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European Association for the Study of Diabetes (EASD): Annual Meeting
When 1 + 1 = 3: Rational drug combinations in type 2 diabetes
MUNICH – Enough studies exist now to support the notion of dual therapy in type 2 diabetes. But, with 13 classes of antihyperglycemic drugs approved in the United States – 7 of which are considered major – how does anyone make sense of the myriad of possible combinations?
It’s not a bad problem to have, Ele Ferrannini, MD, said shortly before the DURATION-8 data were presented at the annual meeting of the European Association for the Study of Diabetes.
“We have seen an explosion of pharmacological treatment options for type 2 diabetes in the last 20 years, which is really unprecedented, especially if we compare that to what has happened in hypertension or cardiology,” said Dr. Ferrannini of the University of Pisa (Italy). “This has given us the blessing of multiple options for treatment. But we are also now at a slight disadvantage. We all agree that we should advocate for combination treatment as early and aggressively as possible for our type 2 diabetes patients, but the question is, What combination?”
The question cannot be answered fully, he said. “If we had to test each possible combination in dual therapy, and counted all 13 classes, that would be 78 combinations. And if we started talking about triple therapy – which may eventually arrive – we could be talking about 286 possible combinations. So it’s just not possible to formally test the efficacy and the risk/benefit profile of every one. That means we have to start thinking about rational combinations based on mechanism of action.”
The combination of dapagliflozin and exenatide, tested in DURATION-8 is a good example, he said. “It’s rational,” because exenatide and dapagliflozin work completely independently of each other, each adding a unique method of action without overtargeting the same system and increasing the risk of adverse events.
Dapagliflozin is an inhibitor of the renal sodium-glucose cotransporter–2 (SGLT-2). This class of drugs works in the proximal renal tubule, where these glucose transporters absorb “huge amounts” of glucose, he said. “Whatever escapes there is then mopped up by the SGLT-1 cotransporters further along the nephron,” Dr. Ferrannini said. “SGLT inhibitors cause an upward and leftward shift of the relationship between plasma glucose and glycosuria for the same glomerular filtration rate.”
In the presence of an SGLT-2 inhibitor, glycosuria is increased, no matter what the plasma glucose level is. “This even takes place well within the euglycemic range, which is why these drugs cause glycosuria even in nondiabetic individuals,” Dr. Ferrannini said.
Numerous studies have shown that this class of drugs works well independently, and also pairs well with metformin, sulfonylureas, dipeptidyl peptidase–4 inhibitors, and insulin. Several studies of dapagliflozin have found that adding 10 mg to monotherapy reduced HbA1c on the order of almost 1%, regardless of the concomitant medication.
Dapagliflozin works especially well in patients with very high HbA1c levels, Dr. Ferrannini said, as shown in a 2010 dose-ranging study he led. “If the initial HbA1c was above 10%, the drop associated with adding dapagliflozin was surprisingly large, on the order of 3%-4%,” he said Diabetes Care 2010 Oct;33(10):2217-24.
The primary response on HbA1c is also quite durable, unlike the response seen in sulfonylureas, for example, which eventually wanes. “Every time you give this pill, you get glycosuria. It just doesn’t change,” he said.
Dapagliflozin also exerts a sustained benefit on systolic blood pressure, and causes a very consistent 2- to 3-kg decrease in body weight, no matter whether it’s given alone or with metformin, insulin, or a sulphonylurea.
But when it comes to shedding calories through urine, the body can’t be tricked forever, it seems. “You could assume very easily that body weight would continue to decline with an SGLT-2 inhibitor, but in fact it levels off after 2-3 kg. There can only be one explanation for this, and that is an increase in calorie intake. The body feels this loss of calories, particularly this massive loss of carbohydrate calories through the urine, and responds by implementing adaptive behaviors that increase calorie intake,” Dr. Ferrannini said.
In other words, hunger strikes. And strikes hard. That’s where the incretins come into play, he said.
