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PEGlispro: the New Standard for Basal Insulin?
STOCKHOLM – PEGylated insulin lispro (PEGlispro) lowered hemoglobin A1c to a greater extent than did insulin glargine in patients with either type 1 or type 2 diabetes mellitus and offered several potential advantages and disadvantage as a basal insulin, judging from results of several trials and analyses, some presented for the first time at the annual meeting of the European Association for the Study of Diabetes.
Data from the phase III, randomized, double-blind IMAGINE 2 trial, for example, showed that in patients with type 2 diabetes treated with oral antidiabetic drugs and who were insulin naive, PEGlispro produced superior reductions in HbA1c when compared directly with insulin glargine. At 1 year of follow-up, the mean change from baseline in HbA1c was –1.56% for PEGlispro-treated (n = 1,003) and –1.27% for glargine-treated (n = 535) patients, representing a statistically significant –0.29% (P less than .001) difference between the two insulins.
Dr. Melanie Davies of the University of Leicester (England) Diabetes Research Centre, who reported the IMAGINE 2 findings said that significantly more PEGlispro- than glargine-treated patients achieved a target HbA1c of less than 7% (57.6% vs. 42.8%; P less than .001) or 6.5% or lower (36% vs. 24%; P less than .001) at 1 year. Importantly, “BIL [basal insulin PEGlispro] resulted in greater reduction in HbA1c with less glycemic variability,” Dr. Davies observed.
While there was no significant differences in the rates of total or serve hypoglycemia between the groups, there were fewer instances of nocturnal hypoglycemia, she said, with an event rate per 30 days of 0.3 vs. 0.4, and overall incidences of 60% and 40% (P less than .001). Patients treated with PEGlispro also experienced less weight gain (+2.1 kg vs. +2.6 kg; P less than .001).
PEGlispro is essentially insulin lispro that has been modified by adding a polyethylene glycol chain. This adaption makes it a larger molecule and results in a half-life of around 2-3 days and a duration of action of 36 hours or more.
Asked in an interview why another basal insulin was needed, Dr. Clifford J. Baileyof Aston University in Birmingham, England, responded: “I suppose the same question was asked when we had NPH [insulin], why would we want a longer-acting insulin?”
Dr. Bailey, who cochaired the sessions in which the IMAGINE 2 findings were presented and who was not involved in the trial, added: “The longer and longer the [duration of] action of insulin, with a flatter [glycemic] profile, the greater the likelihood is that one can control the glucose level to be more consistent with the [normal] physiological delivery of insulin.” Together with improving the way in which insulin is delivered, there may also be the potential for dosing every other day, weekly, or even monthly, he suggested.
The safety profile of longer-acting insulins is something “that may need ironing out,” he acknowledged, which might be addressed by again making a small alteration in the molecule or reducing the size of polyethylene glycol chain, for example.
The effects of PEGlispro appear just as good in patients with type 1 diabetes, according to the findings of the phase II IMAGINE I trial that were also presented at the EASD meeting. This open-label study comprised 455 patients and found those treated with PEGlispro had significantly lower HbA1c (7% vs. 7.4%) at 26 weeks’ follow-up. Again there were fewer episodes of nocturnal hypoglycemia and a weight reduction benefit with PEGlispro. Results from the phase III IMAGINE 3 study were presented as a poster and showed similar beneficial findings on glycemic control.In terms of safety, patients treated with PEGlispro in these IMAGINE trials generally experienced an increase in triglycerides and alanine aminotransferase when compared with glargine, and liver fat was higher in the PEGlispro- than in glargine-treated patients. In a subset of patients who underwent MRI of the liver in IMAGINE 2, liver fat was unchanged from baseline, whereas there was a decrease seen with glargine. In IMAGINE 1 a slight increase in liver fat was seen with PEGlispro.
Dr. Byron Hoogwerf of Eli Lilly presented data on lipid changes seen during 26 weeks of treatment in six phase III IMAGINE trials – four of which were performed in patients with type 2 diabetes. These data had previously been aired at the American Diabetes Association annual scientific sessions, he said, and considered a total of 5,583 randomized patients, 2,179 of whom had type 2 diabetes, were insulin naive, had been treated with basal insulin only; a further 1,835 type 2 patients who had previously been treated with insulin who received either basal only or basal-bolus dosing; and 1,569 patients with type 2 diabetes. In most of the trials, PEGlispro was compared against glargine, but in one of the trials, NPH was used.
The effect of PEGlispro on triglycerides appeared to differ according to the insulin treatment patients had previously received. In patients with type 2 diabetes who were insulin naive, there was no “essentially no change” in triglycerides Dr. Hoogwerf said. Although triglycerides were higher in the PEGlispro group, this could be because both glargine and NPH were associated with decreased levels, he said. In insulin-exposed type 2 diabetics, however, there was an increase in triglycerides when compared with glargine with both basal only and basal-bolus regimens. In those with type 1 diabetes, triglycerides were also higher, an effect that could be from switching the prior basal insulin, he suggested.
Changes on HDL and LDL cholesterol were minimal overall, he maintained, with little effect also on apolipoproteins and fasting free fatty acids. During the discussion, however, it was noted by one delegate that PEGlispro did not appear to be a very “lipid-friendly” drug, but said that it was the “overall package” of effects that mattered.
Dr. Richard Bergenstal of the International Diabetes Center in Minneapolis presented a meta-analysis of data on the cardiovascular safety of the drug. This included data on more than 5,800 patients from two phase II and six phase III studies of PEGlispro vs. an active comparator of glargine or NPH. The overall rate of major adverse cardiovascular events (MACE) – the primary composite endpoint incorporating cardiovascular death, stroke, myocardial infarction, and unstable angina with hospitalization – was 1.4% vs. 1.8%/100 patient-years, respectively, he said.
The overall hazard ratio for at least one MACE comparing PEGlispro with an active comparator was 0.82, with a 95% confidence interval of 0.53-1.27, and the subgroup analyses “did not identify any population of patients with increased treatment-associated risk.”
Eli Lilly funded the studies. Dr. Davies and Dr. Bergenstal have acted as advisory board members, speakers, or received research funding from Eli Lilly as well as several other pharmaceutical companies. Dr. Hoogwerf is an employee of, and minor stockholder in, Eli Lilly. Dr. Bailey had no financial disclosures relevant to his comment.
STOCKHOLM – PEGylated insulin lispro (PEGlispro) lowered hemoglobin A1c to a greater extent than did insulin glargine in patients with either type 1 or type 2 diabetes mellitus and offered several potential advantages and disadvantage as a basal insulin, judging from results of several trials and analyses, some presented for the first time at the annual meeting of the European Association for the Study of Diabetes.
Data from the phase III, randomized, double-blind IMAGINE 2 trial, for example, showed that in patients with type 2 diabetes treated with oral antidiabetic drugs and who were insulin naive, PEGlispro produced superior reductions in HbA1c when compared directly with insulin glargine. At 1 year of follow-up, the mean change from baseline in HbA1c was –1.56% for PEGlispro-treated (n = 1,003) and –1.27% for glargine-treated (n = 535) patients, representing a statistically significant –0.29% (P less than .001) difference between the two insulins.
Dr. Melanie Davies of the University of Leicester (England) Diabetes Research Centre, who reported the IMAGINE 2 findings said that significantly more PEGlispro- than glargine-treated patients achieved a target HbA1c of less than 7% (57.6% vs. 42.8%; P less than .001) or 6.5% or lower (36% vs. 24%; P less than .001) at 1 year. Importantly, “BIL [basal insulin PEGlispro] resulted in greater reduction in HbA1c with less glycemic variability,” Dr. Davies observed.
While there was no significant differences in the rates of total or serve hypoglycemia between the groups, there were fewer instances of nocturnal hypoglycemia, she said, with an event rate per 30 days of 0.3 vs. 0.4, and overall incidences of 60% and 40% (P less than .001). Patients treated with PEGlispro also experienced less weight gain (+2.1 kg vs. +2.6 kg; P less than .001).
PEGlispro is essentially insulin lispro that has been modified by adding a polyethylene glycol chain. This adaption makes it a larger molecule and results in a half-life of around 2-3 days and a duration of action of 36 hours or more.
Asked in an interview why another basal insulin was needed, Dr. Clifford J. Baileyof Aston University in Birmingham, England, responded: “I suppose the same question was asked when we had NPH [insulin], why would we want a longer-acting insulin?”
Dr. Bailey, who cochaired the sessions in which the IMAGINE 2 findings were presented and who was not involved in the trial, added: “The longer and longer the [duration of] action of insulin, with a flatter [glycemic] profile, the greater the likelihood is that one can control the glucose level to be more consistent with the [normal] physiological delivery of insulin.” Together with improving the way in which insulin is delivered, there may also be the potential for dosing every other day, weekly, or even monthly, he suggested.
The safety profile of longer-acting insulins is something “that may need ironing out,” he acknowledged, which might be addressed by again making a small alteration in the molecule or reducing the size of polyethylene glycol chain, for example.
The effects of PEGlispro appear just as good in patients with type 1 diabetes, according to the findings of the phase II IMAGINE I trial that were also presented at the EASD meeting. This open-label study comprised 455 patients and found those treated with PEGlispro had significantly lower HbA1c (7% vs. 7.4%) at 26 weeks’ follow-up. Again there were fewer episodes of nocturnal hypoglycemia and a weight reduction benefit with PEGlispro. Results from the phase III IMAGINE 3 study were presented as a poster and showed similar beneficial findings on glycemic control.In terms of safety, patients treated with PEGlispro in these IMAGINE trials generally experienced an increase in triglycerides and alanine aminotransferase when compared with glargine, and liver fat was higher in the PEGlispro- than in glargine-treated patients. In a subset of patients who underwent MRI of the liver in IMAGINE 2, liver fat was unchanged from baseline, whereas there was a decrease seen with glargine. In IMAGINE 1 a slight increase in liver fat was seen with PEGlispro.
Dr. Byron Hoogwerf of Eli Lilly presented data on lipid changes seen during 26 weeks of treatment in six phase III IMAGINE trials – four of which were performed in patients with type 2 diabetes. These data had previously been aired at the American Diabetes Association annual scientific sessions, he said, and considered a total of 5,583 randomized patients, 2,179 of whom had type 2 diabetes, were insulin naive, had been treated with basal insulin only; a further 1,835 type 2 patients who had previously been treated with insulin who received either basal only or basal-bolus dosing; and 1,569 patients with type 2 diabetes. In most of the trials, PEGlispro was compared against glargine, but in one of the trials, NPH was used.
The effect of PEGlispro on triglycerides appeared to differ according to the insulin treatment patients had previously received. In patients with type 2 diabetes who were insulin naive, there was no “essentially no change” in triglycerides Dr. Hoogwerf said. Although triglycerides were higher in the PEGlispro group, this could be because both glargine and NPH were associated with decreased levels, he said. In insulin-exposed type 2 diabetics, however, there was an increase in triglycerides when compared with glargine with both basal only and basal-bolus regimens. In those with type 1 diabetes, triglycerides were also higher, an effect that could be from switching the prior basal insulin, he suggested.
Changes on HDL and LDL cholesterol were minimal overall, he maintained, with little effect also on apolipoproteins and fasting free fatty acids. During the discussion, however, it was noted by one delegate that PEGlispro did not appear to be a very “lipid-friendly” drug, but said that it was the “overall package” of effects that mattered.
Dr. Richard Bergenstal of the International Diabetes Center in Minneapolis presented a meta-analysis of data on the cardiovascular safety of the drug. This included data on more than 5,800 patients from two phase II and six phase III studies of PEGlispro vs. an active comparator of glargine or NPH. The overall rate of major adverse cardiovascular events (MACE) – the primary composite endpoint incorporating cardiovascular death, stroke, myocardial infarction, and unstable angina with hospitalization – was 1.4% vs. 1.8%/100 patient-years, respectively, he said.
The overall hazard ratio for at least one MACE comparing PEGlispro with an active comparator was 0.82, with a 95% confidence interval of 0.53-1.27, and the subgroup analyses “did not identify any population of patients with increased treatment-associated risk.”
Eli Lilly funded the studies. Dr. Davies and Dr. Bergenstal have acted as advisory board members, speakers, or received research funding from Eli Lilly as well as several other pharmaceutical companies. Dr. Hoogwerf is an employee of, and minor stockholder in, Eli Lilly. Dr. Bailey had no financial disclosures relevant to his comment.
STOCKHOLM – PEGylated insulin lispro (PEGlispro) lowered hemoglobin A1c to a greater extent than did insulin glargine in patients with either type 1 or type 2 diabetes mellitus and offered several potential advantages and disadvantage as a basal insulin, judging from results of several trials and analyses, some presented for the first time at the annual meeting of the European Association for the Study of Diabetes.
Data from the phase III, randomized, double-blind IMAGINE 2 trial, for example, showed that in patients with type 2 diabetes treated with oral antidiabetic drugs and who were insulin naive, PEGlispro produced superior reductions in HbA1c when compared directly with insulin glargine. At 1 year of follow-up, the mean change from baseline in HbA1c was –1.56% for PEGlispro-treated (n = 1,003) and –1.27% for glargine-treated (n = 535) patients, representing a statistically significant –0.29% (P less than .001) difference between the two insulins.
Dr. Melanie Davies of the University of Leicester (England) Diabetes Research Centre, who reported the IMAGINE 2 findings said that significantly more PEGlispro- than glargine-treated patients achieved a target HbA1c of less than 7% (57.6% vs. 42.8%; P less than .001) or 6.5% or lower (36% vs. 24%; P less than .001) at 1 year. Importantly, “BIL [basal insulin PEGlispro] resulted in greater reduction in HbA1c with less glycemic variability,” Dr. Davies observed.
While there was no significant differences in the rates of total or serve hypoglycemia between the groups, there were fewer instances of nocturnal hypoglycemia, she said, with an event rate per 30 days of 0.3 vs. 0.4, and overall incidences of 60% and 40% (P less than .001). Patients treated with PEGlispro also experienced less weight gain (+2.1 kg vs. +2.6 kg; P less than .001).
PEGlispro is essentially insulin lispro that has been modified by adding a polyethylene glycol chain. This adaption makes it a larger molecule and results in a half-life of around 2-3 days and a duration of action of 36 hours or more.
Asked in an interview why another basal insulin was needed, Dr. Clifford J. Baileyof Aston University in Birmingham, England, responded: “I suppose the same question was asked when we had NPH [insulin], why would we want a longer-acting insulin?”
Dr. Bailey, who cochaired the sessions in which the IMAGINE 2 findings were presented and who was not involved in the trial, added: “The longer and longer the [duration of] action of insulin, with a flatter [glycemic] profile, the greater the likelihood is that one can control the glucose level to be more consistent with the [normal] physiological delivery of insulin.” Together with improving the way in which insulin is delivered, there may also be the potential for dosing every other day, weekly, or even monthly, he suggested.
The safety profile of longer-acting insulins is something “that may need ironing out,” he acknowledged, which might be addressed by again making a small alteration in the molecule or reducing the size of polyethylene glycol chain, for example.
The effects of PEGlispro appear just as good in patients with type 1 diabetes, according to the findings of the phase II IMAGINE I trial that were also presented at the EASD meeting. This open-label study comprised 455 patients and found those treated with PEGlispro had significantly lower HbA1c (7% vs. 7.4%) at 26 weeks’ follow-up. Again there were fewer episodes of nocturnal hypoglycemia and a weight reduction benefit with PEGlispro. Results from the phase III IMAGINE 3 study were presented as a poster and showed similar beneficial findings on glycemic control.In terms of safety, patients treated with PEGlispro in these IMAGINE trials generally experienced an increase in triglycerides and alanine aminotransferase when compared with glargine, and liver fat was higher in the PEGlispro- than in glargine-treated patients. In a subset of patients who underwent MRI of the liver in IMAGINE 2, liver fat was unchanged from baseline, whereas there was a decrease seen with glargine. In IMAGINE 1 a slight increase in liver fat was seen with PEGlispro.
Dr. Byron Hoogwerf of Eli Lilly presented data on lipid changes seen during 26 weeks of treatment in six phase III IMAGINE trials – four of which were performed in patients with type 2 diabetes. These data had previously been aired at the American Diabetes Association annual scientific sessions, he said, and considered a total of 5,583 randomized patients, 2,179 of whom had type 2 diabetes, were insulin naive, had been treated with basal insulin only; a further 1,835 type 2 patients who had previously been treated with insulin who received either basal only or basal-bolus dosing; and 1,569 patients with type 2 diabetes. In most of the trials, PEGlispro was compared against glargine, but in one of the trials, NPH was used.
The effect of PEGlispro on triglycerides appeared to differ according to the insulin treatment patients had previously received. In patients with type 2 diabetes who were insulin naive, there was no “essentially no change” in triglycerides Dr. Hoogwerf said. Although triglycerides were higher in the PEGlispro group, this could be because both glargine and NPH were associated with decreased levels, he said. In insulin-exposed type 2 diabetics, however, there was an increase in triglycerides when compared with glargine with both basal only and basal-bolus regimens. In those with type 1 diabetes, triglycerides were also higher, an effect that could be from switching the prior basal insulin, he suggested.
Changes on HDL and LDL cholesterol were minimal overall, he maintained, with little effect also on apolipoproteins and fasting free fatty acids. During the discussion, however, it was noted by one delegate that PEGlispro did not appear to be a very “lipid-friendly” drug, but said that it was the “overall package” of effects that mattered.
Dr. Richard Bergenstal of the International Diabetes Center in Minneapolis presented a meta-analysis of data on the cardiovascular safety of the drug. This included data on more than 5,800 patients from two phase II and six phase III studies of PEGlispro vs. an active comparator of glargine or NPH. The overall rate of major adverse cardiovascular events (MACE) – the primary composite endpoint incorporating cardiovascular death, stroke, myocardial infarction, and unstable angina with hospitalization – was 1.4% vs. 1.8%/100 patient-years, respectively, he said.
The overall hazard ratio for at least one MACE comparing PEGlispro with an active comparator was 0.82, with a 95% confidence interval of 0.53-1.27, and the subgroup analyses “did not identify any population of patients with increased treatment-associated risk.”
