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Intensified approach reduces long-term heart failure risk in T2DM
LISBON – A 70% reduction in the risk of hospitalization for heart failure was achieved in people with type 2 diabetes mellitus (T2DM) given an intensified, multifactorial intervention versus conventional treatment in a long-term follow up of the STENO-2 study.
Over 21 years, 34 (21%) of 160 study subjects developed heart failure; 24 (30%) had initially been treated conventionally, and 10 (13%) had initially received intensive treatment. The annualized rates of heart failure were calculated as a respective 2.4% and 0.8% (hazard ratio, 0.30; P less than .002), Jens Øllgaard, PhD, reported at the annual meeting of the European Association for the Study of Diabetes.
Furthermore, after adjustment was made for subject age, gender, prohormone brain natriuretic peptide levels, and ejection fraction at recruitment, there was a 76% relative risk reduction in heart failure with the intensified strategy versus conventional treatment.
“Heart failure in diabetes is frequent, fatal, and at least until very recently, quite forgotten,” said Dr. Øllgaard, who presented the research performed while he was at the STENO Diabetes Center in Copenhagen.
Dr. Øllgaard, who now works for Novo Nordisk, noted that heart failure was four times more likely to occur in patients with T2DM who had microalbuminuria than in those with normal albumin levels in the urine, and the median survival was around 3.5 years. While there is no regulatory requirement at present to stipulate that heart failure should be assessed in trials looking at the cardiovascular safety of T2DM treatments, recording such information is something that the STENO-2 investigators would recommend.
STENO-2 was an open, parallel group study initiated in 1993 to compare conventional multifactorial treatment of T2DM with an intensified approach over an 8-year period. After the primary composite cardiovascular endpoint was assessed, the trial continued as an observational study, with all patients given the intensified, multifactorial treatment that consisted of lifestyle measures and medications targeting hyperglycemia, hypertension, hypercholesterolemia, and hypercoagulation.
The primary endpoint of the long-term follow-up study was the difference in median survival time between the original treatment groups with and without incident cardiovascular disease. The results showed a 48% relative reduction in the risk of death; those initially given the intensified treatment had an increased lifespan of 7.9 years and an 8.1-year increased survival without cardiovascular disease versus those who had initially received conventional treatment (Diabetologica 2016;59:2298-307).
Dr. Øllgaard presented data on heart failure outcomes obtained from a post-hoc analysis of prospectively collected and externally adjudicated patient records.
In addition to the reductions in the primary outcome of time to heart failure, the secondary outcomes of time to heart failure or cardiovascular mortality (HR, 0.38; P = .006) and heart failure or all-cause mortality (relative risk reduction, 49%; P = .001) also favored initial intensive treatment versus conventional treatment.
The number of patients who would need to be treated for 1 year to prevent one heart failure event was 63. The number needed to treat (NNT) to prevent heart failure or cardiovascular death was 48, and the NNT or heart failure or all-cause death was 37.
“Intensified, multifactorial intervention reduces the risk of heart failure and underlines the need for early, intensive treatment in these patients,” Dr. Øllgaard said. “Diabetologists should be aware of this increased risk and the early clinical signs and biomarkers of heart failure.” He added the study “also emphasizes the need for close collaboration, locally and globally, between endocrinologists and cardiologists.”
The STENO-2 long-term follow-up analysis was sponsored by an unrestricted grant from Novo Nordisk. Dr. Øllgaard disclosed being employed by Novo Nordisk after the submission of the abstract for presentation at the EASD meeting.
LISBON – A 70% reduction in the risk of hospitalization for heart failure was achieved in people with type 2 diabetes mellitus (T2DM) given an intensified, multifactorial intervention versus conventional treatment in a long-term follow up of the STENO-2 study.
Over 21 years, 34 (21%) of 160 study subjects developed heart failure; 24 (30%) had initially been treated conventionally, and 10 (13%) had initially received intensive treatment. The annualized rates of heart failure were calculated as a respective 2.4% and 0.8% (hazard ratio, 0.30; P less than .002), Jens Øllgaard, PhD, reported at the annual meeting of the European Association for the Study of Diabetes.
Furthermore, after adjustment was made for subject age, gender, prohormone brain natriuretic peptide levels, and ejection fraction at recruitment, there was a 76% relative risk reduction in heart failure with the intensified strategy versus conventional treatment.
“Heart failure in diabetes is frequent, fatal, and at least until very recently, quite forgotten,” said Dr. Øllgaard, who presented the research performed while he was at the STENO Diabetes Center in Copenhagen.
Dr. Øllgaard, who now works for Novo Nordisk, noted that heart failure was four times more likely to occur in patients with T2DM who had microalbuminuria than in those with normal albumin levels in the urine, and the median survival was around 3.5 years. While there is no regulatory requirement at present to stipulate that heart failure should be assessed in trials looking at the cardiovascular safety of T2DM treatments, recording such information is something that the STENO-2 investigators would recommend.
STENO-2 was an open, parallel group study initiated in 1993 to compare conventional multifactorial treatment of T2DM with an intensified approach over an 8-year period. After the primary composite cardiovascular endpoint was assessed, the trial continued as an observational study, with all patients given the intensified, multifactorial treatment that consisted of lifestyle measures and medications targeting hyperglycemia, hypertension, hypercholesterolemia, and hypercoagulation.
The primary endpoint of the long-term follow-up study was the difference in median survival time between the original treatment groups with and without incident cardiovascular disease. The results showed a 48% relative reduction in the risk of death; those initially given the intensified treatment had an increased lifespan of 7.9 years and an 8.1-year increased survival without cardiovascular disease versus those who had initially received conventional treatment (Diabetologica 2016;59:2298-307).
Dr. Øllgaard presented data on heart failure outcomes obtained from a post-hoc analysis of prospectively collected and externally adjudicated patient records.
In addition to the reductions in the primary outcome of time to heart failure, the secondary outcomes of time to heart failure or cardiovascular mortality (HR, 0.38; P = .006) and heart failure or all-cause mortality (relative risk reduction, 49%; P = .001) also favored initial intensive treatment versus conventional treatment.
The number of patients who would need to be treated for 1 year to prevent one heart failure event was 63. The number needed to treat (NNT) to prevent heart failure or cardiovascular death was 48, and the NNT or heart failure or all-cause death was 37.
“Intensified, multifactorial intervention reduces the risk of heart failure and underlines the need for early, intensive treatment in these patients,” Dr. Øllgaard said. “Diabetologists should be aware of this increased risk and the early clinical signs and biomarkers of heart failure.” He added the study “also emphasizes the need for close collaboration, locally and globally, between endocrinologists and cardiologists.”
The STENO-2 long-term follow-up analysis was sponsored by an unrestricted grant from Novo Nordisk. Dr. Øllgaard disclosed being employed by Novo Nordisk after the submission of the abstract for presentation at the EASD meeting.
LISBON – A 70% reduction in the risk of hospitalization for heart failure was achieved in people with type 2 diabetes mellitus (T2DM) given an intensified, multifactorial intervention versus conventional treatment in a long-term follow up of the STENO-2 study.
Over 21 years, 34 (21%) of 160 study subjects developed heart failure; 24 (30%) had initially been treated conventionally, and 10 (13%) had initially received intensive treatment. The annualized rates of heart failure were calculated as a respective 2.4% and 0.8% (hazard ratio, 0.30; P less than .002), Jens Øllgaard, PhD, reported at the annual meeting of the European Association for the Study of Diabetes.
Furthermore, after adjustment was made for subject age, gender, prohormone brain natriuretic peptide levels, and ejection fraction at recruitment, there was a 76% relative risk reduction in heart failure with the intensified strategy versus conventional treatment.
“Heart failure in diabetes is frequent, fatal, and at least until very recently, quite forgotten,” said Dr. Øllgaard, who presented the research performed while he was at the STENO Diabetes Center in Copenhagen.
Dr. Øllgaard, who now works for Novo Nordisk, noted that heart failure was four times more likely to occur in patients with T2DM who had microalbuminuria than in those with normal albumin levels in the urine, and the median survival was around 3.5 years. While there is no regulatory requirement at present to stipulate that heart failure should be assessed in trials looking at the cardiovascular safety of T2DM treatments, recording such information is something that the STENO-2 investigators would recommend.
STENO-2 was an open, parallel group study initiated in 1993 to compare conventional multifactorial treatment of T2DM with an intensified approach over an 8-year period. After the primary composite cardiovascular endpoint was assessed, the trial continued as an observational study, with all patients given the intensified, multifactorial treatment that consisted of lifestyle measures and medications targeting hyperglycemia, hypertension, hypercholesterolemia, and hypercoagulation.
The primary endpoint of the long-term follow-up study was the difference in median survival time between the original treatment groups with and without incident cardiovascular disease. The results showed a 48% relative reduction in the risk of death; those initially given the intensified treatment had an increased lifespan of 7.9 years and an 8.1-year increased survival without cardiovascular disease versus those who had initially received conventional treatment (Diabetologica 2016;59:2298-307).
Dr. Øllgaard presented data on heart failure outcomes obtained from a post-hoc analysis of prospectively collected and externally adjudicated patient records.
In addition to the reductions in the primary outcome of time to heart failure, the secondary outcomes of time to heart failure or cardiovascular mortality (HR, 0.38; P = .006) and heart failure or all-cause mortality (relative risk reduction, 49%; P = .001) also favored initial intensive treatment versus conventional treatment.
The number of patients who would need to be treated for 1 year to prevent one heart failure event was 63. The number needed to treat (NNT) to prevent heart failure or cardiovascular death was 48, and the NNT or heart failure or all-cause death was 37.
“Intensified, multifactorial intervention reduces the risk of heart failure and underlines the need for early, intensive treatment in these patients,” Dr. Øllgaard said. “Diabetologists should be aware of this increased risk and the early clinical signs and biomarkers of heart failure.” He added the study “also emphasizes the need for close collaboration, locally and globally, between endocrinologists and cardiologists.”
The STENO-2 long-term follow-up analysis was sponsored by an unrestricted grant from Novo Nordisk. Dr. Øllgaard disclosed being employed by Novo Nordisk after the submission of the abstract for presentation at the EASD meeting.
AT EASD 2017
Key clinical point: Intensified, multifactorial treatment reduces the risk of heart failure in people with type 2 diabetes mellitus versus a conventional treatment approach.
Major finding: The risk of heart failure was reduced by 70% (P = .002).
Data source: Post hoc analysis from 21 years follow-up on the Steno-2 randomized trial conducted in 160 patients with type 2 diabetes and microalbuminuria who were randomized to an intensive or conventional treatment arm.
Disclosures: The STENO-2 long-term follow-up analysis was sponsored by an unrestricted grant from Novo Nordisk. Dr. Øllgaard disclosed being employed by Novo Nordisk after the submission of the abstract for presentation at the EASD meeting.
Insulin pumps associated with lower risk of ketoacidosis and severe hypoglycemia in kids
Children with type 1 diabetes mellitus who use insulin pumps are at a lower risk for ketoacidosis and severe hypoglycemia, compared with those receiving insulin by injection, according to a population-based cohort study from the University of Ulm, Germany.
The study participants were all younger than 20 years of age and were divided into the following groups for data analysis: 1.5-5 years; 6-10 years; 11-15 years; or 16-19 years. The study evaluated both primary and secondary outcomes to analyze the effectiveness of insulin pumps vs. traditional insulin injections. The primary outcomes were the rates of ketoacidosis and hypoglycemia severe enough to require assistance from another person to administer intravenous carbohydrates or induce hypoglycemic coma. The secondary outcomes were serum levels of glycated hemoglobin (HbA1c), daily insulin dose, prandial to total insulin ratio, frequency of self-monitoring blood glucose level, and body mass index, according to Beate Karges, MD, of the University of Aachen (Germany), Division of Endocrinology and Diabetes, and her colleagues.
After applying selection criteria, 30,579 patients treated for type 1 diabetes were selected for analysis. Of the 30,579, a 1 to 1 matched cohort of 19,628 patients, split into equal sized groups, was created for propensity score analysis to compare the effect of treatment between insulin pumps and injects. The matched cohort was also included in the entire cohort for another propensity score analysis. Of the entire 30,579 patients, 14,119 used pump therapy and 16,460 used traditional daily insulin injections.
In the matched cohort, event rates for both severe hypoglycemia and hypoglycemic coma were much lower with insulin pumps than with traditional insulin injections (9.55 vs. 13.97 per 100 patient-years and 2.30 vs. 2.96 per 100 patient-years, respectively). The pattern of pump therapy lowering rates of severe hypoglycemia and hypoglycemic coma was observed in entire cohort as well, according to the investigators (JAMA. 2017 Oct 10;318[14]:1358-66).
The secondary outcomes of the matched cohort did not share as consistent a pattern as the primary outcomes. HbA1c levels were lower in pump users (8.04% vs. 8.22%). Total daily insulin doses were lower in pump users, but the prandial to total insulin ratio was higher. Daily frequency of self-monitoring blood glucose level was also elevated in pump users.
“These findings provide evidence for improved clinical outcomes associated with insulin pump therapy, compared with injection therapy, in children, adolescents, and young adults with type 1 diabetes,” Dr. Karges and her colleagues wrote.
The study was funded by both the Competence Network Diabetes Mellitus and the German Center for Diabetes Research. Thomas Kapellen, MD, had received funding from the European Commission concerning closed-loop systems as well as speaking fees for pharmaceuticals companies including Abbott, Medtronic, and Novo Nordisk. No other authors reported financial conflicts.
Children with type 1 diabetes mellitus who use insulin pumps are at a lower risk for ketoacidosis and severe hypoglycemia, compared with those receiving insulin by injection, according to a population-based cohort study from the University of Ulm, Germany.
The study participants were all younger than 20 years of age and were divided into the following groups for data analysis: 1.5-5 years; 6-10 years; 11-15 years; or 16-19 years. The study evaluated both primary and secondary outcomes to analyze the effectiveness of insulin pumps vs. traditional insulin injections. The primary outcomes were the rates of ketoacidosis and hypoglycemia severe enough to require assistance from another person to administer intravenous carbohydrates or induce hypoglycemic coma. The secondary outcomes were serum levels of glycated hemoglobin (HbA1c), daily insulin dose, prandial to total insulin ratio, frequency of self-monitoring blood glucose level, and body mass index, according to Beate Karges, MD, of the University of Aachen (Germany), Division of Endocrinology and Diabetes, and her colleagues.
After applying selection criteria, 30,579 patients treated for type 1 diabetes were selected for analysis. Of the 30,579, a 1 to 1 matched cohort of 19,628 patients, split into equal sized groups, was created for propensity score analysis to compare the effect of treatment between insulin pumps and injects. The matched cohort was also included in the entire cohort for another propensity score analysis. Of the entire 30,579 patients, 14,119 used pump therapy and 16,460 used traditional daily insulin injections.