“If we could interfere with this response that limits weight loss, we could probably continue to lose weight, and also see general improvements in HbA1c. And a very important element of incretin action is that they restore insulin release in patients with diabetes” and moderate appetite, he said.
Incretins like exenatide, a glucagonlike peptide–1 receptor agonist, impose their weight loss effect through an entirely different system. “By delaying gastric emptying and also – more importantly – through neural signaling, they potentiate satiety, thus limiting calorie intake, reducing energy balance, and leading to a reduction in body weight,” Dr. Ferrannini said.
Therefore, using a combination like dapagliflozin and exenatide makes complete physiologic sense, he said. Both drugs improve HbA1c, and decrease body weight and systolic blood pressure. Dapagliflozin accomplishes these tasks by increasing urinary glucose excretion, which leads to decreased vascular stiffness and better blood pressure. Exenatide works in a completely different pathway - insulin signaling - and has the additional benefit of decreasing inflammation.
The positive results of DURATION-8 support this clinical assumption, he concluded. “I would submit that combination therapy with exenatide and dapagliflozin is a rational approach, and takes advantage of the unique properties of both of these drugs,” he said.
Dr. Ferrannini has received research finding from AstraZeneca, which manufactures dapagliflozin and exenatide, as well as other companies that market diabetes drugs.
On Twitter @Alz_Gal
MUNICH – Enough studies exist now to support the notion of dual therapy in type 2 diabetes. But, with 13 classes of antihyperglycemic drugs approved in the United States – 7 of which are considered major – how does anyone make sense of the myriad of possible combinations?
It’s not a bad problem to have, Ele Ferrannini, MD, said shortly before the DURATION-8 data were presented at the annual meeting of the European Association for the Study of Diabetes.
“We have seen an explosion of pharmacological treatment options for type 2 diabetes in the last 20 years, which is really unprecedented, especially if we compare that to what has happened in hypertension or cardiology,” said Dr. Ferrannini of the University of Pisa (Italy). “This has given us the blessing of multiple options for treatment. But we are also now at a slight disadvantage. We all agree that we should advocate for combination treatment as early and aggressively as possible for our type 2 diabetes patients, but the question is, What combination?”
The question cannot be answered fully, he said. “If we had to test each possible combination in dual therapy, and counted all 13 classes, that would be 78 combinations. And if we started talking about triple therapy – which may eventually arrive – we could be talking about 286 possible combinations. So it’s just not possible to formally test the efficacy and the risk/benefit profile of every one. That means we have to start thinking about rational combinations based on mechanism of action.”
The combination of dapagliflozin and exenatide, tested in DURATION-8 is a good example, he said. “It’s rational,” because exenatide and dapagliflozin work completely independently of each other, each adding a unique method of action without overtargeting the same system and increasing the risk of adverse events.
Dapagliflozin is an inhibitor of the renal sodium-glucose cotransporter–2 (SGLT-2). This class of drugs works in the proximal renal tubule, where these glucose transporters absorb “huge amounts” of glucose, he said. “Whatever escapes there is then mopped up by the SGLT-1 cotransporters further along the nephron,” Dr. Ferrannini said. “SGLT inhibitors cause an upward and leftward shift of the relationship between plasma glucose and glycosuria for the same glomerular filtration rate.”
In the presence of an SGLT-2 inhibitor, glycosuria is increased, no matter what the plasma glucose level is. “This even takes place well within the euglycemic range, which is why these drugs cause glycosuria even in nondiabetic individuals,” Dr. Ferrannini said.
Numerous studies have shown that this class of drugs works well independently, and also pairs well with metformin, sulfonylureas, dipeptidyl peptidase–4 inhibitors, and insulin. Several studies of dapagliflozin have found that adding 10 mg to monotherapy reduced HbA1c on the order of almost 1%, regardless of the concomitant medication.
Dapagliflozin works especially well in patients with very high HbA1c levels, Dr. Ferrannini said, as shown in a 2010 dose-ranging study he led. “If the initial HbA1c was above 10%, the drop associated with adding dapagliflozin was surprisingly large, on the order of 3%-4%,” he said Diabetes Care 2010 Oct;33(10):2217-24.
