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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.