Eli Lilly funded the studies. Dr. Davies and Dr. Bergenstal have acted as advisory board members, speakers, or received research funding from Eli Lilly as well as several other pharmaceutical companies. Dr. Hoogwerf is an employee of, and minor stockholder in, Eli Lilly. Dr. Bailey had no financial disclosures relevant to his comment.
EASD: PEGlispro – the new standard for basal insulin?
STOCKHOLM – PEGylated insulin lispro (PEGlispro) lowered hemoglobin A1c to a greater extent than did insulin glargine in patients with either type 1 or type 2 diabetes mellitus and offered several potential advantages and disadvantage as a basal insulin, judging from results of several trials and analyses, some presented for the first time at the annual meeting of the European Association for the Study of Diabetes.
Data from the phase III, randomized, double-blind IMAGINE 2 trial, for example, showed that in patients with type 2 diabetes treated with oral antidiabetic drugs and who were insulin naive, PEGlispro produced superior reductions in HbA1c when compared directly with insulin glargine. At 1 year of follow-up, the mean change from baseline in HbA1c was –1.56% for PEGlispro-treated (n = 1,003) and –1.27% for glargine-treated (n = 535) patients, representing a statistically significant –0.29% (P less than .001) difference between the two insulins.
Dr. Melanie Davies of the University of Leicester (England) Diabetes Research Centre, who reported the IMAGINE 2 findings said that significantly more PEGlispro- than glargine-treated patients achieved a target HbA1c of less than 7% (57.6% vs. 42.8%; P less than .001) or 6.5% or lower (36% vs. 24%; P less than .001) at 1 year. Importantly, “BIL [basal insulin PEGlispro] resulted in greater reduction in HbA1c with less glycemic variability,” Dr. Davies observed.
While there was no significant differences in the rates of total or serve hypoglycemia between the groups, there were fewer instances of nocturnal hypoglycemia, she said, with an event rate per 30 days of 0.3 vs. 0.4, and overall incidences of 60% and 40% (P less than .001). Patients treated with PEGlispro also experienced less weight gain (+2.1 kg vs. +2.6 kg; P less than .001).
PEGlispro is essentially insulin lispro that has been modified by adding a polyethylene glycol chain. This adaption makes it a larger molecule and results in a half-life of around 2-3 days and a duration of action of 36 hours or more.
Asked in an interview why another basal insulin was needed, Dr. Clifford J. Baileyof Aston University in Birmingham, England, responded: “I suppose the same question was asked when we had NPH [insulin], why would we want a longer-acting insulin?”
Dr. Bailey, who cochaired the sessions in which the IMAGINE 2 findings were presented and who was not involved in the trial, added: “The longer and longer the [duration of] action of insulin, with a flatter [glycemic] profile, the greater the likelihood is that one can control the glucose level to be more consistent with the [normal] physiological delivery of insulin.” Together with improving the way in which insulin is delivered, there may also be the potential for dosing every other day, weekly, or even monthly, he suggested.
The safety profile of longer-acting insulins is something “that may need ironing out,” he acknowledged, which might be addressed by again making a small alteration in the molecule or reducing the size of polyethylene glycol chain, for example.
The effects of PEGlispro appear just as good in patients with type 1 diabetes, according to the findings of the phase II IMAGINE I trial that were also presented at the EASD meeting. This open-label study comprised 455 patients and found those treated with PEGlispro had significantly lower HbA1c (7% vs. 7.4%) at 26 weeks’ follow-up. Again there were fewer episodes of nocturnal hypoglycemia and a weight reduction benefit with PEGlispro. Results from the phase III IMAGINE 3 study were presented as a poster and showed similar beneficial findings on glycemic control.In terms of safety, patients treated with PEGlispro in these IMAGINE trials generally experienced an increase in triglycerides and alanine aminotransferase when compared with glargine, and liver fat was higher in the PEGlispro- than in glargine-treated patients. In a subset of patients who underwent MRI of the liver in IMAGINE 2, liver fat was unchanged from baseline, whereas there was a decrease seen with glargine. In IMAGINE 1 a slight increase in liver fat was seen with PEGlispro.
Dr. Byron Hoogwerf of Eli Lilly presented data on lipid changes seen during 26 weeks of treatment in six phase III IMAGINE trials – four of which were performed in patients with type 2 diabetes. These data had previously been aired at the American Diabetes Association annual scientific sessions, he said, and considered a total of 5,583 randomized patients, 2,179 of whom had type 2 diabetes, were insulin naive, had been treated with basal insulin only; a further 1,835 type 2 patients who had previously been treated with insulin who received either basal only or basal-bolus dosing; and 1,569 patients with type 2 diabetes. In most of the trials, PEGlispro was compared against glargine, but in one of the trials, NPH was used.
The effect of PEGlispro on triglycerides appeared to differ according to the insulin treatment patients had previously received. In patients with type 2 diabetes who were insulin naive, there was no “essentially no change” in triglycerides Dr. Hoogwerf said. Although triglycerides were higher in the PEGlispro group, this could be because both glargine and NPH were associated with decreased levels, he said. In insulin-exposed type 2 diabetics, however, there was an increase in triglycerides when compared with glargine with both basal only and basal-bolus regimens. In those with type 1 diabetes, triglycerides were also higher, an effect that could be from switching the prior basal insulin, he suggested.
Changes on HDL and LDL cholesterol were minimal overall, he maintained, with little effect also on apolipoproteins and fasting free fatty acids. During the discussion, however, it was noted by one delegate that PEGlispro did not appear to be a very “lipid-friendly” drug, but said that it was the “overall package” of effects that mattered.
Dr. Richard Bergenstal of the International Diabetes Center in Minneapolis presented a meta-analysis of data on the cardiovascular safety of the drug. This included data on more than 5,800 patients from two phase II and six phase III studies of PEGlispro vs. an active comparator of glargine or NPH. The overall rate of major adverse cardiovascular events (MACE) – the primary composite endpoint incorporating cardiovascular death, stroke, myocardial infarction, and unstable angina with hospitalization – was 1.4% vs. 1.8%/100 patient-years, respectively, he said.
The overall hazard ratio for at least one MACE comparing PEGlispro with an active comparator was 0.82, with a 95% confidence interval of 0.53-1.27, and the subgroup analyses “did not identify any population of patients with increased treatment-associated risk.”
Eli Lilly funded the studies. Dr. Davies and Dr. Bergenstal have acted as advisory board members, speakers, or received research funding from Eli Lilly as well as several other pharmaceutical companies. Dr. Hoogwerf is an employee of, and minor stockholder in, Eli Lilly. Dr. Bailey had no financial disclosures relevant to his comment.
STOCKHOLM – PEGylated insulin lispro (PEGlispro) lowered hemoglobin A1c to a greater extent than did insulin glargine in patients with either type 1 or type 2 diabetes mellitus and offered several potential advantages and disadvantage as a basal insulin, judging from results of several trials and analyses, some presented for the first time at the annual meeting of the European Association for the Study of Diabetes.
Data from the phase III, randomized, double-blind IMAGINE 2 trial, for example, showed that in patients with type 2 diabetes treated with oral antidiabetic drugs and who were insulin naive, PEGlispro produced superior reductions in HbA1c when compared directly with insulin glargine. At 1 year of follow-up, the mean change from baseline in HbA1c was –1.56% for PEGlispro-treated (n = 1,003) and –1.27% for glargine-treated (n = 535) patients, representing a statistically significant –0.29% (P less than .001) difference between the two insulins.
Dr. Melanie Davies of the University of Leicester (England) Diabetes Research Centre, who reported the IMAGINE 2 findings said that significantly more PEGlispro- than glargine-treated patients achieved a target HbA1c of less than 7% (57.6% vs. 42.8%; P less than .001) or 6.5% or lower (36% vs. 24%; P less than .001) at 1 year. Importantly, “BIL [basal insulin PEGlispro] resulted in greater reduction in HbA1c with less glycemic variability,” Dr. Davies observed.
While there was no significant differences in the rates of total or serve hypoglycemia between the groups, there were fewer instances of nocturnal hypoglycemia, she said, with an event rate per 30 days of 0.3 vs. 0.4, and overall incidences of 60% and 40% (P less than .001). Patients treated with PEGlispro also experienced less weight gain (+2.1 kg vs. +2.6 kg; P less than .001).
PEGlispro is essentially insulin lispro that has been modified by adding a polyethylene glycol chain. This adaption makes it a larger molecule and results in a half-life of around 2-3 days and a duration of action of 36 hours or more.
Asked in an interview why another basal insulin was needed, Dr. Clifford J. Baileyof Aston University in Birmingham, England, responded: “I suppose the same question was asked when we had NPH [insulin], why would we want a longer-acting insulin?”
Dr. Bailey, who cochaired the sessions in which the IMAGINE 2 findings were presented and who was not involved in the trial, added: “The longer and longer the [duration of] action of insulin, with a flatter [glycemic] profile, the greater the likelihood is that one can control the glucose level to be more consistent with the [normal] physiological delivery of insulin.” Together with improving the way in which insulin is delivered, there may also be the potential for dosing every other day, weekly, or even monthly, he suggested.
The safety profile of longer-acting insulins is something “that may need ironing out,” he acknowledged, which might be addressed by again making a small alteration in the molecule or reducing the size of polyethylene glycol chain, for example.
The effects of PEGlispro appear just as good in patients with type 1 diabetes, according to the findings of the phase II IMAGINE I trial that were also presented at the EASD meeting. This open-label study comprised 455 patients and found those treated with PEGlispro had significantly lower HbA1c (7% vs. 7.4%) at 26 weeks’ follow-up. Again there were fewer episodes of nocturnal hypoglycemia and a weight reduction benefit with PEGlispro. Results from the phase III IMAGINE 3 study were presented as a poster and showed similar beneficial findings on glycemic control.In terms of safety, patients treated with PEGlispro in these IMAGINE trials generally experienced an increase in triglycerides and alanine aminotransferase when compared with glargine, and liver fat was higher in the PEGlispro- than in glargine-treated patients. In a subset of patients who underwent MRI of the liver in IMAGINE 2, liver fat was unchanged from baseline, whereas there was a decrease seen with glargine. In IMAGINE 1 a slight increase in liver fat was seen with PEGlispro.
Dr. Byron Hoogwerf of Eli Lilly presented data on lipid changes seen during 26 weeks of treatment in six phase III IMAGINE trials – four of which were performed in patients with type 2 diabetes. These data had previously been aired at the American Diabetes Association annual scientific sessions, he said, and considered a total of 5,583 randomized patients, 2,179 of whom had type 2 diabetes, were insulin naive, had been treated with basal insulin only; a further 1,835 type 2 patients who had previously been treated with insulin who received either basal only or basal-bolus dosing; and 1,569 patients with type 2 diabetes. In most of the trials, PEGlispro was compared against glargine, but in one of the trials, NPH was used.
The effect of PEGlispro on triglycerides appeared to differ according to the insulin treatment patients had previously received. In patients with type 2 diabetes who were insulin naive, there was no “essentially no change” in triglycerides Dr. Hoogwerf said. Although triglycerides were higher in the PEGlispro group, this could be because both glargine and NPH were associated with decreased levels, he said. In insulin-exposed type 2 diabetics, however, there was an increase in triglycerides when compared with glargine with both basal only and basal-bolus regimens. In those with type 1 diabetes, triglycerides were also higher, an effect that could be from switching the prior basal insulin, he suggested.
Changes on HDL and LDL cholesterol were minimal overall, he maintained, with little effect also on apolipoproteins and fasting free fatty acids. During the discussion, however, it was noted by one delegate that PEGlispro did not appear to be a very “lipid-friendly” drug, but said that it was the “overall package” of effects that mattered.
Dr. Richard Bergenstal of the International Diabetes Center in Minneapolis presented a meta-analysis of data on the cardiovascular safety of the drug. This included data on more than 5,800 patients from two phase II and six phase III studies of PEGlispro vs. an active comparator of glargine or NPH. The overall rate of major adverse cardiovascular events (MACE) – the primary composite endpoint incorporating cardiovascular death, stroke, myocardial infarction, and unstable angina with hospitalization – was 1.4% vs. 1.8%/100 patient-years, respectively, he said.
The overall hazard ratio for at least one MACE comparing PEGlispro with an active comparator was 0.82, with a 95% confidence interval of 0.53-1.27, and the subgroup analyses “did not identify any population of patients with increased treatment-associated risk.”
Eli Lilly funded the studies. Dr. Davies and Dr. Bergenstal have acted as advisory board members, speakers, or received research funding from Eli Lilly as well as several other pharmaceutical companies. Dr. Hoogwerf is an employee of, and minor stockholder in, Eli Lilly. Dr. Bailey had no financial disclosures relevant to his comment.
STOCKHOLM – PEGylated insulin lispro (PEGlispro) lowered hemoglobin A1c to a greater extent than did insulin glargine in patients with either type 1 or type 2 diabetes mellitus and offered several potential advantages and disadvantage as a basal insulin, judging from results of several trials and analyses, some presented for the first time at the annual meeting of the European Association for the Study of Diabetes.
Data from the phase III, randomized, double-blind IMAGINE 2 trial, for example, showed that in patients with type 2 diabetes treated with oral antidiabetic drugs and who were insulin naive, PEGlispro produced superior reductions in HbA1c when compared directly with insulin glargine. At 1 year of follow-up, the mean change from baseline in HbA1c was –1.56% for PEGlispro-treated (n = 1,003) and –1.27% for glargine-treated (n = 535) patients, representing a statistically significant –0.29% (P less than .001) difference between the two insulins.
Dr. Melanie Davies of the University of Leicester (England) Diabetes Research Centre, who reported the IMAGINE 2 findings said that significantly more PEGlispro- than glargine-treated patients achieved a target HbA1c of less than 7% (57.6% vs. 42.8%; P less than .001) or 6.5% or lower (36% vs. 24%; P less than .001) at 1 year. Importantly, “BIL [basal insulin PEGlispro] resulted in greater reduction in HbA1c with less glycemic variability,” Dr. Davies observed.
While there was no significant differences in the rates of total or serve hypoglycemia between the groups, there were fewer instances of nocturnal hypoglycemia, she said, with an event rate per 30 days of 0.3 vs. 0.4, and overall incidences of 60% and 40% (P less than .001). Patients treated with PEGlispro also experienced less weight gain (+2.1 kg vs. +2.6 kg; P less than .001).
PEGlispro is essentially insulin lispro that has been modified by adding a polyethylene glycol chain. This adaption makes it a larger molecule and results in a half-life of around 2-3 days and a duration of action of 36 hours or more.
Asked in an interview why another basal insulin was needed, Dr. Clifford J. Baileyof Aston University in Birmingham, England, responded: “I suppose the same question was asked when we had NPH [insulin], why would we want a longer-acting insulin?”
Dr. Bailey, who cochaired the sessions in which the IMAGINE 2 findings were presented and who was not involved in the trial, added: “The longer and longer the [duration of] action of insulin, with a flatter [glycemic] profile, the greater the likelihood is that one can control the glucose level to be more consistent with the [normal] physiological delivery of insulin.” Together with improving the way in which insulin is delivered, there may also be the potential for dosing every other day, weekly, or even monthly, he suggested.
The safety profile of longer-acting insulins is something “that may need ironing out,” he acknowledged, which might be addressed by again making a small alteration in the molecule or reducing the size of polyethylene glycol chain, for example.
The effects of PEGlispro appear just as good in patients with type 1 diabetes, according to the findings of the phase II IMAGINE I trial that were also presented at the EASD meeting. This open-label study comprised 455 patients and found those treated with PEGlispro had significantly lower HbA1c (7% vs. 7.4%) at 26 weeks’ follow-up. Again there were fewer episodes of nocturnal hypoglycemia and a weight reduction benefit with PEGlispro. Results from the phase III IMAGINE 3 study were presented as a poster and showed similar beneficial findings on glycemic control.In terms of safety, patients treated with PEGlispro in these IMAGINE trials generally experienced an increase in triglycerides and alanine aminotransferase when compared with glargine, and liver fat was higher in the PEGlispro- than in glargine-treated patients. In a subset of patients who underwent MRI of the liver in IMAGINE 2, liver fat was unchanged from baseline, whereas there was a decrease seen with glargine. In IMAGINE 1 a slight increase in liver fat was seen with PEGlispro.
Dr. Byron Hoogwerf of Eli Lilly presented data on lipid changes seen during 26 weeks of treatment in six phase III IMAGINE trials – four of which were performed in patients with type 2 diabetes. These data had previously been aired at the American Diabetes Association annual scientific sessions, he said, and considered a total of 5,583 randomized patients, 2,179 of whom had type 2 diabetes, were insulin naive, had been treated with basal insulin only; a further 1,835 type 2 patients who had previously been treated with insulin who received either basal only or basal-bolus dosing; and 1,569 patients with type 2 diabetes. In most of the trials, PEGlispro was compared against glargine, but in one of the trials, NPH was used.
The effect of PEGlispro on triglycerides appeared to differ according to the insulin treatment patients had previously received. In patients with type 2 diabetes who were insulin naive, there was no “essentially no change” in triglycerides Dr. Hoogwerf said. Although triglycerides were higher in the PEGlispro group, this could be because both glargine and NPH were associated with decreased levels, he said. In insulin-exposed type 2 diabetics, however, there was an increase in triglycerides when compared with glargine with both basal only and basal-bolus regimens. In those with type 1 diabetes, triglycerides were also higher, an effect that could be from switching the prior basal insulin, he suggested.
Changes on HDL and LDL cholesterol were minimal overall, he maintained, with little effect also on apolipoproteins and fasting free fatty acids. During the discussion, however, it was noted by one delegate that PEGlispro did not appear to be a very “lipid-friendly” drug, but said that it was the “overall package” of effects that mattered.
Dr. Richard Bergenstal of the International Diabetes Center in Minneapolis presented a meta-analysis of data on the cardiovascular safety of the drug. This included data on more than 5,800 patients from two phase II and six phase III studies of PEGlispro vs. an active comparator of glargine or NPH. The overall rate of major adverse cardiovascular events (MACE) – the primary composite endpoint incorporating cardiovascular death, stroke, myocardial infarction, and unstable angina with hospitalization – was 1.4% vs. 1.8%/100 patient-years, respectively, he said.
