability," were 99.7% for the G4 Platinum, 99.7% for the FreeStyle Navigator, and 97.1% for the Enlite.
However, Dr. Russell noted, CGM calibration errors remain a problem, one that if not resolved will prevent closed-loop systems from use outside a controlled research setting. For example, when the Navigator calibrated at a time when blood glucose was rising sharply, it overestimated glucose for the rest of the day. On the other hand, calibration corrected low readings by the Navigator in another instance. Compared with the earlier comparison study, "the G4 Platinum accuracy is markedly improved over the Seven Plus, and slightly better than the Navigator, and markedly better than the Enlite." However, for all the sensors, "calibration remains an important and, I think, preventable source of error."
The study was supported by the National Institutes of Health, and several research foundations. Technical and material support came from DexCom, Tandem Diabetes, SweetSpot Diabetes, International Biomedical, Hospira, Abbott, Insulet, and Medtronic. Dr. Russell has received research support from Abbott, Dexcom, Insulet, International Biomedical, and Medtronic, and MiniMed.
Current generation continuous glucose monitoring devices continue to improve in accuracy and performance, judging from the results from a comparative study
"Continuous glucose monitoring can improve glucose control when used as an adjunct to intermittent self-monitoring of blood glucose and is a critical component of bionic pancreas devices for automated glucose control," Dr. Steven J. Russell reported during the annual scientific sessions of the American Diabetes Association. "The effectiveness of continuous glucose monitoring in both applications is critically dependent on the accuracy and reliability of the data produced."
In a previous comparative trial with 2,360 reference values, Dr. Russell of the department of medicine at the Massachusetts General Hospital Diabetes Center in Boston and his associates compared three continuous glucose monitoring (CGM) devices: the FreeStyle Navigator (Abbott Diabetes Care; approved in March of 2008), the Seven Plus (DexCom; received premarket approval in November of 2010), and the Guardian (Medtronic; approved in July 2006), which were worn simultaneously by six subjects with type 1 diabetes (Diabetes Care 2013;36:251-9). The FreeStyle Navigator had the best overall accuracy, with an aggregate mean absolute relative difference (MARD) in plasma glucose, relative to venous levels, of all paired points of 11.8%. The Seven Plus and Guardian produced aggregate MARDs of all paired points of 16.5% and 20.3%, respectively.
For the current comparative study with 4,657 reference values, the researchers compared three CGM devices: the G4 Platinum (DexCom; approved in October of 2012), Enlite (Medtronic; not yet available in the United States), and the FreeStyle Navigator, which were worn simultaneously over a 2-day period by 23 volunteers participating in a trial of blood glucose control with a closed-loop artificial pancreas. Every 15 minutes, the researchers obtained venous glucose measurements and paired them in time with the CGM measurements.
Dr. Russell reported that the G4 Platinum and the FreeStyle Navigator had similar accuracy, with an aggregate MARD of 10.8% and 12.3%, respectively, while the aggregate MARD for the Enlite was 17.9%. Data reporting percentages, which the researchers described as a "measure of reliability," were 99.7% for the G4 Platinum, 99.7% for the FreeStyle Navigator, and 97.1% for the Enlite.
However, Dr. Russell noted, CGM calibration errors remain a problem, one that if not resolved will prevent closed-loop systems from use outside a controlled research setting. For example, when the Navigator calibrated at a time when blood glucose was rising sharply, it overestimated glucose for the rest of the day. On the other hand, calibration corrected low readings by the Navigator in another instance. Compared with the earlier comparison study, "the G4 Platinum accuracy is markedly improved over the Seven Plus, and slightly better than the Navigator, and markedly better than the Enlite." However, for all the sensors, "calibration remains an important and, I think, preventable source of error."
The study was supported by the National Institutes of Health, and several research foundations. Technical and material support came from DexCom, Tandem Diabetes, SweetSpot Diabetes, International Biomedical, Hospira, Abbott, Insulet, and Medtronic. Dr. Russell has received research support from Abbott, Dexcom, Insulet, International Biomedical, and Medtronic, and MiniMed.
FROM THE ADA ANNUAL SCIENTIFIC SESSIONS
Major finding: In a comparative study of three continuous glucose monitoring devices, the G4 Platinum and the FreeStyle Navigator had similar accuracy, with aggregate mean absolute relative differences (MARD) of all paired points of 10.8% and 12.5%, respectively, while the Enlite had a MARD of 18.2%.
Data source: A head-to-head comparison study conducted in 23 volunteers who wore the devices simultaneously over a 2-day period.
Disclosures: The study was supported by the National Institutes of Health, and several research foundations. Technical and material support came from DexCom, Tandem Diabetes, SweetSpot Diabetes, International Biomedical, Hospira, Abbott, Insulet, and Medtronic. Dr. Russell has received research support from Abbott, Dexcom, Insulet, International Biomedical, and Medtronic, and MiniMed.
CT angiography predicts cardiac events long-term in diabetics
CHICAGO – Coronary computed tomography angiography provides long-term prognostic information and may predict hard cardiac events in patients with diabetes and suspected coronary artery disease, judging from findings from a new study.
Specifically, diabetic patients with no CT evidence of coronary artery disease (CAD) had an excellent prognosis, with no cardiac events recorded over 62 months of follow-up.