The primary response on HbA1c is also quite durable, unlike the response seen in sulfonylureas, for example, which eventually wanes. “Every time you give this pill, you get glycosuria. It just doesn’t change,” he said.
Dapagliflozin also exerts a sustained benefit on systolic blood pressure, and causes a very consistent 2- to 3-kg decrease in body weight, no matter whether it’s given alone or with metformin, insulin, or a sulphonylurea.
But when it comes to shedding calories through urine, the body can’t be tricked forever, it seems. “You could assume very easily that body weight would continue to decline with an SGLT-2 inhibitor, but in fact it levels off after 2-3 kg. There can only be one explanation for this, and that is an increase in calorie intake. The body feels this loss of calories, particularly this massive loss of carbohydrate calories through the urine, and responds by implementing adaptive behaviors that increase calorie intake,” Dr. Ferrannini said.
In other words, hunger strikes. And strikes hard. That’s where the incretins come into play, he said.
“If we could interfere with this response that limits weight loss, we could probably continue to lose weight, and also see general improvements in HbA1c. And a very important element of incretin action is that they restore insulin release in patients with diabetes” and moderate appetite, he said.
Incretins like exenatide, a glucagonlike peptide–1 receptor agonist, impose their weight loss effect through an entirely different system. “By delaying gastric emptying and also – more importantly – through neural signaling, they potentiate satiety, thus limiting calorie intake, reducing energy balance, and leading to a reduction in body weight,” Dr. Ferrannini said.
Therefore, using a combination like dapagliflozin and exenatide makes complete physiologic sense, he said. Both drugs improve HbA1c, and decrease body weight and systolic blood pressure. Dapagliflozin accomplishes these tasks by increasing urinary glucose excretion, which leads to decreased vascular stiffness and better blood pressure. Exenatide works in a completely different pathway - insulin signaling - and has the additional benefit of decreasing inflammation.
The positive results of DURATION-8 support this clinical assumption, he concluded. “I would submit that combination therapy with exenatide and dapagliflozin is a rational approach, and takes advantage of the unique properties of both of these drugs,” he said.
Dr. Ferrannini has received research finding from AstraZeneca, which manufactures dapagliflozin and exenatide, as well as other companies that market diabetes drugs.
On Twitter @Alz_Gal
MUNICH – Enough studies exist now to support the notion of dual therapy in type 2 diabetes. But, with 13 classes of antihyperglycemic drugs approved in the United States – 7 of which are considered major – how does anyone make sense of the myriad of possible combinations?
It’s not a bad problem to have, Ele Ferrannini, MD, said shortly before the DURATION-8 data were presented at the annual meeting of the European Association for the Study of Diabetes.
“We have seen an explosion of pharmacological treatment options for type 2 diabetes in the last 20 years, which is really unprecedented, especially if we compare that to what has happened in hypertension or cardiology,” said Dr. Ferrannini of the University of Pisa (Italy). “This has given us the blessing of multiple options for treatment. But we are also now at a slight disadvantage. We all agree that we should advocate for combination treatment as early and aggressively as possible for our type 2 diabetes patients, but the question is, What combination?”
The question cannot be answered fully, he said. “If we had to test each possible combination in dual therapy, and counted all 13 classes, that would be 78 combinations. And if we started talking about triple therapy – which may eventually arrive – we could be talking about 286 possible combinations. So it’s just not possible to formally test the efficacy and the risk/benefit profile of every one. That means we have to start thinking about rational combinations based on mechanism of action.”
The combination of dapagliflozin and exenatide, tested in DURATION-8 is a good example, he said. “It’s rational,” because exenatide and dapagliflozin work completely independently of each other, each adding a unique method of action without overtargeting the same system and increasing the risk of adverse events.