The overall hazard ratio for at least one MACE comparing PEGlispro with an active comparator was 0.82, with a 95% confidence interval of 0.53-1.27, and the subgroup analyses “did not identify any population of patients with increased treatment-associated risk.”
Eli Lilly funded the studies. Dr. Davies and Dr. Bergenstal have acted as advisory board members, speakers, or received research funding from Eli Lilly as well as several other pharmaceutical companies. Dr. Hoogwerf is an employee of, and minor stockholder in, Eli Lilly. Dr. Bailey had no financial disclosures relevant to his comment.
Key clinical point: PEGlispro showed superior glycemic control when compared with glargine, with relatively good tolerability and cardiovascular safety.
Major finding: Mean change in hemoglobin A1c from baseline to 1 year was –1.56% for PEGlispro and –1.27% for glargine (–0.29% difference, (P less than .001).
Data source: IMAGINE 2, a phase III, double-blind study of more than 1,500 patients with type 2 diabetes newly starting a basal insulin.
Disclosures: Eli Lilly funded the studies. Dr. Davies and Dr. Bergenstal have acted as advisory board members, speakers, or received research funding from Eli Lilly, as well as several other pharmaceutical companies. Dr. Hoogwerf is an employee of, and minor stockholder in, Eli Lilly. Dr. Bailey had no financial disclosures relevant to his comment.
EASD: Evolocumab shows ‘promising efficacy’ in type 2 diabetes
STOCKHOLM – Evolocumab, used in addition to the standard of care, lowered low-density lipoprotein cholesterol (LDL-C) and improved other lipid parameters in people with type 2 diabetes just as effectively as it did in those without, with no apparent detrimental effects on glycemic control, judging from findings from two open-label extension studies.
According to analysis of 1-year data derived from two multicenter, open-label extension studies of the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, the mean percentage change from baseline in LDL-C with evolocumab was –56.4% in subjects with and –52.2% in subjects without type 2 diabetes. By comparison, there were 3.4% and 6% increases in LDL-C in diabetic and nondiabetic individuals who received standard of care alone.
Similar changes from baseline in non–high-density lipoprotein cholesterol were seen, with –46.4% and –43.9% decreases and 4.3% and 5.6% rises in the diabetic and nondiabetic groups who were or were not treated with evolocumab in addition to standard of care. Triglycerides were also reduced with evolocumab (–13% in diabetic and –7.8% in nondiabetics) vs. the standard of care (1.6% and 3.0% increases, respectively). And, reductions in lipoprotein (a) were observed with evolocumab (–27.5% and –25.1) but not with standard of care alone.
These effects were comparable among a variety of subgroups of patients with type 2 diabetes, said the presenting study investigator Dr. Naveed Sattar, at the annual meeting of the European Association for the Study of Diabetes. The reductions were “comparable among type 2 diabetes subgroups stratified by gender, statin intensity, insulin use, presence or absence of CVD, hemoglobin A1c, and eGFR [epidermal growth factor receptor], with some caveats for HbA1c and eGFR as the numbers were rather small,” he said.
Dr. Sattar, who is professor of metabolic medicine at the Institute of Cardiovascular and Medical Sciences, University of Glasgow, said of this analysis: “I think based on these results, evolocumab, basically the PCSK9 inhibitors, has promising efficacy in patients with type 2 diabetes.”
The lipid analysis was based on data from the OSLER-1 and OSLER-2 studies, which altogether recruited 4,802 (75%) of subjects from the phase II and three studies conducted with evolocumab. Participants in these extension trials were randomized to receive subcutaneous evolocumab 140 mg every 2 weeks or 420 mg monthly in addition to standard of care vs. standard of care alone. There were 852 individuals with type 2 diabetes and 3,950 without diabetes at enrollment into these extension studies.
Glycemic control was looked at in a separate analysis of data from these two studies, with the patients without diabetes at enrollment being categorized into those at high risk (n = 2,432) and those at low risk (n = 1,518) of developing diabetes using standard criteria for the metabolic syndrome, impaired fasting plasma glucose, HbA1c higher than 6%, and a body mass index greater than 30 kg/m2.
The rationale for looking at glycemic control separately was that statins had been shown to increase the risk for diabetes and it was unknown whether or not the newly available PCSK9 inhibitors would have a similar effect, particularly if used in combination with statins. So while the first analysis aimed to see if evolocumab was able to lower lipids in diabetic patients as well as it does in nondiabetic patients, the second looked to see if it could do so without causing problems with glycemic control.
Mean changes in LDL-C from baseline to the end of extension studies showed a similar benefit of evolocumab in patients with type 2 diabetes and those at high or low risk for diabetes (–56%, –54%, and –49%, respectively) which was greater than that seen in patients who received only standard of care (+3%, +5%, and +7%, respectively).
“One year of treatment with evolocumab showed no measurable effect, and I think that’s the key, no measurable effect on glycemic parameters including new onset diabetes versus standard of care alone,” Dr. Sattar reported.
Median change in fasting plasma glucose from baseline to the end of open-label follow-up in patients on evolocumab in addition to standard of care was no different from that in patients who received standard of care alone. Likewise, mean HbA1c changes were marginal, at +0.16% and +0.23% in patients with diabetes, +0.05& and +0.06% in patients at high, and +0.06% and +0.07% in patients at low diabetes risk.
Overall, post baseline rates of new onset diabetes were there same (4%) in patients treated with evolocumab and in those who received standard of care alone. In patients with normal glucose levels at baseline (fasting plasma glucose less than 100 mg/dL) rates were 2% in both groups, and 7% and 8% in those who had impaired fasting glucose (100-125 mg/dL) at baseline.
“Overall the results are encouraging that these [PCSK9 inhibitors] may not cause dysglycemia-like statins do,” Dr. Sattar said.
During the discussion, it was noted that statins were used in the standard of care group, but the number of patients using statins at the start of the open studies was so small that it is unlikely to have biased the results seen and will be addressed when the paper is drafted for publication, he said.
The Food and Drug Administration recently approved evolocumab (Repatha) for use in addition to diet and maximally tolerated statin therapy in adults with heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C.
Amgen sponsored the OSLER studies. Dr Sattar reported financial relationships with Amgen, Merck, and Sanofi.
STOCKHOLM – Evolocumab, used in addition to the standard of care, lowered low-density lipoprotein cholesterol (LDL-C) and improved other lipid parameters in people with type 2 diabetes just as effectively as it did in those without, with no apparent detrimental effects on glycemic control, judging from findings from two open-label extension studies.
According to analysis of 1-year data derived from two multicenter, open-label extension studies of the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, the mean percentage change from baseline in LDL-C with evolocumab was –56.4% in subjects with and –52.2% in subjects without type 2 diabetes. By comparison, there were 3.4% and 6% increases in LDL-C in diabetic and nondiabetic individuals who received standard of care alone.
Similar changes from baseline in non–high-density lipoprotein cholesterol were seen, with –46.4% and –43.9% decreases and 4.3% and 5.6% rises in the diabetic and nondiabetic groups who were or were not treated with evolocumab in addition to standard of care. Triglycerides were also reduced with evolocumab (–13% in diabetic and –7.8% in nondiabetics) vs. the standard of care (1.6% and 3.0% increases, respectively). And, reductions in lipoprotein (a) were observed with evolocumab (–27.5% and –25.1) but not with standard of care alone.
These effects were comparable among a variety of subgroups of patients with type 2 diabetes, said the presenting study investigator Dr. Naveed Sattar, at the annual meeting of the European Association for the Study of Diabetes. The reductions were “comparable among type 2 diabetes subgroups stratified by gender, statin intensity, insulin use, presence or absence of CVD, hemoglobin A1c, and eGFR [epidermal growth factor receptor], with some caveats for HbA1c and eGFR as the numbers were rather small,” he said.
Dr. Sattar, who is professor of metabolic medicine at the Institute of Cardiovascular and Medical Sciences, University of Glasgow, said of this analysis: “I think based on these results, evolocumab, basically the PCSK9 inhibitors, has promising efficacy in patients with type 2 diabetes.”
The lipid analysis was based on data from the OSLER-1 and OSLER-2 studies, which altogether recruited 4,802 (75%) of subjects from the phase II and three studies conducted with evolocumab. Participants in these extension trials were randomized to receive subcutaneous evolocumab 140 mg every 2 weeks or 420 mg monthly in addition to standard of care vs. standard of care alone. There were 852 individuals with type 2 diabetes and 3,950 without diabetes at enrollment into these extension studies.
Glycemic control was looked at in a separate analysis of data from these two studies, with the patients without diabetes at enrollment being categorized into those at high risk (n = 2,432) and those at low risk (n = 1,518) of developing diabetes using standard criteria for the metabolic syndrome, impaired fasting plasma glucose, HbA1c higher than 6%, and a body mass index greater than 30 kg/m2.
The rationale for looking at glycemic control separately was that statins had been shown to increase the risk for diabetes and it was unknown whether or not the newly available PCSK9 inhibitors would have a similar effect, particularly if used in combination with statins. So while the first analysis aimed to see if evolocumab was able to lower lipids in diabetic patients as well as it does in nondiabetic patients, the second looked to see if it could do so without causing problems with glycemic control.
Mean changes in LDL-C from baseline to the end of extension studies showed a similar benefit of evolocumab in patients with type 2 diabetes and those at high or low risk for diabetes (–56%, –54%, and –49%, respectively) which was greater than that seen in patients who received only standard of care (+3%, +5%, and +7%, respectively).
“One year of treatment with evolocumab showed no measurable effect, and I think that’s the key, no measurable effect on glycemic parameters including new onset diabetes versus standard of care alone,” Dr. Sattar reported.
Median change in fasting plasma glucose from baseline to the end of open-label follow-up in patients on evolocumab in addition to standard of care was no different from that in patients who received standard of care alone. Likewise, mean HbA1c changes were marginal, at +0.16% and +0.23% in patients with diabetes, +0.05& and +0.06% in patients at high, and +0.06% and +0.07% in patients at low diabetes risk.
Overall, post baseline rates of new onset diabetes were there same (4%) in patients treated with evolocumab and in those who received standard of care alone. In patients with normal glucose levels at baseline (fasting plasma glucose less than 100 mg/dL) rates were 2% in both groups, and 7% and 8% in those who had impaired fasting glucose (100-125 mg/dL) at baseline.
“Overall the results are encouraging that these [PCSK9 inhibitors] may not cause dysglycemia-like statins do,” Dr. Sattar said.
During the discussion, it was noted that statins were used in the standard of care group, but the number of patients using statins at the start of the open studies was so small that it is unlikely to have biased the results seen and will be addressed when the paper is drafted for publication, he said.
The Food and Drug Administration recently approved evolocumab (Repatha) for use in addition to diet and maximally tolerated statin therapy in adults with heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C.
Amgen sponsored the OSLER studies. Dr Sattar reported financial relationships with Amgen, Merck, and Sanofi.
STOCKHOLM – Evolocumab, used in addition to the standard of care, lowered low-density lipoprotein cholesterol (LDL-C) and improved other lipid parameters in people with type 2 diabetes just as effectively as it did in those without, with no apparent detrimental effects on glycemic control, judging from findings from two open-label extension studies.
According to analysis of 1-year data derived from two multicenter, open-label extension studies of the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, the mean percentage change from baseline in LDL-C with evolocumab was –56.4% in subjects with and –52.2% in subjects without type 2 diabetes. By comparison, there were 3.4% and 6% increases in LDL-C in diabetic and nondiabetic individuals who received standard of care alone.
Similar changes from baseline in non–high-density lipoprotein cholesterol were seen, with –46.4% and –43.9% decreases and 4.3% and 5.6% rises in the diabetic and nondiabetic groups who were or were not treated with evolocumab in addition to standard of care. Triglycerides were also reduced with evolocumab (–13% in diabetic and –7.8% in nondiabetics) vs. the standard of care (1.6% and 3.0% increases, respectively). And, reductions in lipoprotein (a) were observed with evolocumab (–27.5% and –25.1) but not with standard of care alone.
These effects were comparable among a variety of subgroups of patients with type 2 diabetes, said the presenting study investigator Dr. Naveed Sattar, at the annual meeting of the European Association for the Study of Diabetes. The reductions were “comparable among type 2 diabetes subgroups stratified by gender, statin intensity, insulin use, presence or absence of CVD, hemoglobin A1c, and eGFR [epidermal growth factor receptor], with some caveats for HbA1c and eGFR as the numbers were rather small,” he said.
Dr. Sattar, who is professor of metabolic medicine at the Institute of Cardiovascular and Medical Sciences, University of Glasgow, said of this analysis: “I think based on these results, evolocumab, basically the PCSK9 inhibitors, has promising efficacy in patients with type 2 diabetes.”
The lipid analysis was based on data from the OSLER-1 and OSLER-2 studies, which altogether recruited 4,802 (75%) of subjects from the phase II and three studies conducted with evolocumab. Participants in these extension trials were randomized to receive subcutaneous evolocumab 140 mg every 2 weeks or 420 mg monthly in addition to standard of care vs. standard of care alone. There were 852 individuals with type 2 diabetes and 3,950 without diabetes at enrollment into these extension studies.
Glycemic control was looked at in a separate analysis of data from these two studies, with the patients without diabetes at enrollment being categorized into those at high risk (n = 2,432) and those at low risk (n = 1,518) of developing diabetes using standard criteria for the metabolic syndrome, impaired fasting plasma glucose, HbA1c higher than 6%, and a body mass index greater than 30 kg/m2.
The rationale for looking at glycemic control separately was that statins had been shown to increase the risk for diabetes and it was unknown whether or not the newly available PCSK9 inhibitors would have a similar effect, particularly if used in combination with statins. So while the first analysis aimed to see if evolocumab was able to lower lipids in diabetic patients as well as it does in nondiabetic patients, the second looked to see if it could do so without causing problems with glycemic control.
Mean changes in LDL-C from baseline to the end of extension studies showed a similar benefit of evolocumab in patients with type 2 diabetes and those at high or low risk for diabetes (–56%, –54%, and –49%, respectively) which was greater than that seen in patients who received only standard of care (+3%, +5%, and +7%, respectively).
“One year of treatment with evolocumab showed no measurable effect, and I think that’s the key, no measurable effect on glycemic parameters including new onset diabetes versus standard of care alone,” Dr. Sattar reported.
Median change in fasting plasma glucose from baseline to the end of open-label follow-up in patients on evolocumab in addition to standard of care was no different from that in patients who received standard of care alone. Likewise, mean HbA1c changes were marginal, at +0.16% and +0.23% in patients with diabetes, +0.05& and +0.06% in patients at high, and +0.06% and +0.07% in patients at low diabetes risk.
Overall, post baseline rates of new onset diabetes were there same (4%) in patients treated with evolocumab and in those who received standard of care alone. In patients with normal glucose levels at baseline (fasting plasma glucose less than 100 mg/dL) rates were 2% in both groups, and 7% and 8% in those who had impaired fasting glucose (100-125 mg/dL) at baseline.
“Overall the results are encouraging that these [PCSK9 inhibitors] may not cause dysglycemia-like statins do,” Dr. Sattar said.
During the discussion, it was noted that statins were used in the standard of care group, but the number of patients using statins at the start of the open studies was so small that it is unlikely to have biased the results seen and will be addressed when the paper is drafted for publication, he said.
The Food and Drug Administration recently approved evolocumab (Repatha) for use in addition to diet and maximally tolerated statin therapy in adults with heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C.
Amgen sponsored the OSLER studies. Dr Sattar reported financial relationships with Amgen, Merck, and Sanofi.
Depression, hypertension combo compounds cardiovascular risk
LONDON – The combination of depression and very high systolic blood pressure increased the risk for a major cardiovascular event by 83%, compared with normal blood pressure and no depression, in patients with existing heart disease, diabetes, or stroke.
In a large family practice–based study, the hazard ratio for first hospital admission due to myocardial infarction, stroke or heart failure, or cardiovascular death in patients with high (at least 160 mm Hg) systolic blood pressure who were also depressed was 1.83, a highly significant difference compared with individuals with normal BP and no depression.
The presence of depression also significantly increased the risk for these cardiovascular events by 36% in patients with lower systolic BPs, compared with those with normal BP and no depression.
“Patients with existing heart disease, diabetes, or stroke are more likely to have another heart attack or another stroke or die from heart problems than the general population,” Dr. Bhautesh Jani of the Institute of Health and Wellbeing, University of Glasgow (Scotland), said at the annual congress of the European Society of Cardiology.
“In particular, those who have extremes of blood pressure or those who have depressive symptoms are at higher risk, which has been shown by previous evidence. What is relatively unknown is the combined effect of having extremes of blood pressure and depressive symptoms together, and our study tried to address that problem,” Dr. Jani explained.
The study involved more than 35,500 individuals with existing heart disease, diabetes, or stroke living in Scotland, of whom 3,939 (11%) had at least one major cardiovascular event that needed hospital admission during a 4-year period. Patients had been divided into groups based on their systolic BP, and depressive symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS) during 2008-2009. A HADS score of more than 7 was considered indicative of depression.
Dr. Jani noted that all the results were adjusted for multiple confounding factors, including age, gender, socioeconomic status, number of comorbid conditions, total cholesterol values, body mass index, and the initiation of antidepressant medication.
“The key implications I would suggest are for secondary prevention and to perhaps focus our resources on monitoring blood pressure and providing treatment in patients with associated depressive symptoms,” Dr. Jani proposed.
Dr. Christi Deaton, professor of clinical nursing research at the University of Cambridge (England), who commented on the study findings, noted that it highlighted the importance of raising awareness among both clinicians and patients of the potential risk associated with a combination of hypertension and depression, particularly among patients with a high level of other risk factors for further cardiovascular events.
“Screening patients for depression is very simple to do and you can start with a couple of questions asking about whether or not the patient felt sad or had low mood, and then go on to use other screening tools,” she observed. “All providers should be screening patients and thinking about the synergy of these two risk factors,” she said.
Other research presented at the ESC Congress by cardiologist Dr. Salim Hayek of Emory University in Atlanta also highlighted the importance of screening for depression, this time in patients with angina. In a study of 5,202 adults enrolled in the university’s biobank between 2004 and 2013 and who underwent left heart catheterization, patients with frequent chest pain were found to have more depressive symptoms than those without angina. Depressive symptoms in this study were assessed using the Patient Health Questionnaire (PHQ-9).
