AACE 2014

Treatment with saxagliptin was not associated with an increased risk of major adverse cardiovascular events or heart failure in a pooled analysis of 20 studies of patients with type 2 diabetes.

The analysis also found no association with saxagliptin therapy and individual components of the major adverse cardiovascular events (MACE) endpoint, a composite of cardiovascular death, myocardial infarction, and stroke, according to a study being presented at the meeting. The results were released May 15 at the annual meeting of the American Association of Clinical Endocrinologists in Las Vegas.

Saxagliptin, a dipeptidyl peptidase–4 (DPP-44) inhibitor taken orally, was approved by the Food and Drug Administration in 2009 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

The study evaluated adjudicated reports of MACE and investigator reports of heart failure associated with saxagliptin in 20 studies of saxagliptin as monotherapy or as add-on therapy in 9,156 patients with type 2 diabetes. Unlike the SAVOR-TIMI 53 study (Saxagliptin Assessment of Vascular Outcomes Recorded in Patient With Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) study, published in 2013, which found an increased risk of heart failure hospitalizations in patients with prior CV disease or multiple CV risk factors, the patients with type 2 diabetes enrolled in the 20 studies were at lower risk for CV events.

In the SAVOR-TIMI 53, which evaluated the drug’s cardiovascular safety in more than 16,000 patients with type 2 diabetes and established cardiovascular disease or risk factors for CHD, treatment with saxagliptin was not associated with an increased or reduced risk of ischemic risk for the composite of CV death, MI, or ischemic stroke, the primary endpoint, over a median of 2 years. But it was associated with a significantly greater risk of being hospitalized for heart failure (hazard ratio, 1.27) (N. Engl. J. Med. 2013;369:1317-26). In a January 2014 safety alert, the FDA said that the agency had requested the manufacturer of saxagliptin study “a possible association” between the use of the drug and heart failure, because of the increased risk of heart failure hospitalizations in that study.

In the 20-study analysis, based on 43 MACE reports in patients treated with saxagliptin and 31 MACE reports among controls, the MACE incidence rate (IR) – the number of events per 100 person-years – was 0.85/100 person-years for those on saxagliptin and 1.12/100 person-years for the controls. The IR ratio (the number of reports among saxagliptin-treated patients divided by the number of reports among the controls), was 0.74. The hazard ratio was 0.75, which suggests there is no increased risk of MACE associated with saxagliptin.

In a subset of 11 studies that evaluated saxagliptin as add-on therapy to metformin in 5,171 patients, the incidence rates were similar: 0.79/100 person-years for those on saxagliptin and 0.85/100 person-years for controls, with an IR ratio of 0.93.

In the 20 studies, the components of the MACE endpoint were also not statistically significantly different between those on saxagliptin and controls, and 21 patients on saxagliptin and 18 controls had heart failure, with an IR ratio of 0.55, he said.

Consistent with the SAVOR-TIMI 53 study, which analyzed MACE in patients with type 2 diabetes and cardiovascular disease or multiple cardiovascular risk factors, this 20-trial pooled analysis of patients from the general type 2 diabetes population found that saxagliptin was not associated with an increased risk of MACE or its components, or heart failure.

The pooled results “are somewhat reassuring in that the use of saxagliptin in patients with type 2 diabetes at lower risk for cardiovascular events is not associated with increased MACE risk,” and would have passed the FDA-recommended boundary for unacceptable risk for diabetes drugs (HR, 1.3), Dr. Sanjay Kaul said in an interview. However, he added, “it is disappointing that glycemic control did not translate into a macrovascular benefit, even though a lower risk population was evaluated.”

Moreover, the study “did not yield a sufficient number of heart failure events to reliably adjudicate the risk of heart failure in this patient population,” noted Dr. Kaul, professor of medicine, University of California, Los Angeles, who was not at the meeting. Dr. Kaul was a panelist at the FDA advisory panel meeting that reviewed the cardiovascular safety of rosiglitazone (Avandia) last year.