In the matched cohort, event rates for both severe hypoglycemia and hypoglycemic coma were much lower with insulin pumps than with traditional insulin injections (9.55 vs. 13.97 per 100 patient-years and 2.30 vs. 2.96 per 100 patient-years, respectively). The pattern of pump therapy lowering rates of severe hypoglycemia and hypoglycemic coma was observed in entire cohort as well, according to the investigators (JAMA. 2017 Oct 10;318[14]:1358-66).
The secondary outcomes of the matched cohort did not share as consistent a pattern as the primary outcomes. HbA1c levels were lower in pump users (8.04% vs. 8.22%). Total daily insulin doses were lower in pump users, but the prandial to total insulin ratio was higher. Daily frequency of self-monitoring blood glucose level was also elevated in pump users.
“These findings provide evidence for improved clinical outcomes associated with insulin pump therapy, compared with injection therapy, in children, adolescents, and young adults with type 1 diabetes,” Dr. Karges and her colleagues wrote.
The study was funded by both the Competence Network Diabetes Mellitus and the German Center for Diabetes Research. Thomas Kapellen, MD, had received funding from the European Commission concerning closed-loop systems as well as speaking fees for pharmaceuticals companies including Abbott, Medtronic, and Novo Nordisk. No other authors reported financial conflicts.
Children with type 1 diabetes mellitus who use insulin pumps are at a lower risk for ketoacidosis and severe hypoglycemia, compared with those receiving insulin by injection, according to a population-based cohort study from the University of Ulm, Germany.
The study participants were all younger than 20 years of age and were divided into the following groups for data analysis: 1.5-5 years; 6-10 years; 11-15 years; or 16-19 years. The study evaluated both primary and secondary outcomes to analyze the effectiveness of insulin pumps vs. traditional insulin injections. The primary outcomes were the rates of ketoacidosis and hypoglycemia severe enough to require assistance from another person to administer intravenous carbohydrates or induce hypoglycemic coma. The secondary outcomes were serum levels of glycated hemoglobin (HbA1c), daily insulin dose, prandial to total insulin ratio, frequency of self-monitoring blood glucose level, and body mass index, according to Beate Karges, MD, of the University of Aachen (Germany), Division of Endocrinology and Diabetes, and her colleagues.
After applying selection criteria, 30,579 patients treated for type 1 diabetes were selected for analysis. Of the 30,579, a 1 to 1 matched cohort of 19,628 patients, split into equal sized groups, was created for propensity score analysis to compare the effect of treatment between insulin pumps and injects. The matched cohort was also included in the entire cohort for another propensity score analysis. Of the entire 30,579 patients, 14,119 used pump therapy and 16,460 used traditional daily insulin injections.
In the matched cohort, event rates for both severe hypoglycemia and hypoglycemic coma were much lower with insulin pumps than with traditional insulin injections (9.55 vs. 13.97 per 100 patient-years and 2.30 vs. 2.96 per 100 patient-years, respectively). The pattern of pump therapy lowering rates of severe hypoglycemia and hypoglycemic coma was observed in entire cohort as well, according to the investigators (JAMA. 2017 Oct 10;318[14]:1358-66).
The secondary outcomes of the matched cohort did not share as consistent a pattern as the primary outcomes. HbA1c levels were lower in pump users (8.04% vs. 8.22%). Total daily insulin doses were lower in pump users, but the prandial to total insulin ratio was higher. Daily frequency of self-monitoring blood glucose level was also elevated in pump users.
“These findings provide evidence for improved clinical outcomes associated with insulin pump therapy, compared with injection therapy, in children, adolescents, and young adults with type 1 diabetes,” Dr. Karges and her colleagues wrote.
The study was funded by both the Competence Network Diabetes Mellitus and the German Center for Diabetes Research. Thomas Kapellen, MD, had received funding from the European Commission concerning closed-loop systems as well as speaking fees for pharmaceuticals companies including Abbott, Medtronic, and Novo Nordisk. No other authors reported financial conflicts.
FROM JAMA
Key clinical point:
Major finding: Patients using insulin pumps had lower rates of hypoglycemia (9.55 per 100 patient-years) and severe ketoacidosis (3.64 per 100 patient-years).
Data source: Population cohort study of 30,579 patients from the Diabetes Prospective Follow-up Initiative Database.
Disclosures: The study was funded by both the Competence Network Diabetes Mellitus and the German Center for Diabetes Research. Thomas Kapellen, MD, had received funding from the European Commission concerning closed-loop systems as well as speaking fees for pharmaceutical companies including Abbott, Medtronic, and Novo Nordisk. No other authors reported financial conflicts.
CDC: Forty percent of cancers linked to overweight or obesity
Being overweight or obese significantly increased the risk of developing at least 13 types of cancer, according to a report by the Centers for Disease Control and Prevention.
Now that a larger proportion of the American population is overweight or obese, the rates of obesity-related cancers have increased. Between 2005 and 2014, the rate of obesity-related cancers, excluding colorectal cancer, increased by 7%. Over the same period, non–obesity-related cancers declined, according to C. Brooke Steele, DO, of the CDC’s Division of Cancer Prevention and Control, and her associates (MMWR Morb Mortal Wkly Rep. 2017 Oct 3;66[39]:1052-8).
They found that 631,604 people were diagnosed with an overweight- or obesity-related cancer, 40% of nearly 1.6 million of all cancer diagnoses in 2014. The effect was more pronounced in older people (age at least 50 years), compared with younger people, with two-thirds of cases occurring in the 50- to 74-year-old age range.
Women were much more likely to have overweight- and obesity-related cancers, with higher incidence rates (218.1 per 100,000 population) than those of men (115.0 per 100,000). A contributing factor for this difference between men and women was female-specific cancers such as endometrial, ovarian, and postmenopausal breast cancers, which accounted for 42% (268,091) of overweight- and obesity-related cancers.
Researchers found that, between 2005 and 2014, the overall incidence of overweight- and obesity-related cancers (including colorectal cancer) decreased by 2%, colorectal cancer decreased by 23%, and cancers unrelated to body weight decreased by 13%. A contributing factor to the decrease in colorectal cancer was most likely cancer screening tests, which can detect and lead to the removal of precancerous polyps.
“A majority of American adults weigh more than recommended – and being overweight or obese puts people at higher risk for a number of cancers – so these findings are a cause for concern,” CDC Director Brenda Fitzgerald, MD, said in a statement. “By getting to and keeping a healthy weight, we all can play a role in cancer prevention.”
The researchers had no conflicts of interest to report.
Being overweight or obese significantly increased the risk of developing at least 13 types of cancer, according to a report by the Centers for Disease Control and Prevention.
Now that a larger proportion of the American population is overweight or obese, the rates of obesity-related cancers have increased. Between 2005 and 2014, the rate of obesity-related cancers, excluding colorectal cancer, increased by 7%. Over the same period, non–obesity-related cancers declined, according to C. Brooke Steele, DO, of the CDC’s Division of Cancer Prevention and Control, and her associates (MMWR Morb Mortal Wkly Rep. 2017 Oct 3;66[39]:1052-8).
They found that 631,604 people were diagnosed with an overweight- or obesity-related cancer, 40% of nearly 1.6 million of all cancer diagnoses in 2014. The effect was more pronounced in older people (age at least 50 years), compared with younger people, with two-thirds of cases occurring in the 50- to 74-year-old age range.
Women were much more likely to have overweight- and obesity-related cancers, with higher incidence rates (218.1 per 100,000 population) than those of men (115.0 per 100,000). A contributing factor for this difference between men and women was female-specific cancers such as endometrial, ovarian, and postmenopausal breast cancers, which accounted for 42% (268,091) of overweight- and obesity-related cancers.
Researchers found that, between 2005 and 2014, the overall incidence of overweight- and obesity-related cancers (including colorectal cancer) decreased by 2%, colorectal cancer decreased by 23%, and cancers unrelated to body weight decreased by 13%. A contributing factor to the decrease in colorectal cancer was most likely cancer screening tests, which can detect and lead to the removal of precancerous polyps.
“A majority of American adults weigh more than recommended – and being overweight or obese puts people at higher risk for a number of cancers – so these findings are a cause for concern,” CDC Director Brenda Fitzgerald, MD, said in a statement. “By getting to and keeping a healthy weight, we all can play a role in cancer prevention.”
The researchers had no conflicts of interest to report.
Being overweight or obese significantly increased the risk of developing at least 13 types of cancer, according to a report by the Centers for Disease Control and Prevention.
Now that a larger proportion of the American population is overweight or obese, the rates of obesity-related cancers have increased. Between 2005 and 2014, the rate of obesity-related cancers, excluding colorectal cancer, increased by 7%. Over the same period, non–obesity-related cancers declined, according to C. Brooke Steele, DO, of the CDC’s Division of Cancer Prevention and Control, and her associates (MMWR Morb Mortal Wkly Rep. 2017 Oct 3;66[39]:1052-8).
They found that 631,604 people were diagnosed with an overweight- or obesity-related cancer, 40% of nearly 1.6 million of all cancer diagnoses in 2014. The effect was more pronounced in older people (age at least 50 years), compared with younger people, with two-thirds of cases occurring in the 50- to 74-year-old age range.
Women were much more likely to have overweight- and obesity-related cancers, with higher incidence rates (218.1 per 100,000 population) than those of men (115.0 per 100,000). A contributing factor for this difference between men and women was female-specific cancers such as endometrial, ovarian, and postmenopausal breast cancers, which accounted for 42% (268,091) of overweight- and obesity-related cancers.
Researchers found that, between 2005 and 2014, the overall incidence of overweight- and obesity-related cancers (including colorectal cancer) decreased by 2%, colorectal cancer decreased by 23%, and cancers unrelated to body weight decreased by 13%. A contributing factor to the decrease in colorectal cancer was most likely cancer screening tests, which can detect and lead to the removal of precancerous polyps.
“A majority of American adults weigh more than recommended – and being overweight or obese puts people at higher risk for a number of cancers – so these findings are a cause for concern,” CDC Director Brenda Fitzgerald, MD, said in a statement. “By getting to and keeping a healthy weight, we all can play a role in cancer prevention.”
The researchers had no conflicts of interest to report.
FROM MORBIDITY AND MORTALITY WEEKLY REPORT
Key clinical point:
Major finding: In the United States, more than 631,000 patients received cancer diagnoses related to overweight or obesity, representing 40% of nearly 1.6 million cancer diagnoses in 2014.
Data source: An analysis of United States Cancer Statistics data from 2005 to 2014.
Disclosures: The researchers had no conflicts of interest to report.
Semaglutide aids T2DM weight loss over 2 years
LISBON – The investigational glucagon-like peptide (GLP)-1 receptor agonist semaglutide added to standard care for type 2 diabetes mellitus (T2DM) resulted in clinically significant weight loss over 2 years in the SUSTAIN-6 phase 3 trial.
Participants treated with semaglutide in the study lost an average of 3.6 to 4.9 kg, depending on the dose they were given (0.5 mg or 1.0 mg), which was significantly (P less than .0001) more than those who were randomized to matching placebos (-0.7 mg and -0.5 mg).
Semaglutide is under development by Novo Nordisk and is currently under review by regulatory agencies in the United States, Europe, and Japan. It has 94% homology to human GLP-1 and modifications have been made to help it avoid degradation and which give it a half-life that allows it to be given once a week.
SUSTAIN 6 is part of an ongoing phase 3 program and is a long-term outcome study with the primary objective of evaluating the cardiovascular safety of semaglutide. Effects on macro- and microvascular complications, glycemic control, body weight, body mass index and weight circumference are key secondary endpoints, together with assessment of its overall safety and tolerability.
Other trials in the program, have evaluated treatment with semaglutide as monotherapy (SUSTAIN 1; Lancet Diabetes Endocrinol. 2017;5:251-60) or versus other treatments including sitagliptin (Januvia, Merck; SUSTAIN 2; Lancet Diabetes Endocrinol. 2017;5:341-54), exenatide extended release (Bydureon, AstraZeneca; SUSTAIN 3), or insulin glargine (SUSTAIN 4), as add-on to basal insulin with or without metformin (SUSTAIN 5), and most recently, versus dulaglutide (Trulicity, Eli Lilly; SUSTAIN 7).
SUSTAIN 6 involved 3,297 people with T2DM with established cardiovascular disease or chronic kidney disease or otherwise identified as being at increased cardiovascular risk, according to Dr. Consoli, who is an endocrinologist and professor at the University of Chieti-Pescara, Italy. The results of the primary endpoint have been reported (N Engl J Med. 2016; 375:1834-44) and showed that the composite rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo. The hazard ratio for the reduction in the composite endpoint was 0.74 (95% CI, 0.58-.95; P less than .001 for noninferiority).
Results of the secondary analyses reported by Dr. Consoli at EASD 2017 showed that semaglutide could help more patients than placebo achieve significant weight loss, which could help further reduce their cardiovascular risk. He reported that a 5% or greater weight loss at 2 years was achieved by 36% and 47% of patients treated with semaglutide 0.5 mg and 1 mg groups, respectively, and by 18% and 19% of patients in the matching placebo groups (P less than .0001 for both comparisons). A 10% or greater weight loss was achieved by 13% and 21% of the semaglutide-treated patients and by 6% and 7% of those given placebo.
“The effect of weight was not dependent on BMI [body mass index] at baseline,” Dr. Consoli said, emphasizing that there was a consistent reduction in the weight in all BMI categories. Importantly, Dr. Consoli observed, the effects of semaglutide on weight seen were not driven by just a few patients losing weight, and around 80% of patients in the study experienced some degree of weight loss.
“As expected, the subjects treated with the GLP-1a had more GI [gastrointestinal] effects,” Dr. Consoli reported. Nausea or vomiting were reported in twice as many patients treated with semaglutide 0.5 mg (21.9%) and 1 mg (27.3%) as their placebo-matched counterparts (10.8% and 10.6%).
A post-hoc analysis found that the effect of semaglutide on weight loss was not likely to be down to these side effects, however, with a similar weight reductions seen in those who did and did not experience nausea or vomiting. The “estimated natural direct effect of treatment” was -2.75 kg for the 0.5 mg dose and -4.32 for the 1 mg dose of semaglutide versus their placebos Dr. Consoli said. GI drove the weigjht loss to a small degree; -0.12 kg and -0.04 kg of weight loss seen in the 0.5 mg and 1 mg semaglutide groups versus their placebos could be ascribed to nausea or vomiting.
In a poster presentation at the meeting, data on another post-hoc analysis from the SUSTAIN phase 3 program were reported. In a responder analysis of T2DM patients achieving glycemic and weight loss thresholds, a greater proportion of those treated with semaglutide achieved clinically meaningful reductions in both glycated hemoglobin (HbA1c) and body weight than those given comparator treatments.