Dapagliflozin is an inhibitor of the renal sodium-glucose cotransporter–2 (SGLT-2). This class of drugs works in the proximal renal tubule, where these glucose transporters absorb “huge amounts” of glucose, he said. “Whatever escapes there is then mopped up by the SGLT-1 cotransporters further along the nephron,” Dr. Ferrannini said. “SGLT inhibitors cause an upward and leftward shift of the relationship between plasma glucose and glycosuria for the same glomerular filtration rate.”
In the presence of an SGLT-2 inhibitor, glycosuria is increased, no matter what the plasma glucose level is. “This even takes place well within the euglycemic range, which is why these drugs cause glycosuria even in nondiabetic individuals,” Dr. Ferrannini said.
Numerous studies have shown that this class of drugs works well independently, and also pairs well with metformin, sulfonylureas, dipeptidyl peptidase–4 inhibitors, and insulin. Several studies of dapagliflozin have found that adding 10 mg to monotherapy reduced HbA1c on the order of almost 1%, regardless of the concomitant medication.
Dapagliflozin works especially well in patients with very high HbA1c levels, Dr. Ferrannini said, as shown in a 2010 dose-ranging study he led. “If the initial HbA1c was above 10%, the drop associated with adding dapagliflozin was surprisingly large, on the order of 3%-4%,” he said Diabetes Care 2010 Oct;33(10):2217-24.
The primary response on HbA1c is also quite durable, unlike the response seen in sulfonylureas, for example, which eventually wanes. “Every time you give this pill, you get glycosuria. It just doesn’t change,” he said.
Dapagliflozin also exerts a sustained benefit on systolic blood pressure, and causes a very consistent 2- to 3-kg decrease in body weight, no matter whether it’s given alone or with metformin, insulin, or a sulphonylurea.
But when it comes to shedding calories through urine, the body can’t be tricked forever, it seems. “You could assume very easily that body weight would continue to decline with an SGLT-2 inhibitor, but in fact it levels off after 2-3 kg. There can only be one explanation for this, and that is an increase in calorie intake. The body feels this loss of calories, particularly this massive loss of carbohydrate calories through the urine, and responds by implementing adaptive behaviors that increase calorie intake,” Dr. Ferrannini said.
In other words, hunger strikes. And strikes hard. That’s where the incretins come into play, he said.
“If we could interfere with this response that limits weight loss, we could probably continue to lose weight, and also see general improvements in HbA1c. And a very important element of incretin action is that they restore insulin release in patients with diabetes” and moderate appetite, he said.
Incretins like exenatide, a glucagonlike peptide–1 receptor agonist, impose their weight loss effect through an entirely different system. “By delaying gastric emptying and also – more importantly – through neural signaling, they potentiate satiety, thus limiting calorie intake, reducing energy balance, and leading to a reduction in body weight,” Dr. Ferrannini said.
Therefore, using a combination like dapagliflozin and exenatide makes complete physiologic sense, he said. Both drugs improve HbA1c, and decrease body weight and systolic blood pressure. Dapagliflozin accomplishes these tasks by increasing urinary glucose excretion, which leads to decreased vascular stiffness and better blood pressure. Exenatide works in a completely different pathway - insulin signaling - and has the additional benefit of decreasing inflammation.
The positive results of DURATION-8 support this clinical assumption, he concluded. “I would submit that combination therapy with exenatide and dapagliflozin is a rational approach, and takes advantage of the unique properties of both of these drugs,” he said.
Dr. Ferrannini has received research finding from AstraZeneca, which manufactures dapagliflozin and exenatide, as well as other companies that market diabetes drugs.
On Twitter @Alz_Gal
EXPERT ANALYSIS FROM EASD 2016
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.
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.
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
EASD: 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
Key clinical point: Once-monthly efpeglenatide therapy was efficacious in patients whose type 2 diabetes was inadequately controlled with metformin, but observed differences in tolerability of the three doses tested suggest the need for further investigation.
Major finding: The mean changes in HbA1c from baseline to week 17 were –0.66%, –0.67%, and –0.79% for the 8-mg, 12-mg, and 16-mg doses of efpeglenatide and –0.32% for placebo.
