ELIXA trial: No cardiovascular risk with GLP-1 receptor agonist lixisenatide

BOSTON – The glucagon-like peptide 1 (GLP-1) receptor agonist lixisenatide does not increase the risk for cardiovascular problems in diabetic patients, according to findings from the first cardiovascular disease outcomes trial for this widely prescribed class of glucose-lowering drugs.

The findings of the randomized, placebo-controlled Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial, presented at the annual scientific sessions of the American Diabetes Association, dissipate the “cloud of suspicion” that has cast a shadow over GLP-1 agonists with regard to their possible effects on cardiovascular risk, the investigators said.

“We have shown that patients and their health care providers should have no cause for concern, even if they are at high risk of heart-related problems,” said principal investigator Dr. Marc Pfeffer, professor of medicine at Harvard University and senior physician in the division of cardiology at Brigham and Women’s Hospital, Boston.

Dr. Pfeffer and his colleagues studied 6,068 patients who were randomized to receive placebo or lixisenatide (Lyxumia), which is investigational in the United States but approved in more than 50 countries worldwide. The study subjects were followed for a mean of 2.1 years.

The composite primary outcome of cardiovascular death, myocardial infarction, stroke, or unstable angina occurred in 399 of 3,304 placebo-group patients (13.2%) and in 406 of 3,034 treatment-group patients (13.4%; hazard ratio, 1.02), Dr. Pfeffer said.

No difference was seen between the groups for any of the individual components of the composite outcome (HR: 0.98 for cardiovascular death, 1.03 for MI, 1.12 for stroke, and 1.11 for unstable angina), and no differences were seen based on sex, age, race, or region.

“No sign of interactions, and no patterns emerged in older patients or sicker patients,” Dr. Pfeffer added.

Heart failure, which is “a very important outcome,” did occur more often in those with heart failure prior to randomization, but again, the outcomes did not differ between the placebo and treatment group (HR, 0.97 for cardiovascular death plus heart failure hospitalization), he noted.

All-cause death also occurred at a similar rate in both groups: 7.4% and 7% for the placebo vs. treatment groups (HR, 0.94).

Treatment can confidently be said to be safe, as well as neutral, with respect to the various outcome measures, he said.

Dr. Matthew Riddle of Oregon Health and Science University, Portland, further reported that patients in the lixisenatide group were more likely than those who received placebo to experience a modest benefit in terms of weight. Those in the treatment group did not gain weight, while those in the placebo group did (–0.7 kg between-group difference from baseline), he said, noting that this is a finding that “has some possibility of clinical relevance.”

A similar pattern was seen with systolic blood pressure, with treatment-group patients experiencing a modest but statistically significant improvement (–0.8 mm Hg between-group difference from baseline).

The treatment-group patients were not more likely than those who received placebo to experience hypoglycemia, despite better glucose control, nor were they more likely to experience pancreatitis or pancreatic cancer, he said.

A modest significant difference was seen with respect to HbA_1c levels and fasting plasma glucose with treatment vs. placebo (–0.27% mean postbaseline difference for each).

Patients included in the ELIXA trial were adults over age 30 years who had experienced a recent acute coronary syndrome event. They were enrolled from 782 sites in 49 countries within 180 days (mean, 72 days) of the event, which was MI in most cases.

Patients received a single injection each day of either lixisenatide or volume-matched placebo before breakfast. The dosage could be titrated up from 10 mcg to 20 mcg, or down for those not able to tolerate the full dose. Other than adjustments to prevent hypoglycemia, local standards of care for lifestyle, glycemic targets, and risk factor management were followed.

At least one adverse event was reported by 77% and 81% of placebo and treatment-group patients, with nausea and vomiting – common side effects for GLP-1 agonists – accounting for most of the difference. No difference was seen between the groups with respect to serious adverse events (22% in each arm reported serious events).

Adverse events, however, led to treatment discontinuation in 7.2% of placebo-group patients, compared with 11.4% of lixisenatide-group patients.

The findings confirm that lixisenatide does not increase the risk of major adverse cardiac events, and no signal was seen for pancreatic cancer, pancreatitis, other cancers, or heart failure, said discussant Dr. Silvio Inzucchi, professor of medicine and director of the Yale Diabetes Center at Yale University in New Haven, Conn., who was invited by the ADA to comment on the findings.