The composite endpoint of at least a 1% reduction in HbA1c and a 5% or greater decrease in body weight was achieved by 25%–35% of patients treated with the 0.5 mg dose of semaglutide, by 38%–56% of those given the higher dose, and by 2%–13% or all comparators (P less than .0001). The higher dose of semaglutide also allowed more people to achieve this endpoint than the lower dose.
Novo Nordisk supported the study. Dr. Consoli disclosed receiving research funding from AstraZeneca and Novo Nordisk and speaker’s bureau or consultation fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., Merck, Sharp & Dohme, Novartis, Sanofi-Aventis, and Takeda.
LISBON – The investigational glucagon-like peptide (GLP)-1 receptor agonist semaglutide added to standard care for type 2 diabetes mellitus (T2DM) resulted in clinically significant weight loss over 2 years in the SUSTAIN-6 phase 3 trial.
Participants treated with semaglutide in the study lost an average of 3.6 to 4.9 kg, depending on the dose they were given (0.5 mg or 1.0 mg), which was significantly (P less than .0001) more than those who were randomized to matching placebos (-0.7 mg and -0.5 mg).
Semaglutide is under development by Novo Nordisk and is currently under review by regulatory agencies in the United States, Europe, and Japan. It has 94% homology to human GLP-1 and modifications have been made to help it avoid degradation and which give it a half-life that allows it to be given once a week.
SUSTAIN 6 is part of an ongoing phase 3 program and is a long-term outcome study with the primary objective of evaluating the cardiovascular safety of semaglutide. Effects on macro- and microvascular complications, glycemic control, body weight, body mass index and weight circumference are key secondary endpoints, together with assessment of its overall safety and tolerability.
Other trials in the program, have evaluated treatment with semaglutide as monotherapy (SUSTAIN 1; Lancet Diabetes Endocrinol. 2017;5:251-60) or versus other treatments including sitagliptin (Januvia, Merck; SUSTAIN 2; Lancet Diabetes Endocrinol. 2017;5:341-54), exenatide extended release (Bydureon, AstraZeneca; SUSTAIN 3), or insulin glargine (SUSTAIN 4), as add-on to basal insulin with or without metformin (SUSTAIN 5), and most recently, versus dulaglutide (Trulicity, Eli Lilly; SUSTAIN 7).
SUSTAIN 6 involved 3,297 people with T2DM with established cardiovascular disease or chronic kidney disease or otherwise identified as being at increased cardiovascular risk, according to Dr. Consoli, who is an endocrinologist and professor at the University of Chieti-Pescara, Italy. The results of the primary endpoint have been reported (N Engl J Med. 2016; 375:1834-44) and showed that the composite rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo. The hazard ratio for the reduction in the composite endpoint was 0.74 (95% CI, 0.58-.95; P less than .001 for noninferiority).
Results of the secondary analyses reported by Dr. Consoli at EASD 2017 showed that semaglutide could help more patients than placebo achieve significant weight loss, which could help further reduce their cardiovascular risk. He reported that a 5% or greater weight loss at 2 years was achieved by 36% and 47% of patients treated with semaglutide 0.5 mg and 1 mg groups, respectively, and by 18% and 19% of patients in the matching placebo groups (P less than .0001 for both comparisons). A 10% or greater weight loss was achieved by 13% and 21% of the semaglutide-treated patients and by 6% and 7% of those given placebo.
“The effect of weight was not dependent on BMI [body mass index] at baseline,” Dr. Consoli said, emphasizing that there was a consistent reduction in the weight in all BMI categories. Importantly, Dr. Consoli observed, the effects of semaglutide on weight seen were not driven by just a few patients losing weight, and around 80% of patients in the study experienced some degree of weight loss.
“As expected, the subjects treated with the GLP-1a had more GI [gastrointestinal] effects,” Dr. Consoli reported. Nausea or vomiting were reported in twice as many patients treated with semaglutide 0.5 mg (21.9%) and 1 mg (27.3%) as their placebo-matched counterparts (10.8% and 10.6%).
A post-hoc analysis found that the effect of semaglutide on weight loss was not likely to be down to these side effects, however, with a similar weight reductions seen in those who did and did not experience nausea or vomiting. The “estimated natural direct effect of treatment” was -2.75 kg for the 0.5 mg dose and -4.32 for the 1 mg dose of semaglutide versus their placebos Dr. Consoli said. GI drove the weigjht loss to a small degree; -0.12 kg and -0.04 kg of weight loss seen in the 0.5 mg and 1 mg semaglutide groups versus their placebos could be ascribed to nausea or vomiting.
In a poster presentation at the meeting, data on another post-hoc analysis from the SUSTAIN phase 3 program were reported. In a responder analysis of T2DM patients achieving glycemic and weight loss thresholds, a greater proportion of those treated with semaglutide achieved clinically meaningful reductions in both glycated hemoglobin (HbA1c) and body weight than those given comparator treatments.
The composite endpoint of at least a 1% reduction in HbA1c and a 5% or greater decrease in body weight was achieved by 25%–35% of patients treated with the 0.5 mg dose of semaglutide, by 38%–56% of those given the higher dose, and by 2%–13% or all comparators (P less than .0001). The higher dose of semaglutide also allowed more people to achieve this endpoint than the lower dose.
Novo Nordisk supported the study. Dr. Consoli disclosed receiving research funding from AstraZeneca and Novo Nordisk and speaker’s bureau or consultation fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., Merck, Sharp & Dohme, Novartis, Sanofi-Aventis, and Takeda.
LISBON – The investigational glucagon-like peptide (GLP)-1 receptor agonist semaglutide added to standard care for type 2 diabetes mellitus (T2DM) resulted in clinically significant weight loss over 2 years in the SUSTAIN-6 phase 3 trial.
Participants treated with semaglutide in the study lost an average of 3.6 to 4.9 kg, depending on the dose they were given (0.5 mg or 1.0 mg), which was significantly (P less than .0001) more than those who were randomized to matching placebos (-0.7 mg and -0.5 mg).
Semaglutide is under development by Novo Nordisk and is currently under review by regulatory agencies in the United States, Europe, and Japan. It has 94% homology to human GLP-1 and modifications have been made to help it avoid degradation and which give it a half-life that allows it to be given once a week.
SUSTAIN 6 is part of an ongoing phase 3 program and is a long-term outcome study with the primary objective of evaluating the cardiovascular safety of semaglutide. Effects on macro- and microvascular complications, glycemic control, body weight, body mass index and weight circumference are key secondary endpoints, together with assessment of its overall safety and tolerability.
Other trials in the program, have evaluated treatment with semaglutide as monotherapy (SUSTAIN 1; Lancet Diabetes Endocrinol. 2017;5:251-60) or versus other treatments including sitagliptin (Januvia, Merck; SUSTAIN 2; Lancet Diabetes Endocrinol. 2017;5:341-54), exenatide extended release (Bydureon, AstraZeneca; SUSTAIN 3), or insulin glargine (SUSTAIN 4), as add-on to basal insulin with or without metformin (SUSTAIN 5), and most recently, versus dulaglutide (Trulicity, Eli Lilly; SUSTAIN 7).
SUSTAIN 6 involved 3,297 people with T2DM with established cardiovascular disease or chronic kidney disease or otherwise identified as being at increased cardiovascular risk, according to Dr. Consoli, who is an endocrinologist and professor at the University of Chieti-Pescara, Italy. The results of the primary endpoint have been reported (N Engl J Med. 2016; 375:1834-44) and showed that the composite rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo. The hazard ratio for the reduction in the composite endpoint was 0.74 (95% CI, 0.58-.95; P less than .001 for noninferiority).
Results of the secondary analyses reported by Dr. Consoli at EASD 2017 showed that semaglutide could help more patients than placebo achieve significant weight loss, which could help further reduce their cardiovascular risk. He reported that a 5% or greater weight loss at 2 years was achieved by 36% and 47% of patients treated with semaglutide 0.5 mg and 1 mg groups, respectively, and by 18% and 19% of patients in the matching placebo groups (P less than .0001 for both comparisons). A 10% or greater weight loss was achieved by 13% and 21% of the semaglutide-treated patients and by 6% and 7% of those given placebo.
“The effect of weight was not dependent on BMI [body mass index] at baseline,” Dr. Consoli said, emphasizing that there was a consistent reduction in the weight in all BMI categories. Importantly, Dr. Consoli observed, the effects of semaglutide on weight seen were not driven by just a few patients losing weight, and around 80% of patients in the study experienced some degree of weight loss.
“As expected, the subjects treated with the GLP-1a had more GI [gastrointestinal] effects,” Dr. Consoli reported. Nausea or vomiting were reported in twice as many patients treated with semaglutide 0.5 mg (21.9%) and 1 mg (27.3%) as their placebo-matched counterparts (10.8% and 10.6%).
A post-hoc analysis found that the effect of semaglutide on weight loss was not likely to be down to these side effects, however, with a similar weight reductions seen in those who did and did not experience nausea or vomiting. The “estimated natural direct effect of treatment” was -2.75 kg for the 0.5 mg dose and -4.32 for the 1 mg dose of semaglutide versus their placebos Dr. Consoli said. GI drove the weigjht loss to a small degree; -0.12 kg and -0.04 kg of weight loss seen in the 0.5 mg and 1 mg semaglutide groups versus their placebos could be ascribed to nausea or vomiting.
In a poster presentation at the meeting, data on another post-hoc analysis from the SUSTAIN phase 3 program were reported. In a responder analysis of T2DM patients achieving glycemic and weight loss thresholds, a greater proportion of those treated with semaglutide achieved clinically meaningful reductions in both glycated hemoglobin (HbA1c) and body weight than those given comparator treatments.
The composite endpoint of at least a 1% reduction in HbA1c and a 5% or greater decrease in body weight was achieved by 25%–35% of patients treated with the 0.5 mg dose of semaglutide, by 38%–56% of those given the higher dose, and by 2%–13% or all comparators (P less than .0001). The higher dose of semaglutide also allowed more people to achieve this endpoint than the lower dose.
Novo Nordisk supported the study. Dr. Consoli disclosed receiving research funding from AstraZeneca and Novo Nordisk and speaker’s bureau or consultation fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., Merck, Sharp & Dohme, Novartis, Sanofi-Aventis, and Takeda.
AT EASD 2017
Key clinical point: Semaglutide added to standard of care was associated with significant weight loss independent of any gastrointestinal side effects.
Major finding: There was a -2.87 kg to -4.35 kg change in body weight comparing two doses of semaglutide with matching placebos (both P less than .0001).
Data source: SUSTAIN-6: A long-term outcomes study in 3,297 patients with type 2 diabetes treated with once-weekly semaglutide or placebo for 104 weeks.
Disclosures: Novo Nordisk supported the study. Dr. Consoli disclosed receiving research funding from AstraZeneca and Novo Nordisk and speaker’s bureau or consultation fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck, Sharp & Dohme, Novartis, Sanofi-Aventis, and Takeda.
HOPE-3 wades into fray regarding optimal blood pressure targets
BARCELONA – How low to go in treating hypertension is a topic of considerable recent controversy. Now the HOPE-3 trial investigators have weighed in, reporting that optimal outcomes in their landmark randomized trial were seen with an achieved, on-treatment systolic blood pressure of 130-140 mm Hg and a diastolic blood pressure of 75-80 mm Hg, Eva M. Lonn, MD, reported at the annual congress of the European Society of Cardiology.
Those results stand in glaring contrast to the findings of the much-discussed SPRINT trial, in which hypertensive patients fared best with an on-treatment SBP driven below 120 mm Hg (N Engl J Med. 2015 Nov 26; 373:2103-16).
“Please note that lower blood pressures, both systolic and diastolic, weren’t associated with lower risk, whereas higher blood pressures considerably increased the risk for major vascular events,” she added.
HOPE-3 (the Third Heart Outcomes Prevention Evaluation) included 12,705 patients in 21 countries who did not have cardiovascular disease and were at intermediate risk, with an average age of 65 years at enrollment and a Framinhgam Risk Score of about 10%. They were randomized double-blind in a 2x2 factorial design to rosuvastatin at 10 mg per day or placebo and/or candesartan at 16 mg plus hydrochlorothiazide at 12.5 mg per day or placebo and prospectively followed for a median of 5.6 years.
The primary outcomes of HOPE-3 have been published (N Engl J Med. 2016 May 26;374[21]:2009-20 and 2021-31). This was a practice-changing trial that opened the door to broader use of statin therapy for primary prevention.
At the ESC congress in Barcelona, Dr. Lonn presented a secondary post-hoc analysis that focused on the impact of antihypertensive therapy in HOPE-3. The results shed new light on the optimal blood pressure levels for triggering initation of antihypertensive therapy, as well as defining the achieved blood pressures that resulted in the greatest reductions in major vascular events.
As this was essentially an all-comers trial of intermediate-risk patients, participants presented with a range of blood pressures at baseline. But more than 4,700 subjects had a baseline SBP of 140-159.9 mm Hg, and 833 had an SBP of 160 mm Hg or more.
The candesartan/hydrochlorothiazide regimen resulted in what Dr. Lonn termed a “moderate” net placebo-subtracted blood pressure reduction of 6/3 mm Hg. The higher the baseline blood pressure, the bigger the reduction.
In the one-third of subjects with a baseline SBP greater than 143.5 mm Hg, antihypertensive therapy resulted in a significant 27% reduction in the composite endpoint of cardiovascular death, MI, or stroke compared with placebo. Those with a baseline SBP of 150 mm Hg or more showed even greater benefit from antihypertensive therapy, with a composite event rate of 4.8% compared with 7.2% for placebo, representing a 34% relative risk reduction in which the event curves began separating at about 2 years.
In contrast, antihypertensive therapy brought no significant reduction in events in patients in the lower two tertiles of baseline SBP. And there was no association at all between baseline DBP and major cardiovascular events across the range of DBP values evaluated in HOPE-3.
But wait: Things get more interesting, according to the cardiac electrophysiologist.
“I find the association between mean in-trial blood pressure as recorded in many measurements and vascular outcomes to be the most interesting analysis. This may be a better look at the association between blood pressure and outcomes than a measurement obtained just once or twice at baseline,” she explained.
Of note, among the 6,356 subjects on candesartan/hydrochlorothiazide, those with a mean on-treatment SBP of 160 mm Hg or more had a 2.61% per year rate of the composite of cardiovascular death, MI, stroke, rescue from cardiac arrest, heart failure, or revascularization. This was more than three-fold higher than the 0.75% per year rate in patients with an on-treatment SBP of 120-139.9 mm Hg. The composite event rate was also significantly higher in those with a mean on-treatment SBP of 140-159.9 mm Hg, at 1.4% per year. The event rate in patients with an on-treatment SBP below 120 mm Hg was identical to that of patients with a value of 120-139.9 mm Hg.