“Chest pain was more frequent in patients with mild depression with and without coronary artery disease, regardless of sex or history of myocardial infarction,” Dr. Hayek said. After multivariate analysis, depression was the most important predictor of frequent chest pain, he added. Other factors independently associated with chest pain frequency were female sex, coronary artery disease severity, history of MI, body mass index, and high blood lipid levels.
“At follow-up, a decrease in depressive symptoms was associated with improvement in chest pain,” Dr. Hayek said, but patients with depression who were revascularized did not show an improvement in chest pain.
The findings suggest that the association between chest pain and depression was independent of the underlying arterial disease and further studies are needed to look at the effect of revascularization and angina relief on depressive symptoms, and conversely if antidepressant medications could help alleviate chest pain.
The study Dr. Jani presented was funded by the Scottish Government. Dr. Jani and Dr. Hayek both reported having no disclosures.
This article was updated February 3, 2016.
LONDON – The combination of depression and very high systolic blood pressure increased the risk for a major cardiovascular event by 83%, compared with normal blood pressure and no depression, in patients with existing heart disease, diabetes, or stroke.
In a large family practice–based study, the hazard ratio for first hospital admission due to myocardial infarction, stroke or heart failure, or cardiovascular death in patients with high (at least 160 mm Hg) systolic blood pressure who were also depressed was 1.83, a highly significant difference compared with individuals with normal BP and no depression.
The presence of depression also significantly increased the risk for these cardiovascular events by 36% in patients with lower systolic BPs, compared with those with normal BP and no depression.
“Patients with existing heart disease, diabetes, or stroke are more likely to have another heart attack or another stroke or die from heart problems than the general population,” Dr. Bhautesh Jani of the Institute of Health and Wellbeing, University of Glasgow (Scotland), said at the annual congress of the European Society of Cardiology.
“In particular, those who have extremes of blood pressure or those who have depressive symptoms are at higher risk, which has been shown by previous evidence. What is relatively unknown is the combined effect of having extremes of blood pressure and depressive symptoms together, and our study tried to address that problem,” Dr. Jani explained.
The study involved more than 35,500 individuals with existing heart disease, diabetes, or stroke living in Scotland, of whom 3,939 (11%) had at least one major cardiovascular event that needed hospital admission during a 4-year period. Patients had been divided into groups based on their systolic BP, and depressive symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS) during 2008-2009. A HADS score of more than 7 was considered indicative of depression.
Dr. Jani noted that all the results were adjusted for multiple confounding factors, including age, gender, socioeconomic status, number of comorbid conditions, total cholesterol values, body mass index, and the initiation of antidepressant medication.
“The key implications I would suggest are for secondary prevention and to perhaps focus our resources on monitoring blood pressure and providing treatment in patients with associated depressive symptoms,” Dr. Jani proposed.
Dr. Christi Deaton, professor of clinical nursing research at the University of Cambridge (England), who commented on the study findings, noted that it highlighted the importance of raising awareness among both clinicians and patients of the potential risk associated with a combination of hypertension and depression, particularly among patients with a high level of other risk factors for further cardiovascular events.
“Screening patients for depression is very simple to do and you can start with a couple of questions asking about whether or not the patient felt sad or had low mood, and then go on to use other screening tools,” she observed. “All providers should be screening patients and thinking about the synergy of these two risk factors,” she said.
Other research presented at the ESC Congress by cardiologist Dr. Salim Hayek of Emory University in Atlanta also highlighted the importance of screening for depression, this time in patients with angina. In a study of 5,202 adults enrolled in the university’s biobank between 2004 and 2013 and who underwent left heart catheterization, patients with frequent chest pain were found to have more depressive symptoms than those without angina. Depressive symptoms in this study were assessed using the Patient Health Questionnaire (PHQ-9).
“Chest pain was more frequent in patients with mild depression with and without coronary artery disease, regardless of sex or history of myocardial infarction,” Dr. Hayek said. After multivariate analysis, depression was the most important predictor of frequent chest pain, he added. Other factors independently associated with chest pain frequency were female sex, coronary artery disease severity, history of MI, body mass index, and high blood lipid levels.
“At follow-up, a decrease in depressive symptoms was associated with improvement in chest pain,” Dr. Hayek said, but patients with depression who were revascularized did not show an improvement in chest pain.
The findings suggest that the association between chest pain and depression was independent of the underlying arterial disease and further studies are needed to look at the effect of revascularization and angina relief on depressive symptoms, and conversely if antidepressant medications could help alleviate chest pain.
The study Dr. Jani presented was funded by the Scottish Government. Dr. Jani and Dr. Hayek both reported having no disclosures.
This article was updated February 3, 2016.
LONDON – The combination of depression and very high systolic blood pressure increased the risk for a major cardiovascular event by 83%, compared with normal blood pressure and no depression, in patients with existing heart disease, diabetes, or stroke.
In a large family practice–based study, the hazard ratio for first hospital admission due to myocardial infarction, stroke or heart failure, or cardiovascular death in patients with high (at least 160 mm Hg) systolic blood pressure who were also depressed was 1.83, a highly significant difference compared with individuals with normal BP and no depression.
The presence of depression also significantly increased the risk for these cardiovascular events by 36% in patients with lower systolic BPs, compared with those with normal BP and no depression.
“Patients with existing heart disease, diabetes, or stroke are more likely to have another heart attack or another stroke or die from heart problems than the general population,” Dr. Bhautesh Jani of the Institute of Health and Wellbeing, University of Glasgow (Scotland), said at the annual congress of the European Society of Cardiology.
“In particular, those who have extremes of blood pressure or those who have depressive symptoms are at higher risk, which has been shown by previous evidence. What is relatively unknown is the combined effect of having extremes of blood pressure and depressive symptoms together, and our study tried to address that problem,” Dr. Jani explained.
The study involved more than 35,500 individuals with existing heart disease, diabetes, or stroke living in Scotland, of whom 3,939 (11%) had at least one major cardiovascular event that needed hospital admission during a 4-year period. Patients had been divided into groups based on their systolic BP, and depressive symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS) during 2008-2009. A HADS score of more than 7 was considered indicative of depression.
Dr. Jani noted that all the results were adjusted for multiple confounding factors, including age, gender, socioeconomic status, number of comorbid conditions, total cholesterol values, body mass index, and the initiation of antidepressant medication.
“The key implications I would suggest are for secondary prevention and to perhaps focus our resources on monitoring blood pressure and providing treatment in patients with associated depressive symptoms,” Dr. Jani proposed.
Dr. Christi Deaton, professor of clinical nursing research at the University of Cambridge (England), who commented on the study findings, noted that it highlighted the importance of raising awareness among both clinicians and patients of the potential risk associated with a combination of hypertension and depression, particularly among patients with a high level of other risk factors for further cardiovascular events.
“Screening patients for depression is very simple to do and you can start with a couple of questions asking about whether or not the patient felt sad or had low mood, and then go on to use other screening tools,” she observed. “All providers should be screening patients and thinking about the synergy of these two risk factors,” she said.
Other research presented at the ESC Congress by cardiologist Dr. Salim Hayek of Emory University in Atlanta also highlighted the importance of screening for depression, this time in patients with angina. In a study of 5,202 adults enrolled in the university’s biobank between 2004 and 2013 and who underwent left heart catheterization, patients with frequent chest pain were found to have more depressive symptoms than those without angina. Depressive symptoms in this study were assessed using the Patient Health Questionnaire (PHQ-9).
“Chest pain was more frequent in patients with mild depression with and without coronary artery disease, regardless of sex or history of myocardial infarction,” Dr. Hayek said. After multivariate analysis, depression was the most important predictor of frequent chest pain, he added. Other factors independently associated with chest pain frequency were female sex, coronary artery disease severity, history of MI, body mass index, and high blood lipid levels.
“At follow-up, a decrease in depressive symptoms was associated with improvement in chest pain,” Dr. Hayek said, but patients with depression who were revascularized did not show an improvement in chest pain.
The findings suggest that the association between chest pain and depression was independent of the underlying arterial disease and further studies are needed to look at the effect of revascularization and angina relief on depressive symptoms, and conversely if antidepressant medications could help alleviate chest pain.
The study Dr. Jani presented was funded by the Scottish Government. Dr. Jani and Dr. Hayek both reported having no disclosures.
This article was updated February 3, 2016.
AT THE ESC CONGRESS 2015
Key clinical point: Better monitoring and management of both hypertension and depression could help reduce further cardiovascular morbidity and mortality.
Major finding: The rate of major cardiovascular events was 83% higher in depressed patients with very high (at least 160 mm Hg) systolic BP, compared with individuals with normal pressure and no depression.
Data source: Large family practice study of 35,537 patients with existing coronary heart disease, diabetes, or stroke followed up for 4 years.
Disclosures: The study Dr. Jani presented was funded by the Scottish Government. Dr. Jani had no disclosures.
ESC: Air quality level linked to STEMI risk in men
LONDON – The risk for ST-elevation myocardial infarction (STEMI) increased in men when air quality dipped below acceptable levels as designated by the World Health Organization (WHO), based on the results of an observational study in Belgian.
The relative risk for a STEMI increased by 2.8% (1.026; 95% confidence interval, 1.005-1.048) for every 10 mcg/cm3 rise in fine particulate air pollution and by 5.1% (RR, 1.051; 95% CI, 1.018-1.084) for a comparable rise in nitric oxide air pollution. Ozone level was not associated with the risk for STEMI. Air pollution levels did not affect in-hospital mortality due to STEMI and had no clear effect on patients with coronary artery disease, diabetes or hypertension.
“Of course, it is very interesting that the results are only observed in men. This may be due to a statistical issue, because in our study population, the female group represents less than 25% of the population,” Dr. Jean-François Argacha, a study investigator, said during a press briefing at the annual congress of the European Society of Cardiology.
Subgroup analysis suggested that patients who were aged 75 years and older were more likely to develop STEMI in relation to exposure to particulate matter (RR, 1.046; 95% CI, 1.002-1.092, P = .041). Those aged 54 years and younger seemed more susceptible to nitric oxide levels (RR, 1.071; 95% CI, 1.010-1.136; P = .021).“The detrimental impact of nitric oxide exceeded that of fine particles and may be of particular concern in the younger population,” said Dr. Argacha, a cardiologist at University Hospital Brussels.
Previous research had shown that particulate matter is associated with an increased risk for acute myocardial infarction, but there had been no specific assessments on air pollution’s potential effects on STEMI, according to Dr. Argacha.
The study considered information on 11,428 patients in the Belgian Interdisciplinary Working Group on Acute Cardiology STEMI Registry between 2009 and 2013. Data on national air pollution parameters – particulate matter with an aerodynamic diameter of less than 10 (PM10) or 2.5 (PM2.5) mcm, nitric oxide and ozone – and air temperature were obtained from the Belgian Environment Agency database and adjusted for population density.
A case crossover analysis of STEMI risk was then performed, with risk being adjusted for ambient temperature, day of the week, and the season. The study’s case crossover design ensured that the effects were limited to air pollution and excluded other confounders including respiratory disease and air temperature.
Worldwide, WHO has estimated that poor urban air quality is responsible for around 1.3 million deaths per year, Dr. Argacha observed, noting that air pollution consists of fine (PM2.5) and larger (PM10) particles, nitric oxide, and ozone as well as sulfur dioxide and carbon monoxide.
During the observation period, the mean air pollution levels over the course of 1 year in Belgium were 23.9 mcg/cm3 for PM10, 16.1 mcg/cm3 for PM2.5, and 23.7 mcg/cm3 for nitric oxide. WHO guidelines set a daily limit of 25 mcg/cm3 for PM2.5. Dr. Argacha noted that this limit was exceeded in Belgium on 17.5% of days in the study.
Dr. Oscar Franco, professor of preventative medicine at the Erasmus University Medical Center in Rotterdam, the Netherlands, who cochaired the press conference noted that the European Society of Cardiology recently published a position paper on air pollution on cardiovascular disease (Eur Heart J. 2015;36:83-93) and has launched a major campaign to raise awareness of the detrimental effects that the environment can have on the heart.
The campaign notes that air and noise pollution are modifiable risk factors for the prevention and control of cardiovascular diseases, and advocated for acceptable limits that reflect WHO levels. Individuals “need to take action,” Dr. Franco urged. The decisions that people make every day – how they get to work for example – could have a potentially huge impact on the environment and health.
Dr. Argacha and Dr. Franco had no disclosures to report.
LONDON – The risk for ST-elevation myocardial infarction (STEMI) increased in men when air quality dipped below acceptable levels as designated by the World Health Organization (WHO), based on the results of an observational study in Belgian.
The relative risk for a STEMI increased by 2.8% (1.026; 95% confidence interval, 1.005-1.048) for every 10 mcg/cm3 rise in fine particulate air pollution and by 5.1% (RR, 1.051; 95% CI, 1.018-1.084) for a comparable rise in nitric oxide air pollution. Ozone level was not associated with the risk for STEMI. Air pollution levels did not affect in-hospital mortality due to STEMI and had no clear effect on patients with coronary artery disease, diabetes or hypertension.
“Of course, it is very interesting that the results are only observed in men. This may be due to a statistical issue, because in our study population, the female group represents less than 25% of the population,” Dr. Jean-François Argacha, a study investigator, said during a press briefing at the annual congress of the European Society of Cardiology.
Subgroup analysis suggested that patients who were aged 75 years and older were more likely to develop STEMI in relation to exposure to particulate matter (RR, 1.046; 95% CI, 1.002-1.092, P = .041). Those aged 54 years and younger seemed more susceptible to nitric oxide levels (RR, 1.071; 95% CI, 1.010-1.136; P = .021).“The detrimental impact of nitric oxide exceeded that of fine particles and may be of particular concern in the younger population,” said Dr. Argacha, a cardiologist at University Hospital Brussels.
Previous research had shown that particulate matter is associated with an increased risk for acute myocardial infarction, but there had been no specific assessments on air pollution’s potential effects on STEMI, according to Dr. Argacha.
The study considered information on 11,428 patients in the Belgian Interdisciplinary Working Group on Acute Cardiology STEMI Registry between 2009 and 2013. Data on national air pollution parameters – particulate matter with an aerodynamic diameter of less than 10 (PM10) or 2.5 (PM2.5) mcm, nitric oxide and ozone – and air temperature were obtained from the Belgian Environment Agency database and adjusted for population density.
A case crossover analysis of STEMI risk was then performed, with risk being adjusted for ambient temperature, day of the week, and the season. The study’s case crossover design ensured that the effects were limited to air pollution and excluded other confounders including respiratory disease and air temperature.
Worldwide, WHO has estimated that poor urban air quality is responsible for around 1.3 million deaths per year, Dr. Argacha observed, noting that air pollution consists of fine (PM2.5) and larger (PM10) particles, nitric oxide, and ozone as well as sulfur dioxide and carbon monoxide.
During the observation period, the mean air pollution levels over the course of 1 year in Belgium were 23.9 mcg/cm3 for PM10, 16.1 mcg/cm3 for PM2.5, and 23.7 mcg/cm3 for nitric oxide. WHO guidelines set a daily limit of 25 mcg/cm3 for PM2.5. Dr. Argacha noted that this limit was exceeded in Belgium on 17.5% of days in the study.
Dr. Oscar Franco, professor of preventative medicine at the Erasmus University Medical Center in Rotterdam, the Netherlands, who cochaired the press conference noted that the European Society of Cardiology recently published a position paper on air pollution on cardiovascular disease (Eur Heart J. 2015;36:83-93) and has launched a major campaign to raise awareness of the detrimental effects that the environment can have on the heart.
The campaign notes that air and noise pollution are modifiable risk factors for the prevention and control of cardiovascular diseases, and advocated for acceptable limits that reflect WHO levels. Individuals “need to take action,” Dr. Franco urged. The decisions that people make every day – how they get to work for example – could have a potentially huge impact on the environment and health.
Dr. Argacha and Dr. Franco had no disclosures to report.
LONDON – The risk for ST-elevation myocardial infarction (STEMI) increased in men when air quality dipped below acceptable levels as designated by the World Health Organization (WHO), based on the results of an observational study in Belgian.
The relative risk for a STEMI increased by 2.8% (1.026; 95% confidence interval, 1.005-1.048) for every 10 mcg/cm3 rise in fine particulate air pollution and by 5.1% (RR, 1.051; 95% CI, 1.018-1.084) for a comparable rise in nitric oxide air pollution. Ozone level was not associated with the risk for STEMI. Air pollution levels did not affect in-hospital mortality due to STEMI and had no clear effect on patients with coronary artery disease, diabetes or hypertension.
“Of course, it is very interesting that the results are only observed in men. This may be due to a statistical issue, because in our study population, the female group represents less than 25% of the population,” Dr. Jean-François Argacha, a study investigator, said during a press briefing at the annual congress of the European Society of Cardiology.
Subgroup analysis suggested that patients who were aged 75 years and older were more likely to develop STEMI in relation to exposure to particulate matter (RR, 1.046; 95% CI, 1.002-1.092, P = .041). Those aged 54 years and younger seemed more susceptible to nitric oxide levels (RR, 1.071; 95% CI, 1.010-1.136; P = .021).“The detrimental impact of nitric oxide exceeded that of fine particles and may be of particular concern in the younger population,” said Dr. Argacha, a cardiologist at University Hospital Brussels.
Previous research had shown that particulate matter is associated with an increased risk for acute myocardial infarction, but there had been no specific assessments on air pollution’s potential effects on STEMI, according to Dr. Argacha.
The study considered information on 11,428 patients in the Belgian Interdisciplinary Working Group on Acute Cardiology STEMI Registry between 2009 and 2013. Data on national air pollution parameters – particulate matter with an aerodynamic diameter of less than 10 (PM10) or 2.5 (PM2.5) mcm, nitric oxide and ozone – and air temperature were obtained from the Belgian Environment Agency database and adjusted for population density.
A case crossover analysis of STEMI risk was then performed, with risk being adjusted for ambient temperature, day of the week, and the season. The study’s case crossover design ensured that the effects were limited to air pollution and excluded other confounders including respiratory disease and air temperature.