In contrast, cumulative event-free survival rates for hard cardiac events and all cardiac events were 78% and 56% in patients with nonobstructive CAD, and 60% and 16% in those with obstructive CAD (P = .0001), Dr. Daniele Andreini reported at the annual scientific sessions of the American Diabetes Association.
"The excellent outcome in diabetic patients with completely absent [disease findings on] CTs is clinically relevant because it suggests that CT angiography can help to identify the truly low-risk patient, and can be used to reassure regarding the outcome of diabetes with suspicion of coronary artery disease, with a warranty period of 5 years," said Dr. Andreini of Istituto di Ricovero e Cura a Carattere Scientifico, Milan.
The study provides much-needed data on the long-term prognostic role of CT angiography in diabetic patients, with just two prior studies limited to 20 and 33 months’ follow-up reporting that multidetector CT angiography can predict major adverse events (Diabetes Care. 2010;33:1358-63 and Radiology 2010;256:83-92).
Session moderator Dr. William Cefalu, chief and professor of endocrinology, diabetes, and metabolism at Louisiana State University, New Orleans, asked how likely it is that clinicians will order CT screening in diabetics in light of the controversy over screening asymptomatic patients.
The American Heart Association, American College of Cardiology, and Society for Computed Tomography have recommended against the use of CT angiography for screening, especially in nonsymptomatic patients, responded Dr. Andreini, "But I am not so sure that this is correct in diabetes." He suggested that screening in this subset of patients can be performed with a very low dose of less than 1 millisievert of ionizing radiation, and that "other methods we use to screen diabetics are completely lacking in accuracy."
In a separate interview, Dr. Cefalu said the study was well characterized and the analysis comprehensive but that it may be a matter of comparing apples to oranges in terms of translating the results to the community where CT machine settings and precision varies. The other question is how cost effective screening would be.
"Whether this can be applicable in the community, it has to be cost effective, it has to be precise and it has to have prognostic value, and for a lot of the CT scans we have in the community, we don’t have that information just yet for translating these findings to the community," he said.
Study details
The study involved 429 consecutive patients with diabetes who were prospectively enrolled after presenting to an outpatient clinic or were admitted to hospital for cardiac evaluation for new onset chest pain (35%), abnormal stress test (27%), or multiple cardiovascular risk factors (27%). All multidetector CT coronary angiography exams were performed with a 64-slice scanner (VCT, GE Medical Systems), with dose modulation attained with electrocardiographic gaiting. Images were analyzed via multiplanar reconstruction on postprocessing work stations and interpreted by two expert readers, who were blinded to the patients’ clinical data. The mean effective radiation dose of the exams was 8.7 mSv.
The patients’ mean age was 65 years, mean body mass index 27.2 kg/m2, and 33% had a high pretest likelihood of CAD.
Among 390 evaluable patients, 90 patients had no coronary disease, 69 nonobstructive (<50%) CAD, and 231 obstructive (at least 50%) disease.
After an average clinical follow-up of 62 months, 279 events occurred, of which 117 were hard events (9 cardiac deaths, 66 nonfatal myocardial infarctions, and 42 unstable anginas) and 162 late revascularizations, Dr Andreini said.
In multivariate analysis, significant independent predictors of hard cardiac events were: three-vessel disease at least 50% (hazard ratio 5.21; P = .01), left main coronary artery disease at least 50% (HR 5.35; P = .01), and the number of segments with noncalcified (HR 1.84; P less than .0001), mixed (HR 1.39; P =.003), and calcified plaques (HR 1.62; P less than .0001).
Significant independent predictors of all cardiac events (including revascularization) were one-vessel disease (HR 3.94; P = .006), two-vessel disease (HR 4.82; P = .0001), three-vessel disease (HR 7.93; P less than .0001), left main CAD (HR 7.92; P = .005) and number of segments with mixed (HR 1.40; P less than .0001), and calcified (HR 1.18; P = .01) plaques, he reported.
Dr. Andreini and a coauthor reported serving on the speakers bureau for GE Healthcare.
CHICAGO – Coronary computed tomography angiography provides long-term prognostic information and may predict hard cardiac events in patients with diabetes and suspected coronary artery disease, judging from findings from a new study.
Specifically, diabetic patients with no CT evidence of coronary artery disease (CAD) had an excellent prognosis, with no cardiac events recorded over 62 months of follow-up.
In contrast, cumulative event-free survival rates for hard cardiac events and all cardiac events were 78% and 56% in patients with nonobstructive CAD, and 60% and 16% in those with obstructive CAD (P = .0001), Dr. Daniele Andreini reported at the annual scientific sessions of the American Diabetes Association.
"The excellent outcome in diabetic patients with completely absent [disease findings on] CTs is clinically relevant because it suggests that CT angiography can help to identify the truly low-risk patient, and can be used to reassure regarding the outcome of diabetes with suspicion of coronary artery disease, with a warranty period of 5 years," said Dr. Andreini of Istituto di Ricovero e Cura a Carattere Scientifico, Milan.
The study provides much-needed data on the long-term prognostic role of CT angiography in diabetic patients, with just two prior studies limited to 20 and 33 months’ follow-up reporting that multidetector CT angiography can predict major adverse events (Diabetes Care. 2010;33:1358-63 and Radiology 2010;256:83-92).
Session moderator Dr. William Cefalu, chief and professor of endocrinology, diabetes, and metabolism at Louisiana State University, New Orleans, asked how likely it is that clinicians will order CT screening in diabetics in light of the controversy over screening asymptomatic patients.