Only among patients with an on-treatment DBP of 90 mm Hg or more was the composite event rate significantly greater than in those with a DBP of 70-79.9 mm Hg, who had the lowest event rate by a margin of 1.89% versus 0.75% per year.
An Australian cardiologist in the audience who has been involved in revamping hypertension treatment guidelines Down Under expressed frustration. He only recently succeeded in wrangling his fellow panelists into incorporating the SPRINT results into the draft guidelines; now HOPE-3 is sending a very different message. What gives? Could the disparate findings simply be due to play of chance? he asked.
Highly unlikely, Dr. Lonn replied.
“There were substantial differences between our trials,” she explained. “First of all, the SPRINT population was at substantially higher risk. They either had to have established cardiovascular disease – we eliminated those people – or significant renal disease – we eliminated those people, too – or age greater than 75, or a Framingham Risk Score above 15%.”
Also, the SPRINT protocol controversially called for unattended blood pressure measurement.
“This is a very pure way ot eliminating white coat hypertension, but it is different from other studies, so it is very difficult to compare SPRINT to older studies or to HOPE-3. Some other investigators have suggested that the difference between attended and unattended blood pressure is close to 10 mm Hg. So our SBP of 130 mm Hg, which had the best outcomes in HOPE-3, may be the same as about 120 mm Hg in SPRINT,” according to Dr. Lonn.
HOPE-3 was funded by the Canadian Institutes of Health Research and AstraZeneca. Dr. Lonn reported serving as a consultant to and receiving research grants from AstraZeneca, Amgen, Bayer, and Novartis.
BARCELONA – How low to go in treating hypertension is a topic of considerable recent controversy. Now the HOPE-3 trial investigators have weighed in, reporting that optimal outcomes in their landmark randomized trial were seen with an achieved, on-treatment systolic blood pressure of 130-140 mm Hg and a diastolic blood pressure of 75-80 mm Hg, Eva M. Lonn, MD, reported at the annual congress of the European Society of Cardiology.
Those results stand in glaring contrast to the findings of the much-discussed SPRINT trial, in which hypertensive patients fared best with an on-treatment SBP driven below 120 mm Hg (N Engl J Med. 2015 Nov 26; 373:2103-16).
“Please note that lower blood pressures, both systolic and diastolic, weren’t associated with lower risk, whereas higher blood pressures considerably increased the risk for major vascular events,” she added.
HOPE-3 (the Third Heart Outcomes Prevention Evaluation) included 12,705 patients in 21 countries who did not have cardiovascular disease and were at intermediate risk, with an average age of 65 years at enrollment and a Framinhgam Risk Score of about 10%. They were randomized double-blind in a 2x2 factorial design to rosuvastatin at 10 mg per day or placebo and/or candesartan at 16 mg plus hydrochlorothiazide at 12.5 mg per day or placebo and prospectively followed for a median of 5.6 years.
The primary outcomes of HOPE-3 have been published (N Engl J Med. 2016 May 26;374[21]:2009-20 and 2021-31). This was a practice-changing trial that opened the door to broader use of statin therapy for primary prevention.
At the ESC congress in Barcelona, Dr. Lonn presented a secondary post-hoc analysis that focused on the impact of antihypertensive therapy in HOPE-3. The results shed new light on the optimal blood pressure levels for triggering initation of antihypertensive therapy, as well as defining the achieved blood pressures that resulted in the greatest reductions in major vascular events.
As this was essentially an all-comers trial of intermediate-risk patients, participants presented with a range of blood pressures at baseline. But more than 4,700 subjects had a baseline SBP of 140-159.9 mm Hg, and 833 had an SBP of 160 mm Hg or more.
The candesartan/hydrochlorothiazide regimen resulted in what Dr. Lonn termed a “moderate” net placebo-subtracted blood pressure reduction of 6/3 mm Hg. The higher the baseline blood pressure, the bigger the reduction.
In the one-third of subjects with a baseline SBP greater than 143.5 mm Hg, antihypertensive therapy resulted in a significant 27% reduction in the composite endpoint of cardiovascular death, MI, or stroke compared with placebo. Those with a baseline SBP of 150 mm Hg or more showed even greater benefit from antihypertensive therapy, with a composite event rate of 4.8% compared with 7.2% for placebo, representing a 34% relative risk reduction in which the event curves began separating at about 2 years.
In contrast, antihypertensive therapy brought no significant reduction in events in patients in the lower two tertiles of baseline SBP. And there was no association at all between baseline DBP and major cardiovascular events across the range of DBP values evaluated in HOPE-3.
But wait: Things get more interesting, according to the cardiac electrophysiologist.
“I find the association between mean in-trial blood pressure as recorded in many measurements and vascular outcomes to be the most interesting analysis. This may be a better look at the association between blood pressure and outcomes than a measurement obtained just once or twice at baseline,” she explained.
Of note, among the 6,356 subjects on candesartan/hydrochlorothiazide, those with a mean on-treatment SBP of 160 mm Hg or more had a 2.61% per year rate of the composite of cardiovascular death, MI, stroke, rescue from cardiac arrest, heart failure, or revascularization. This was more than three-fold higher than the 0.75% per year rate in patients with an on-treatment SBP of 120-139.9 mm Hg. The composite event rate was also significantly higher in those with a mean on-treatment SBP of 140-159.9 mm Hg, at 1.4% per year. The event rate in patients with an on-treatment SBP below 120 mm Hg was identical to that of patients with a value of 120-139.9 mm Hg.
Only among patients with an on-treatment DBP of 90 mm Hg or more was the composite event rate significantly greater than in those with a DBP of 70-79.9 mm Hg, who had the lowest event rate by a margin of 1.89% versus 0.75% per year.
An Australian cardiologist in the audience who has been involved in revamping hypertension treatment guidelines Down Under expressed frustration. He only recently succeeded in wrangling his fellow panelists into incorporating the SPRINT results into the draft guidelines; now HOPE-3 is sending a very different message. What gives? Could the disparate findings simply be due to play of chance? he asked.
Highly unlikely, Dr. Lonn replied.
“There were substantial differences between our trials,” she explained. “First of all, the SPRINT population was at substantially higher risk. They either had to have established cardiovascular disease – we eliminated those people – or significant renal disease – we eliminated those people, too – or age greater than 75, or a Framingham Risk Score above 15%.”
Also, the SPRINT protocol controversially called for unattended blood pressure measurement.
“This is a very pure way ot eliminating white coat hypertension, but it is different from other studies, so it is very difficult to compare SPRINT to older studies or to HOPE-3. Some other investigators have suggested that the difference between attended and unattended blood pressure is close to 10 mm Hg. So our SBP of 130 mm Hg, which had the best outcomes in HOPE-3, may be the same as about 120 mm Hg in SPRINT,” according to Dr. Lonn.
HOPE-3 was funded by the Canadian Institutes of Health Research and AstraZeneca. Dr. Lonn reported serving as a consultant to and receiving research grants from AstraZeneca, Amgen, Bayer, and Novartis.
BARCELONA – How low to go in treating hypertension is a topic of considerable recent controversy. Now the HOPE-3 trial investigators have weighed in, reporting that optimal outcomes in their landmark randomized trial were seen with an achieved, on-treatment systolic blood pressure of 130-140 mm Hg and a diastolic blood pressure of 75-80 mm Hg, Eva M. Lonn, MD, reported at the annual congress of the European Society of Cardiology.
Those results stand in glaring contrast to the findings of the much-discussed SPRINT trial, in which hypertensive patients fared best with an on-treatment SBP driven below 120 mm Hg (N Engl J Med. 2015 Nov 26; 373:2103-16).
“Please note that lower blood pressures, both systolic and diastolic, weren’t associated with lower risk, whereas higher blood pressures considerably increased the risk for major vascular events,” she added.
HOPE-3 (the Third Heart Outcomes Prevention Evaluation) included 12,705 patients in 21 countries who did not have cardiovascular disease and were at intermediate risk, with an average age of 65 years at enrollment and a Framinhgam Risk Score of about 10%. They were randomized double-blind in a 2x2 factorial design to rosuvastatin at 10 mg per day or placebo and/or candesartan at 16 mg plus hydrochlorothiazide at 12.5 mg per day or placebo and prospectively followed for a median of 5.6 years.
The primary outcomes of HOPE-3 have been published (N Engl J Med. 2016 May 26;374[21]:2009-20 and 2021-31). This was a practice-changing trial that opened the door to broader use of statin therapy for primary prevention.
At the ESC congress in Barcelona, Dr. Lonn presented a secondary post-hoc analysis that focused on the impact of antihypertensive therapy in HOPE-3. The results shed new light on the optimal blood pressure levels for triggering initation of antihypertensive therapy, as well as defining the achieved blood pressures that resulted in the greatest reductions in major vascular events.
As this was essentially an all-comers trial of intermediate-risk patients, participants presented with a range of blood pressures at baseline. But more than 4,700 subjects had a baseline SBP of 140-159.9 mm Hg, and 833 had an SBP of 160 mm Hg or more.
The candesartan/hydrochlorothiazide regimen resulted in what Dr. Lonn termed a “moderate” net placebo-subtracted blood pressure reduction of 6/3 mm Hg. The higher the baseline blood pressure, the bigger the reduction.
In the one-third of subjects with a baseline SBP greater than 143.5 mm Hg, antihypertensive therapy resulted in a significant 27% reduction in the composite endpoint of cardiovascular death, MI, or stroke compared with placebo. Those with a baseline SBP of 150 mm Hg or more showed even greater benefit from antihypertensive therapy, with a composite event rate of 4.8% compared with 7.2% for placebo, representing a 34% relative risk reduction in which the event curves began separating at about 2 years.
In contrast, antihypertensive therapy brought no significant reduction in events in patients in the lower two tertiles of baseline SBP. And there was no association at all between baseline DBP and major cardiovascular events across the range of DBP values evaluated in HOPE-3.
But wait: Things get more interesting, according to the cardiac electrophysiologist.
“I find the association between mean in-trial blood pressure as recorded in many measurements and vascular outcomes to be the most interesting analysis. This may be a better look at the association between blood pressure and outcomes than a measurement obtained just once or twice at baseline,” she explained.
Of note, among the 6,356 subjects on candesartan/hydrochlorothiazide, those with a mean on-treatment SBP of 160 mm Hg or more had a 2.61% per year rate of the composite of cardiovascular death, MI, stroke, rescue from cardiac arrest, heart failure, or revascularization. This was more than three-fold higher than the 0.75% per year rate in patients with an on-treatment SBP of 120-139.9 mm Hg. The composite event rate was also significantly higher in those with a mean on-treatment SBP of 140-159.9 mm Hg, at 1.4% per year. The event rate in patients with an on-treatment SBP below 120 mm Hg was identical to that of patients with a value of 120-139.9 mm Hg.
Only among patients with an on-treatment DBP of 90 mm Hg or more was the composite event rate significantly greater than in those with a DBP of 70-79.9 mm Hg, who had the lowest event rate by a margin of 1.89% versus 0.75% per year.
An Australian cardiologist in the audience who has been involved in revamping hypertension treatment guidelines Down Under expressed frustration. He only recently succeeded in wrangling his fellow panelists into incorporating the SPRINT results into the draft guidelines; now HOPE-3 is sending a very different message. What gives? Could the disparate findings simply be due to play of chance? he asked.
Highly unlikely, Dr. Lonn replied.
“There were substantial differences between our trials,” she explained. “First of all, the SPRINT population was at substantially higher risk. They either had to have established cardiovascular disease – we eliminated those people – or significant renal disease – we eliminated those people, too – or age greater than 75, or a Framingham Risk Score above 15%.”
Also, the SPRINT protocol controversially called for unattended blood pressure measurement.
“This is a very pure way ot eliminating white coat hypertension, but it is different from other studies, so it is very difficult to compare SPRINT to older studies or to HOPE-3. Some other investigators have suggested that the difference between attended and unattended blood pressure is close to 10 mm Hg. So our SBP of 130 mm Hg, which had the best outcomes in HOPE-3, may be the same as about 120 mm Hg in SPRINT,” according to Dr. Lonn.
HOPE-3 was funded by the Canadian Institutes of Health Research and AstraZeneca. Dr. Lonn reported serving as a consultant to and receiving research grants from AstraZeneca, Amgen, Bayer, and Novartis.
AT THE ESC CONGRESS 2017
Key clinical point:
Major finding: The on-treatment systolic blood pressure target associated with the greatest reduction in vascular events in the HOPE-3 trial was 130-140 mm Hg.
Data source: The HOPE-3 trial was a randomized, double-blind, placebo-controlled study of 12,705 intermediate-cardiovascular-risk patients in 21 countries who were prospectively followed for a median 5.6 years.
Disclosures: HOPE-3 was funded by the Canadian Institutes of Health Research and AstraZeneca. The presenter reported serving as a consultant to and receiving research grants from AstraZeneca, Amgen, Bayer, and Novartis.
How to apply SPRINT findings to elderly patients
SAN FRANCISCO – The benefit of lowering blood pressure exceeded the potential for harm, even among the most frail elderly, in SPRINT, but it’s important to remember who was excluded from the trial when using the findings in the clinic, according to Mark Supiano, MD.
SPRINT (Systolic Blood Pressure Intervention Trial) excluded people with histories of stroke, diabetes, heart failure, and chronic kidney disease with a markedly reduced glomerular filtration rate. People living in nursing homes, assisted living centers, and those with prevalent dementia were also excluded, as were individuals with a standing systolic pressure below 110 mm Hg (N Engl J Med. 2015 Nov 26;373:2103-16).
Even with those exclusions, however, the 2,636 patients in SPRINT who were 75 years and older “were not a super healthy group of older people,” Dr. Supiano said at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.
They were at high risk for cardiovascular disease (CVD), with a median 10-year Framingham risk score of almost 25%. More than a quarter had gait speeds below 0.8 m/sec, and almost a third were classified as frail. Many had mild cognitive impairment at baseline.
In the United States, Dr. Supiano and his colleagues estimate that there are almost 6 million similar people 75 years or older with hypertension who would likely achieve the same benefits from hypertension control as elderly subjects in the trial. “As a geriatrician, there are very few things that I can offer patients 75 years and older that will have a profound improvement in their overall mortality.” Blood pressure control is one of them, said Dr. Supiano, chief of geriatrics at the University of Utah, Salt Lake City, and a SPRINT investigator.
In SPRINT, intensive treatment to systolic pressure below 120 mm Hg showed greater benefit for patients 75 years and older than it did for younger patients, even among the frail, with a 34% reduction in fatal and nonfatal CVD events versus patients treated to below 140 mm Hg, and a 33% lower rate of death from any cause.