Three of the five authors are employed by Bristol-Myers Squibb; two are employed by AstraZeneca Dr. Kaul had no relevant disclosures related to saxagliptin; he has disclosures for diabetes agents manufactured by other companies.

Saxagliptin is marketed as Onglyza by AstraZeneca.

[email protected]

Treatment with saxagliptin was not associated with an increased risk of major adverse cardiovascular events or heart failure in a pooled analysis of 20 studies of patients with type 2 diabetes.

The analysis also found no association with saxagliptin therapy and individual components of the major adverse cardiovascular events (MACE) endpoint, a composite of cardiovascular death, myocardial infarction, and stroke, according to a study being presented at the meeting. The results were released May 15 at the annual meeting of the American Association of Clinical Endocrinologists in Las Vegas.

Saxagliptin, a dipeptidyl peptidase–4 (DPP-44) inhibitor taken orally, was approved by the Food and Drug Administration in 2009 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

The study evaluated adjudicated reports of MACE and investigator reports of heart failure associated with saxagliptin in 20 studies of saxagliptin as monotherapy or as add-on therapy in 9,156 patients with type 2 diabetes. Unlike the SAVOR-TIMI 53 study (Saxagliptin Assessment of Vascular Outcomes Recorded in Patient With Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) study, published in 2013, which found an increased risk of heart failure hospitalizations in patients with prior CV disease or multiple CV risk factors, the patients with type 2 diabetes enrolled in the 20 studies were at lower risk for CV events.

In the SAVOR-TIMI 53, which evaluated the drug’s cardiovascular safety in more than 16,000 patients with type 2 diabetes and established cardiovascular disease or risk factors for CHD, treatment with saxagliptin was not associated with an increased or reduced risk of ischemic risk for the composite of CV death, MI, or ischemic stroke, the primary endpoint, over a median of 2 years. But it was associated with a significantly greater risk of being hospitalized for heart failure (hazard ratio, 1.27) (N. Engl. J. Med. 2013;369:1317-26). In a January 2014 safety alert, the FDA said that the agency had requested the manufacturer of saxagliptin study “a possible association” between the use of the drug and heart failure, because of the increased risk of heart failure hospitalizations in that study.

In the 20-study analysis, based on 43 MACE reports in patients treated with saxagliptin and 31 MACE reports among controls, the MACE incidence rate (IR) – the number of events per 100 person-years – was 0.85/100 person-years for those on saxagliptin and 1.12/100 person-years for the controls. The IR ratio (the number of reports among saxagliptin-treated patients divided by the number of reports among the controls), was 0.74. The hazard ratio was 0.75, which suggests there is no increased risk of MACE associated with saxagliptin.

In a subset of 11 studies that evaluated saxagliptin as add-on therapy to metformin in 5,171 patients, the incidence rates were similar: 0.79/100 person-years for those on saxagliptin and 0.85/100 person-years for controls, with an IR ratio of 0.93.

In the 20 studies, the components of the MACE endpoint were also not statistically significantly different between those on saxagliptin and controls, and 21 patients on saxagliptin and 18 controls had heart failure, with an IR ratio of 0.55, he said.

Consistent with the SAVOR-TIMI 53 study, which analyzed MACE in patients with type 2 diabetes and cardiovascular disease or multiple cardiovascular risk factors, this 20-trial pooled analysis of patients from the general type 2 diabetes population found that saxagliptin was not associated with an increased risk of MACE or its components, or heart failure.

The pooled results “are somewhat reassuring in that the use of saxagliptin in patients with type 2 diabetes at lower risk for cardiovascular events is not associated with increased MACE risk,” and would have passed the FDA-recommended boundary for unacceptable risk for diabetes drugs (HR, 1.3), Dr. Sanjay Kaul said in an interview. However, he added, “it is disappointing that glycemic control did not translate into a macrovascular benefit, even though a lower risk population was evaluated.”