The American Heart Association, American College of Cardiology, and Society for Computed Tomography have recommended against the use of CT angiography for screening, especially in nonsymptomatic patients, responded Dr. Andreini, "But I am not so sure that this is correct in diabetes." He suggested that screening in this subset of patients can be performed with a very low dose of less than 1 millisievert of ionizing radiation, and that "other methods we use to screen diabetics are completely lacking in accuracy."
In a separate interview, Dr. Cefalu said the study was well characterized and the analysis comprehensive but that it may be a matter of comparing apples to oranges in terms of translating the results to the community where CT machine settings and precision varies. The other question is how cost effective screening would be.
"Whether this can be applicable in the community, it has to be cost effective, it has to be precise and it has to have prognostic value, and for a lot of the CT scans we have in the community, we don’t have that information just yet for translating these findings to the community," he said.
Study details
The study involved 429 consecutive patients with diabetes who were prospectively enrolled after presenting to an outpatient clinic or were admitted to hospital for cardiac evaluation for new onset chest pain (35%), abnormal stress test (27%), or multiple cardiovascular risk factors (27%). All multidetector CT coronary angiography exams were performed with a 64-slice scanner (VCT, GE Medical Systems), with dose modulation attained with electrocardiographic gaiting. Images were analyzed via multiplanar reconstruction on postprocessing work stations and interpreted by two expert readers, who were blinded to the patients’ clinical data. The mean effective radiation dose of the exams was 8.7 mSv.
The patients’ mean age was 65 years, mean body mass index 27.2 kg/m2, and 33% had a high pretest likelihood of CAD.
Among 390 evaluable patients, 90 patients had no coronary disease, 69 nonobstructive (<50%) CAD, and 231 obstructive (at least 50%) disease.
After an average clinical follow-up of 62 months, 279 events occurred, of which 117 were hard events (9 cardiac deaths, 66 nonfatal myocardial infarctions, and 42 unstable anginas) and 162 late revascularizations, Dr Andreini said.
In multivariate analysis, significant independent predictors of hard cardiac events were: three-vessel disease at least 50% (hazard ratio 5.21; P = .01), left main coronary artery disease at least 50% (HR 5.35; P = .01), and the number of segments with noncalcified (HR 1.84; P less than .0001), mixed (HR 1.39; P =.003), and calcified plaques (HR 1.62; P less than .0001).
Significant independent predictors of all cardiac events (including revascularization) were one-vessel disease (HR 3.94; P = .006), two-vessel disease (HR 4.82; P = .0001), three-vessel disease (HR 7.93; P less than .0001), left main CAD (HR 7.92; P = .005) and number of segments with mixed (HR 1.40; P less than .0001), and calcified (HR 1.18; P = .01) plaques, he reported.
Dr. Andreini and a coauthor reported serving on the speakers bureau for GE Healthcare.
CHICAGO – Coronary computed tomography angiography provides long-term prognostic information and may predict hard cardiac events in patients with diabetes and suspected coronary artery disease, judging from findings from a new study.
Specifically, diabetic patients with no CT evidence of coronary artery disease (CAD) had an excellent prognosis, with no cardiac events recorded over 62 months of follow-up.
In contrast, cumulative event-free survival rates for hard cardiac events and all cardiac events were 78% and 56% in patients with nonobstructive CAD, and 60% and 16% in those with obstructive CAD (P = .0001), Dr. Daniele Andreini reported at the annual scientific sessions of the American Diabetes Association.
"The excellent outcome in diabetic patients with completely absent [disease findings on] CTs is clinically relevant because it suggests that CT angiography can help to identify the truly low-risk patient, and can be used to reassure regarding the outcome of diabetes with suspicion of coronary artery disease, with a warranty period of 5 years," said Dr. Andreini of Istituto di Ricovero e Cura a Carattere Scientifico, Milan.
The study provides much-needed data on the long-term prognostic role of CT angiography in diabetic patients, with just two prior studies limited to 20 and 33 months’ follow-up reporting that multidetector CT angiography can predict major adverse events (Diabetes Care. 2010;33:1358-63 and Radiology 2010;256:83-92).
Session moderator Dr. William Cefalu, chief and professor of endocrinology, diabetes, and metabolism at Louisiana State University, New Orleans, asked how likely it is that clinicians will order CT screening in diabetics in light of the controversy over screening asymptomatic patients.
The American Heart Association, American College of Cardiology, and Society for Computed Tomography have recommended against the use of CT angiography for screening, especially in nonsymptomatic patients, responded Dr. Andreini, "But I am not so sure that this is correct in diabetes." He suggested that screening in this subset of patients can be performed with a very low dose of less than 1 millisievert of ionizing radiation, and that "other methods we use to screen diabetics are completely lacking in accuracy."
In a separate interview, Dr. Cefalu said the study was well characterized and the analysis comprehensive but that it may be a matter of comparing apples to oranges in terms of translating the results to the community where CT machine settings and precision varies. The other question is how cost effective screening would be.
"Whether this can be applicable in the community, it has to be cost effective, it has to be precise and it has to have prognostic value, and for a lot of the CT scans we have in the community, we don’t have that information just yet for translating these findings to the community," he said.