It should be no surprise that older patients had greater benefit from tighter control, because elderly patients have “a greater CVD risk. There’s more bang for the buck” with blood pressure lowering in an older population. “Overall, benefits exceed the potential for harm, even among the frailest older patients,” Dr. Supiano said.
“A systemic target of less than 140 mm Hg is, I believe, appropriate for most healthy people age 60 and older. A benefit-based systemic target of less than 120 mm Hg may be appropriate for those at higher CVD risk.” Among patients 60-75 years old, that would include those with a Framingham score above 15%. Among patients older than age 75 with an elevated CVD risk, treatment to below 120 mm Hg makes sense if it aligns with patient’s goals of care, Dr. Supiano said.
The 120–mm Hg target in SPRINT was associated with a greater incidence of some transient side effects in the elderly, including hypotension, syncope, acute kidney injury, and electrolyte imbalance, but not a higher risk of serious adverse events or injurious falls.
There were concerns raised at the joint sessions about the effect of blood pressure lowering on the cognitive function of older people. Dr. Supiano noted that the cognitive outcomes in SPRINT, as well as outcomes in patients with chronic kidney disease, have not yet been released, but are expected soon.
Dr. Supiano had no relevant disclosures.
SAN FRANCISCO – The benefit of lowering blood pressure exceeded the potential for harm, even among the most frail elderly, in SPRINT, but it’s important to remember who was excluded from the trial when using the findings in the clinic, according to Mark Supiano, MD.
SPRINT (Systolic Blood Pressure Intervention Trial) excluded people with histories of stroke, diabetes, heart failure, and chronic kidney disease with a markedly reduced glomerular filtration rate. People living in nursing homes, assisted living centers, and those with prevalent dementia were also excluded, as were individuals with a standing systolic pressure below 110 mm Hg (N Engl J Med. 2015 Nov 26;373:2103-16).
Even with those exclusions, however, the 2,636 patients in SPRINT who were 75 years and older “were not a super healthy group of older people,” Dr. Supiano said at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.
They were at high risk for cardiovascular disease (CVD), with a median 10-year Framingham risk score of almost 25%. More than a quarter had gait speeds below 0.8 m/sec, and almost a third were classified as frail. Many had mild cognitive impairment at baseline.
In the United States, Dr. Supiano and his colleagues estimate that there are almost 6 million similar people 75 years or older with hypertension who would likely achieve the same benefits from hypertension control as elderly subjects in the trial. “As a geriatrician, there are very few things that I can offer patients 75 years and older that will have a profound improvement in their overall mortality.” Blood pressure control is one of them, said Dr. Supiano, chief of geriatrics at the University of Utah, Salt Lake City, and a SPRINT investigator.
In SPRINT, intensive treatment to systolic pressure below 120 mm Hg showed greater benefit for patients 75 years and older than it did for younger patients, even among the frail, with a 34% reduction in fatal and nonfatal CVD events versus patients treated to below 140 mm Hg, and a 33% lower rate of death from any cause.
It should be no surprise that older patients had greater benefit from tighter control, because elderly patients have “a greater CVD risk. There’s more bang for the buck” with blood pressure lowering in an older population. “Overall, benefits exceed the potential for harm, even among the frailest older patients,” Dr. Supiano said.
“A systemic target of less than 140 mm Hg is, I believe, appropriate for most healthy people age 60 and older. A benefit-based systemic target of less than 120 mm Hg may be appropriate for those at higher CVD risk.” Among patients 60-75 years old, that would include those with a Framingham score above 15%. Among patients older than age 75 with an elevated CVD risk, treatment to below 120 mm Hg makes sense if it aligns with patient’s goals of care, Dr. Supiano said.
The 120–mm Hg target in SPRINT was associated with a greater incidence of some transient side effects in the elderly, including hypotension, syncope, acute kidney injury, and electrolyte imbalance, but not a higher risk of serious adverse events or injurious falls.
There were concerns raised at the joint sessions about the effect of blood pressure lowering on the cognitive function of older people. Dr. Supiano noted that the cognitive outcomes in SPRINT, as well as outcomes in patients with chronic kidney disease, have not yet been released, but are expected soon.
Dr. Supiano had no relevant disclosures.
SAN FRANCISCO – The benefit of lowering blood pressure exceeded the potential for harm, even among the most frail elderly, in SPRINT, but it’s important to remember who was excluded from the trial when using the findings in the clinic, according to Mark Supiano, MD.
SPRINT (Systolic Blood Pressure Intervention Trial) excluded people with histories of stroke, diabetes, heart failure, and chronic kidney disease with a markedly reduced glomerular filtration rate. People living in nursing homes, assisted living centers, and those with prevalent dementia were also excluded, as were individuals with a standing systolic pressure below 110 mm Hg (N Engl J Med. 2015 Nov 26;373:2103-16).
Even with those exclusions, however, the 2,636 patients in SPRINT who were 75 years and older “were not a super healthy group of older people,” Dr. Supiano said at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.
They were at high risk for cardiovascular disease (CVD), with a median 10-year Framingham risk score of almost 25%. More than a quarter had gait speeds below 0.8 m/sec, and almost a third were classified as frail. Many had mild cognitive impairment at baseline.
In the United States, Dr. Supiano and his colleagues estimate that there are almost 6 million similar people 75 years or older with hypertension who would likely achieve the same benefits from hypertension control as elderly subjects in the trial. “As a geriatrician, there are very few things that I can offer patients 75 years and older that will have a profound improvement in their overall mortality.” Blood pressure control is one of them, said Dr. Supiano, chief of geriatrics at the University of Utah, Salt Lake City, and a SPRINT investigator.
In SPRINT, intensive treatment to systolic pressure below 120 mm Hg showed greater benefit for patients 75 years and older than it did for younger patients, even among the frail, with a 34% reduction in fatal and nonfatal CVD events versus patients treated to below 140 mm Hg, and a 33% lower rate of death from any cause.
It should be no surprise that older patients had greater benefit from tighter control, because elderly patients have “a greater CVD risk. There’s more bang for the buck” with blood pressure lowering in an older population. “Overall, benefits exceed the potential for harm, even among the frailest older patients,” Dr. Supiano said.
“A systemic target of less than 140 mm Hg is, I believe, appropriate for most healthy people age 60 and older. A benefit-based systemic target of less than 120 mm Hg may be appropriate for those at higher CVD risk.” Among patients 60-75 years old, that would include those with a Framingham score above 15%. Among patients older than age 75 with an elevated CVD risk, treatment to below 120 mm Hg makes sense if it aligns with patient’s goals of care, Dr. Supiano said.
The 120–mm Hg target in SPRINT was associated with a greater incidence of some transient side effects in the elderly, including hypotension, syncope, acute kidney injury, and electrolyte imbalance, but not a higher risk of serious adverse events or injurious falls.
There were concerns raised at the joint sessions about the effect of blood pressure lowering on the cognitive function of older people. Dr. Supiano noted that the cognitive outcomes in SPRINT, as well as outcomes in patients with chronic kidney disease, have not yet been released, but are expected soon.
Dr. Supiano had no relevant disclosures.
EXPERT ANALYSIS FROM JOINT HYPERTENSION 2017
Fasting glucose fluctuations, severe hypoglycemia up T2DM death risk
AT EASD 2017
LISBON –
A second wave of results from the DEVOTE study, which compared the cardiovascular safety of insulin degludec (Tresiba, Novo Nordisk) versus insulin glargine, found that day-to-day variability in fasting plasma glucose (FPG) versus no FPG variability was significantly associated with both severe hypoglycemia (adjusted hazard ratio, 3.37; 95% confidence interval, 2.52-4.50; P less than .001), and all-cause mortality (aHR, 1.33; 95% CI, 1.01-1.75; P = .00432).
In addition, severe hypoglycemia was linked to all-cause mortality, with a temporal relationship seen such that the risk for death was higher the more recent the episode of severe hypoglycemia had been. Indeed, while the risk of death was 2.5 times higher at any time after an episode of severe hypoglycemia than if no prior severe hypoglycemia occurred (HR, 2.51; 95% CI, 1.35-13.09), it was four times higher 15 days after severe hypoglycemia than after no such event (HR, 4.20; 95% CI, 1.9-3.50).
These results of DEVOTE 2 and DEVOTE 3 were presented at the annual meeting of the European Association for the Study of Diabetes and published in Diabetologia on Sept. 15.
What do the results mean for current practice?
“There’s great interest in knowing whether glucose variability and severe hypoglycemia are associated with cardiovascular risk and mortality; these data are therefore important and timely,” said the invited commentator and editorialist for the study Martin Rutter, MD, a senior lecturer in cardiometabolic medicine at the University of Manchester and an honorary consultant physician at Manchester Royal Infirmary, England.
“Only further clinical trials can genuinely guide clinicians on whether to target glucose variability and risk for severe hypos to reduce the risk of cardiovascular events in people with type 2 diabetes. My hope is that these data will help to build a case for such trials,” Dr. Rutter said.
DEVOTE: main findings and secondary analyses
The main findings from the DEVOTE study were reported in June during the American Diabetes Association’s Annual Scientific Sessions and simultaneously published in the New England Journal of Medicine (2017 Aug 24;377[8]:723-32). These showed that insulin degludec was noninferior to insulin glargine, with a similar rate of major cardiovascular events (MACE), which comprised nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death (8.5% vs. 9.3%; HR, 0.91; 95% CI, 0.78-1.06; P less than .001). The rate of severe hypoglycemia was significantly (P less than .001) lower in the degludec than glargine arm, however, occurring in a respective 4.9% and 6.6% of patients in each group (odds ratio, 0.73).
“DEVOTE confirms the cardiovascular safety of insulin degludec, compared with glargine,” said DEVOTE study investigator, Neil Poulter, MD, FMedSci, of the Imperial Clinical Trials Unit at Imperial College London. “The rate of severe hypoglycemia was significantly reduced [with insulin degludec vs. glargine] in the DEVOTE trial.”
Role of glycemic variability
“It is well established that there is a relationship between glycemic variability and hypoglycemia,” said Bernard Zinman, MD, director of the Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital in Toronto, who presented the DEVOTE 2 findings. He commented that the “very dense data” collected during the main study had enabled a fuller analysis of glycemic variability. Dr. Zinman was keen to emphasize that it was the fasting variability that was studied.
Looking at outcomes, there was a dose relationship seen from low to high glycemic variability with increasing rates of severe hypoglycemia, MACE, and all-cause mortality the higher the variability, Dr. Zinman reported.
Although initially there was an increased risk for MACE with increasing glycemic variability, “the association was not maintained after adjusting for baseline characteristics and the most recent A1c,” Dr. Zinman said.
Timing of severe hypoglycemia could be vital
Severe hypoglycemia is under-reported and there is still concern over inducing hypoglycemia, which “conflicts with treatment success,” observed Thomas Pieber, MD, who presented the DEVOTE 3 findings on the relationship between severe hypoglycemia and outcomes.
“Up to 80% of us are concerned about the risk of hypoglycemia and we are not treating glycemic control as aggressively as we would do if there was not any worry about hypoglycemia,” Dr. Pieber said, referring to primary care physicians and diabetes specialists.
Talking about the DEVOTE 3 results, Dr. Pieber noted: “There was no significant association between severe hypoglycemia and MACE, but there was a significantly higher risk of cardiovascular death following a severe hypoglycemia event.” He reminded the audience that an episode of severe hypoglycemia was one which required the assistance of another person, as defined by International Hypoglycemia Study Group which has been acknowledged by both the ADA and EASD.
“These data we have analyzed support a temporal relationship between severe hypoglycemia and all-cause mortality,” Dr. Pieber, adding “the findings indicate that severe hypoglycemia is associated with higher subsequent mortality.”
Predicting severe hypos
“There are well-known factors that influence the risk of having a severe hypoglycemic event,” commented another of the DEVOTE study investigators, John Buse, MD, PhD, of the University of North Carolina School of Medicine at Chapel Hill. These include the insulin treatment regimen, the duration of diabetes, sex, and baseline HbA1c, to pick the more traditional ones. Additional ones that a post-hoc analysis of the DEVOTE data identified are baseline renal function, prior stroke, low-to-high-density lipoprotein ratio, diastolic blood pressure, hepatic impairment, and smoking status. Age, another traditional risk factor, was identified as well and all these went in to create the DEVOTE severe hypoglycemia risk prediction model.
The DEVOTE hypoglycemia risk score is currently a work in progress; the app can be seen at http://www.hyporiskscore.com/. DEVOTE was funded by Novo Nordisk. Slides presented at the EASD meeting are available for download at https://tracs.unc.edu/DEVOTE.
Dr. Rutter disclosed receiving honoraria and funding to attend educational meetings from Novo Nordisk and honoraria and consulting fees from Ascensia, Cell Catapult, and Roche Diabetes Care.
Dr. Poulter has received speaker fees and consultancy fees from Novo Nordisk, Servier, Takeda, and AstraZeneca; and grants for his research group relating to type 2 diabetes mellitus from Diabetes UK, the National Institute for Health Research Efficacy and Mechanism Evaluation, and the Julius Clinical and the British Heart Foundation.
Dr. Zinman has received grant support from Novo Nordisk, Boehringer Ingelheim, and AstraZeneca. He disclosed receiving consulting fees from Novo Nordisk, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck, Sharp & Dohme, and Sanofi.
Dr. Pieber disclosed receiving received research support from Novo Nordisk and AstraZeneca paid directly to his institution and personal honoraria from Novo Nordisk, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Roche Diabetes Care. Dr. Pieber is the Chief Scientific Officer of the Center for Biomarker Research in Medicine, a publicly funded biomarker research company.
Dr. Buse reported receiving contracted consulting fees, paid to his institution, and travel support from Novo Nordisk, Eli Lilly and Company, GI Dynamics, Elcelyx, Merck, Metavention, vTv Pharma, PhaseBio, AstraZeneca, Dance Biopharm, Sanofi, Lexicon Pharmaceuticals, Orexigen, Takeda, Adocia, Roche, NovaTarg, Shenzhen High Tide, Fractyl, and Dexcom. He has also received consultancy fees and grant support from Eli Lilly and Company, Bristol-Myers Squibb, GI Dynamics, Merck, PhaseBio, AstraZeneca, Medtronic Minimed, Sanofi, Johnson & Johnson, Andromeda, Boehringer Ingelheim, GlaxoSmithKline, MacroGenics, Intarcia Therapeutics, Lexicon Pharmaceuticals, Scion NeuroStim, Orexigen, Takeda, Theracos, and Bayer. Dr. Buse has also received fees and holds stock options in PhaseBio and Insulin Algorithm, as well as serving on the board of the AstraZeneca Healthcare Foundation.