Moreover, the study “did not yield a sufficient number of heart failure events to reliably adjudicate the risk of heart failure in this patient population,” noted Dr. Kaul, professor of medicine, University of California, Los Angeles, who was not at the meeting. Dr. Kaul was a panelist at the FDA advisory panel meeting that reviewed the cardiovascular safety of rosiglitazone (Avandia) last year.

Three of the five authors are employed by Bristol-Myers Squibb; two are employed by AstraZeneca Dr. Kaul had no relevant disclosures related to saxagliptin; he has disclosures for diabetes agents manufactured by other companies.

Saxagliptin is marketed as Onglyza by AstraZeneca.

[email protected]

Treatment with saxagliptin was not associated with an increased risk of major adverse cardiovascular events or heart failure in a pooled analysis of 20 studies of patients with type 2 diabetes.

The analysis also found no association with saxagliptin therapy and individual components of the major adverse cardiovascular events (MACE) endpoint, a composite of cardiovascular death, myocardial infarction, and stroke, according to a study being presented at the meeting. The results were released May 15 at the annual meeting of the American Association of Clinical Endocrinologists in Las Vegas.

Saxagliptin, a dipeptidyl peptidase–4 (DPP-44) inhibitor taken orally, was approved by the Food and Drug Administration in 2009 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

The study evaluated adjudicated reports of MACE and investigator reports of heart failure associated with saxagliptin in 20 studies of saxagliptin as monotherapy or as add-on therapy in 9,156 patients with type 2 diabetes. Unlike the SAVOR-TIMI 53 study (Saxagliptin Assessment of Vascular Outcomes Recorded in Patient With Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) study, published in 2013, which found an increased risk of heart failure hospitalizations in patients with prior CV disease or multiple CV risk factors, the patients with type 2 diabetes enrolled in the 20 studies were at lower risk for CV events.

In the SAVOR-TIMI 53, which evaluated the drug’s cardiovascular safety in more than 16,000 patients with type 2 diabetes and established cardiovascular disease or risk factors for CHD, treatment with saxagliptin was not associated with an increased or reduced risk of ischemic risk for the composite of CV death, MI, or ischemic stroke, the primary endpoint, over a median of 2 years. But it was associated with a significantly greater risk of being hospitalized for heart failure (hazard ratio, 1.27) (N. Engl. J. Med. 2013;369:1317-26). In a January 2014 safety alert, the FDA said that the agency had requested the manufacturer of saxagliptin study “a possible association” between the use of the drug and heart failure, because of the increased risk of heart failure hospitalizations in that study.

In the 20-study analysis, based on 43 MACE reports in patients treated with saxagliptin and 31 MACE reports among controls, the MACE incidence rate (IR) – the number of events per 100 person-years – was 0.85/100 person-years for those on saxagliptin and 1.12/100 person-years for the controls. The IR ratio (the number of reports among saxagliptin-treated patients divided by the number of reports among the controls), was 0.74. The hazard ratio was 0.75, which suggests there is no increased risk of MACE associated with saxagliptin.

In a subset of 11 studies that evaluated saxagliptin as add-on therapy to metformin in 5,171 patients, the incidence rates were similar: 0.79/100 person-years for those on saxagliptin and 0.85/100 person-years for controls, with an IR ratio of 0.93.

In the 20 studies, the components of the MACE endpoint were also not statistically significantly different between those on saxagliptin and controls, and 21 patients on saxagliptin and 18 controls had heart failure, with an IR ratio of 0.55, he said.

Consistent with the SAVOR-TIMI 53 study, which analyzed MACE in patients with type 2 diabetes and cardiovascular disease or multiple cardiovascular risk factors, this 20-trial pooled analysis of patients from the general type 2 diabetes population found that saxagliptin was not associated with an increased risk of MACE or its components, or heart failure.

The pooled results “are somewhat reassuring in that the use of saxagliptin in patients with type 2 diabetes at lower risk for cardiovascular events is not associated with increased MACE risk,” and would have passed the FDA-recommended boundary for unacceptable risk for diabetes drugs (HR, 1.3), Dr. Sanjay Kaul said in an interview. However, he added, “it is disappointing that glycemic control did not translate into a macrovascular benefit, even though a lower risk population was evaluated.”