Study details
The study involved 429 consecutive patients with diabetes who were prospectively enrolled after presenting to an outpatient clinic or were admitted to hospital for cardiac evaluation for new onset chest pain (35%), abnormal stress test (27%), or multiple cardiovascular risk factors (27%). All multidetector CT coronary angiography exams were performed with a 64-slice scanner (VCT, GE Medical Systems), with dose modulation attained with electrocardiographic gaiting. Images were analyzed via multiplanar reconstruction on postprocessing work stations and interpreted by two expert readers, who were blinded to the patients’ clinical data. The mean effective radiation dose of the exams was 8.7 mSv.
The patients’ mean age was 65 years, mean body mass index 27.2 kg/m2, and 33% had a high pretest likelihood of CAD.
Among 390 evaluable patients, 90 patients had no coronary disease, 69 nonobstructive (<50%) CAD, and 231 obstructive (at least 50%) disease.
After an average clinical follow-up of 62 months, 279 events occurred, of which 117 were hard events (9 cardiac deaths, 66 nonfatal myocardial infarctions, and 42 unstable anginas) and 162 late revascularizations, Dr Andreini said.
In multivariate analysis, significant independent predictors of hard cardiac events were: three-vessel disease at least 50% (hazard ratio 5.21; P = .01), left main coronary artery disease at least 50% (HR 5.35; P = .01), and the number of segments with noncalcified (HR 1.84; P less than .0001), mixed (HR 1.39; P =.003), and calcified plaques (HR 1.62; P less than .0001).
Significant independent predictors of all cardiac events (including revascularization) were one-vessel disease (HR 3.94; P = .006), two-vessel disease (HR 4.82; P = .0001), three-vessel disease (HR 7.93; P less than .0001), left main CAD (HR 7.92; P = .005) and number of segments with mixed (HR 1.40; P less than .0001), and calcified (HR 1.18; P = .01) plaques, he reported.
Dr. Andreini and a coauthor reported serving on the speakers bureau for GE Healthcare.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Major finding: Cumulative event-free survival for patients with normal coronary arteries on CT was 100% for hard cardiac events and all cardiac events.
Data source: Retrospective analysis of 405 consecutive patients with diabetes undergoing computed tomography coronary angiography for suspected coronary artery disease.
Disclosures: Dr. Andreini and a coauthor reported serving on the speakers bureau for GE Healthcare.
Investigational basal insulin has less nocturnal hypoglycemia
CHICAGO – A new longer-acting basal insulin glargine formulation was as effective as the familiar insulin glargine 100 U/mL/Lantus in controlling glycemia while producing a 21% lower rate of severe nocturnal hypoglycemic events in the phase III EDITION I trial.
The investigational formulation contains insulin glargine 300 U/mL and is known as U300. Like insulin glargine U100, the investigational agent is a once-daily, long-acting insulin analog. But U300 has an even flatter, longer, and more stable pharmacodynamic profile, which translates into a lower risk of hypoglycemia, as shown in the EDITION I trial, principal investigator Dr. Matthew C. Riddle explained at the annual scientific sessions of the American Diabetes Association.
EDITION I included 807 adults with type 2 diabetes who were on an established treatment with at least 42 U/day of basal glargine or NPH along with mealtime insulin with or without metformin. Their mean duration of diabetes was 15.8 years, and their mean body mass index was 36.6 kg/m2. They were randomized to 6 months of open-label insulin glargine U300 or insulin glargine U100 once daily in the evening while continuing on their mealtime insulin. The basal insulin was titrated to achieve a fasting plasma glucose of 80-100 mg/dL.
The primary efficacy endpoint was change in hemoglobin A1c from baseline through month 6. The reductions were the same in both groups: a mean decrease of 0.83%.
The chief secondary endpoint was the occurrence of one or more episodes of severe and/or confirmed nocturnal hypoglycemia to a level of 70 mg/dL or less during months 3-6. The rate was 36.1% in the U300 group, compared with 46% with U100, for a highly significant 21% risk reduction, said Dr. Riddle, professor of medicine at the Oregon Health and Science Center, Portland.
Any nocturnal hypoglycemia during the 6-month study occurred in 45.3% of patients on U300 vs. 59.7% on U100, for a 24% relative risk reduction, he added.
EDITION I is the first in a large worldwide series of phase III trials of the investigational insulin. The recently completed EDITION II trial replicated the EDITION I findings blood glucose reductions similar to those seen in patients taking Lantus, with fewer serious nocturnal hypoglycemic events – in 811 type 2 diabetic patients with earlier-stage disease as evidenced by the enrollment requirement that they be established on basal insulin and oral antidiabetic therapy. EDITION III is ongoing in insulin-naive type 2 diabetic patients, EDITION IV focuses on patients with type 1 diabetes, and EDITION JP I and II are ongoing in Japan. These trials are designed to assess the relative performance of U100 and the investigational insulin in a range of common clinical scenarios.
"The question is what proportion of patients is going to have a clinically relevant difference in success with the new formulation versus the old one. I don’t know the answer to that yet," Dr. Riddle said in an interview. "U100 has been a really successful insulin, and the likelihood of it going away is really, really low. We’ll probably end up dividing the basal insulin patients into a good many continuing on Lantus U100, and a good many others using newer, longer-acting insulins, U300 being one, but not the only one. When affordability is an issue, taking any insulin is better than not taking it at all."