As for whether the ELIXA trial represents a high-quality study with believable results and an important endpoint, “the answer is a resounding yes,” he said.

Lixisenatide was approved in Europe in 2013 for the treatment of adults with type 2 diabetes mellitus to achieve glycemic control in combination with oral glucose-lowering medical products and/or basal insulin when these, together with diet and exercise, do not provide adequate glycemic control.

According to Sanofi, a New Drug Application for lixisenatide is on track to be resubmitted to the Food and Drug Administration in the third quarter of 2015. An initial application was accepted for review in 2013, but Sanofi delayed the approval process based on concerns regarding cardiovascular risk. The application to be resubmitted later this year will include findings from the GetGoal Duo-2 clinical trial, which were reported in a poster at the ADA meeting; all coprimary endpoints in the 26-week, randomized, open-label trial were met, reported Dr. Julio Rosenstock, director of the Dallas Diabetes and Endocrine Center.

In GetGoal Duo-2, lixisenatide was compared as a once-daily 20 mcg add-on to optimally titrated insulin glargine with or without metformin vs. the addition of rapid-acting insulin glulisine with or without metformin injected once daily at the time of the patient’s main meal (basal-plus), or three times daily at meal time (basal-bolus). Subjects were adults with poorly controlled diabetes on basal insulin with or without oral antidiabetic drugs for at least 6 months.

In 890 patients included in an intention-to-treat analysis, lixisenatide was noninferior to both comparator insulin regimens for reducing HbA_1c levels (mean difference, –0.05% vs. basal plus and 0.21% vs. basal bolus), and was shown to be statistically superior to basal-bolus for body weight change (mean difference, –2 kg), Dr. Rosenstock said.

Postprandial glucose also was significantly reduced with lixisenatide vs. both insulin glulisine regimens (mean difference, –37 mg/dL vs. basal plus and –40 mg/dL vs. basal bolus), as was hypoglycemia (estimated rate ratios, 0.8 and 0.5, respectively).

Nausea occurred in 25% of the lixisenatide patients vs. 1% and 2% of the basal plus and basal bolus patients, respectively, and vomiting and diarrhea occurred in 9% and 7%, respectively, of the lixisenatide patients.

Both lixisenatide studies were sponsored by Sanofi. Dr. Pfeffer reported receiving honoraria and/or research grants from, or serving as a consultant for, Aastrom, Amgen, Bristol-Myers Squibb, Celladon, Concert, Hamilton Health Sciences, Keryx, Medtronic, Merck, Novartis, Roche, Sanofi-Aventis, Servier, Teva, University of Oxford, and Xoma. The Brigham and Women’s Hospital has patents for the use of inhibitors of the renin-angiotensin system in survivors of MI with Novartis.

sworcester@frontlinemedcom.com

BOSTON – The glucagon-like peptide 1 (GLP-1) receptor agonist lixisenatide does not increase the risk for cardiovascular problems in diabetic patients, according to findings from the first cardiovascular disease outcomes trial for this widely prescribed class of glucose-lowering drugs.

The findings of the randomized, placebo-controlled Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial, presented at the annual scientific sessions of the American Diabetes Association, dissipate the “cloud of suspicion” that has cast a shadow over GLP-1 agonists with regard to their possible effects on cardiovascular risk, the investigators said.

“We have shown that patients and their health care providers should have no cause for concern, even if they are at high risk of heart-related problems,” said principal investigator Dr. Marc Pfeffer, professor of medicine at Harvard University and senior physician in the division of cardiology at Brigham and Women’s Hospital, Boston.

Dr. Pfeffer and his colleagues studied 6,068 patients who were randomized to receive placebo or lixisenatide (Lyxumia), which is investigational in the United States but approved in more than 50 countries worldwide. The study subjects were followed for a mean of 2.1 years.

The composite primary outcome of cardiovascular death, myocardial infarction, stroke, or unstable angina occurred in 399 of 3,304 placebo-group patients (13.2%) and in 406 of 3,034 treatment-group patients (13.4%; hazard ratio, 1.02), Dr. Pfeffer said.