Moreover, the study “did not yield a sufficient number of heart failure events to reliably adjudicate the risk of heart failure in this patient population,” noted Dr. Kaul, professor of medicine, University of California, Los Angeles, who was not at the meeting. Dr. Kaul was a panelist at the FDA advisory panel meeting that reviewed the cardiovascular safety of rosiglitazone (Avandia) last year.

Three of the five authors are employed by Bristol-Myers Squibb; two are employed by AstraZeneca Dr. Kaul had no relevant disclosures related to saxagliptin; he has disclosures for diabetes agents manufactured by other companies.

Saxagliptin is marketed as Onglyza by AstraZeneca.

[email protected]

Treatment with empagliflozin, an investigational sodium-glucose cotransporter 2 (SGLT2) inhibitor, was associated with benefits for blood pressure as well as glycemic control in a 3-month study of more than 800 patients with type 2 diabetes and hypertension.

The study results were released May 15 at the annual meeting of the American Association of Clinical Endocrinologists, held in Las Vegas, by Dr. Afshin Salsali, an endocrinologist and executive director, diabetes and metabolism, at Boehringer Ingelheim Pharmaceuticals, the manufacturer of the drug.

Since hypertension is common among patients with type 2 diabetes and is associated with diabetes-related complications, a treatment approach that includes control of blood pressure and hyperglycemia might reduce the risk of cardiovascular complications and mortality in these patients, Dr. Salsali said in an interview before the meeting.

In the phase III randomized, controlled study, 823 patients were treated with either 10 mg of empagliflozin (276 patients), 25 mg of empagliflozin (276), or placebo (271), once a day for 12 weeks. At baseline, the patients’ mean seated systolic and diastolic blood pressures were 130-159 mm Hg and 80-99 mm Hg, respectively; their mean age was 60 years; and their mean body mass index was about 33 kg/m², in the obese category.

The two primary endpoints were changes from baseline in hemoglobin A_1c and mean 24-hour systolic blood pressure as measured by ambulatory blood pressure monitoring, at week 12.

At 12 weeks, the mean reductions in HbA_1c from baseline over placebo were 0.62% for those on the 10-mg dose and 0.65% among those on the 25-mg dose, both significant differences. The reductions in mean 24-hour systolic blood pressure were also significant, compared with placebo: They were 3.44 mm Hg with the 10-mg dose and 4.16 mm Hg with the 25-mg dose, according to Dr. Salsali.

In addition, the mean reductions from baseline in 24-hour diastolic blood pressure were significant at week 12, compared with placebo, a secondary endpoint. Those reductions were 1.36 mm Hg for patients on the 10-mg dose and 1.72 mm Hg for those on the 25-mg dose.

About half of the patients in each group reported adverse events. "Events consistent with volume depletion" were reported in one patient on the 10-mg dose of empagliflozin and one in the placebo group.

This study is unique because it utilized the gold standard for monitoring blood pressure to evaluate the effects of the drug on blood pressure, Dr. Salsali said.

Currently, empagliflozin is approved only in Australia, and it is under review in the United States and Europe. In March, Boehringer Ingelheim and Eli Lilly announced that the Food and Drug Administration had issued a complete response letter stating that deficiencies at a site where empagliflozin would be manufactured needed to be resolved before approval. But the FDA has not requested that any new clinical trials be completed for approval, according to the statement issued by Boehringer Ingelheim.

In March, the drug was recommended for approval by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency for treating adults with type 2 diabetes.

In January, the FDA approved the SGLT2 inhibitor dapagliflozin for the treatment of type 2 diabetes. The first drug in this class to be approved in the United States was canagliflozin (Invokana), approved in March 2013. These agents, taken orally, work by inhibiting SGLT2 that is expressed in the kidney, reducing renal glucose reabsorption, increasing urinary excretion of glucose, and reducing plasma glucose levels.