Dr. Riddle receives research grant support from and is paid consultant to several pharmaceutical companies, among them Sanofi, which sponsors the EDITION trials.
CHICAGO – A new longer-acting basal insulin glargine formulation was as effective as the familiar insulin glargine 100 U/mL/Lantus in controlling glycemia while producing a 21% lower rate of severe nocturnal hypoglycemic events in the phase III EDITION I trial.
The investigational formulation contains insulin glargine 300 U/mL and is known as U300. Like insulin glargine U100, the investigational agent is a once-daily, long-acting insulin analog. But U300 has an even flatter, longer, and more stable pharmacodynamic profile, which translates into a lower risk of hypoglycemia, as shown in the EDITION I trial, principal investigator Dr. Matthew C. Riddle explained at the annual scientific sessions of the American Diabetes Association.
EDITION I included 807 adults with type 2 diabetes who were on an established treatment with at least 42 U/day of basal glargine or NPH along with mealtime insulin with or without metformin. Their mean duration of diabetes was 15.8 years, and their mean body mass index was 36.6 kg/m2. They were randomized to 6 months of open-label insulin glargine U300 or insulin glargine U100 once daily in the evening while continuing on their mealtime insulin. The basal insulin was titrated to achieve a fasting plasma glucose of 80-100 mg/dL.
The primary efficacy endpoint was change in hemoglobin A1c from baseline through month 6. The reductions were the same in both groups: a mean decrease of 0.83%.
The chief secondary endpoint was the occurrence of one or more episodes of severe and/or confirmed nocturnal hypoglycemia to a level of 70 mg/dL or less during months 3-6. The rate was 36.1% in the U300 group, compared with 46% with U100, for a highly significant 21% risk reduction, said Dr. Riddle, professor of medicine at the Oregon Health and Science Center, Portland.
Any nocturnal hypoglycemia during the 6-month study occurred in 45.3% of patients on U300 vs. 59.7% on U100, for a 24% relative risk reduction, he added.
EDITION I is the first in a large worldwide series of phase III trials of the investigational insulin. The recently completed EDITION II trial replicated the EDITION I findings blood glucose reductions similar to those seen in patients taking Lantus, with fewer serious nocturnal hypoglycemic events – in 811 type 2 diabetic patients with earlier-stage disease as evidenced by the enrollment requirement that they be established on basal insulin and oral antidiabetic therapy. EDITION III is ongoing in insulin-naive type 2 diabetic patients, EDITION IV focuses on patients with type 1 diabetes, and EDITION JP I and II are ongoing in Japan. These trials are designed to assess the relative performance of U100 and the investigational insulin in a range of common clinical scenarios.
"The question is what proportion of patients is going to have a clinically relevant difference in success with the new formulation versus the old one. I don’t know the answer to that yet," Dr. Riddle said in an interview. "U100 has been a really successful insulin, and the likelihood of it going away is really, really low. We’ll probably end up dividing the basal insulin patients into a good many continuing on Lantus U100, and a good many others using newer, longer-acting insulins, U300 being one, but not the only one. When affordability is an issue, taking any insulin is better than not taking it at all."
Dr. Riddle receives research grant support from and is paid consultant to several pharmaceutical companies, among them Sanofi, which sponsors the EDITION trials.
CHICAGO – A new longer-acting basal insulin glargine formulation was as effective as the familiar insulin glargine 100 U/mL/Lantus in controlling glycemia while producing a 21% lower rate of severe nocturnal hypoglycemic events in the phase III EDITION I trial.
The investigational formulation contains insulin glargine 300 U/mL and is known as U300. Like insulin glargine U100, the investigational agent is a once-daily, long-acting insulin analog. But U300 has an even flatter, longer, and more stable pharmacodynamic profile, which translates into a lower risk of hypoglycemia, as shown in the EDITION I trial, principal investigator Dr. Matthew C. Riddle explained at the annual scientific sessions of the American Diabetes Association.
EDITION I included 807 adults with type 2 diabetes who were on an established treatment with at least 42 U/day of basal glargine or NPH along with mealtime insulin with or without metformin. Their mean duration of diabetes was 15.8 years, and their mean body mass index was 36.6 kg/m2. They were randomized to 6 months of open-label insulin glargine U300 or insulin glargine U100 once daily in the evening while continuing on their mealtime insulin. The basal insulin was titrated to achieve a fasting plasma glucose of 80-100 mg/dL.
The primary efficacy endpoint was change in hemoglobin A1c from baseline through month 6. The reductions were the same in both groups: a mean decrease of 0.83%.
The chief secondary endpoint was the occurrence of one or more episodes of severe and/or confirmed nocturnal hypoglycemia to a level of 70 mg/dL or less during months 3-6. The rate was 36.1% in the U300 group, compared with 46% with U100, for a highly significant 21% risk reduction, said Dr. Riddle, professor of medicine at the Oregon Health and Science Center, Portland.
Any nocturnal hypoglycemia during the 6-month study occurred in 45.3% of patients on U300 vs. 59.7% on U100, for a 24% relative risk reduction, he added.
EDITION I is the first in a large worldwide series of phase III trials of the investigational insulin. The recently completed EDITION II trial replicated the EDITION I findings blood glucose reductions similar to those seen in patients taking Lantus, with fewer serious nocturnal hypoglycemic events – in 811 type 2 diabetic patients with earlier-stage disease as evidenced by the enrollment requirement that they be established on basal insulin and oral antidiabetic therapy. EDITION III is ongoing in insulin-naive type 2 diabetic patients, EDITION IV focuses on patients with type 1 diabetes, and EDITION JP I and II are ongoing in Japan. These trials are designed to assess the relative performance of U100 and the investigational insulin in a range of common clinical scenarios.