Data source: Interim data on 209 patients randomized in a phase II, 16-week study comparing three monthly doses of efpeglenatide to placebo.
Disclosures: Hanmi Pharmaceutical sponsored the study. Dr. Del Prato has acted as a consultant for the company and disclosed receiving research support from Merck Sharpe & Dohme, Novartis, and Novo Nordisk, and participating in advisory boards for several other pharmaceutical companies.
Lipid-lowering Benefits of Alirocumab Extend to Patients With High-risk Diabetes
STOCKHOLM – The lipid-lowering drug alirocumab significantly lowered low-density lipoprotein cholesterol level to a similar extent in people with diabetes mellitus as in those without diabetes, based on a subanalysis of data from the ODYSSEY Long-Term study.
The calculated change in low-density lipoprotein cholesterol from baseline to 24 weeks was –60.1% with alirocumab vs. –0.9% with placebo, for an overall difference of –59.2% in those with diabetes. By comparison, the corresponding mean changes in LDL cholesterol were –61.5% and –1.8% (a difference of –59.7%) in nondiabetic individuals.
Improvements in other parameters – including triglycerides, high-density lipoprotein cholesterol, and lipoprotein(a) (Lp[a]) – were also similar in individuals with and without diabetes.
“The ODYSSEY Long-Term study is the longest study in the ODYSSEY phase III program,” said study investigator Dr. Helen Colhoun of the University of Dundee (Scotland). The primary endpoint was assessed at 24 weeks, but the trial ran for a further 54 weeks to gather as much lipid and general safety data as possible, she explained at the annual meeting of the European Association for the Study of Diabetes.
Alirocumab (Praulent) is a fully human monoclonal antibody that binds PCSK9 (proprotein convertase subtilisin/kexin type 9) that was recently approved by the Food and Drug Administration for use as an adjunct to diet and maximally tolerated statin therapy in people with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease who need additional LDL-cholesterol lowering.
The main results of the ODYSSEY Long-Term study were published in the New England Journal of Medicine in April (2015;372:1489-99 doi: 10.1056/NEJMoa1501031) and showed a –62% difference (P less than .001) in the mean percentage change from baseline in calculated LDL cholesterol between the alirocumab and placebo groups at 24 weeks. The difference remained consistent over the 78 weeks of follow-up.
Overall, the study included 2,341 individuals at high risk for cardiovascular disease with an LDL cholesterol level of more than 70 mg/dL despite being treated with maximally tolerated doses of statins with or without additional lipid-lowering therapy. Of these, just over one third of the population (35.7%, n = 838) had diabetes. Patients in the trial were randomized 2:1 to receive either alirocumab 150 mg or matching placebo as a 1-mL injection once every 2 weeks.
The present analysis looked at the long-term efficacy and safety of alirocumab in the diabetic subpopulation. Baseline demographic and lipid characteristics of the 838 patients with diabetes were broadly similar to the 1,503 patients in the trial who did not have diabetes, with mean ages of 61 and 60 years. Dr. Colhoun pointed out that virtually all patients (999; 100%) were taking a background statin, and well over one-third of those with diabetes and half of those without were taking a high-dose statin. Approximately 26% of the diabetic population were receiving insulin. Diabetic patients had slightly lower LDL cholesterol and higher triglycerides than their nondiabetic counterparts at baseline, as would be expected, she added.
Similarly high proportions of patients with (78.4% vs. 10.6%, P less than .0001) and without (79.7% vs. 6.6%, P less than .0001) diabetes who were treated with alirocumab vs. placebo achieved a target LDL cholesterol level of less than 70 mg/dL at 24 weeks.
Alirocumab treatment was associated with a 3.5% increase in HDL cholesterol in patients with diabetes and a 5.6% increase in those without, and triglycerides were reduced by a respective –18.5% and –16.7%. The adjusted mean differences in Lp(a) were –27.2% and –24.9%, an effect not seen with statins, Dr. Colhoun said.