AT EASD 2017
LISBON –
A second wave of results from the DEVOTE study, which compared the cardiovascular safety of insulin degludec (Tresiba, Novo Nordisk) versus insulin glargine, found that day-to-day variability in fasting plasma glucose (FPG) versus no FPG variability was significantly associated with both severe hypoglycemia (adjusted hazard ratio, 3.37; 95% confidence interval, 2.52-4.50; P less than .001), and all-cause mortality (aHR, 1.33; 95% CI, 1.01-1.75; P = .00432).
In addition, severe hypoglycemia was linked to all-cause mortality, with a temporal relationship seen such that the risk for death was higher the more recent the episode of severe hypoglycemia had been. Indeed, while the risk of death was 2.5 times higher at any time after an episode of severe hypoglycemia than if no prior severe hypoglycemia occurred (HR, 2.51; 95% CI, 1.35-13.09), it was four times higher 15 days after severe hypoglycemia than after no such event (HR, 4.20; 95% CI, 1.9-3.50).
These results of DEVOTE 2 and DEVOTE 3 were presented at the annual meeting of the European Association for the Study of Diabetes and published in Diabetologia on Sept. 15.
What do the results mean for current practice?
“There’s great interest in knowing whether glucose variability and severe hypoglycemia are associated with cardiovascular risk and mortality; these data are therefore important and timely,” said the invited commentator and editorialist for the study Martin Rutter, MD, a senior lecturer in cardiometabolic medicine at the University of Manchester and an honorary consultant physician at Manchester Royal Infirmary, England.
“Only further clinical trials can genuinely guide clinicians on whether to target glucose variability and risk for severe hypos to reduce the risk of cardiovascular events in people with type 2 diabetes. My hope is that these data will help to build a case for such trials,” Dr. Rutter said.
DEVOTE: main findings and secondary analyses
The main findings from the DEVOTE study were reported in June during the American Diabetes Association’s Annual Scientific Sessions and simultaneously published in the New England Journal of Medicine (2017 Aug 24;377[8]:723-32). These showed that insulin degludec was noninferior to insulin glargine, with a similar rate of major cardiovascular events (MACE), which comprised nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death (8.5% vs. 9.3%; HR, 0.91; 95% CI, 0.78-1.06; P less than .001). The rate of severe hypoglycemia was significantly (P less than .001) lower in the degludec than glargine arm, however, occurring in a respective 4.9% and 6.6% of patients in each group (odds ratio, 0.73).
“DEVOTE confirms the cardiovascular safety of insulin degludec, compared with glargine,” said DEVOTE study investigator, Neil Poulter, MD, FMedSci, of the Imperial Clinical Trials Unit at Imperial College London. “The rate of severe hypoglycemia was significantly reduced [with insulin degludec vs. glargine] in the DEVOTE trial.”
Role of glycemic variability
“It is well established that there is a relationship between glycemic variability and hypoglycemia,” said Bernard Zinman, MD, director of the Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital in Toronto, who presented the DEVOTE 2 findings. He commented that the “very dense data” collected during the main study had enabled a fuller analysis of glycemic variability. Dr. Zinman was keen to emphasize that it was the fasting variability that was studied.
Looking at outcomes, there was a dose relationship seen from low to high glycemic variability with increasing rates of severe hypoglycemia, MACE, and all-cause mortality the higher the variability, Dr. Zinman reported.
Although initially there was an increased risk for MACE with increasing glycemic variability, “the association was not maintained after adjusting for baseline characteristics and the most recent A1c,” Dr. Zinman said.
Timing of severe hypoglycemia could be vital
Severe hypoglycemia is under-reported and there is still concern over inducing hypoglycemia, which “conflicts with treatment success,” observed Thomas Pieber, MD, who presented the DEVOTE 3 findings on the relationship between severe hypoglycemia and outcomes.
“Up to 80% of us are concerned about the risk of hypoglycemia and we are not treating glycemic control as aggressively as we would do if there was not any worry about hypoglycemia,” Dr. Pieber said, referring to primary care physicians and diabetes specialists.
Talking about the DEVOTE 3 results, Dr. Pieber noted: “There was no significant association between severe hypoglycemia and MACE, but there was a significantly higher risk of cardiovascular death following a severe hypoglycemia event.” He reminded the audience that an episode of severe hypoglycemia was one which required the assistance of another person, as defined by International Hypoglycemia Study Group which has been acknowledged by both the ADA and EASD.
“These data we have analyzed support a temporal relationship between severe hypoglycemia and all-cause mortality,” Dr. Pieber, adding “the findings indicate that severe hypoglycemia is associated with higher subsequent mortality.”
Predicting severe hypos
“There are well-known factors that influence the risk of having a severe hypoglycemic event,” commented another of the DEVOTE study investigators, John Buse, MD, PhD, of the University of North Carolina School of Medicine at Chapel Hill. These include the insulin treatment regimen, the duration of diabetes, sex, and baseline HbA1c, to pick the more traditional ones. Additional ones that a post-hoc analysis of the DEVOTE data identified are baseline renal function, prior stroke, low-to-high-density lipoprotein ratio, diastolic blood pressure, hepatic impairment, and smoking status. Age, another traditional risk factor, was identified as well and all these went in to create the DEVOTE severe hypoglycemia risk prediction model.
The DEVOTE hypoglycemia risk score is currently a work in progress; the app can be seen at http://www.hyporiskscore.com/. DEVOTE was funded by Novo Nordisk. Slides presented at the EASD meeting are available for download at https://tracs.unc.edu/DEVOTE.
Dr. Rutter disclosed receiving honoraria and funding to attend educational meetings from Novo Nordisk and honoraria and consulting fees from Ascensia, Cell Catapult, and Roche Diabetes Care.
Dr. Poulter has received speaker fees and consultancy fees from Novo Nordisk, Servier, Takeda, and AstraZeneca; and grants for his research group relating to type 2 diabetes mellitus from Diabetes UK, the National Institute for Health Research Efficacy and Mechanism Evaluation, and the Julius Clinical and the British Heart Foundation.
Dr. Zinman has received grant support from Novo Nordisk, Boehringer Ingelheim, and AstraZeneca. He disclosed receiving consulting fees from Novo Nordisk, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck, Sharp & Dohme, and Sanofi.
Dr. Pieber disclosed receiving received research support from Novo Nordisk and AstraZeneca paid directly to his institution and personal honoraria from Novo Nordisk, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Roche Diabetes Care. Dr. Pieber is the Chief Scientific Officer of the Center for Biomarker Research in Medicine, a publicly funded biomarker research company.
Dr. Buse reported receiving contracted consulting fees, paid to his institution, and travel support from Novo Nordisk, Eli Lilly and Company, GI Dynamics, Elcelyx, Merck, Metavention, vTv Pharma, PhaseBio, AstraZeneca, Dance Biopharm, Sanofi, Lexicon Pharmaceuticals, Orexigen, Takeda, Adocia, Roche, NovaTarg, Shenzhen High Tide, Fractyl, and Dexcom. He has also received consultancy fees and grant support from Eli Lilly and Company, Bristol-Myers Squibb, GI Dynamics, Merck, PhaseBio, AstraZeneca, Medtronic Minimed, Sanofi, Johnson & Johnson, Andromeda, Boehringer Ingelheim, GlaxoSmithKline, MacroGenics, Intarcia Therapeutics, Lexicon Pharmaceuticals, Scion NeuroStim, Orexigen, Takeda, Theracos, and Bayer. Dr. Buse has also received fees and holds stock options in PhaseBio and Insulin Algorithm, as well as serving on the board of the AstraZeneca Healthcare Foundation.
AT EASD 2017
LISBON –
A second wave of results from the DEVOTE study, which compared the cardiovascular safety of insulin degludec (Tresiba, Novo Nordisk) versus insulin glargine, found that day-to-day variability in fasting plasma glucose (FPG) versus no FPG variability was significantly associated with both severe hypoglycemia (adjusted hazard ratio, 3.37; 95% confidence interval, 2.52-4.50; P less than .001), and all-cause mortality (aHR, 1.33; 95% CI, 1.01-1.75; P = .00432).
In addition, severe hypoglycemia was linked to all-cause mortality, with a temporal relationship seen such that the risk for death was higher the more recent the episode of severe hypoglycemia had been. Indeed, while the risk of death was 2.5 times higher at any time after an episode of severe hypoglycemia than if no prior severe hypoglycemia occurred (HR, 2.51; 95% CI, 1.35-13.09), it was four times higher 15 days after severe hypoglycemia than after no such event (HR, 4.20; 95% CI, 1.9-3.50).
These results of DEVOTE 2 and DEVOTE 3 were presented at the annual meeting of the European Association for the Study of Diabetes and published in Diabetologia on Sept. 15.
What do the results mean for current practice?
“There’s great interest in knowing whether glucose variability and severe hypoglycemia are associated with cardiovascular risk and mortality; these data are therefore important and timely,” said the invited commentator and editorialist for the study Martin Rutter, MD, a senior lecturer in cardiometabolic medicine at the University of Manchester and an honorary consultant physician at Manchester Royal Infirmary, England.
“Only further clinical trials can genuinely guide clinicians on whether to target glucose variability and risk for severe hypos to reduce the risk of cardiovascular events in people with type 2 diabetes. My hope is that these data will help to build a case for such trials,” Dr. Rutter said.
DEVOTE: main findings and secondary analyses
The main findings from the DEVOTE study were reported in June during the American Diabetes Association’s Annual Scientific Sessions and simultaneously published in the New England Journal of Medicine (2017 Aug 24;377[8]:723-32). These showed that insulin degludec was noninferior to insulin glargine, with a similar rate of major cardiovascular events (MACE), which comprised nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death (8.5% vs. 9.3%; HR, 0.91; 95% CI, 0.78-1.06; P less than .001). The rate of severe hypoglycemia was significantly (P less than .001) lower in the degludec than glargine arm, however, occurring in a respective 4.9% and 6.6% of patients in each group (odds ratio, 0.73).
“DEVOTE confirms the cardiovascular safety of insulin degludec, compared with glargine,” said DEVOTE study investigator, Neil Poulter, MD, FMedSci, of the Imperial Clinical Trials Unit at Imperial College London. “The rate of severe hypoglycemia was significantly reduced [with insulin degludec vs. glargine] in the DEVOTE trial.”
Role of glycemic variability
“It is well established that there is a relationship between glycemic variability and hypoglycemia,” said Bernard Zinman, MD, director of the Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital in Toronto, who presented the DEVOTE 2 findings. He commented that the “very dense data” collected during the main study had enabled a fuller analysis of glycemic variability. Dr. Zinman was keen to emphasize that it was the fasting variability that was studied.
Looking at outcomes, there was a dose relationship seen from low to high glycemic variability with increasing rates of severe hypoglycemia, MACE, and all-cause mortality the higher the variability, Dr. Zinman reported.
Although initially there was an increased risk for MACE with increasing glycemic variability, “the association was not maintained after adjusting for baseline characteristics and the most recent A1c,” Dr. Zinman said.
Timing of severe hypoglycemia could be vital
Severe hypoglycemia is under-reported and there is still concern over inducing hypoglycemia, which “conflicts with treatment success,” observed Thomas Pieber, MD, who presented the DEVOTE 3 findings on the relationship between severe hypoglycemia and outcomes.
“Up to 80% of us are concerned about the risk of hypoglycemia and we are not treating glycemic control as aggressively as we would do if there was not any worry about hypoglycemia,” Dr. Pieber said, referring to primary care physicians and diabetes specialists.
Talking about the DEVOTE 3 results, Dr. Pieber noted: “There was no significant association between severe hypoglycemia and MACE, but there was a significantly higher risk of cardiovascular death following a severe hypoglycemia event.” He reminded the audience that an episode of severe hypoglycemia was one which required the assistance of another person, as defined by International Hypoglycemia Study Group which has been acknowledged by both the ADA and EASD.
“These data we have analyzed support a temporal relationship between severe hypoglycemia and all-cause mortality,” Dr. Pieber, adding “the findings indicate that severe hypoglycemia is associated with higher subsequent mortality.”
Predicting severe hypos
“There are well-known factors that influence the risk of having a severe hypoglycemic event,” commented another of the DEVOTE study investigators, John Buse, MD, PhD, of the University of North Carolina School of Medicine at Chapel Hill. These include the insulin treatment regimen, the duration of diabetes, sex, and baseline HbA1c, to pick the more traditional ones. Additional ones that a post-hoc analysis of the DEVOTE data identified are baseline renal function, prior stroke, low-to-high-density lipoprotein ratio, diastolic blood pressure, hepatic impairment, and smoking status. Age, another traditional risk factor, was identified as well and all these went in to create the DEVOTE severe hypoglycemia risk prediction model.
The DEVOTE hypoglycemia risk score is currently a work in progress; the app can be seen at http://www.hyporiskscore.com/. DEVOTE was funded by Novo Nordisk. Slides presented at the EASD meeting are available for download at https://tracs.unc.edu/DEVOTE.
Dr. Rutter disclosed receiving honoraria and funding to attend educational meetings from Novo Nordisk and honoraria and consulting fees from Ascensia, Cell Catapult, and Roche Diabetes Care.
Dr. Poulter has received speaker fees and consultancy fees from Novo Nordisk, Servier, Takeda, and AstraZeneca; and grants for his research group relating to type 2 diabetes mellitus from Diabetes UK, the National Institute for Health Research Efficacy and Mechanism Evaluation, and the Julius Clinical and the British Heart Foundation.
Dr. Zinman has received grant support from Novo Nordisk, Boehringer Ingelheim, and AstraZeneca. He disclosed receiving consulting fees from Novo Nordisk, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Merck, Sharp & Dohme, and Sanofi.
Dr. Pieber disclosed receiving received research support from Novo Nordisk and AstraZeneca paid directly to his institution and personal honoraria from Novo Nordisk, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Roche Diabetes Care. Dr. Pieber is the Chief Scientific Officer of the Center for Biomarker Research in Medicine, a publicly funded biomarker research company.
Dr. Buse reported receiving contracted consulting fees, paid to his institution, and travel support from Novo Nordisk, Eli Lilly and Company, GI Dynamics, Elcelyx, Merck, Metavention, vTv Pharma, PhaseBio, AstraZeneca, Dance Biopharm, Sanofi, Lexicon Pharmaceuticals, Orexigen, Takeda, Adocia, Roche, NovaTarg, Shenzhen High Tide, Fractyl, and Dexcom. He has also received consultancy fees and grant support from Eli Lilly and Company, Bristol-Myers Squibb, GI Dynamics, Merck, PhaseBio, AstraZeneca, Medtronic Minimed, Sanofi, Johnson & Johnson, Andromeda, Boehringer Ingelheim, GlaxoSmithKline, MacroGenics, Intarcia Therapeutics, Lexicon Pharmaceuticals, Scion NeuroStim, Orexigen, Takeda, Theracos, and Bayer. Dr. Buse has also received fees and holds stock options in PhaseBio and Insulin Algorithm, as well as serving on the board of the AstraZeneca Healthcare Foundation.