"The question is what proportion of patients is going to have a clinically relevant difference in success with the new formulation versus the old one. I don’t know the answer to that yet," Dr. Riddle said in an interview. "U100 has been a really successful insulin, and the likelihood of it going away is really, really low. We’ll probably end up dividing the basal insulin patients into a good many continuing on Lantus U100, and a good many others using newer, longer-acting insulins, U300 being one, but not the only one. When affordability is an issue, taking any insulin is better than not taking it at all."
Dr. Riddle receives research grant support from and is paid consultant to several pharmaceutical companies, among them Sanofi, which sponsors the EDITION trials.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Major Finding: An investigational longer-acting insulin glargine formulation resulted in equivalent glucose control with a 21% reduction in the risk of severe nocturnal hypoglycemic events, compared with insulin glargine 100 U/mL (Lantus) in type 2 diabetes patients.
Data Source: EDITION I, a 6-month, open-label, phase III randomized trial in 807 patients with type 2 diabetes on mealtime and basal insulin with or without oral therapy.
Disclosures: The EDITION I trial was sponsored by Sanofi. The presenter is a consultant to Sanofi and several other pharmaceutical companies.
Initial triple-drug therapy best in new T2DM
CHICAGO – Starting patients with newly diagnosed type 2 diabetes on the combination of metformin, pioglitazone, and exenatide from the get-go proved superior to standard guideline-recommended sequential add-on therapy with metformin, a sulfonylurea, and basal insulin in a 2-year randomized trial.
The triple-therapy group achieved significantly greater and more durable reductions in hemoglobin A1c with less risk of hypoglycemia than patients on the conventional treatment strategy. They also experienced weight loss rather than the weight gain seen with conventional management, Dr. Muhammad A. Abdul-Ghani reported at the annual scientific sessions of the American Diabetes Association.
The observed differences in therapeutic effectiveness and safety validate the strategy behind initial triple therapy, namely that it’s better to target the insulin resistance and progressive beta cell failure that constitute the core metabolic defects responsible for hyperglycemia and type 2 diabetes instead of simply focusing on lowering plasma glucose, added Dr. Abdul-Ghani of the University of Texas Health Science Center, San Antonio.
"My take home message for you is when you treat people with type 2 diabetes, treat the disease – diabetes – not the symptom of hyperglycemia," he declared.
The open-label study comprised 155 patients who had been recently diagnosed with type 2 diabetes. Average age was 47 years, average body mass index was 30.5 kg/m2, and average baseline HbA1c was 8.6%. Those randomized to triple therapy started on metformin at 1,000 mg/day, pioglitazone at 15 mg/day, and exenatide at 5 mcg twice daily. After 1 month, the doses of all three drugs were doubled. If 3 months into the study a patient hadn’t achieved the goal of an HbA1c below 6.5%, pioglitazone was boosted to 45 mg/day.
The conventional treatment group started on metformin followed by sequential addition of glipizide and then basal insulin as needed in an effort to reach an HbA1c below 6.5%.
The primary outcome was the HbA1c difference between the two groups at 2 years. The mean HbA1c decreased from 8.6% at baseline to 6% in the triple-therapy group, significantly better than the 6.6% with conventional therapy. The median HbA1c was 5.8% with triple therapy compared to 6.4% with add-on therapy. In the triple therapy group, 60% had an HbA1c below 6% compared to 27% of controls. In the triple therapy, 92% met the ADA target of an HbA1c below 7% compared to 72% on conventional therapy.
Participants were seen in the clinic every 3 months. Treatment failure, defined as an HbA1c above 6.5% on two consecutive visits 3 months apart, occurred in 17% of the triple-therapy group and 42% on conventional therapy.
Even though the mean HbA1c was 0.5% lower in the triple-therapy group, their incidence of hypoglycemia over the course of 2 years was also significantly lower: 15% versus 46% in the conventional therapy group, the diabetologist continued.
Patients receiving triple therapy had a mean 1.2-kg weight loss over 24 months versus a 4.1-kg weight gain with conventional therapy.
In a multivariate regression analysis, triple-therapy was associated with an 84% reduction in the risk of treatment failure. The other protective factor was age: for each decade beyond age 40 years, a patient’s risk of treatment failure was reduced by 64%.
"We don’t know yet whether this is an issue of patient compliance with therapy or there is something in the pathophysiology of the disease that makes age protective against treatment failure," Dr. Abdul-Ghani said.
Metformin was selected for inclusion in the triple-drug regimen because it corrects insulin resistance in the liver, pioglitazone because it corrects insulin resistance in adipocytes and muscle along with preserving beta cell function, and exenatide because it enhances beta cell function, the physician explained.
Several audience members called the study controversial, noting that it was a single-center study with fewer than 200 patients, yet it aims to overturn current guideline-based clinical practice.
In an interview, Dr. Abdul-Ghani said he and his coinvestigators are trying to drum up support for a larger, multicenter follow-up study featuring microvascular complications as a primary endpoint.