No difference was seen between the groups for any of the individual components of the composite outcome (HR: 0.98 for cardiovascular death, 1.03 for MI, 1.12 for stroke, and 1.11 for unstable angina), and no differences were seen based on sex, age, race, or region.

“No sign of interactions, and no patterns emerged in older patients or sicker patients,” Dr. Pfeffer added.

Heart failure, which is “a very important outcome,” did occur more often in those with heart failure prior to randomization, but again, the outcomes did not differ between the placebo and treatment group (HR, 0.97 for cardiovascular death plus heart failure hospitalization), he noted.

All-cause death also occurred at a similar rate in both groups: 7.4% and 7% for the placebo vs. treatment groups (HR, 0.94).

Treatment can confidently be said to be safe, as well as neutral, with respect to the various outcome measures, he said.

Dr. Matthew Riddle of Oregon Health and Science University, Portland, further reported that patients in the lixisenatide group were more likely than those who received placebo to experience a modest benefit in terms of weight. Those in the treatment group did not gain weight, while those in the placebo group did (–0.7 kg between-group difference from baseline), he said, noting that this is a finding that “has some possibility of clinical relevance.”

A similar pattern was seen with systolic blood pressure, with treatment-group patients experiencing a modest but statistically significant improvement (–0.8 mm Hg between-group difference from baseline).

The treatment-group patients were not more likely than those who received placebo to experience hypoglycemia, despite better glucose control, nor were they more likely to experience pancreatitis or pancreatic cancer, he said.

A modest significant difference was seen with respect to HbA_1c levels and fasting plasma glucose with treatment vs. placebo (–0.27% mean postbaseline difference for each).

Patients included in the ELIXA trial were adults over age 30 years who had experienced a recent acute coronary syndrome event. They were enrolled from 782 sites in 49 countries within 180 days (mean, 72 days) of the event, which was MI in most cases.

Patients received a single injection each day of either lixisenatide or volume-matched placebo before breakfast. The dosage could be titrated up from 10 mcg to 20 mcg, or down for those not able to tolerate the full dose. Other than adjustments to prevent hypoglycemia, local standards of care for lifestyle, glycemic targets, and risk factor management were followed.

At least one adverse event was reported by 77% and 81% of placebo and treatment-group patients, with nausea and vomiting – common side effects for GLP-1 agonists – accounting for most of the difference. No difference was seen between the groups with respect to serious adverse events (22% in each arm reported serious events).

Adverse events, however, led to treatment discontinuation in 7.2% of placebo-group patients, compared with 11.4% of lixisenatide-group patients.

The findings confirm that lixisenatide does not increase the risk of major adverse cardiac events, and no signal was seen for pancreatic cancer, pancreatitis, other cancers, or heart failure, said discussant Dr. Silvio Inzucchi, professor of medicine and director of the Yale Diabetes Center at Yale University in New Haven, Conn., who was invited by the ADA to comment on the findings.

As for whether the ELIXA trial represents a high-quality study with believable results and an important endpoint, “the answer is a resounding yes,” he said.

Lixisenatide was approved in Europe in 2013 for the treatment of adults with type 2 diabetes mellitus to achieve glycemic control in combination with oral glucose-lowering medical products and/or basal insulin when these, together with diet and exercise, do not provide adequate glycemic control.

According to Sanofi, a New Drug Application for lixisenatide is on track to be resubmitted to the Food and Drug Administration in the third quarter of 2015. An initial application was accepted for review in 2013, but Sanofi delayed the approval process based on concerns regarding cardiovascular risk. The application to be resubmitted later this year will include findings from the GetGoal Duo-2 clinical trial, which were reported in a poster at the ADA meeting; all coprimary endpoints in the 26-week, randomized, open-label trial were met, reported Dr. Julio Rosenstock, director of the Dallas Diabetes and Endocrine Center.

In GetGoal Duo-2, lixisenatide was compared as a once-daily 20 mcg add-on to optimally titrated insulin glargine with or without metformin vs. the addition of rapid-acting insulin glulisine with or without metformin injected once daily at the time of the patient’s main meal (basal-plus), or three times daily at meal time (basal-bolus). Subjects were adults with poorly controlled diabetes on basal insulin with or without oral antidiabetic drugs for at least 6 months.