Worldwide, WHO has estimated that poor urban air quality is responsible for around 1.3 million deaths per year, Dr. Argacha observed, noting that air pollution consists of fine (PM2.5) and larger (PM10) particles, nitric oxide, and ozone as well as sulfur dioxide and carbon monoxide.
During the observation period, the mean air pollution levels over the course of 1 year in Belgium were 23.9 mcg/cm3 for PM10, 16.1 mcg/cm3 for PM2.5, and 23.7 mcg/cm3 for nitric oxide. WHO guidelines set a daily limit of 25 mcg/cm3 for PM2.5. Dr. Argacha noted that this limit was exceeded in Belgium on 17.5% of days in the study.
Dr. Oscar Franco, professor of preventative medicine at the Erasmus University Medical Center in Rotterdam, the Netherlands, who cochaired the press conference noted that the European Society of Cardiology recently published a position paper on air pollution on cardiovascular disease (Eur Heart J. 2015;36:83-93) and has launched a major campaign to raise awareness of the detrimental effects that the environment can have on the heart.
The campaign notes that air and noise pollution are modifiable risk factors for the prevention and control of cardiovascular diseases, and advocated for acceptable limits that reflect WHO levels. Individuals “need to take action,” Dr. Franco urged. The decisions that people make every day – how they get to work for example – could have a potentially huge impact on the environment and health.
Dr. Argacha and Dr. Franco had no disclosures to report.
AT THE ESC CONGRESS 2015
Key clinical point: Air pollution may be a potentially modifiable risk factor for STEMI in men.
Major finding: The relative risk for a STEMI increased by 2.8% for a 10 mcg/cm3 rise in fine particulate air pollution and by 5.1% for a comparable rise in nitric oxide air pollution.
Data source: 11,428 patients logged in the Belgian Interdisciplinary Working Group on Acute Cardiology STEMI Registry between 2009 and 2013.
Disclosures: Dr. Argacha and Dr. Franco had no disclosures to report.
EASD: Studies slam cardiovascular safety of sulfonylureas
STOCKHOLM – While they are effective glucose-lowering agents, sulfonylureas seem to substantially increase the risk for cardiovascular events relative to other antihyperglycemic agents, according to several presentations given at the annual meeting of the European Association for the Study of Diabetes.
In a systematic review and meta-analysis of 84 randomized controlled trials (RCTs) and 26 observational studies, accounting for more than 36,573 and more than 1.5 million subjects with type 2 diabetes mellitus, respectively, treatment with a sulfonylurea was found to significantly increase all-cause mortality and cardiovascular-related mortality when compared to no active treatment or placebo and to other antidiabetic drugs.
In the RCTs, the hazard ratios comparing sulfonylureas to all treatments combined were 1.26 (95% confidence interval, 1.10-1.44) for all-cause mortality and 1.46 (95% CI, 1.21-1.77) for cardiovascular mortality. HR for CV mortality was highest when comparing sulfonylureas with GLP-1 agonists and SGLT-2 inhibitors, at 45.4 (95% CI, 2.07-362.8) and 42.6 (95% CI, 1.71-359.1), with significantly elevated risk also seen when compared with DPP-4 inhibitors (HR, 4.42; 95% CI, 1.92-13.0), thiazolidinediones (HR, 3.05; 95% CI, 1.79-5.54), and insulin (HR, 1.30; 95% CI, 1.02-1.66).
There was also an increase in the risk for acute myocardial infarction and stroke in some comparisons of sulfonylureas versus other treatments.
“We think this study is the most comprehensive review of RCTs and observational studies to compare CV-related outcomes and all-cause mortality among patients receiving sulfonylureas versus [other] antidiabetic agents,” said Dr. Steve Bain of Abertawe Bro Morgannwg University NHS Trust in Swansea, England.
“We accept that the confidence intervals were wide, but there is a tendency for all significant results to trend in the same direction.” Results of the observational studies analyses generally supported the results from the RCTs, he added. A notable limitation was that there had been no differentiation between the risk according to different sulfonylureas. Dr. Bain said this was to try to keep the number of patients available for analysis as high as possible in the sulfonylurea group.
Data from the German CREST (CV Risk and Events on SU Treatment) study also showed that there was a higher CV risk associated with sulfonylureas when compared with metformin in patients newly diagnosed with type 2 diabetes mellitus. The retrospective cohort database study included more than 35,000 individuals, of whom 26,883 received no antihyperglycemic treatment or treatment with an antihyperglycemic agent other than a sulfonylurea or metformin between January 2010 and December 2011, leaving 7,874 who were given metformin monotherapy and 904 given sulfonylurea monotherapy. Propensity score matching was used to form the final study groups consisting of 730 patients each.
Crude, propensity-matched, and adjusted HRs for death comparing sulfonylurea with metformin as first-line treatment were 3.32 (95% CI, 2.6-4.3; P less than .001), 1.4 (95% CI, 0.9-2.3; P less than .12), and 2.01 (95% CI, 1.5-2.6; P less than .001), respectively. Corresponding HRs for major cardiovascular events (MACE) were 1.9 (95% CI, 1.4-2.4; P less than .001), 1.4 (95% CI, 0.9-2.2; P less than .14), and 1.3 (95% CI, 1.03-1.74; P less than .05).
Dr. Thomas Wilke of the University of Wismar (Germany) who presented the CREST study findings, noted that there were some differences between the groups in terms of the baseline demographics, with those receiving sulfonylureas being somewhat older and more likely to be women, have comorbid disease, and discontinue monotherapy earlier than patients treated with metformin, or possibly be more likely to have contraindications to the use of metformin.
“Taking these differences into account, patients treated with sulfonylureas seem to be at increased risk of death, MACE, and type 2 diabetes hospitalization, compared with metformin-treated patients,” in this German population, Dr. Wilke concluded.
Finally, Dr. Jan Eriksson of Uppsala (Sweden) University presented findings from an observational study of more than 50,000 patients with type 2 diabetes treated with a combination of two noninsulin antidiabetic agents between 2006 and 2013. Of these, 40,736 had received metformin in combination with a sulfonylurea and 12,024 had received a combination of metformin and a DPP-4 inhibitor and were studied further.
Compared with the patients who received a DPP-4 inhibitor on top of metformin, those who received a sulfonylurea had an increased risk of both fatal and nonfatal cardiovascular disease (HR, 1.17; 95% CI, 1.01-1.37) and death from any cause (HR, 1.25; 95% CI, 1.02-1.54) even in the presence of confounding factors such as age, gender, existing cardiovascular disease, and cardio-preventative medication use.
The risk for severe hypoglycemia was also greater with sulfonylurea than DPP-4 use (HR, 2.07; 95% CI, 1.11-3.86), and experiencing severe hypoglycemia was associated with an increased risk for cardiovascular events (HR, 1.51; 95% CI, 1.21-1.88).
“Hypoglycemia may contribute to the increased CVD risk associated with sulfonylureas,” Dr. Eriksson suggested. He concluded that the results of ongoing and future randomized trials would be important in order to understand the cardiovascular risk associated with sulfonylureas better and try to figure out any underlying mechanisms.
Dr. Raz Itamar, head of the diabetes unit at Hadassah Medical Center in Jerusalem, chaired the session during which all these study findings were presented and provided a general comment in an interview on why the cardiovascular safety of sulfonylureas was a particular issue that these studies looked at.
He noted that a study performed in the United States in the 1970s had raised suspicion that there might be an increased cardiovascular risk associated with the sulfonylureas, but the current concerns really started with findings from the UKPDS [United Kingdom Prospective Diabetes Study] and the Women’s Health Study (WHS), for example.
“In the UKPDS, patients who were on metformin and a sulfonylurea demonstrated a doubling in the cardiovascular event rate,” Dr. Itamar said, adding that the WHS data also showed a doubling of the risk.
There is a lack of head-to-head, randomized, controlled data, he emphasized and commented that there were many limitations to the analyses presented at the session. These included the small sample sizes and short duration of follow-up, among others. There is also evidence in the literature suggesting that the cardiovascular risk of individual sulfonylureas may be different. So the results need to be reviewed with caution, he advised.
“As a clinician, I try to give a sulfonylurea which seems to have a safer cardiovascular profile, like glimepiride and gliclazide,” Dr. Itamar said. He noted that there was a randomized controlled trial currently recruiting a projected 6,000 patients that would compare glimepiride with a DPP-4 inhibitor directly for several years that should provide additional and much needed information on the cardiovascular safety of sulfonylureas.
Merck UK funded the systematic review and meta-analysis. AstraZeneca supported the CREST study and the sulfonylureas versus DPP4 inhibitor comparison study. Dr. Bain disclosed he had received honoraria, teaching, and research sponsorship or grants from multiple pharmaceutical companies including Merck Sharp & Dohme and AstraZeneca. Dr. Wilke did not report his disclosures. Dr. Eriksson disclosed receiving research grants or honoraria from AstraZeneca and Merck Sharp & Dohme, among others, and that he had previously been an employee of AstraZeneca. Dr. Itamar did not report having any relevant disclosures.
STOCKHOLM – While they are effective glucose-lowering agents, sulfonylureas seem to substantially increase the risk for cardiovascular events relative to other antihyperglycemic agents, according to several presentations given at the annual meeting of the European Association for the Study of Diabetes.
In a systematic review and meta-analysis of 84 randomized controlled trials (RCTs) and 26 observational studies, accounting for more than 36,573 and more than 1.5 million subjects with type 2 diabetes mellitus, respectively, treatment with a sulfonylurea was found to significantly increase all-cause mortality and cardiovascular-related mortality when compared to no active treatment or placebo and to other antidiabetic drugs.
In the RCTs, the hazard ratios comparing sulfonylureas to all treatments combined were 1.26 (95% confidence interval, 1.10-1.44) for all-cause mortality and 1.46 (95% CI, 1.21-1.77) for cardiovascular mortality. HR for CV mortality was highest when comparing sulfonylureas with GLP-1 agonists and SGLT-2 inhibitors, at 45.4 (95% CI, 2.07-362.8) and 42.6 (95% CI, 1.71-359.1), with significantly elevated risk also seen when compared with DPP-4 inhibitors (HR, 4.42; 95% CI, 1.92-13.0), thiazolidinediones (HR, 3.05; 95% CI, 1.79-5.54), and insulin (HR, 1.30; 95% CI, 1.02-1.66).
There was also an increase in the risk for acute myocardial infarction and stroke in some comparisons of sulfonylureas versus other treatments.
“We think this study is the most comprehensive review of RCTs and observational studies to compare CV-related outcomes and all-cause mortality among patients receiving sulfonylureas versus [other] antidiabetic agents,” said Dr. Steve Bain of Abertawe Bro Morgannwg University NHS Trust in Swansea, England.
“We accept that the confidence intervals were wide, but there is a tendency for all significant results to trend in the same direction.” Results of the observational studies analyses generally supported the results from the RCTs, he added. A notable limitation was that there had been no differentiation between the risk according to different sulfonylureas. Dr. Bain said this was to try to keep the number of patients available for analysis as high as possible in the sulfonylurea group.
Data from the German CREST (CV Risk and Events on SU Treatment) study also showed that there was a higher CV risk associated with sulfonylureas when compared with metformin in patients newly diagnosed with type 2 diabetes mellitus. The retrospective cohort database study included more than 35,000 individuals, of whom 26,883 received no antihyperglycemic treatment or treatment with an antihyperglycemic agent other than a sulfonylurea or metformin between January 2010 and December 2011, leaving 7,874 who were given metformin monotherapy and 904 given sulfonylurea monotherapy. Propensity score matching was used to form the final study groups consisting of 730 patients each.
Crude, propensity-matched, and adjusted HRs for death comparing sulfonylurea with metformin as first-line treatment were 3.32 (95% CI, 2.6-4.3; P less than .001), 1.4 (95% CI, 0.9-2.3; P less than .12), and 2.01 (95% CI, 1.5-2.6; P less than .001), respectively. Corresponding HRs for major cardiovascular events (MACE) were 1.9 (95% CI, 1.4-2.4; P less than .001), 1.4 (95% CI, 0.9-2.2; P less than .14), and 1.3 (95% CI, 1.03-1.74; P less than .05).
Dr. Thomas Wilke of the University of Wismar (Germany) who presented the CREST study findings, noted that there were some differences between the groups in terms of the baseline demographics, with those receiving sulfonylureas being somewhat older and more likely to be women, have comorbid disease, and discontinue monotherapy earlier than patients treated with metformin, or possibly be more likely to have contraindications to the use of metformin.
“Taking these differences into account, patients treated with sulfonylureas seem to be at increased risk of death, MACE, and type 2 diabetes hospitalization, compared with metformin-treated patients,” in this German population, Dr. Wilke concluded.
Finally, Dr. Jan Eriksson of Uppsala (Sweden) University presented findings from an observational study of more than 50,000 patients with type 2 diabetes treated with a combination of two noninsulin antidiabetic agents between 2006 and 2013. Of these, 40,736 had received metformin in combination with a sulfonylurea and 12,024 had received a combination of metformin and a DPP-4 inhibitor and were studied further.
Compared with the patients who received a DPP-4 inhibitor on top of metformin, those who received a sulfonylurea had an increased risk of both fatal and nonfatal cardiovascular disease (HR, 1.17; 95% CI, 1.01-1.37) and death from any cause (HR, 1.25; 95% CI, 1.02-1.54) even in the presence of confounding factors such as age, gender, existing cardiovascular disease, and cardio-preventative medication use.
The risk for severe hypoglycemia was also greater with sulfonylurea than DPP-4 use (HR, 2.07; 95% CI, 1.11-3.86), and experiencing severe hypoglycemia was associated with an increased risk for cardiovascular events (HR, 1.51; 95% CI, 1.21-1.88).
“Hypoglycemia may contribute to the increased CVD risk associated with sulfonylureas,” Dr. Eriksson suggested. He concluded that the results of ongoing and future randomized trials would be important in order to understand the cardiovascular risk associated with sulfonylureas better and try to figure out any underlying mechanisms.
Dr. Raz Itamar, head of the diabetes unit at Hadassah Medical Center in Jerusalem, chaired the session during which all these study findings were presented and provided a general comment in an interview on why the cardiovascular safety of sulfonylureas was a particular issue that these studies looked at.
He noted that a study performed in the United States in the 1970s had raised suspicion that there might be an increased cardiovascular risk associated with the sulfonylureas, but the current concerns really started with findings from the UKPDS [United Kingdom Prospective Diabetes Study] and the Women’s Health Study (WHS), for example.
“In the UKPDS, patients who were on metformin and a sulfonylurea demonstrated a doubling in the cardiovascular event rate,” Dr. Itamar said, adding that the WHS data also showed a doubling of the risk.
There is a lack of head-to-head, randomized, controlled data, he emphasized and commented that there were many limitations to the analyses presented at the session. These included the small sample sizes and short duration of follow-up, among others. There is also evidence in the literature suggesting that the cardiovascular risk of individual sulfonylureas may be different. So the results need to be reviewed with caution, he advised.
“As a clinician, I try to give a sulfonylurea which seems to have a safer cardiovascular profile, like glimepiride and gliclazide,” Dr. Itamar said. He noted that there was a randomized controlled trial currently recruiting a projected 6,000 patients that would compare glimepiride with a DPP-4 inhibitor directly for several years that should provide additional and much needed information on the cardiovascular safety of sulfonylureas.
Merck UK funded the systematic review and meta-analysis. AstraZeneca supported the CREST study and the sulfonylureas versus DPP4 inhibitor comparison study. Dr. Bain disclosed he had received honoraria, teaching, and research sponsorship or grants from multiple pharmaceutical companies including Merck Sharp & Dohme and AstraZeneca. Dr. Wilke did not report his disclosures. Dr. Eriksson disclosed receiving research grants or honoraria from AstraZeneca and Merck Sharp & Dohme, among others, and that he had previously been an employee of AstraZeneca. Dr. Itamar did not report having any relevant disclosures.
STOCKHOLM – While they are effective glucose-lowering agents, sulfonylureas seem to substantially increase the risk for cardiovascular events relative to other antihyperglycemic agents, according to several presentations given at the annual meeting of the European Association for the Study of Diabetes.
In a systematic review and meta-analysis of 84 randomized controlled trials (RCTs) and 26 observational studies, accounting for more than 36,573 and more than 1.5 million subjects with type 2 diabetes mellitus, respectively, treatment with a sulfonylurea was found to significantly increase all-cause mortality and cardiovascular-related mortality when compared to no active treatment or placebo and to other antidiabetic drugs.
In the RCTs, the hazard ratios comparing sulfonylureas to all treatments combined were 1.26 (95% confidence interval, 1.10-1.44) for all-cause mortality and 1.46 (95% CI, 1.21-1.77) for cardiovascular mortality. HR for CV mortality was highest when comparing sulfonylureas with GLP-1 agonists and SGLT-2 inhibitors, at 45.4 (95% CI, 2.07-362.8) and 42.6 (95% CI, 1.71-359.1), with significantly elevated risk also seen when compared with DPP-4 inhibitors (HR, 4.42; 95% CI, 1.92-13.0), thiazolidinediones (HR, 3.05; 95% CI, 1.79-5.54), and insulin (HR, 1.30; 95% CI, 1.02-1.66).
There was also an increase in the risk for acute myocardial infarction and stroke in some comparisons of sulfonylureas versus other treatments.
“We think this study is the most comprehensive review of RCTs and observational studies to compare CV-related outcomes and all-cause mortality among patients receiving sulfonylureas versus [other] antidiabetic agents,” said Dr. Steve Bain of Abertawe Bro Morgannwg University NHS Trust in Swansea, England.
“We accept that the confidence intervals were wide, but there is a tendency for all significant results to trend in the same direction.” Results of the observational studies analyses generally supported the results from the RCTs, he added. A notable limitation was that there had been no differentiation between the risk according to different sulfonylureas. Dr. Bain said this was to try to keep the number of patients available for analysis as high as possible in the sulfonylurea group.
Data from the German CREST (CV Risk and Events on SU Treatment) study also showed that there was a higher CV risk associated with sulfonylureas when compared with metformin in patients newly diagnosed with type 2 diabetes mellitus. The retrospective cohort database study included more than 35,000 individuals, of whom 26,883 received no antihyperglycemic treatment or treatment with an antihyperglycemic agent other than a sulfonylurea or metformin between January 2010 and December 2011, leaving 7,874 who were given metformin monotherapy and 904 given sulfonylurea monotherapy. Propensity score matching was used to form the final study groups consisting of 730 patients each.