"Every novel approach is controversial at first. But if the difference we’ve seen in A1c can be maintained for longer than 24 months it could result in a substantially reduced risk of microvascular complications. That would really be a game changer in terms of attitudes toward patient treatment," he observed.
He added that even in the absence of data showing a reduction in retinopathy and other microvascular complications, he would "absolutely" recommend that physicians start applying initial triple therapy in their patients with newly diagnosed type 2 diabetes.
"Our data are so strong: there is no increased risk, and so many benefits," according to Dr. Abdul-Ghani.
Both metformin and pioglitazone are available as low-cost generics, and with so many new GLP-1 agonists in the developmental pipeline, the cost of an older, twice-daily agent such as exenatide might come down, he said.
The study was funded by the American Diabetes Association with support from Amylin Pharmaceuticals and Takeda. Dr. Abdul-Ghani reported having no conflicts of interest.
CHICAGO – Starting patients with newly diagnosed type 2 diabetes on the combination of metformin, pioglitazone, and exenatide from the get-go proved superior to standard guideline-recommended sequential add-on therapy with metformin, a sulfonylurea, and basal insulin in a 2-year randomized trial.
The triple-therapy group achieved significantly greater and more durable reductions in hemoglobin A1c with less risk of hypoglycemia than patients on the conventional treatment strategy. They also experienced weight loss rather than the weight gain seen with conventional management, Dr. Muhammad A. Abdul-Ghani reported at the annual scientific sessions of the American Diabetes Association.
The observed differences in therapeutic effectiveness and safety validate the strategy behind initial triple therapy, namely that it’s better to target the insulin resistance and progressive beta cell failure that constitute the core metabolic defects responsible for hyperglycemia and type 2 diabetes instead of simply focusing on lowering plasma glucose, added Dr. Abdul-Ghani of the University of Texas Health Science Center, San Antonio.
"My take home message for you is when you treat people with type 2 diabetes, treat the disease – diabetes – not the symptom of hyperglycemia," he declared.
The open-label study comprised 155 patients who had been recently diagnosed with type 2 diabetes. Average age was 47 years, average body mass index was 30.5 kg/m2, and average baseline HbA1c was 8.6%. Those randomized to triple therapy started on metformin at 1,000 mg/day, pioglitazone at 15 mg/day, and exenatide at 5 mcg twice daily. After 1 month, the doses of all three drugs were doubled. If 3 months into the study a patient hadn’t achieved the goal of an HbA1c below 6.5%, pioglitazone was boosted to 45 mg/day.
The conventional treatment group started on metformin followed by sequential addition of glipizide and then basal insulin as needed in an effort to reach an HbA1c below 6.5%.
The primary outcome was the HbA1c difference between the two groups at 2 years. The mean HbA1c decreased from 8.6% at baseline to 6% in the triple-therapy group, significantly better than the 6.6% with conventional therapy. The median HbA1c was 5.8% with triple therapy compared to 6.4% with add-on therapy. In the triple therapy group, 60% had an HbA1c below 6% compared to 27% of controls. In the triple therapy, 92% met the ADA target of an HbA1c below 7% compared to 72% on conventional therapy.
Participants were seen in the clinic every 3 months. Treatment failure, defined as an HbA1c above 6.5% on two consecutive visits 3 months apart, occurred in 17% of the triple-therapy group and 42% on conventional therapy.
Even though the mean HbA1c was 0.5% lower in the triple-therapy group, their incidence of hypoglycemia over the course of 2 years was also significantly lower: 15% versus 46% in the conventional therapy group, the diabetologist continued.
Patients receiving triple therapy had a mean 1.2-kg weight loss over 24 months versus a 4.1-kg weight gain with conventional therapy.
In a multivariate regression analysis, triple-therapy was associated with an 84% reduction in the risk of treatment failure. The other protective factor was age: for each decade beyond age 40 years, a patient’s risk of treatment failure was reduced by 64%.
"We don’t know yet whether this is an issue of patient compliance with therapy or there is something in the pathophysiology of the disease that makes age protective against treatment failure," Dr. Abdul-Ghani said.
Metformin was selected for inclusion in the triple-drug regimen because it corrects insulin resistance in the liver, pioglitazone because it corrects insulin resistance in adipocytes and muscle along with preserving beta cell function, and exenatide because it enhances beta cell function, the physician explained.
Several audience members called the study controversial, noting that it was a single-center study with fewer than 200 patients, yet it aims to overturn current guideline-based clinical practice.
In an interview, Dr. Abdul-Ghani said he and his coinvestigators are trying to drum up support for a larger, multicenter follow-up study featuring microvascular complications as a primary endpoint.
"Every novel approach is controversial at first. But if the difference we’ve seen in A1c can be maintained for longer than 24 months it could result in a substantially reduced risk of microvascular complications. That would really be a game changer in terms of attitudes toward patient treatment," he observed.
He added that even in the absence of data showing a reduction in retinopathy and other microvascular complications, he would "absolutely" recommend that physicians start applying initial triple therapy in their patients with newly diagnosed type 2 diabetes.
"Our data are so strong: there is no increased risk, and so many benefits," according to Dr. Abdul-Ghani.
Both metformin and pioglitazone are available as low-cost generics, and with so many new GLP-1 agonists in the developmental pipeline, the cost of an older, twice-daily agent such as exenatide might come down, he said.