In 890 patients included in an intention-to-treat analysis, lixisenatide was noninferior to both comparator insulin regimens for reducing HbA_1c levels (mean difference, –0.05% vs. basal plus and 0.21% vs. basal bolus), and was shown to be statistically superior to basal-bolus for body weight change (mean difference, –2 kg), Dr. Rosenstock said.

Postprandial glucose also was significantly reduced with lixisenatide vs. both insulin glulisine regimens (mean difference, –37 mg/dL vs. basal plus and –40 mg/dL vs. basal bolus), as was hypoglycemia (estimated rate ratios, 0.8 and 0.5, respectively).

Nausea occurred in 25% of the lixisenatide patients vs. 1% and 2% of the basal plus and basal bolus patients, respectively, and vomiting and diarrhea occurred in 9% and 7%, respectively, of the lixisenatide patients.

Both lixisenatide studies were sponsored by Sanofi. Dr. Pfeffer reported receiving honoraria and/or research grants from, or serving as a consultant for, Aastrom, Amgen, Bristol-Myers Squibb, Celladon, Concert, Hamilton Health Sciences, Keryx, Medtronic, Merck, Novartis, Roche, Sanofi-Aventis, Servier, Teva, University of Oxford, and Xoma. The Brigham and Women’s Hospital has patents for the use of inhibitors of the renin-angiotensin system in survivors of MI with Novartis.

sworcester@frontlinemedcom.com

BOSTON – The glucagon-like peptide 1 (GLP-1) receptor agonist lixisenatide does not increase the risk for cardiovascular problems in diabetic patients, according to findings from the first cardiovascular disease outcomes trial for this widely prescribed class of glucose-lowering drugs.

The findings of the randomized, placebo-controlled Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial, presented at the annual scientific sessions of the American Diabetes Association, dissipate the “cloud of suspicion” that has cast a shadow over GLP-1 agonists with regard to their possible effects on cardiovascular risk, the investigators said.

“We have shown that patients and their health care providers should have no cause for concern, even if they are at high risk of heart-related problems,” said principal investigator Dr. Marc Pfeffer, professor of medicine at Harvard University and senior physician in the division of cardiology at Brigham and Women’s Hospital, Boston.

Dr. Pfeffer and his colleagues studied 6,068 patients who were randomized to receive placebo or lixisenatide (Lyxumia), which is investigational in the United States but approved in more than 50 countries worldwide. The study subjects were followed for a mean of 2.1 years.

The composite primary outcome of cardiovascular death, myocardial infarction, stroke, or unstable angina occurred in 399 of 3,304 placebo-group patients (13.2%) and in 406 of 3,034 treatment-group patients (13.4%; hazard ratio, 1.02), Dr. Pfeffer said.

No difference was seen between the groups for any of the individual components of the composite outcome (HR: 0.98 for cardiovascular death, 1.03 for MI, 1.12 for stroke, and 1.11 for unstable angina), and no differences were seen based on sex, age, race, or region.

“No sign of interactions, and no patterns emerged in older patients or sicker patients,” Dr. Pfeffer added.

Heart failure, which is “a very important outcome,” did occur more often in those with heart failure prior to randomization, but again, the outcomes did not differ between the placebo and treatment group (HR, 0.97 for cardiovascular death plus heart failure hospitalization), he noted.

All-cause death also occurred at a similar rate in both groups: 7.4% and 7% for the placebo vs. treatment groups (HR, 0.94).

Treatment can confidently be said to be safe, as well as neutral, with respect to the various outcome measures, he said.

Dr. Matthew Riddle of Oregon Health and Science University, Portland, further reported that patients in the lixisenatide group were more likely than those who received placebo to experience a modest benefit in terms of weight. Those in the treatment group did not gain weight, while those in the placebo group did (–0.7 kg between-group difference from baseline), he said, noting that this is a finding that “has some possibility of clinical relevance.”

A similar pattern was seen with systolic blood pressure, with treatment-group patients experiencing a modest but statistically significant improvement (–0.8 mm Hg between-group difference from baseline).

The treatment-group patients were not more likely than those who received placebo to experience hypoglycemia, despite better glucose control, nor were they more likely to experience pancreatitis or pancreatic cancer, he said.