Crude, propensity-matched, and adjusted HRs for death comparing sulfonylurea with metformin as first-line treatment were 3.32 (95% CI, 2.6-4.3; P less than .001), 1.4 (95% CI, 0.9-2.3; P less than .12), and 2.01 (95% CI, 1.5-2.6; P less than .001), respectively. Corresponding HRs for major cardiovascular events (MACE) were 1.9 (95% CI, 1.4-2.4; P less than .001), 1.4 (95% CI, 0.9-2.2; P less than .14), and 1.3 (95% CI, 1.03-1.74; P less than .05).
Dr. Thomas Wilke of the University of Wismar (Germany) who presented the CREST study findings, noted that there were some differences between the groups in terms of the baseline demographics, with those receiving sulfonylureas being somewhat older and more likely to be women, have comorbid disease, and discontinue monotherapy earlier than patients treated with metformin, or possibly be more likely to have contraindications to the use of metformin.
“Taking these differences into account, patients treated with sulfonylureas seem to be at increased risk of death, MACE, and type 2 diabetes hospitalization, compared with metformin-treated patients,” in this German population, Dr. Wilke concluded.
Finally, Dr. Jan Eriksson of Uppsala (Sweden) University presented findings from an observational study of more than 50,000 patients with type 2 diabetes treated with a combination of two noninsulin antidiabetic agents between 2006 and 2013. Of these, 40,736 had received metformin in combination with a sulfonylurea and 12,024 had received a combination of metformin and a DPP-4 inhibitor and were studied further.
Compared with the patients who received a DPP-4 inhibitor on top of metformin, those who received a sulfonylurea had an increased risk of both fatal and nonfatal cardiovascular disease (HR, 1.17; 95% CI, 1.01-1.37) and death from any cause (HR, 1.25; 95% CI, 1.02-1.54) even in the presence of confounding factors such as age, gender, existing cardiovascular disease, and cardio-preventative medication use.
The risk for severe hypoglycemia was also greater with sulfonylurea than DPP-4 use (HR, 2.07; 95% CI, 1.11-3.86), and experiencing severe hypoglycemia was associated with an increased risk for cardiovascular events (HR, 1.51; 95% CI, 1.21-1.88).
“Hypoglycemia may contribute to the increased CVD risk associated with sulfonylureas,” Dr. Eriksson suggested. He concluded that the results of ongoing and future randomized trials would be important in order to understand the cardiovascular risk associated with sulfonylureas better and try to figure out any underlying mechanisms.
Dr. Raz Itamar, head of the diabetes unit at Hadassah Medical Center in Jerusalem, chaired the session during which all these study findings were presented and provided a general comment in an interview on why the cardiovascular safety of sulfonylureas was a particular issue that these studies looked at.
He noted that a study performed in the United States in the 1970s had raised suspicion that there might be an increased cardiovascular risk associated with the sulfonylureas, but the current concerns really started with findings from the UKPDS [United Kingdom Prospective Diabetes Study] and the Women’s Health Study (WHS), for example.
“In the UKPDS, patients who were on metformin and a sulfonylurea demonstrated a doubling in the cardiovascular event rate,” Dr. Itamar said, adding that the WHS data also showed a doubling of the risk.
There is a lack of head-to-head, randomized, controlled data, he emphasized and commented that there were many limitations to the analyses presented at the session. These included the small sample sizes and short duration of follow-up, among others. There is also evidence in the literature suggesting that the cardiovascular risk of individual sulfonylureas may be different. So the results need to be reviewed with caution, he advised.
“As a clinician, I try to give a sulfonylurea which seems to have a safer cardiovascular profile, like glimepiride and gliclazide,” Dr. Itamar said. He noted that there was a randomized controlled trial currently recruiting a projected 6,000 patients that would compare glimepiride with a DPP-4 inhibitor directly for several years that should provide additional and much needed information on the cardiovascular safety of sulfonylureas.
Merck UK funded the systematic review and meta-analysis. AstraZeneca supported the CREST study and the sulfonylureas versus DPP4 inhibitor comparison study. Dr. Bain disclosed he had received honoraria, teaching, and research sponsorship or grants from multiple pharmaceutical companies including Merck Sharp & Dohme and AstraZeneca. Dr. Wilke did not report his disclosures. Dr. Eriksson disclosed receiving research grants or honoraria from AstraZeneca and Merck Sharp & Dohme, among others, and that he had previously been an employee of AstraZeneca. Dr. Itamar did not report having any relevant disclosures.
AT EASD 2015
Key clinical point:Cardiovascular risk appears elevated with sulfonylurea use, but studies were small and had limited follow-up. Randomized controlled trials are still needed.
Major findings: Sulfonylurea use increased the risk for all-cause mortality by 26% and cardiovascular mortality by 46% relative to other antidiabetic treatments in a meta-analysis of randomized controlled trial data.
Data source: A systematic review and meta-analysis and two separate studies comparing the cardiovascular safety of sulfonylureas versus all other antidiabetic agents combined.
Disclosures: Merck UK funded the systematic review and meta-analysis. AstraZeneca supported the CREST study and the sulfonylureas versus DPP4 inhibitor comparison study. Dr. Bain disclosed he had received honoraria, teaching, and research sponsorship or grants from multiple pharmaceutical companies including Merck Sharp & Dohme and AstraZeneca. Dr. Wilke did not report his disclosures. Dr. Eriksson disclosed receiving research grants or honoraria from AstraZeneca and Merck Sharp & Dohme, among others, and that he had previously been an employee of AstraZeneca. Dr. Itamar did not report having any relevant disclosures.
ESC: Strong coffee raises hypertension and prediabetes risk
LONDON – Drinking three or more cups of caffeinated espresso per day predicted increasing blood pressure and rising blood glucose, according to the results of the Hypertension and Ambulatory Recording Venetia Study (HARVEST), a multicenter, observational study that began in Italy in 1990 and recruited more than 1,000 patients aged 18-45 years who had stage I hypertension and did not have diabetes.
Further, the risk of a cardiovascular event was increased by 50% in these study participants based on a total of 60 events during a mean of 12.5 years of follow-up.
“Controversy still exists about the long-term cardiovascular and metabolic effects of coffee consumption in hypertension,” Dr. Lucio Mos of Hospital San Daniele del Friuli in Udine, Italy, said during a press conference at the annual congress of the European Society of Cardiology.
Stage 1 hypertension was defined as a diastolic blood pressure of 90-99 mm Hg and a systolic blood pressure of 140-159 mm Hg and diagnosed on the basis of six office-based readings obtained on two separate visits. Enrolled participants underwent ambulatory blood pressure monitoring and three office-based measurements were repeated at 1, 2, 3 and 6 months, and at 6-month intervals thereafter. The endpoint was hypertension requiring any antihypertensive treatment according to international guidelines.
During the study, 24-hour urine samples were collected to assess catecholamine levels. Lifestyle factors such as body weight, physical activity, smoking status, and blood glucose were measured. Patients underwent echocardiography.
They were divided into three groups according to their caffeinated coffee intake: 316 (26%) were designated as abstainers because they did not drink coffee; 767 (64%) drank 1-2 cups a day and were categorized as moderate drinkers; and 119 (10%) drank three or more cups of coffee a day and were defined as heavy drinkers.
“I want to underline that, in this part of Italy, we have a population that drinks mainly espresso coffee and drinking American-style coffee is not usual,” Dr. Mos said.
Around 70% of the study population was male, with similar baseline blood pressures and heart rates among the groups. Heavy coffee drinkers tended to be older (37 years) than those who were more moderate drinkers (34 years) or those who abstained (31 years). They had significantly higher body weights (P less than .001), with a body mass index of 26.1 kg/m2 vs. 25.7 kg/m2 and 24.6 kg/m2, respectively.
Dr. Mos reported that in multivariate analysis, coffee consumption was a significant predictor for developing hypertension that required antihypertensive therapy, with a hazard ratio (HR) of 1.5 (95% confidence interval [CI], 1.1-1.19) for heavy drinkers and 1.1 (95% confidence interval, 1.1-1.19) for moderate drinkers, compared to abstainers. The difference was significant (P = .004) only for heavy coffee consumption.
“Coffee consumption was also a predictor of future prediabetes,” Dr. Mos reported. Indeed, the incidence of prediabetes was highest in the heavy coffee drinkers, and significantly predicted the risk of developing prediabetes compared to abstainers (HR, 2, 95% CI, 1.3-3.1. P = .0017). There was a nonsignificant trend for moderate drinkers also to be at risk for prediabetes when compared to nondrinkers (HR, 1.3, 95% CI 0.9-1.7).
Looking at the risk for prediabetes in relation to caffeine metabolism by analyzing patients by their CYP1A2 genotype, it was found that heavy coffee drinkers who were slow metabolizers of caffeine were at highest risk, with a HR of 2.78 (95% CI, 1.32-5.88). Furthermore, individuals were particularly at risk if they were also overweight or obese.
There was a significant (P = .0017) linear relationship found after multivariate adjustment between coffee intake and cardiovascular events such as heart attacks, with the risk increasing with higher coffee intake. Even moderate coffee intake, defined as one to three cups per day, could up the risk of a cardiovascular event when compared to that of non–coffee drinkers.
“The coffee story was very topical a couple of years ago so it is interesting to see it revisited,” said Dr. Ian Graham of Trinity College Dublin and one of the experts who chaired the press briefing on the study results. “We need a randomized controlled trial,” Dr. Graham suggested, noting that there were several prior studies that suggested there were beneficial effects of coffee.
Cochair Dr. José Gonzalez-Juanatey of Hospital Clínico Universitario de Santiago de Compostela in Spain observed: “The recommendation could be that if you are a young or middle-aged, stage 1 hypertensive patient probably you have to reduce your coffee intake. This is the take-home message based on the results of an observational study well performed and well conducted.”
LONDON – Drinking three or more cups of caffeinated espresso per day predicted increasing blood pressure and rising blood glucose, according to the results of the Hypertension and Ambulatory Recording Venetia Study (HARVEST), a multicenter, observational study that began in Italy in 1990 and recruited more than 1,000 patients aged 18-45 years who had stage I hypertension and did not have diabetes.
Further, the risk of a cardiovascular event was increased by 50% in these study participants based on a total of 60 events during a mean of 12.5 years of follow-up.
“Controversy still exists about the long-term cardiovascular and metabolic effects of coffee consumption in hypertension,” Dr. Lucio Mos of Hospital San Daniele del Friuli in Udine, Italy, said during a press conference at the annual congress of the European Society of Cardiology.
Stage 1 hypertension was defined as a diastolic blood pressure of 90-99 mm Hg and a systolic blood pressure of 140-159 mm Hg and diagnosed on the basis of six office-based readings obtained on two separate visits. Enrolled participants underwent ambulatory blood pressure monitoring and three office-based measurements were repeated at 1, 2, 3 and 6 months, and at 6-month intervals thereafter. The endpoint was hypertension requiring any antihypertensive treatment according to international guidelines.
During the study, 24-hour urine samples were collected to assess catecholamine levels. Lifestyle factors such as body weight, physical activity, smoking status, and blood glucose were measured. Patients underwent echocardiography.
They were divided into three groups according to their caffeinated coffee intake: 316 (26%) were designated as abstainers because they did not drink coffee; 767 (64%) drank 1-2 cups a day and were categorized as moderate drinkers; and 119 (10%) drank three or more cups of coffee a day and were defined as heavy drinkers.
“I want to underline that, in this part of Italy, we have a population that drinks mainly espresso coffee and drinking American-style coffee is not usual,” Dr. Mos said.
Around 70% of the study population was male, with similar baseline blood pressures and heart rates among the groups. Heavy coffee drinkers tended to be older (37 years) than those who were more moderate drinkers (34 years) or those who abstained (31 years). They had significantly higher body weights (P less than .001), with a body mass index of 26.1 kg/m2 vs. 25.7 kg/m2 and 24.6 kg/m2, respectively.
Dr. Mos reported that in multivariate analysis, coffee consumption was a significant predictor for developing hypertension that required antihypertensive therapy, with a hazard ratio (HR) of 1.5 (95% confidence interval [CI], 1.1-1.19) for heavy drinkers and 1.1 (95% confidence interval, 1.1-1.19) for moderate drinkers, compared to abstainers. The difference was significant (P = .004) only for heavy coffee consumption.
“Coffee consumption was also a predictor of future prediabetes,” Dr. Mos reported. Indeed, the incidence of prediabetes was highest in the heavy coffee drinkers, and significantly predicted the risk of developing prediabetes compared to abstainers (HR, 2, 95% CI, 1.3-3.1. P = .0017). There was a nonsignificant trend for moderate drinkers also to be at risk for prediabetes when compared to nondrinkers (HR, 1.3, 95% CI 0.9-1.7).
Looking at the risk for prediabetes in relation to caffeine metabolism by analyzing patients by their CYP1A2 genotype, it was found that heavy coffee drinkers who were slow metabolizers of caffeine were at highest risk, with a HR of 2.78 (95% CI, 1.32-5.88). Furthermore, individuals were particularly at risk if they were also overweight or obese.
There was a significant (P = .0017) linear relationship found after multivariate adjustment between coffee intake and cardiovascular events such as heart attacks, with the risk increasing with higher coffee intake. Even moderate coffee intake, defined as one to three cups per day, could up the risk of a cardiovascular event when compared to that of non–coffee drinkers.
“The coffee story was very topical a couple of years ago so it is interesting to see it revisited,” said Dr. Ian Graham of Trinity College Dublin and one of the experts who chaired the press briefing on the study results. “We need a randomized controlled trial,” Dr. Graham suggested, noting that there were several prior studies that suggested there were beneficial effects of coffee.
Cochair Dr. José Gonzalez-Juanatey of Hospital Clínico Universitario de Santiago de Compostela in Spain observed: “The recommendation could be that if you are a young or middle-aged, stage 1 hypertensive patient probably you have to reduce your coffee intake. This is the take-home message based on the results of an observational study well performed and well conducted.”
LONDON – Drinking three or more cups of caffeinated espresso per day predicted increasing blood pressure and rising blood glucose, according to the results of the Hypertension and Ambulatory Recording Venetia Study (HARVEST), a multicenter, observational study that began in Italy in 1990 and recruited more than 1,000 patients aged 18-45 years who had stage I hypertension and did not have diabetes.
Further, the risk of a cardiovascular event was increased by 50% in these study participants based on a total of 60 events during a mean of 12.5 years of follow-up.
“Controversy still exists about the long-term cardiovascular and metabolic effects of coffee consumption in hypertension,” Dr. Lucio Mos of Hospital San Daniele del Friuli in Udine, Italy, said during a press conference at the annual congress of the European Society of Cardiology.
Stage 1 hypertension was defined as a diastolic blood pressure of 90-99 mm Hg and a systolic blood pressure of 140-159 mm Hg and diagnosed on the basis of six office-based readings obtained on two separate visits. Enrolled participants underwent ambulatory blood pressure monitoring and three office-based measurements were repeated at 1, 2, 3 and 6 months, and at 6-month intervals thereafter. The endpoint was hypertension requiring any antihypertensive treatment according to international guidelines.
During the study, 24-hour urine samples were collected to assess catecholamine levels. Lifestyle factors such as body weight, physical activity, smoking status, and blood glucose were measured. Patients underwent echocardiography.
They were divided into three groups according to their caffeinated coffee intake: 316 (26%) were designated as abstainers because they did not drink coffee; 767 (64%) drank 1-2 cups a day and were categorized as moderate drinkers; and 119 (10%) drank three or more cups of coffee a day and were defined as heavy drinkers.
“I want to underline that, in this part of Italy, we have a population that drinks mainly espresso coffee and drinking American-style coffee is not usual,” Dr. Mos said.
Around 70% of the study population was male, with similar baseline blood pressures and heart rates among the groups. Heavy coffee drinkers tended to be older (37 years) than those who were more moderate drinkers (34 years) or those who abstained (31 years). They had significantly higher body weights (P less than .001), with a body mass index of 26.1 kg/m2 vs. 25.7 kg/m2 and 24.6 kg/m2, respectively.
Dr. Mos reported that in multivariate analysis, coffee consumption was a significant predictor for developing hypertension that required antihypertensive therapy, with a hazard ratio (HR) of 1.5 (95% confidence interval [CI], 1.1-1.19) for heavy drinkers and 1.1 (95% confidence interval, 1.1-1.19) for moderate drinkers, compared to abstainers. The difference was significant (P = .004) only for heavy coffee consumption.
“Coffee consumption was also a predictor of future prediabetes,” Dr. Mos reported. Indeed, the incidence of prediabetes was highest in the heavy coffee drinkers, and significantly predicted the risk of developing prediabetes compared to abstainers (HR, 2, 95% CI, 1.3-3.1. P = .0017). There was a nonsignificant trend for moderate drinkers also to be at risk for prediabetes when compared to nondrinkers (HR, 1.3, 95% CI 0.9-1.7).
Looking at the risk for prediabetes in relation to caffeine metabolism by analyzing patients by their CYP1A2 genotype, it was found that heavy coffee drinkers who were slow metabolizers of caffeine were at highest risk, with a HR of 2.78 (95% CI, 1.32-5.88). Furthermore, individuals were particularly at risk if they were also overweight or obese.
There was a significant (P = .0017) linear relationship found after multivariate adjustment between coffee intake and cardiovascular events such as heart attacks, with the risk increasing with higher coffee intake. Even moderate coffee intake, defined as one to three cups per day, could up the risk of a cardiovascular event when compared to that of non–coffee drinkers.
“The coffee story was very topical a couple of years ago so it is interesting to see it revisited,” said Dr. Ian Graham of Trinity College Dublin and one of the experts who chaired the press briefing on the study results. “We need a randomized controlled trial,” Dr. Graham suggested, noting that there were several prior studies that suggested there were beneficial effects of coffee.
Cochair Dr. José Gonzalez-Juanatey of Hospital Clínico Universitario de Santiago de Compostela in Spain observed: “The recommendation could be that if you are a young or middle-aged, stage 1 hypertensive patient probably you have to reduce your coffee intake. This is the take-home message based on the results of an observational study well performed and well conducted.”