The study was funded by the American Diabetes Association with support from Amylin Pharmaceuticals and Takeda. Dr. Abdul-Ghani reported having no conflicts of interest.
CHICAGO – Starting patients with newly diagnosed type 2 diabetes on the combination of metformin, pioglitazone, and exenatide from the get-go proved superior to standard guideline-recommended sequential add-on therapy with metformin, a sulfonylurea, and basal insulin in a 2-year randomized trial.
The triple-therapy group achieved significantly greater and more durable reductions in hemoglobin A1c with less risk of hypoglycemia than patients on the conventional treatment strategy. They also experienced weight loss rather than the weight gain seen with conventional management, Dr. Muhammad A. Abdul-Ghani reported at the annual scientific sessions of the American Diabetes Association.
The observed differences in therapeutic effectiveness and safety validate the strategy behind initial triple therapy, namely that it’s better to target the insulin resistance and progressive beta cell failure that constitute the core metabolic defects responsible for hyperglycemia and type 2 diabetes instead of simply focusing on lowering plasma glucose, added Dr. Abdul-Ghani of the University of Texas Health Science Center, San Antonio.
"My take home message for you is when you treat people with type 2 diabetes, treat the disease – diabetes – not the symptom of hyperglycemia," he declared.
The open-label study comprised 155 patients who had been recently diagnosed with type 2 diabetes. Average age was 47 years, average body mass index was 30.5 kg/m2, and average baseline HbA1c was 8.6%. Those randomized to triple therapy started on metformin at 1,000 mg/day, pioglitazone at 15 mg/day, and exenatide at 5 mcg twice daily. After 1 month, the doses of all three drugs were doubled. If 3 months into the study a patient hadn’t achieved the goal of an HbA1c below 6.5%, pioglitazone was boosted to 45 mg/day.
The conventional treatment group started on metformin followed by sequential addition of glipizide and then basal insulin as needed in an effort to reach an HbA1c below 6.5%.
The primary outcome was the HbA1c difference between the two groups at 2 years. The mean HbA1c decreased from 8.6% at baseline to 6% in the triple-therapy group, significantly better than the 6.6% with conventional therapy. The median HbA1c was 5.8% with triple therapy compared to 6.4% with add-on therapy. In the triple therapy group, 60% had an HbA1c below 6% compared to 27% of controls. In the triple therapy, 92% met the ADA target of an HbA1c below 7% compared to 72% on conventional therapy.
Participants were seen in the clinic every 3 months. Treatment failure, defined as an HbA1c above 6.5% on two consecutive visits 3 months apart, occurred in 17% of the triple-therapy group and 42% on conventional therapy.
Even though the mean HbA1c was 0.5% lower in the triple-therapy group, their incidence of hypoglycemia over the course of 2 years was also significantly lower: 15% versus 46% in the conventional therapy group, the diabetologist continued.
Patients receiving triple therapy had a mean 1.2-kg weight loss over 24 months versus a 4.1-kg weight gain with conventional therapy.
In a multivariate regression analysis, triple-therapy was associated with an 84% reduction in the risk of treatment failure. The other protective factor was age: for each decade beyond age 40 years, a patient’s risk of treatment failure was reduced by 64%.
"We don’t know yet whether this is an issue of patient compliance with therapy or there is something in the pathophysiology of the disease that makes age protective against treatment failure," Dr. Abdul-Ghani said.
Metformin was selected for inclusion in the triple-drug regimen because it corrects insulin resistance in the liver, pioglitazone because it corrects insulin resistance in adipocytes and muscle along with preserving beta cell function, and exenatide because it enhances beta cell function, the physician explained.
Several audience members called the study controversial, noting that it was a single-center study with fewer than 200 patients, yet it aims to overturn current guideline-based clinical practice.
In an interview, Dr. Abdul-Ghani said he and his coinvestigators are trying to drum up support for a larger, multicenter follow-up study featuring microvascular complications as a primary endpoint.
"Every novel approach is controversial at first. But if the difference we’ve seen in A1c can be maintained for longer than 24 months it could result in a substantially reduced risk of microvascular complications. That would really be a game changer in terms of attitudes toward patient treatment," he observed.
He added that even in the absence of data showing a reduction in retinopathy and other microvascular complications, he would "absolutely" recommend that physicians start applying initial triple therapy in their patients with newly diagnosed type 2 diabetes.
"Our data are so strong: there is no increased risk, and so many benefits," according to Dr. Abdul-Ghani.
Both metformin and pioglitazone are available as low-cost generics, and with so many new GLP-1 agonists in the developmental pipeline, the cost of an older, twice-daily agent such as exenatide might come down, he said.
The study was funded by the American Diabetes Association with support from Amylin Pharmaceuticals and Takeda. Dr. Abdul-Ghani reported having no conflicts of interest.
AT THE ADA ANNUAL SCIENTIFIC SESSIONS
Major Finding: Patients with recently diagnosed type 2 diabetes who were managed from the outset with the triple-drug combination of metformin, pioglitazone, and exenatide went from a mean A1c of 8.6% at baseline to 6% at 2 years, significantly better than the 6.6% achieved with conventional sequential add-on therapy with metformin, a sulfonylurea, and basal insulin.
Data Source: A single-center, open-label, randomized trial involving 155 patients with newly diagnosed type 2 diabetes.
Disclosures: The study was funded by the American Diabetes Association. The presenter reported having no financial conflicts.