“Overall the safety profile was excellent with this new class of drug, and there weren’t any major surprises or differences in safety profile between those with diabetes receiving alirocumab and those without diabetes,” she noted. Less than 10% of adverse events led to treatment discontinuation, at 8.3% vs. 5.0% for active and placebo treatment in the diabetic group and 6.5% vs. 6.3% in those without diabetes.
Data on the risk for new-onset or worsening diabetes in the ODYSSEY program will be presented at the scientific sessions of the American Heart Association in November, Dr. Colhoun said, giving a sneak peak of the findings from the ODYSSEY Long-Term study that indicated that there was no increased risk for either. Rates of new-onset diabetes were 1.8% in the alirocumab-treated group and 2% in the placebo group and of worsening diabetes, were 12.9% and 13.6%, respectively.
Treatment-emergent major cardiovascular events (MACE) were evaluated as a safety parameter in a post hoc analysis. Although not a main endpoint of the study, the results showed a lower rate of MACE in the overall population with alirocumab than placebo treatment (1.7% vs. 3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31-0.90) and in both diabetic (2.5% vs. 4.3%; HR, 0.58; 95% CI, 0.27-1.25) and nondiabetic subjects (1.3% vs. 2.8%; HR, 0.47; 95% CI, 0.22-1.0). “This is reassuring, but it is not by any means definitive evidence of a [cardiovascular disease] benefit,” Dr. Colhoun stressed.
The potential for alirocumab to reduce cardiovascular events will be investigated in the large, phase III ODYSSEY Outcomes study. This trial is currently recruiting and aims to accrue around 18,000 high-risk patients including those with diabetes. The study is projected to complete by the end of 2017.
STOCKHOLM – The lipid-lowering drug alirocumab significantly lowered low-density lipoprotein cholesterol level to a similar extent in people with diabetes mellitus as in those without diabetes, based on a subanalysis of data from the ODYSSEY Long-Term study.
The calculated change in low-density lipoprotein cholesterol from baseline to 24 weeks was –60.1% with alirocumab vs. –0.9% with placebo, for an overall difference of –59.2% in those with diabetes. By comparison, the corresponding mean changes in LDL cholesterol were –61.5% and –1.8% (a difference of –59.7%) in nondiabetic individuals.
Improvements in other parameters – including triglycerides, high-density lipoprotein cholesterol, and lipoprotein(a) (Lp[a]) – were also similar in individuals with and without diabetes.
“The ODYSSEY Long-Term study is the longest study in the ODYSSEY phase III program,” said study investigator Dr. Helen Colhoun of the University of Dundee (Scotland). The primary endpoint was assessed at 24 weeks, but the trial ran for a further 54 weeks to gather as much lipid and general safety data as possible, she explained at the annual meeting of the European Association for the Study of Diabetes.
Alirocumab (Praulent) is a fully human monoclonal antibody that binds PCSK9 (proprotein convertase subtilisin/kexin type 9) that was recently approved by the Food and Drug Administration for use as an adjunct to diet and maximally tolerated statin therapy in people with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease who need additional LDL-cholesterol lowering.
The main results of the ODYSSEY Long-Term study were published in the New England Journal of Medicine in April (2015;372:1489-99 doi: 10.1056/NEJMoa1501031) and showed a –62% difference (P less than .001) in the mean percentage change from baseline in calculated LDL cholesterol between the alirocumab and placebo groups at 24 weeks. The difference remained consistent over the 78 weeks of follow-up.
Overall, the study included 2,341 individuals at high risk for cardiovascular disease with an LDL cholesterol level of more than 70 mg/dL despite being treated with maximally tolerated doses of statins with or without additional lipid-lowering therapy. Of these, just over one third of the population (35.7%, n = 838) had diabetes. Patients in the trial were randomized 2:1 to receive either alirocumab 150 mg or matching placebo as a 1-mL injection once every 2 weeks.