AT THE ESC CONGRESS 2015
Key clinical point: There is a potential a risk for hypertension and prediabetes in relation to high caffeine consumption among adults with mild hypertension.
Major finding: Drinking more than three cups of caffeinated espresso per day increased the relative risk of a cardiovascular event by 50%, based on 60 events in 1,212 adults during a mean 12.5 years of follow-up.
Data source: Prospective, observational study of adults (mostly men) aged 18-45 years with stage 1, untreated hypertension.
Disclosures: Dr. Mos reported he had no disclosures.
EASD: Once-weekly omarigliptin as effective as daily sitagliptin
STOCKHOLM – Once-weekly treatment with the investigational, oral dipeptidyl peptidase-4 (DPP-4) inhibitor omarigliptin lowered hemoglobin A1c as effectively as daily sitagliptin in a large, head-to-head, phase III trial of patients with type 2 diabetes.
Results of the O-QWEST noninferiority to sitagliptin study showed similar reductions in HbA1c from baseline to week 24 of treatment comparing omarigliptin (–0.47%) and sitagliptin (–0.43%) with an overall difference of just –0.03% (P = 0.561). The mean HbA1c at baseline in both groups was around 7.5%.
Patients with higher HbA1c values at baseline achieved greater reductions in HbA1c than those with lower starting HbA1c values, although there was no significant difference between the two treatments.
A similar percentage of patients in the omarigliptin and sitagliptin groups achieved target HbA1c values of less than 7% (54.4% vs. 52.4%; P = .619) and less than 6.5% (28.8% vs. 24.4%; P = .212), and there was no significant difference in fasting plasma glucose levels, with a mean difference overall of –0.2 mmol/L.
“According to a relatively recent joint position statement by the ADA and EASD (Diabetes Care. 2012;35:1364-1379) providing care that is responsive to individual patient preferences and needs is a recommended approach to health care in chronic diseases such as type 2 diabetes,” said Dr. Ira Gantz, who presented the study findings.
“Providing patients with medications tailored to their individual preferences and needs is consistent with this patient-centered approach, and the convenience of an effective, well-tolerated, weekly, oral, DPP-4 inhibitor may be an attractive option for some patients,” added Dr. Gantz, who is an employee of Merck & Co.
While an oral drug that is delivered weekly might prove more convenient and potentially improve patients’ adherence and quality of life, this was not possible to measure in the present study, Dr. Gantz noted during the discussion that followed his presentation of the results at the annual meeting of the European Association for the Study of Diabetes.
“The design of the study and of our other phase III programs makes that difficult because they’re double dummy, and the patients in this study who were taking omarigliptin also took daily sitagliptin [or placebo pill] and vice versa – those taking sitagliptin took a weekly placebo pill,” Dr. Gantz explained.
The global study compared the efficacy and safety of omarigliptin given at a once-weekly dose of 25 mg with that of sitagliptin (Januvia) at a daily dose of 100 mg in 642 patients with type 2 diabetes who were not achieving adequate glucose control despite being on metformin. The mean age of patients enrolled was around 57 years in both groups, with around half being male; the average duration of type 2 diabetes was 7 years.
Very small reductions in body weight were seen with both drugs but “no meaningful differences” in specific adverse events were seen, Dr. Gantz reported. Hypoglycemia developed in 3.7% of patients on the weekly regimen versus 4.7% in the subjects taking the daily DPP-4 inhibitor.
No confirmed cases of pancreatitis were reported in either treatment group. Two instances of angioedema, which was a prespecified hypersensitivity adverse event, of the tongue were noted in one subject in the omarigliptin group. There were some small increases in serum amylase and lipase in both groups although these were within normal laboratory limits and did not result in any treatment discontinuations.
Asked if there was any advantage of weekly over daily administration of a DPP-4 inhibitor in terms of renal function, Dr. Gantz replied that it might allow for “broader dose adjustment.” Patents with mild to moderate renal insufficiency would probably not need dose adjustment of omarigliptin, but for those with severe impairment and those on dialysis there would be a recommendation to halve the dose to 12.5 mg/week.
Dr. Gantz observed: “I think the major selling point is that it provides options for patients, as far as a weekly administration it’s a patient-centric approach.”
The study was funded by Merck & Co. Dr. Gantz and his coinvestigators are all employees of the company.
STOCKHOLM – Once-weekly treatment with the investigational, oral dipeptidyl peptidase-4 (DPP-4) inhibitor omarigliptin lowered hemoglobin A1c as effectively as daily sitagliptin in a large, head-to-head, phase III trial of patients with type 2 diabetes.
Results of the O-QWEST noninferiority to sitagliptin study showed similar reductions in HbA1c from baseline to week 24 of treatment comparing omarigliptin (–0.47%) and sitagliptin (–0.43%) with an overall difference of just –0.03% (P = 0.561). The mean HbA1c at baseline in both groups was around 7.5%.
Patients with higher HbA1c values at baseline achieved greater reductions in HbA1c than those with lower starting HbA1c values, although there was no significant difference between the two treatments.
A similar percentage of patients in the omarigliptin and sitagliptin groups achieved target HbA1c values of less than 7% (54.4% vs. 52.4%; P = .619) and less than 6.5% (28.8% vs. 24.4%; P = .212), and there was no significant difference in fasting plasma glucose levels, with a mean difference overall of –0.2 mmol/L.
“According to a relatively recent joint position statement by the ADA and EASD (Diabetes Care. 2012;35:1364-1379) providing care that is responsive to individual patient preferences and needs is a recommended approach to health care in chronic diseases such as type 2 diabetes,” said Dr. Ira Gantz, who presented the study findings.
“Providing patients with medications tailored to their individual preferences and needs is consistent with this patient-centered approach, and the convenience of an effective, well-tolerated, weekly, oral, DPP-4 inhibitor may be an attractive option for some patients,” added Dr. Gantz, who is an employee of Merck & Co.
While an oral drug that is delivered weekly might prove more convenient and potentially improve patients’ adherence and quality of life, this was not possible to measure in the present study, Dr. Gantz noted during the discussion that followed his presentation of the results at the annual meeting of the European Association for the Study of Diabetes.
“The design of the study and of our other phase III programs makes that difficult because they’re double dummy, and the patients in this study who were taking omarigliptin also took daily sitagliptin [or placebo pill] and vice versa – those taking sitagliptin took a weekly placebo pill,” Dr. Gantz explained.
The global study compared the efficacy and safety of omarigliptin given at a once-weekly dose of 25 mg with that of sitagliptin (Januvia) at a daily dose of 100 mg in 642 patients with type 2 diabetes who were not achieving adequate glucose control despite being on metformin. The mean age of patients enrolled was around 57 years in both groups, with around half being male; the average duration of type 2 diabetes was 7 years.
Very small reductions in body weight were seen with both drugs but “no meaningful differences” in specific adverse events were seen, Dr. Gantz reported. Hypoglycemia developed in 3.7% of patients on the weekly regimen versus 4.7% in the subjects taking the daily DPP-4 inhibitor.
No confirmed cases of pancreatitis were reported in either treatment group. Two instances of angioedema, which was a prespecified hypersensitivity adverse event, of the tongue were noted in one subject in the omarigliptin group. There were some small increases in serum amylase and lipase in both groups although these were within normal laboratory limits and did not result in any treatment discontinuations.
Asked if there was any advantage of weekly over daily administration of a DPP-4 inhibitor in terms of renal function, Dr. Gantz replied that it might allow for “broader dose adjustment.” Patents with mild to moderate renal insufficiency would probably not need dose adjustment of omarigliptin, but for those with severe impairment and those on dialysis there would be a recommendation to halve the dose to 12.5 mg/week.
Dr. Gantz observed: “I think the major selling point is that it provides options for patients, as far as a weekly administration it’s a patient-centric approach.”
The study was funded by Merck & Co. Dr. Gantz and his coinvestigators are all employees of the company.
STOCKHOLM – Once-weekly treatment with the investigational, oral dipeptidyl peptidase-4 (DPP-4) inhibitor omarigliptin lowered hemoglobin A1c as effectively as daily sitagliptin in a large, head-to-head, phase III trial of patients with type 2 diabetes.
Results of the O-QWEST noninferiority to sitagliptin study showed similar reductions in HbA1c from baseline to week 24 of treatment comparing omarigliptin (–0.47%) and sitagliptin (–0.43%) with an overall difference of just –0.03% (P = 0.561). The mean HbA1c at baseline in both groups was around 7.5%.
Patients with higher HbA1c values at baseline achieved greater reductions in HbA1c than those with lower starting HbA1c values, although there was no significant difference between the two treatments.
A similar percentage of patients in the omarigliptin and sitagliptin groups achieved target HbA1c values of less than 7% (54.4% vs. 52.4%; P = .619) and less than 6.5% (28.8% vs. 24.4%; P = .212), and there was no significant difference in fasting plasma glucose levels, with a mean difference overall of –0.2 mmol/L.
“According to a relatively recent joint position statement by the ADA and EASD (Diabetes Care. 2012;35:1364-1379) providing care that is responsive to individual patient preferences and needs is a recommended approach to health care in chronic diseases such as type 2 diabetes,” said Dr. Ira Gantz, who presented the study findings.
“Providing patients with medications tailored to their individual preferences and needs is consistent with this patient-centered approach, and the convenience of an effective, well-tolerated, weekly, oral, DPP-4 inhibitor may be an attractive option for some patients,” added Dr. Gantz, who is an employee of Merck & Co.
While an oral drug that is delivered weekly might prove more convenient and potentially improve patients’ adherence and quality of life, this was not possible to measure in the present study, Dr. Gantz noted during the discussion that followed his presentation of the results at the annual meeting of the European Association for the Study of Diabetes.
“The design of the study and of our other phase III programs makes that difficult because they’re double dummy, and the patients in this study who were taking omarigliptin also took daily sitagliptin [or placebo pill] and vice versa – those taking sitagliptin took a weekly placebo pill,” Dr. Gantz explained.
The global study compared the efficacy and safety of omarigliptin given at a once-weekly dose of 25 mg with that of sitagliptin (Januvia) at a daily dose of 100 mg in 642 patients with type 2 diabetes who were not achieving adequate glucose control despite being on metformin. The mean age of patients enrolled was around 57 years in both groups, with around half being male; the average duration of type 2 diabetes was 7 years.
Very small reductions in body weight were seen with both drugs but “no meaningful differences” in specific adverse events were seen, Dr. Gantz reported. Hypoglycemia developed in 3.7% of patients on the weekly regimen versus 4.7% in the subjects taking the daily DPP-4 inhibitor.
No confirmed cases of pancreatitis were reported in either treatment group. Two instances of angioedema, which was a prespecified hypersensitivity adverse event, of the tongue were noted in one subject in the omarigliptin group. There were some small increases in serum amylase and lipase in both groups although these were within normal laboratory limits and did not result in any treatment discontinuations.
Asked if there was any advantage of weekly over daily administration of a DPP-4 inhibitor in terms of renal function, Dr. Gantz replied that it might allow for “broader dose adjustment.” Patents with mild to moderate renal insufficiency would probably not need dose adjustment of omarigliptin, but for those with severe impairment and those on dialysis there would be a recommendation to halve the dose to 12.5 mg/week.
Dr. Gantz observed: “I think the major selling point is that it provides options for patients, as far as a weekly administration it’s a patient-centric approach.”
The study was funded by Merck & Co. Dr. Gantz and his coinvestigators are all employees of the company.
AT EASD 2015
Key clinical point: Weekly administration of a DPP-4 inhibitor proved efficacious and well tolerated and could offer a convenient alternative to daily treatment in type 2 diabetes.
Major finding: Omarigliptin was noninferior to sitagliptin for reducing HbA1c from baseline to week 24 of treatment (–0.47% vs. –0.43%; P = .561).
Data source: Phase III, randomized, double-blind, double dummy study of 642 patients with type 2 diabetes who were not achieving adequate glycemic control despite being on metformin.
Disclosures: The study was funded by Merck & Co. Dr. Gantz and his coinvestigators are all employees of the company.
EASD: Once-weekly omarigliptin as effective as daily sitagliptin
STOCKHOLM – Once-weekly treatment with the investigational, oral dipeptidyl peptidase-4 (DPP-4) inhibitor omarigliptin lowered hemoglobin A1c as effectively as daily sitagliptin in a large, head-to-head, phase III trial of patients with type 2 diabetes.
Results of the O-QWEST noninferiority to sitagliptin study showed similar reductions in HbA1c from baseline to week 24 of treatment comparing omarigliptin (–0.47%) and sitagliptin (–0.43%) with an overall difference of just –0.03% (P = 0.561). The mean HbA1c at baseline in both groups was around 7.5%.
Patients with higher HbA1c values at baseline achieved greater reductions in HbA1c than those with lower starting HbA1c values, although there was no significant difference between the two treatments.
A similar percentage of patients in the omarigliptin and sitagliptin groups achieved target HbA1c values of less than 7% (54.4% vs. 52.4%; P = .619) and less than 6.5% (28.8% vs. 24.4%; P = .212), and there was no significant difference in fasting plasma glucose levels, with a mean difference overall of –0.2 mmol/L.
“According to a relatively recent joint position statement by the ADA and EASD (Diabetes Care. 2012;35:1364-1379) providing care that is responsive to individual patient preferences and needs is a recommended approach to health care in chronic diseases such as type 2 diabetes,” said Dr. Ira Gantz, who presented the study findings.
“Providing patients with medications tailored to their individual preferences and needs is consistent with this patient-centered approach, and the convenience of an effective, well-tolerated, weekly, oral, DPP-4 inhibitor may be an attractive option for some patients,” added Dr. Gantz, who is an employee of Merck & Co.
While an oral drug that is delivered weekly might prove more convenient and potentially improve patients’ adherence and quality of life, this was not possible to measure in the present study, Dr. Gantz noted during the discussion that followed his presentation of the results at the annual meeting of the European Association for the Study of Diabetes.
“The design of the study and of our other phase III programs makes that difficult because they’re double dummy, and the patients in this study who were taking omarigliptin also took daily sitagliptin [or placebo pill] and vice versa – those taking sitagliptin took a weekly placebo pill,” Dr. Gantz explained.
The global study compared the efficacy and safety of omarigliptin given at a once-weekly dose of 25 mg with that of sitagliptin (Januvia) at a daily dose of 100 mg in 642 patients with type 2 diabetes who were not achieving adequate glucose control despite being on metformin. The mean age of patients enrolled was around 57 years in both groups, with around half being male; the average duration of type 2 diabetes was 7 years.
Very small reductions in body weight were seen with both drugs but “no meaningful differences” in specific adverse events were seen, Dr. Gantz reported. Hypoglycemia developed in 3.7% of patients on the weekly regimen versus 4.7% in the subjects taking the daily DPP-4 inhibitor.
No confirmed cases of pancreatitis were reported in either treatment group. Two instances of angioedema, which was a prespecified hypersensitivity adverse event, of the tongue were noted in one subject in the omarigliptin group. There were some small increases in serum amylase and lipase in both groups although these were within normal laboratory limits and did not result in any treatment discontinuations.
Asked if there was any advantage of weekly over daily administration of a DPP-4 inhibitor in terms of renal function, Dr. Gantz replied that it might allow for “broader dose adjustment.” Patents with mild to moderate renal insufficiency would probably not need dose adjustment of omarigliptin, but for those with severe impairment and those on dialysis there would be a recommendation to halve the dose to 12.5 mg/week.
Dr. Gantz observed: “I think the major selling point is that it provides options for patients, as far as a weekly administration it’s a patient-centric approach.”
The study was funded by Merck & Co. Dr. Gantz and his coinvestigators are all employees of the company.
STOCKHOLM – Once-weekly treatment with the investigational, oral dipeptidyl peptidase-4 (DPP-4) inhibitor omarigliptin lowered hemoglobin A1c as effectively as daily sitagliptin in a large, head-to-head, phase III trial of patients with type 2 diabetes.
Results of the O-QWEST noninferiority to sitagliptin study showed similar reductions in HbA1c from baseline to week 24 of treatment comparing omarigliptin (–0.47%) and sitagliptin (–0.43%) with an overall difference of just –0.03% (P = 0.561). The mean HbA1c at baseline in both groups was around 7.5%.
Patients with higher HbA1c values at baseline achieved greater reductions in HbA1c than those with lower starting HbA1c values, although there was no significant difference between the two treatments.
A similar percentage of patients in the omarigliptin and sitagliptin groups achieved target HbA1c values of less than 7% (54.4% vs. 52.4%; P = .619) and less than 6.5% (28.8% vs. 24.4%; P = .212), and there was no significant difference in fasting plasma glucose levels, with a mean difference overall of –0.2 mmol/L.
“According to a relatively recent joint position statement by the ADA and EASD (Diabetes Care. 2012;35:1364-1379) providing care that is responsive to individual patient preferences and needs is a recommended approach to health care in chronic diseases such as type 2 diabetes,” said Dr. Ira Gantz, who presented the study findings.
“Providing patients with medications tailored to their individual preferences and needs is consistent with this patient-centered approach, and the convenience of an effective, well-tolerated, weekly, oral, DPP-4 inhibitor may be an attractive option for some patients,” added Dr. Gantz, who is an employee of Merck & Co.
While an oral drug that is delivered weekly might prove more convenient and potentially improve patients’ adherence and quality of life, this was not possible to measure in the present study, Dr. Gantz noted during the discussion that followed his presentation of the results at the annual meeting of the European Association for the Study of Diabetes.
“The design of the study and of our other phase III programs makes that difficult because they’re double dummy, and the patients in this study who were taking omarigliptin also took daily sitagliptin [or placebo pill] and vice versa – those taking sitagliptin took a weekly placebo pill,” Dr. Gantz explained.
The global study compared the efficacy and safety of omarigliptin given at a once-weekly dose of 25 mg with that of sitagliptin (Januvia) at a daily dose of 100 mg in 642 patients with type 2 diabetes who were not achieving adequate glucose control despite being on metformin. The mean age of patients enrolled was around 57 years in both groups, with around half being male; the average duration of type 2 diabetes was 7 years.