Key clinical point: Evenly maintained blood glucose levels may save lives in T2DM.
Major finding: Patients with greater fluctuations of fasting plasma glucose were more likely to die than were those with more episodes of severe hypoglycemia.
Data source: Further analysis of data from both DEVOTE 2 and DEVOTE 3, involving 7,637 patients with type 2 diabetes who were treated with either insulin degludec or insulin glargine.
Disclosures: The study was funded by Novo Nordisk. All presenters have received consulting fees from Novo Nordisk among other pharmaceutical companies. Two presenters (Dr. Zinman and Dr. Pieber) also disclosed receiving research support from the company.
Many years on metformin linked to anemia risk
LISBON – People with type 2 diabetes who take metformin for many years are more likely to develop anemia than are those who do not, according to the results of a large analysis of data from an observational, population-based study with 20 years of follow-up.
“Metformin treatment was associated with a 6% higher risk of anemia for every cumulative year of metformin exposure,” Louise Donnelly, PhD, and her associates reported in a poster presentation at the annual meeting of the European Association for the Study of Diabetes.
In an interview, Dr. Donnelly, a postdoctoral research assistant at the University of Dundee (Scotland), explained why they looked at the use of metformin and anemia risk in people with type 2 diabetes.
“The Diabetes Prevention Program (DPP) study showed that long-term metformin use in individuals with impaired glucose tolerance was associated with an increased risk of anemia, and this was independent of vitamin B12 status,” she said (J Clin Endocrinol Metab. 2016;101:1754-61). “Anemia is a common finding in people with type 2 diabetes, but the impact of long-term metformin use on anemia hasn’t been studied.”
Dr. Donnelly and her associates obtained detailed information on metformin prescribing and hematology measures from electronic patient medical records from the Genetics of Diabetes Audit and Research in Tayside and Scotland (GoDARTS) cohort, based in Scotland. This database contains information on individuals with type 2 diabetes and matching controls and is available to researchers worldwide.
For the analysis, the team looked for people diagnosed from 1996 onward who had a baseline hemoglobin measurement. Of 6,440 individuals with type 2 diabetes in the GoDARTS cohort, just over half had a hemoglobin measurement.
“We used a definition of ‘moderate’ anemia and we excluded patients with mild anemia or worse at diabetes diagnosis,” Dr. Donnelly observed. Anemia was considered to be a hemoglobin level of less than 12 g/dL in women and less than 13 g/dL in men. In all, 280 individuals with anemia were excluded from further analysis as the aim was to follow people until they developed anemia, died, left the area, or until the end of the follow-up period, which was set at September 30, 2015. A discrete-time failure analysis was used to model the effect of cumulative metformin exposure on anemia risk.
After a median follow-up of 8 years and a median number of 11 hemoglobin measurements per patient, 2,487 study subjects (71%) had some exposure to metformin and 1,458 of the whole sample (41.8%) had become anemic. Of those who developed anemia, 745 (51%) were current metformin users, 194 (13%) were former users, and 519 (36%) had never taken metformin.
“Cumulative metformin use was independently associated with an increased risk of anemia,” Dr. Donnelly noted (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.02-1.09; P = .0006). This association was not seen when they examined the data based on sulfonylurea use (OR 1.0; 95% CI 0.97-1.04, P = .8), she added.
“Anemia risk was higher with age at diagnosis, duration of diabetes, lower hemoglobin at baseline, and lower eGFR [estimated glomerular filtration rate],” she observed. ORs for first anemia event were 1.03 (95% CI, 1.02-1.04) for every year of increasing age, 1.05 (95% CI, 1.03-1.08) for every additional year since diabetes diagnosis, 0.70 (95% CI, 0.66-0.74) per 1 g/dL of hemoglobin at diagnosis, and eGFR 0.98 (95% CI, 0.98-1.01) per additional 1 mL/min per 1.732 (P less than .0001 for all).
Why cumulative metformin use is associated with an increased of anemia is unclear, however, and Dr. Donnelly noted that this needs further investigation. “We do have data from two other clinical trials now, showing similar results, and maybe through those data we might be able to untangle it.”
The team does not think the anemia is related to B12 deficiency, however, as people who developed anemia while taking metformin were more likely to develop microcytic (12% vs. 7.3%) than macrocytic (7.6% vs. 12.3%), anemia, compared with people with anemia who were not exposed to metformin (P less than .0001).
“In terms of mechanism, we can only conjecture,” Ewan Pearson, MB, senior author of the study and professor of medicine at the University of Dundee, said during a discussion at the poster presentation. “It is important to stress that metformin is a great drug and we shouldn’t stop it because of a potentially increased risk of anemia.”
The Medical Research Council supported the work. Dr. Donnelly reported having no financial disclosures.
LISBON – People with type 2 diabetes who take metformin for many years are more likely to develop anemia than are those who do not, according to the results of a large analysis of data from an observational, population-based study with 20 years of follow-up.
“Metformin treatment was associated with a 6% higher risk of anemia for every cumulative year of metformin exposure,” Louise Donnelly, PhD, and her associates reported in a poster presentation at the annual meeting of the European Association for the Study of Diabetes.
In an interview, Dr. Donnelly, a postdoctoral research assistant at the University of Dundee (Scotland), explained why they looked at the use of metformin and anemia risk in people with type 2 diabetes.
“The Diabetes Prevention Program (DPP) study showed that long-term metformin use in individuals with impaired glucose tolerance was associated with an increased risk of anemia, and this was independent of vitamin B12 status,” she said (J Clin Endocrinol Metab. 2016;101:1754-61). “Anemia is a common finding in people with type 2 diabetes, but the impact of long-term metformin use on anemia hasn’t been studied.”
Dr. Donnelly and her associates obtained detailed information on metformin prescribing and hematology measures from electronic patient medical records from the Genetics of Diabetes Audit and Research in Tayside and Scotland (GoDARTS) cohort, based in Scotland. This database contains information on individuals with type 2 diabetes and matching controls and is available to researchers worldwide.
For the analysis, the team looked for people diagnosed from 1996 onward who had a baseline hemoglobin measurement. Of 6,440 individuals with type 2 diabetes in the GoDARTS cohort, just over half had a hemoglobin measurement.
“We used a definition of ‘moderate’ anemia and we excluded patients with mild anemia or worse at diabetes diagnosis,” Dr. Donnelly observed. Anemia was considered to be a hemoglobin level of less than 12 g/dL in women and less than 13 g/dL in men. In all, 280 individuals with anemia were excluded from further analysis as the aim was to follow people until they developed anemia, died, left the area, or until the end of the follow-up period, which was set at September 30, 2015. A discrete-time failure analysis was used to model the effect of cumulative metformin exposure on anemia risk.
After a median follow-up of 8 years and a median number of 11 hemoglobin measurements per patient, 2,487 study subjects (71%) had some exposure to metformin and 1,458 of the whole sample (41.8%) had become anemic. Of those who developed anemia, 745 (51%) were current metformin users, 194 (13%) were former users, and 519 (36%) had never taken metformin.
“Cumulative metformin use was independently associated with an increased risk of anemia,” Dr. Donnelly noted (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.02-1.09; P = .0006). This association was not seen when they examined the data based on sulfonylurea use (OR 1.0; 95% CI 0.97-1.04, P = .8), she added.
“Anemia risk was higher with age at diagnosis, duration of diabetes, lower hemoglobin at baseline, and lower eGFR [estimated glomerular filtration rate],” she observed. ORs for first anemia event were 1.03 (95% CI, 1.02-1.04) for every year of increasing age, 1.05 (95% CI, 1.03-1.08) for every additional year since diabetes diagnosis, 0.70 (95% CI, 0.66-0.74) per 1 g/dL of hemoglobin at diagnosis, and eGFR 0.98 (95% CI, 0.98-1.01) per additional 1 mL/min per 1.732 (P less than .0001 for all).
Why cumulative metformin use is associated with an increased of anemia is unclear, however, and Dr. Donnelly noted that this needs further investigation. “We do have data from two other clinical trials now, showing similar results, and maybe through those data we might be able to untangle it.”
The team does not think the anemia is related to B12 deficiency, however, as people who developed anemia while taking metformin were more likely to develop microcytic (12% vs. 7.3%) than macrocytic (7.6% vs. 12.3%), anemia, compared with people with anemia who were not exposed to metformin (P less than .0001).
“In terms of mechanism, we can only conjecture,” Ewan Pearson, MB, senior author of the study and professor of medicine at the University of Dundee, said during a discussion at the poster presentation. “It is important to stress that metformin is a great drug and we shouldn’t stop it because of a potentially increased risk of anemia.”
The Medical Research Council supported the work. Dr. Donnelly reported having no financial disclosures.
LISBON – People with type 2 diabetes who take metformin for many years are more likely to develop anemia than are those who do not, according to the results of a large analysis of data from an observational, population-based study with 20 years of follow-up.
“Metformin treatment was associated with a 6% higher risk of anemia for every cumulative year of metformin exposure,” Louise Donnelly, PhD, and her associates reported in a poster presentation at the annual meeting of the European Association for the Study of Diabetes.
In an interview, Dr. Donnelly, a postdoctoral research assistant at the University of Dundee (Scotland), explained why they looked at the use of metformin and anemia risk in people with type 2 diabetes.
“The Diabetes Prevention Program (DPP) study showed that long-term metformin use in individuals with impaired glucose tolerance was associated with an increased risk of anemia, and this was independent of vitamin B12 status,” she said (J Clin Endocrinol Metab. 2016;101:1754-61). “Anemia is a common finding in people with type 2 diabetes, but the impact of long-term metformin use on anemia hasn’t been studied.”
Dr. Donnelly and her associates obtained detailed information on metformin prescribing and hematology measures from electronic patient medical records from the Genetics of Diabetes Audit and Research in Tayside and Scotland (GoDARTS) cohort, based in Scotland. This database contains information on individuals with type 2 diabetes and matching controls and is available to researchers worldwide.
For the analysis, the team looked for people diagnosed from 1996 onward who had a baseline hemoglobin measurement. Of 6,440 individuals with type 2 diabetes in the GoDARTS cohort, just over half had a hemoglobin measurement.
“We used a definition of ‘moderate’ anemia and we excluded patients with mild anemia or worse at diabetes diagnosis,” Dr. Donnelly observed. Anemia was considered to be a hemoglobin level of less than 12 g/dL in women and less than 13 g/dL in men. In all, 280 individuals with anemia were excluded from further analysis as the aim was to follow people until they developed anemia, died, left the area, or until the end of the follow-up period, which was set at September 30, 2015. A discrete-time failure analysis was used to model the effect of cumulative metformin exposure on anemia risk.
After a median follow-up of 8 years and a median number of 11 hemoglobin measurements per patient, 2,487 study subjects (71%) had some exposure to metformin and 1,458 of the whole sample (41.8%) had become anemic. Of those who developed anemia, 745 (51%) were current metformin users, 194 (13%) were former users, and 519 (36%) had never taken metformin.
“Cumulative metformin use was independently associated with an increased risk of anemia,” Dr. Donnelly noted (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.02-1.09; P = .0006). This association was not seen when they examined the data based on sulfonylurea use (OR 1.0; 95% CI 0.97-1.04, P = .8), she added.
“Anemia risk was higher with age at diagnosis, duration of diabetes, lower hemoglobin at baseline, and lower eGFR [estimated glomerular filtration rate],” she observed. ORs for first anemia event were 1.03 (95% CI, 1.02-1.04) for every year of increasing age, 1.05 (95% CI, 1.03-1.08) for every additional year since diabetes diagnosis, 0.70 (95% CI, 0.66-0.74) per 1 g/dL of hemoglobin at diagnosis, and eGFR 0.98 (95% CI, 0.98-1.01) per additional 1 mL/min per 1.732 (P less than .0001 for all).
Why cumulative metformin use is associated with an increased of anemia is unclear, however, and Dr. Donnelly noted that this needs further investigation. “We do have data from two other clinical trials now, showing similar results, and maybe through those data we might be able to untangle it.”
The team does not think the anemia is related to B12 deficiency, however, as people who developed anemia while taking metformin were more likely to develop microcytic (12% vs. 7.3%) than macrocytic (7.6% vs. 12.3%), anemia, compared with people with anemia who were not exposed to metformin (P less than .0001).
“In terms of mechanism, we can only conjecture,” Ewan Pearson, MB, senior author of the study and professor of medicine at the University of Dundee, said during a discussion at the poster presentation. “It is important to stress that metformin is a great drug and we shouldn’t stop it because of a potentially increased risk of anemia.”
The Medical Research Council supported the work. Dr. Donnelly reported having no financial disclosures.
AT EASD 2017
Key clinical point: Cumulative metformin use was associated with an increased risk for anemia in patients with type 2 diabetes.
Major finding: For every additional year of metformin use, there was a 6% increase in the risk for anemia.
Data source: Data analysis of 3,435 individuals with type 2 diabetes who participated in a large observational, population-based study with almost 20 years of follow-up.
Disclosures: The Medical Research Council supported the work. Dr. Donnelly reported having no financial disclosures.
FDA approves first non–finger-stick glucose monitoring system
The Food and Drug Administration has approved the FreeStyle Libre Flash Glucose Monitoring System for the continuous monitoring of glucose in adults with diabetes, the first system of its type that does not require blood samples for calibration, according to a press release.
Instead of using a more standard finger stick with which patients must draw blood samples multiple times a day to measure glucose levels, the FreeStyle Libre Flash Glucose Monitoring System uses a thin wire less than 0.4-mm thick inserted underneath the skin in the back of the upper arm to continually monitor glucose. Blood glucose levels are read by swiping a mobile reader over the wire. After a 12-hour start-up period, the wire can be worn for 10 days.
FDA approval was based on results from a study of diabetes patients older than 18 years, as well as a performance review comparing readings obtained by the device with readings obtained in a traditional laboratory method utilizing blood samples.
“This system allows people with diabetes to avoid the additional step of finger-stick calibration, which can sometimes be painful, but still provides necessary information for treating their diabetes – with a wave of the mobile reader,” Donald St. Pierre, acting director of the Office of In Vitro Diagnostics and Radiological Health and deputy director of new product evaluation in the FDA’s Center for Devices and Radiological Health, said in the press release.
Find the full press release on the FDA website.