A modest significant difference was seen with respect to HbA_1c levels and fasting plasma glucose with treatment vs. placebo (–0.27% mean postbaseline difference for each).

Patients included in the ELIXA trial were adults over age 30 years who had experienced a recent acute coronary syndrome event. They were enrolled from 782 sites in 49 countries within 180 days (mean, 72 days) of the event, which was MI in most cases.

Patients received a single injection each day of either lixisenatide or volume-matched placebo before breakfast. The dosage could be titrated up from 10 mcg to 20 mcg, or down for those not able to tolerate the full dose. Other than adjustments to prevent hypoglycemia, local standards of care for lifestyle, glycemic targets, and risk factor management were followed.

At least one adverse event was reported by 77% and 81% of placebo and treatment-group patients, with nausea and vomiting – common side effects for GLP-1 agonists – accounting for most of the difference. No difference was seen between the groups with respect to serious adverse events (22% in each arm reported serious events).

Adverse events, however, led to treatment discontinuation in 7.2% of placebo-group patients, compared with 11.4% of lixisenatide-group patients.

The findings confirm that lixisenatide does not increase the risk of major adverse cardiac events, and no signal was seen for pancreatic cancer, pancreatitis, other cancers, or heart failure, said discussant Dr. Silvio Inzucchi, professor of medicine and director of the Yale Diabetes Center at Yale University in New Haven, Conn., who was invited by the ADA to comment on the findings.

As for whether the ELIXA trial represents a high-quality study with believable results and an important endpoint, “the answer is a resounding yes,” he said.

Lixisenatide was approved in Europe in 2013 for the treatment of adults with type 2 diabetes mellitus to achieve glycemic control in combination with oral glucose-lowering medical products and/or basal insulin when these, together with diet and exercise, do not provide adequate glycemic control.

According to Sanofi, a New Drug Application for lixisenatide is on track to be resubmitted to the Food and Drug Administration in the third quarter of 2015. An initial application was accepted for review in 2013, but Sanofi delayed the approval process based on concerns regarding cardiovascular risk. The application to be resubmitted later this year will include findings from the GetGoal Duo-2 clinical trial, which were reported in a poster at the ADA meeting; all coprimary endpoints in the 26-week, randomized, open-label trial were met, reported Dr. Julio Rosenstock, director of the Dallas Diabetes and Endocrine Center.

In GetGoal Duo-2, lixisenatide was compared as a once-daily 20 mcg add-on to optimally titrated insulin glargine with or without metformin vs. the addition of rapid-acting insulin glulisine with or without metformin injected once daily at the time of the patient’s main meal (basal-plus), or three times daily at meal time (basal-bolus). Subjects were adults with poorly controlled diabetes on basal insulin with or without oral antidiabetic drugs for at least 6 months.

In 890 patients included in an intention-to-treat analysis, lixisenatide was noninferior to both comparator insulin regimens for reducing HbA_1c levels (mean difference, –0.05% vs. basal plus and 0.21% vs. basal bolus), and was shown to be statistically superior to basal-bolus for body weight change (mean difference, –2 kg), Dr. Rosenstock said.

Postprandial glucose also was significantly reduced with lixisenatide vs. both insulin glulisine regimens (mean difference, –37 mg/dL vs. basal plus and –40 mg/dL vs. basal bolus), as was hypoglycemia (estimated rate ratios, 0.8 and 0.5, respectively).

Nausea occurred in 25% of the lixisenatide patients vs. 1% and 2% of the basal plus and basal bolus patients, respectively, and vomiting and diarrhea occurred in 9% and 7%, respectively, of the lixisenatide patients.

Both lixisenatide studies were sponsored by Sanofi. Dr. Pfeffer reported receiving honoraria and/or research grants from, or serving as a consultant for, Aastrom, Amgen, Bristol-Myers Squibb, Celladon, Concert, Hamilton Health Sciences, Keryx, Medtronic, Merck, Novartis, Roche, Sanofi-Aventis, Servier, Teva, University of Oxford, and Xoma. The Brigham and Women’s Hospital has patents for the use of inhibitors of the renin-angiotensin system in survivors of MI with Novartis.

sworcester@frontlinemedcom.com