The present analysis looked at the long-term efficacy and safety of alirocumab in the diabetic subpopulation. Baseline demographic and lipid characteristics of the 838 patients with diabetes were broadly similar to the 1,503 patients in the trial who did not have diabetes, with mean ages of 61 and 60 years. Dr. Colhoun pointed out that virtually all patients (999; 100%) were taking a background statin, and well over one-third of those with diabetes and half of those without were taking a high-dose statin. Approximately 26% of the diabetic population were receiving insulin. Diabetic patients had slightly lower LDL cholesterol and higher triglycerides than their nondiabetic counterparts at baseline, as would be expected, she added.
Similarly high proportions of patients with (78.4% vs. 10.6%, P less than .0001) and without (79.7% vs. 6.6%, P less than .0001) diabetes who were treated with alirocumab vs. placebo achieved a target LDL cholesterol level of less than 70 mg/dL at 24 weeks.
Alirocumab treatment was associated with a 3.5% increase in HDL cholesterol in patients with diabetes and a 5.6% increase in those without, and triglycerides were reduced by a respective –18.5% and –16.7%. The adjusted mean differences in Lp(a) were –27.2% and –24.9%, an effect not seen with statins, Dr. Colhoun said.
“Overall the safety profile was excellent with this new class of drug, and there weren’t any major surprises or differences in safety profile between those with diabetes receiving alirocumab and those without diabetes,” she noted. Less than 10% of adverse events led to treatment discontinuation, at 8.3% vs. 5.0% for active and placebo treatment in the diabetic group and 6.5% vs. 6.3% in those without diabetes.
Data on the risk for new-onset or worsening diabetes in the ODYSSEY program will be presented at the scientific sessions of the American Heart Association in November, Dr. Colhoun said, giving a sneak peak of the findings from the ODYSSEY Long-Term study that indicated that there was no increased risk for either. Rates of new-onset diabetes were 1.8% in the alirocumab-treated group and 2% in the placebo group and of worsening diabetes, were 12.9% and 13.6%, respectively.
Treatment-emergent major cardiovascular events (MACE) were evaluated as a safety parameter in a post hoc analysis. Although not a main endpoint of the study, the results showed a lower rate of MACE in the overall population with alirocumab than placebo treatment (1.7% vs. 3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31-0.90) and in both diabetic (2.5% vs. 4.3%; HR, 0.58; 95% CI, 0.27-1.25) and nondiabetic subjects (1.3% vs. 2.8%; HR, 0.47; 95% CI, 0.22-1.0). “This is reassuring, but it is not by any means definitive evidence of a [cardiovascular disease] benefit,” Dr. Colhoun stressed.
The potential for alirocumab to reduce cardiovascular events will be investigated in the large, phase III ODYSSEY Outcomes study. This trial is currently recruiting and aims to accrue around 18,000 high-risk patients including those with diabetes. The study is projected to complete by the end of 2017.
STOCKHOLM – The lipid-lowering drug alirocumab significantly lowered low-density lipoprotein cholesterol level to a similar extent in people with diabetes mellitus as in those without diabetes, based on a subanalysis of data from the ODYSSEY Long-Term study.
The calculated change in low-density lipoprotein cholesterol from baseline to 24 weeks was –60.1% with alirocumab vs. –0.9% with placebo, for an overall difference of –59.2% in those with diabetes. By comparison, the corresponding mean changes in LDL cholesterol were –61.5% and –1.8% (a difference of –59.7%) in nondiabetic individuals.
Improvements in other parameters – including triglycerides, high-density lipoprotein cholesterol, and lipoprotein(a) (Lp[a]) – were also similar in individuals with and without diabetes.
“The ODYSSEY Long-Term study is the longest study in the ODYSSEY phase III program,” said study investigator Dr. Helen Colhoun of the University of Dundee (Scotland). The primary endpoint was assessed at 24 weeks, but the trial ran for a further 54 weeks to gather as much lipid and general safety data as possible, she explained at the annual meeting of the European Association for the Study of Diabetes.