Very small reductions in body weight were seen with both drugs but “no meaningful differences” in specific adverse events were seen, Dr. Gantz reported. Hypoglycemia developed in 3.7% of patients on the weekly regimen versus 4.7% in the subjects taking the daily DPP-4 inhibitor.
No confirmed cases of pancreatitis were reported in either treatment group. Two instances of angioedema, which was a prespecified hypersensitivity adverse event, of the tongue were noted in one subject in the omarigliptin group. There were some small increases in serum amylase and lipase in both groups although these were within normal laboratory limits and did not result in any treatment discontinuations.
Asked if there was any advantage of weekly over daily administration of a DPP-4 inhibitor in terms of renal function, Dr. Gantz replied that it might allow for “broader dose adjustment.” Patents with mild to moderate renal insufficiency would probably not need dose adjustment of omarigliptin, but for those with severe impairment and those on dialysis there would be a recommendation to halve the dose to 12.5 mg/week.
Dr. Gantz observed: “I think the major selling point is that it provides options for patients, as far as a weekly administration it’s a patient-centric approach.”
The study was funded by Merck & Co. Dr. Gantz and his coinvestigators are all employees of the company.
STOCKHOLM – Once-weekly treatment with the investigational, oral dipeptidyl peptidase-4 (DPP-4) inhibitor omarigliptin lowered hemoglobin A1c as effectively as daily sitagliptin in a large, head-to-head, phase III trial of patients with type 2 diabetes.
Results of the O-QWEST noninferiority to sitagliptin study showed similar reductions in HbA1c from baseline to week 24 of treatment comparing omarigliptin (–0.47%) and sitagliptin (–0.43%) with an overall difference of just –0.03% (P = 0.561). The mean HbA1c at baseline in both groups was around 7.5%.
Patients with higher HbA1c values at baseline achieved greater reductions in HbA1c than those with lower starting HbA1c values, although there was no significant difference between the two treatments.
A similar percentage of patients in the omarigliptin and sitagliptin groups achieved target HbA1c values of less than 7% (54.4% vs. 52.4%; P = .619) and less than 6.5% (28.8% vs. 24.4%; P = .212), and there was no significant difference in fasting plasma glucose levels, with a mean difference overall of –0.2 mmol/L.
“According to a relatively recent joint position statement by the ADA and EASD (Diabetes Care. 2012;35:1364-1379) providing care that is responsive to individual patient preferences and needs is a recommended approach to health care in chronic diseases such as type 2 diabetes,” said Dr. Ira Gantz, who presented the study findings.
“Providing patients with medications tailored to their individual preferences and needs is consistent with this patient-centered approach, and the convenience of an effective, well-tolerated, weekly, oral, DPP-4 inhibitor may be an attractive option for some patients,” added Dr. Gantz, who is an employee of Merck & Co.
While an oral drug that is delivered weekly might prove more convenient and potentially improve patients’ adherence and quality of life, this was not possible to measure in the present study, Dr. Gantz noted during the discussion that followed his presentation of the results at the annual meeting of the European Association for the Study of Diabetes.
“The design of the study and of our other phase III programs makes that difficult because they’re double dummy, and the patients in this study who were taking omarigliptin also took daily sitagliptin [or placebo pill] and vice versa – those taking sitagliptin took a weekly placebo pill,” Dr. Gantz explained.
The global study compared the efficacy and safety of omarigliptin given at a once-weekly dose of 25 mg with that of sitagliptin (Januvia) at a daily dose of 100 mg in 642 patients with type 2 diabetes who were not achieving adequate glucose control despite being on metformin. The mean age of patients enrolled was around 57 years in both groups, with around half being male; the average duration of type 2 diabetes was 7 years.
Very small reductions in body weight were seen with both drugs but “no meaningful differences” in specific adverse events were seen, Dr. Gantz reported. Hypoglycemia developed in 3.7% of patients on the weekly regimen versus 4.7% in the subjects taking the daily DPP-4 inhibitor.
No confirmed cases of pancreatitis were reported in either treatment group. Two instances of angioedema, which was a prespecified hypersensitivity adverse event, of the tongue were noted in one subject in the omarigliptin group. There were some small increases in serum amylase and lipase in both groups although these were within normal laboratory limits and did not result in any treatment discontinuations.
Asked if there was any advantage of weekly over daily administration of a DPP-4 inhibitor in terms of renal function, Dr. Gantz replied that it might allow for “broader dose adjustment.” Patents with mild to moderate renal insufficiency would probably not need dose adjustment of omarigliptin, but for those with severe impairment and those on dialysis there would be a recommendation to halve the dose to 12.5 mg/week.
Dr. Gantz observed: “I think the major selling point is that it provides options for patients, as far as a weekly administration it’s a patient-centric approach.”
The study was funded by Merck & Co. Dr. Gantz and his coinvestigators are all employees of the company.
AT EASD 2015
Key clinical point: Weekly administration of a DPP-4 inhibitor proved efficacious and well tolerated and could offer a convenient alternative to daily treatment in type 2 diabetes.
Major finding: Omarigliptin was noninferior to sitagliptin for reducing HbA1c from baseline to week 24 of treatment (–0.47% vs. –0.43%; P = .561).
Data source: Phase III, randomized, double-blind, double dummy study of 642 patients with type 2 diabetes who were not achieving adequate glycemic control despite being on metformin.
Disclosures: The study was funded by Merck & Co. Dr. Gantz and his coinvestigators are all employees of the company.
Monthly Incretin-based Therapy Shows Promise in Type 2 Diabetes
STOCKHOLM – The ultra-long-acting GLP-1 receptor agonist efpeglenatide was efficacious when given once a month and improved glycemic control versus placebo, according to interim data from a 16-week, phase II study involving just over 200 patients with type 2 diabetes.
However, “tolerability and safety seem critical for final dose selection of a monthly regimen,” said Dr. Stefano Del Prato of the University of Pisa in Italy. He presented the findings at the annual meeting of the European Association for the Study of Diabetes.
Efpeglenatide is a new incretin-based therapy being developed by the South Korea–based company Hanmi Pharmaceutical. It has been created via the company’s LAPSCOVERY (Long Acting Protein/Peptide Discovery Platform) Technology whereby the therapeutic agent (GLP-1) is conjugated with a human immunoglobulin G Fc fragment via a linking molecule. This makes a larger molecule that extends the half-life to make it suitable for less frequent (weekly or monthly) dosing.
Dr. Del Prato noted that in a previous study reported at the American Diabetes Association annual scientific sessions in June (Diabetes. 2015;64:A73), efpeglenatide administered once weekly had been shown to be noninferior to once-daily liraglutide in terms of improved hemoglobin A1c from baseline. The aim of the present study was to see whether the interval between doses could be extended further and what might be the optimal dose for monthly administration.
Data were presented on 209 patients enrolled in the trial. The mean age was 56 years and mean diabetes duration, 7 years. Patients had been treated with metformin for an average of 4 years but had unsatisfactory glycemic control despite being on stable doses for at least 3 months.
Patients were randomized to treatment with one of three monthly doses of efpeglenatide (8 mg, 12 mg, or 16 mg) or to placebo. Initially all patients randomized to the active treatment received a 4-mg weekly dose for 4 weeks before the dose was increased to a monthly 8-mg dose for 4 weeks, then either continued (n = 51) or raised again to 12 mg (n = 52) or 16 mg (n = 53) for the remainder of the study.
Overall, 158 patients completed the 16-week trial and a 6-week follow-up phase. The main reasons for treatment discontinuation was patient decision (n = 11), nausea (n = 5), or vomiting (n = 7) in the active treatment groups, or serious adverse event (n = 4).
The mean change in HbA1c over time was the primary endpoint and all three doses of efpeglenatide significantly reduced HbA1c to a greater extent than did placebo, with final recorded values of 6.92%, 6.64%, and 6.74% for the 8-mg, 12-mg, and 16-mg doses, respectively, and 7.56% for placebo. There was no significant difference seen between the three efpeglenatide doses. The respective mean changes in HbA1c from baseline to week 17 were –0.66%, –0.67%, –0.79%, and –0.32%.
The percentage of patients achieving an HbA1c of less than 7% or 6.5% or lower were 57.7% and 34.6% for the 8-mg dose, 63.5% and 50% for the 12-mg dose, 57.7% and 36.5% for the 16-mg dose, and 30.6% and 12.2% for placebo. The differences between the doses were not significant, but all values were significant versus placebo.
Greater reductions in fasting plasma glucose were seen comparing active treatment (–0.78, –0.45, –0.79 mmol/L) versus placebo (–0.07 mmol/L). Body weight was lowered to a greater extent by all doses of efpeglenatide when compared to placebo (–1.78, –3.05, –2.20 kg vs. –0.34 kg).
Dr. Del Prato noted that all three doses seemed effective and were likely to be within the maximal dosage range. There might be some differences in tolerability, however, with patient-reported hypoglycemia occurring more frequently with the highest dose use (17% vs. 2% for placebo and 11.5% for the 8-mg and 13.5% for the 12-mg doses). Nausea and vomiting, which subsided over the course of treatment, tended to recur after the second monthly dose and thereafter with the highest doses of efpeglenatide.
A slight increase of five to eight or nine beats per minute was observed in the patients who received efpeglenatide versus placebo, and there was a slight drop in systolic blood pressure over time.
“The use of GLP-1 receptor agonists, in particular long-acting GLP-1 receptor agonists, is becoming more common, because of their well-known effects on glucose-dependent insulin secretion and glucose-dependent inhibitor of glucagon release,” Dr. Del Prato observed. “These effects, together with the reduction in body weight and effect on gastric emptying results in very appealing possibilities or opportunities for treatment in type 2 diabetes.”
He concluded: “Once-monthly efpeglenatide therapy is efficacious in type 2 diabetic patients inadequately controlled with metformin.”
STOCKHOLM – The ultra-long-acting GLP-1 receptor agonist efpeglenatide was efficacious when given once a month and improved glycemic control versus placebo, according to interim data from a 16-week, phase II study involving just over 200 patients with type 2 diabetes.
However, “tolerability and safety seem critical for final dose selection of a monthly regimen,” said Dr. Stefano Del Prato of the University of Pisa in Italy. He presented the findings at the annual meeting of the European Association for the Study of Diabetes.
Efpeglenatide is a new incretin-based therapy being developed by the South Korea–based company Hanmi Pharmaceutical. It has been created via the company’s LAPSCOVERY (Long Acting Protein/Peptide Discovery Platform) Technology whereby the therapeutic agent (GLP-1) is conjugated with a human immunoglobulin G Fc fragment via a linking molecule. This makes a larger molecule that extends the half-life to make it suitable for less frequent (weekly or monthly) dosing.
Dr. Del Prato noted that in a previous study reported at the American Diabetes Association annual scientific sessions in June (Diabetes. 2015;64:A73), efpeglenatide administered once weekly had been shown to be noninferior to once-daily liraglutide in terms of improved hemoglobin A1c from baseline. The aim of the present study was to see whether the interval between doses could be extended further and what might be the optimal dose for monthly administration.
Data were presented on 209 patients enrolled in the trial. The mean age was 56 years and mean diabetes duration, 7 years. Patients had been treated with metformin for an average of 4 years but had unsatisfactory glycemic control despite being on stable doses for at least 3 months.
Patients were randomized to treatment with one of three monthly doses of efpeglenatide (8 mg, 12 mg, or 16 mg) or to placebo. Initially all patients randomized to the active treatment received a 4-mg weekly dose for 4 weeks before the dose was increased to a monthly 8-mg dose for 4 weeks, then either continued (n = 51) or raised again to 12 mg (n = 52) or 16 mg (n = 53) for the remainder of the study.
Overall, 158 patients completed the 16-week trial and a 6-week follow-up phase. The main reasons for treatment discontinuation was patient decision (n = 11), nausea (n = 5), or vomiting (n = 7) in the active treatment groups, or serious adverse event (n = 4).
The mean change in HbA1c over time was the primary endpoint and all three doses of efpeglenatide significantly reduced HbA1c to a greater extent than did placebo, with final recorded values of 6.92%, 6.64%, and 6.74% for the 8-mg, 12-mg, and 16-mg doses, respectively, and 7.56% for placebo. There was no significant difference seen between the three efpeglenatide doses. The respective mean changes in HbA1c from baseline to week 17 were –0.66%, –0.67%, –0.79%, and –0.32%.
The percentage of patients achieving an HbA1c of less than 7% or 6.5% or lower were 57.7% and 34.6% for the 8-mg dose, 63.5% and 50% for the 12-mg dose, 57.7% and 36.5% for the 16-mg dose, and 30.6% and 12.2% for placebo. The differences between the doses were not significant, but all values were significant versus placebo.
Greater reductions in fasting plasma glucose were seen comparing active treatment (–0.78, –0.45, –0.79 mmol/L) versus placebo (–0.07 mmol/L). Body weight was lowered to a greater extent by all doses of efpeglenatide when compared to placebo (–1.78, –3.05, –2.20 kg vs. –0.34 kg).
Dr. Del Prato noted that all three doses seemed effective and were likely to be within the maximal dosage range. There might be some differences in tolerability, however, with patient-reported hypoglycemia occurring more frequently with the highest dose use (17% vs. 2% for placebo and 11.5% for the 8-mg and 13.5% for the 12-mg doses). Nausea and vomiting, which subsided over the course of treatment, tended to recur after the second monthly dose and thereafter with the highest doses of efpeglenatide.
A slight increase of five to eight or nine beats per minute was observed in the patients who received efpeglenatide versus placebo, and there was a slight drop in systolic blood pressure over time.
“The use of GLP-1 receptor agonists, in particular long-acting GLP-1 receptor agonists, is becoming more common, because of their well-known effects on glucose-dependent insulin secretion and glucose-dependent inhibitor of glucagon release,” Dr. Del Prato observed. “These effects, together with the reduction in body weight and effect on gastric emptying results in very appealing possibilities or opportunities for treatment in type 2 diabetes.”
He concluded: “Once-monthly efpeglenatide therapy is efficacious in type 2 diabetic patients inadequately controlled with metformin.”
STOCKHOLM – The ultra-long-acting GLP-1 receptor agonist efpeglenatide was efficacious when given once a month and improved glycemic control versus placebo, according to interim data from a 16-week, phase II study involving just over 200 patients with type 2 diabetes.
However, “tolerability and safety seem critical for final dose selection of a monthly regimen,” said Dr. Stefano Del Prato of the University of Pisa in Italy. He presented the findings at the annual meeting of the European Association for the Study of Diabetes.
Efpeglenatide is a new incretin-based therapy being developed by the South Korea–based company Hanmi Pharmaceutical. It has been created via the company’s LAPSCOVERY (Long Acting Protein/Peptide Discovery Platform) Technology whereby the therapeutic agent (GLP-1) is conjugated with a human immunoglobulin G Fc fragment via a linking molecule. This makes a larger molecule that extends the half-life to make it suitable for less frequent (weekly or monthly) dosing.
Dr. Del Prato noted that in a previous study reported at the American Diabetes Association annual scientific sessions in June (Diabetes. 2015;64:A73), efpeglenatide administered once weekly had been shown to be noninferior to once-daily liraglutide in terms of improved hemoglobin A1c from baseline. The aim of the present study was to see whether the interval between doses could be extended further and what might be the optimal dose for monthly administration.
Data were presented on 209 patients enrolled in the trial. The mean age was 56 years and mean diabetes duration, 7 years. Patients had been treated with metformin for an average of 4 years but had unsatisfactory glycemic control despite being on stable doses for at least 3 months.
Patients were randomized to treatment with one of three monthly doses of efpeglenatide (8 mg, 12 mg, or 16 mg) or to placebo. Initially all patients randomized to the active treatment received a 4-mg weekly dose for 4 weeks before the dose was increased to a monthly 8-mg dose for 4 weeks, then either continued (n = 51) or raised again to 12 mg (n = 52) or 16 mg (n = 53) for the remainder of the study.
Overall, 158 patients completed the 16-week trial and a 6-week follow-up phase. The main reasons for treatment discontinuation was patient decision (n = 11), nausea (n = 5), or vomiting (n = 7) in the active treatment groups, or serious adverse event (n = 4).
The mean change in HbA1c over time was the primary endpoint and all three doses of efpeglenatide significantly reduced HbA1c to a greater extent than did placebo, with final recorded values of 6.92%, 6.64%, and 6.74% for the 8-mg, 12-mg, and 16-mg doses, respectively, and 7.56% for placebo. There was no significant difference seen between the three efpeglenatide doses. The respective mean changes in HbA1c from baseline to week 17 were –0.66%, –0.67%, –0.79%, and –0.32%.
The percentage of patients achieving an HbA1c of less than 7% or 6.5% or lower were 57.7% and 34.6% for the 8-mg dose, 63.5% and 50% for the 12-mg dose, 57.7% and 36.5% for the 16-mg dose, and 30.6% and 12.2% for placebo. The differences between the doses were not significant, but all values were significant versus placebo.
Greater reductions in fasting plasma glucose were seen comparing active treatment (–0.78, –0.45, –0.79 mmol/L) versus placebo (–0.07 mmol/L). Body weight was lowered to a greater extent by all doses of efpeglenatide when compared to placebo (–1.78, –3.05, –2.20 kg vs. –0.34 kg).
Dr. Del Prato noted that all three doses seemed effective and were likely to be within the maximal dosage range. There might be some differences in tolerability, however, with patient-reported hypoglycemia occurring more frequently with the highest dose use (17% vs. 2% for placebo and 11.5% for the 8-mg and 13.5% for the 12-mg doses). Nausea and vomiting, which subsided over the course of treatment, tended to recur after the second monthly dose and thereafter with the highest doses of efpeglenatide.
A slight increase of five to eight or nine beats per minute was observed in the patients who received efpeglenatide versus placebo, and there was a slight drop in systolic blood pressure over time.
“The use of GLP-1 receptor agonists, in particular long-acting GLP-1 receptor agonists, is becoming more common, because of their well-known effects on glucose-dependent insulin secretion and glucose-dependent inhibitor of glucagon release,” Dr. Del Prato observed. “These effects, together with the reduction in body weight and effect on gastric emptying results in very appealing possibilities or opportunities for treatment in type 2 diabetes.”
He concluded: “Once-monthly efpeglenatide therapy is efficacious in type 2 diabetic patients inadequately controlled with metformin.”
AT EASD 2015