The Food and Drug Administration has approved the FreeStyle Libre Flash Glucose Monitoring System for the continuous monitoring of glucose in adults with diabetes, the first system of its type that does not require blood samples for calibration, according to a press release.
Instead of using a more standard finger stick with which patients must draw blood samples multiple times a day to measure glucose levels, the FreeStyle Libre Flash Glucose Monitoring System uses a thin wire less than 0.4-mm thick inserted underneath the skin in the back of the upper arm to continually monitor glucose. Blood glucose levels are read by swiping a mobile reader over the wire. After a 12-hour start-up period, the wire can be worn for 10 days.
FDA approval was based on results from a study of diabetes patients older than 18 years, as well as a performance review comparing readings obtained by the device with readings obtained in a traditional laboratory method utilizing blood samples.
“This system allows people with diabetes to avoid the additional step of finger-stick calibration, which can sometimes be painful, but still provides necessary information for treating their diabetes – with a wave of the mobile reader,” Donald St. Pierre, acting director of the Office of In Vitro Diagnostics and Radiological Health and deputy director of new product evaluation in the FDA’s Center for Devices and Radiological Health, said in the press release.
Find the full press release on the FDA website.
The Food and Drug Administration has approved the FreeStyle Libre Flash Glucose Monitoring System for the continuous monitoring of glucose in adults with diabetes, the first system of its type that does not require blood samples for calibration, according to a press release.
Instead of using a more standard finger stick with which patients must draw blood samples multiple times a day to measure glucose levels, the FreeStyle Libre Flash Glucose Monitoring System uses a thin wire less than 0.4-mm thick inserted underneath the skin in the back of the upper arm to continually monitor glucose. Blood glucose levels are read by swiping a mobile reader over the wire. After a 12-hour start-up period, the wire can be worn for 10 days.
FDA approval was based on results from a study of diabetes patients older than 18 years, as well as a performance review comparing readings obtained by the device with readings obtained in a traditional laboratory method utilizing blood samples.
“This system allows people with diabetes to avoid the additional step of finger-stick calibration, which can sometimes be painful, but still provides necessary information for treating their diabetes – with a wave of the mobile reader,” Donald St. Pierre, acting director of the Office of In Vitro Diagnostics and Radiological Health and deputy director of new product evaluation in the FDA’s Center for Devices and Radiological Health, said in the press release.
Find the full press release on the FDA website.
Empagliflozin’s effects independent of CVD risk factors
LISBON – The mortality reductions that can be achieved with the sodium–glucose cotransporter 2 inhibitor empagliflozin versus placebo in people with type 2 diabetes remained after investigators controlled for traditional cardiovascular (CV) risk factors over time, analyses from the EMPA-REG OUTCOME trial showed.
The 38% reduction in CV deaths and 32% reduction in all-cause mortality that were observed in the main trial (N Engl J Med. 2015;373:2117-28) were “largely unchanged when adjusted for control of blood pressure, LDL cholesterol, and glycated hemoglobin (HbA1c) during the study,” David Fitchett, MD, reported at the annual meeting of the European Association for the Study of Diabetes.
“EMPA-REG OUTCOME was the first diabetes outcome trial to show a reduction in the primary cardiovascular endpoint,” Dr. Fitchett, a cardiologist on the staff of St. Michael’s Hospital, University of Toronto, said. “It was designed as a safety study, but the statistical analysis allowed for an efficacy analysis once safety had been proven.”
EMPA-REG OUTCOME was an international, multicenter, phase 3, randomized, double-blind, placebo-controlled trial set up to look at the effects of a once-daily dose of empagliflozin (Jardiance) versus placebo on CV events in 7,020 adults with type 2 diabetes with established CV disease. Empagliflozin (10 mg or 25 mg) or placebo was given in addition to the standard of care, with the design stipulating that glucose-lowering treatment should be unchanged for the first 3 months.
The trial continued until an adjudicated primary outcome event, defined as a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke, had occurred in at least 691 patients. This three-point major cardiovascular outcome (MACE) occurred in 10.5% of patients treated with empagliflozin and in 12.5% of those who had been given placebo, with a 14% reduction overall (HR, 0.86; 95% CI, 0.74–0.99; P = .04). Almost all of this benefit was due to the reduction in CV deaths, Dr. Fitchett noted, which in turn drove the reduction in all-cause mortality.
The question, then, was how did empagliflozin have this apparent cardiovascular effect? Seeking an answer, the core EMPA-REG OUTCOME investigators looked to see if it could be explained by changes in blood pressure, LDL cholesterol, or HbA1c level, as small reductions had been seen in the main trial. Cox proportional analyses were performed to see how controlling for each of these might affect the results. In these analyses, control of blood pressure was defined as achieving a systolic value of less than 140 mm Hg and a diastolic value of less than 90 mm Hg; control of LDL cholesterol as a value of less than 100 mg/dL, and control of HbA1c level as a value below 7.5%.
Comparing baseline values to the last recorded values, the proportions of patients who achieved control of HbA1c with empagliflozin were a respective 26.7% and 46.7% versus 25.5% and 34% for placebo. LDL cholesterol was controlled in 70.6% and 68.7%, respectively, with empagliflozin and in 72.9% and 70% with placebo. The proportions of patients who achieved control of HbA1c, LDL cholesterol, and blood pressure were 12.6% and 21.8% for empagliflozin and 11.7% and 16.7% for placebo.*
The latest findings “suggest that the mortality reductions in the EMPA-REG OUTCOME trial were not driven by control of these standard cardiovascular risk factors during the trial,” Dr. Fitchett concluded.
In a separate poster presentation at the meeting, EMPA-REG OUTCOME investigators reported that empagliflozin also reduced heart failure outcomes, regardless of blood pressure, LDL cholesterol, or HbA1c control. Hazard ratios for hospitalization for heart failure with or without CV death were 0.64-0.67 (95% CIs, 0.49–0.87). Other subanalyses from the study showed that neither baseline HbA1c nor change in HbA1c predicted the reduction in CV deaths with empagliflozin and that background glucose-lowering treatment – metformin or sulfonylurea use – did not change the results.
The Boehringer Ingelheim and Lilly Diabetes Alliance funded the study. Dr. Fitchett disclosed receiving honoraria from Sanofi, Merck, Amgen, AstraZeneca, Eli Lilly, and Boehringer Ingelheim.
*This article was updated Sept. 28, 2017.
LISBON – The mortality reductions that can be achieved with the sodium–glucose cotransporter 2 inhibitor empagliflozin versus placebo in people with type 2 diabetes remained after investigators controlled for traditional cardiovascular (CV) risk factors over time, analyses from the EMPA-REG OUTCOME trial showed.
The 38% reduction in CV deaths and 32% reduction in all-cause mortality that were observed in the main trial (N Engl J Med. 2015;373:2117-28) were “largely unchanged when adjusted for control of blood pressure, LDL cholesterol, and glycated hemoglobin (HbA1c) during the study,” David Fitchett, MD, reported at the annual meeting of the European Association for the Study of Diabetes.
“EMPA-REG OUTCOME was the first diabetes outcome trial to show a reduction in the primary cardiovascular endpoint,” Dr. Fitchett, a cardiologist on the staff of St. Michael’s Hospital, University of Toronto, said. “It was designed as a safety study, but the statistical analysis allowed for an efficacy analysis once safety had been proven.”
EMPA-REG OUTCOME was an international, multicenter, phase 3, randomized, double-blind, placebo-controlled trial set up to look at the effects of a once-daily dose of empagliflozin (Jardiance) versus placebo on CV events in 7,020 adults with type 2 diabetes with established CV disease. Empagliflozin (10 mg or 25 mg) or placebo was given in addition to the standard of care, with the design stipulating that glucose-lowering treatment should be unchanged for the first 3 months.
The trial continued until an adjudicated primary outcome event, defined as a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke, had occurred in at least 691 patients. This three-point major cardiovascular outcome (MACE) occurred in 10.5% of patients treated with empagliflozin and in 12.5% of those who had been given placebo, with a 14% reduction overall (HR, 0.86; 95% CI, 0.74–0.99; P = .04). Almost all of this benefit was due to the reduction in CV deaths, Dr. Fitchett noted, which in turn drove the reduction in all-cause mortality.
The question, then, was how did empagliflozin have this apparent cardiovascular effect? Seeking an answer, the core EMPA-REG OUTCOME investigators looked to see if it could be explained by changes in blood pressure, LDL cholesterol, or HbA1c level, as small reductions had been seen in the main trial. Cox proportional analyses were performed to see how controlling for each of these might affect the results. In these analyses, control of blood pressure was defined as achieving a systolic value of less than 140 mm Hg and a diastolic value of less than 90 mm Hg; control of LDL cholesterol as a value of less than 100 mg/dL, and control of HbA1c level as a value below 7.5%.
Comparing baseline values to the last recorded values, the proportions of patients who achieved control of HbA1c with empagliflozin were a respective 26.7% and 46.7% versus 25.5% and 34% for placebo. LDL cholesterol was controlled in 70.6% and 68.7%, respectively, with empagliflozin and in 72.9% and 70% with placebo. The proportions of patients who achieved control of HbA1c, LDL cholesterol, and blood pressure were 12.6% and 21.8% for empagliflozin and 11.7% and 16.7% for placebo.*
The latest findings “suggest that the mortality reductions in the EMPA-REG OUTCOME trial were not driven by control of these standard cardiovascular risk factors during the trial,” Dr. Fitchett concluded.
In a separate poster presentation at the meeting, EMPA-REG OUTCOME investigators reported that empagliflozin also reduced heart failure outcomes, regardless of blood pressure, LDL cholesterol, or HbA1c control. Hazard ratios for hospitalization for heart failure with or without CV death were 0.64-0.67 (95% CIs, 0.49–0.87). Other subanalyses from the study showed that neither baseline HbA1c nor change in HbA1c predicted the reduction in CV deaths with empagliflozin and that background glucose-lowering treatment – metformin or sulfonylurea use – did not change the results.
The Boehringer Ingelheim and Lilly Diabetes Alliance funded the study. Dr. Fitchett disclosed receiving honoraria from Sanofi, Merck, Amgen, AstraZeneca, Eli Lilly, and Boehringer Ingelheim.
*This article was updated Sept. 28, 2017.
LISBON – The mortality reductions that can be achieved with the sodium–glucose cotransporter 2 inhibitor empagliflozin versus placebo in people with type 2 diabetes remained after investigators controlled for traditional cardiovascular (CV) risk factors over time, analyses from the EMPA-REG OUTCOME trial showed.
The 38% reduction in CV deaths and 32% reduction in all-cause mortality that were observed in the main trial (N Engl J Med. 2015;373:2117-28) were “largely unchanged when adjusted for control of blood pressure, LDL cholesterol, and glycated hemoglobin (HbA1c) during the study,” David Fitchett, MD, reported at the annual meeting of the European Association for the Study of Diabetes.
“EMPA-REG OUTCOME was the first diabetes outcome trial to show a reduction in the primary cardiovascular endpoint,” Dr. Fitchett, a cardiologist on the staff of St. Michael’s Hospital, University of Toronto, said. “It was designed as a safety study, but the statistical analysis allowed for an efficacy analysis once safety had been proven.”
EMPA-REG OUTCOME was an international, multicenter, phase 3, randomized, double-blind, placebo-controlled trial set up to look at the effects of a once-daily dose of empagliflozin (Jardiance) versus placebo on CV events in 7,020 adults with type 2 diabetes with established CV disease. Empagliflozin (10 mg or 25 mg) or placebo was given in addition to the standard of care, with the design stipulating that glucose-lowering treatment should be unchanged for the first 3 months.
The trial continued until an adjudicated primary outcome event, defined as a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke, had occurred in at least 691 patients. This three-point major cardiovascular outcome (MACE) occurred in 10.5% of patients treated with empagliflozin and in 12.5% of those who had been given placebo, with a 14% reduction overall (HR, 0.86; 95% CI, 0.74–0.99; P = .04). Almost all of this benefit was due to the reduction in CV deaths, Dr. Fitchett noted, which in turn drove the reduction in all-cause mortality.
The question, then, was how did empagliflozin have this apparent cardiovascular effect? Seeking an answer, the core EMPA-REG OUTCOME investigators looked to see if it could be explained by changes in blood pressure, LDL cholesterol, or HbA1c level, as small reductions had been seen in the main trial. Cox proportional analyses were performed to see how controlling for each of these might affect the results. In these analyses, control of blood pressure was defined as achieving a systolic value of less than 140 mm Hg and a diastolic value of less than 90 mm Hg; control of LDL cholesterol as a value of less than 100 mg/dL, and control of HbA1c level as a value below 7.5%.
Comparing baseline values to the last recorded values, the proportions of patients who achieved control of HbA1c with empagliflozin were a respective 26.7% and 46.7% versus 25.5% and 34% for placebo. LDL cholesterol was controlled in 70.6% and 68.7%, respectively, with empagliflozin and in 72.9% and 70% with placebo. The proportions of patients who achieved control of HbA1c, LDL cholesterol, and blood pressure were 12.6% and 21.8% for empagliflozin and 11.7% and 16.7% for placebo.*
The latest findings “suggest that the mortality reductions in the EMPA-REG OUTCOME trial were not driven by control of these standard cardiovascular risk factors during the trial,” Dr. Fitchett concluded.
In a separate poster presentation at the meeting, EMPA-REG OUTCOME investigators reported that empagliflozin also reduced heart failure outcomes, regardless of blood pressure, LDL cholesterol, or HbA1c control. Hazard ratios for hospitalization for heart failure with or without CV death were 0.64-0.67 (95% CIs, 0.49–0.87). Other subanalyses from the study showed that neither baseline HbA1c nor change in HbA1c predicted the reduction in CV deaths with empagliflozin and that background glucose-lowering treatment – metformin or sulfonylurea use – did not change the results.
The Boehringer Ingelheim and Lilly Diabetes Alliance funded the study. Dr. Fitchett disclosed receiving honoraria from Sanofi, Merck, Amgen, AstraZeneca, Eli Lilly, and Boehringer Ingelheim.
*This article was updated Sept. 28, 2017.
AT EASD 2017
Key clinical point:
Major finding: The 38% reduction in CV deaths and 32% reduction in all-cause mortality were largely unchanged after adjustment for blood pressure, LDL cholesterol, and HbA1c at baseline and during the study.
Data source: Secondary analyses of EMPA-REG OUTCOME, a phase 3, randomized controlled trial of 7,020 people with type 2 diabetes at high risk for cardiovascular events who were receiving standard care.
Disclosures: The Boehringer Ingelheim and Lilly Diabetes Alliance funded the study. Dr. Fitchett disclosed receiving honoraria from Sanofi, Merck, Amgen, AstraZeneca, Eli Lilly, and Boehringer Ingelheim.