Alirocumab (Praulent) is a fully human monoclonal antibody that binds PCSK9 (proprotein convertase subtilisin/kexin type 9) that was recently approved by the Food and Drug Administration for use as an adjunct to diet and maximally tolerated statin therapy in people with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease who need additional LDL-cholesterol lowering.
The main results of the ODYSSEY Long-Term study were published in the New England Journal of Medicine in April (2015;372:1489-99 doi: 10.1056/NEJMoa1501031) and showed a –62% difference (P less than .001) in the mean percentage change from baseline in calculated LDL cholesterol between the alirocumab and placebo groups at 24 weeks. The difference remained consistent over the 78 weeks of follow-up.
Overall, the study included 2,341 individuals at high risk for cardiovascular disease with an LDL cholesterol level of more than 70 mg/dL despite being treated with maximally tolerated doses of statins with or without additional lipid-lowering therapy. Of these, just over one third of the population (35.7%, n = 838) had diabetes. Patients in the trial were randomized 2:1 to receive either alirocumab 150 mg or matching placebo as a 1-mL injection once every 2 weeks.
The present analysis looked at the long-term efficacy and safety of alirocumab in the diabetic subpopulation. Baseline demographic and lipid characteristics of the 838 patients with diabetes were broadly similar to the 1,503 patients in the trial who did not have diabetes, with mean ages of 61 and 60 years. Dr. Colhoun pointed out that virtually all patients (999; 100%) were taking a background statin, and well over one-third of those with diabetes and half of those without were taking a high-dose statin. Approximately 26% of the diabetic population were receiving insulin. Diabetic patients had slightly lower LDL cholesterol and higher triglycerides than their nondiabetic counterparts at baseline, as would be expected, she added.
Similarly high proportions of patients with (78.4% vs. 10.6%, P less than .0001) and without (79.7% vs. 6.6%, P less than .0001) diabetes who were treated with alirocumab vs. placebo achieved a target LDL cholesterol level of less than 70 mg/dL at 24 weeks.
Alirocumab treatment was associated with a 3.5% increase in HDL cholesterol in patients with diabetes and a 5.6% increase in those without, and triglycerides were reduced by a respective –18.5% and –16.7%. The adjusted mean differences in Lp(a) were –27.2% and –24.9%, an effect not seen with statins, Dr. Colhoun said.
“Overall the safety profile was excellent with this new class of drug, and there weren’t any major surprises or differences in safety profile between those with diabetes receiving alirocumab and those without diabetes,” she noted. Less than 10% of adverse events led to treatment discontinuation, at 8.3% vs. 5.0% for active and placebo treatment in the diabetic group and 6.5% vs. 6.3% in those without diabetes.
Data on the risk for new-onset or worsening diabetes in the ODYSSEY program will be presented at the scientific sessions of the American Heart Association in November, Dr. Colhoun said, giving a sneak peak of the findings from the ODYSSEY Long-Term study that indicated that there was no increased risk for either. Rates of new-onset diabetes were 1.8% in the alirocumab-treated group and 2% in the placebo group and of worsening diabetes, were 12.9% and 13.6%, respectively.
Treatment-emergent major cardiovascular events (MACE) were evaluated as a safety parameter in a post hoc analysis. Although not a main endpoint of the study, the results showed a lower rate of MACE in the overall population with alirocumab than placebo treatment (1.7% vs. 3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31-0.90) and in both diabetic (2.5% vs. 4.3%; HR, 0.58; 95% CI, 0.27-1.25) and nondiabetic subjects (1.3% vs. 2.8%; HR, 0.47; 95% CI, 0.22-1.0). “This is reassuring, but it is not by any means definitive evidence of a [cardiovascular disease] benefit,” Dr. Colhoun stressed.
The potential for alirocumab to reduce cardiovascular events will be investigated in the large, phase III ODYSSEY Outcomes study. This trial is currently recruiting and aims to accrue around 18,000 high-risk patients including those with diabetes. The study is projected to complete by the end of 2017.
AT EASD 2015