The study was sponsored by Boehringer Ingelheim; Eli Lilly was a collaborator. Dr. Salsali is an employee of Boehringer Ingelheim USA. Other authors of the study included employees of Boehringer Ingelheim, including Boehringer Ingelheim Finland.

[email protected]

Treatment with empagliflozin, an investigational sodium-glucose cotransporter 2 (SGLT2) inhibitor, was associated with benefits for blood pressure as well as glycemic control in a 3-month study of more than 800 patients with type 2 diabetes and hypertension.

The study results were released May 15 at the annual meeting of the American Association of Clinical Endocrinologists, held in Las Vegas, by Dr. Afshin Salsali, an endocrinologist and executive director, diabetes and metabolism, at Boehringer Ingelheim Pharmaceuticals, the manufacturer of the drug.

Since hypertension is common among patients with type 2 diabetes and is associated with diabetes-related complications, a treatment approach that includes control of blood pressure and hyperglycemia might reduce the risk of cardiovascular complications and mortality in these patients, Dr. Salsali said in an interview before the meeting.

In the phase III randomized, controlled study, 823 patients were treated with either 10 mg of empagliflozin (276 patients), 25 mg of empagliflozin (276), or placebo (271), once a day for 12 weeks. At baseline, the patients’ mean seated systolic and diastolic blood pressures were 130-159 mm Hg and 80-99 mm Hg, respectively; their mean age was 60 years; and their mean body mass index was about 33 kg/m², in the obese category.

The two primary endpoints were changes from baseline in hemoglobin A_1c and mean 24-hour systolic blood pressure as measured by ambulatory blood pressure monitoring, at week 12.

At 12 weeks, the mean reductions in HbA_1c from baseline over placebo were 0.62% for those on the 10-mg dose and 0.65% among those on the 25-mg dose, both significant differences. The reductions in mean 24-hour systolic blood pressure were also significant, compared with placebo: They were 3.44 mm Hg with the 10-mg dose and 4.16 mm Hg with the 25-mg dose, according to Dr. Salsali.

In addition, the mean reductions from baseline in 24-hour diastolic blood pressure were significant at week 12, compared with placebo, a secondary endpoint. Those reductions were 1.36 mm Hg for patients on the 10-mg dose and 1.72 mm Hg for those on the 25-mg dose.

About half of the patients in each group reported adverse events. "Events consistent with volume depletion" were reported in one patient on the 10-mg dose of empagliflozin and one in the placebo group.

This study is unique because it utilized the gold standard for monitoring blood pressure to evaluate the effects of the drug on blood pressure, Dr. Salsali said.

Currently, empagliflozin is approved only in Australia, and it is under review in the United States and Europe. In March, Boehringer Ingelheim and Eli Lilly announced that the Food and Drug Administration had issued a complete response letter stating that deficiencies at a site where empagliflozin would be manufactured needed to be resolved before approval. But the FDA has not requested that any new clinical trials be completed for approval, according to the statement issued by Boehringer Ingelheim.

In March, the drug was recommended for approval by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency for treating adults with type 2 diabetes.

In January, the FDA approved the SGLT2 inhibitor dapagliflozin for the treatment of type 2 diabetes. The first drug in this class to be approved in the United States was canagliflozin (Invokana), approved in March 2013. These agents, taken orally, work by inhibiting SGLT2 that is expressed in the kidney, reducing renal glucose reabsorption, increasing urinary excretion of glucose, and reducing plasma glucose levels.

The study was sponsored by Boehringer Ingelheim; Eli Lilly was a collaborator. Dr. Salsali is an employee of Boehringer Ingelheim USA. Other authors of the study included employees of Boehringer Ingelheim, including Boehringer Ingelheim Finland.

[email protected]

Treatment with empagliflozin, an investigational sodium-glucose cotransporter 2 (SGLT2) inhibitor, was associated with benefits for blood pressure as well as glycemic control in a 3-month study of more than 800 patients with type 2 diabetes and hypertension.

The study results were released May 15 at the annual meeting of the American Association of Clinical Endocrinologists, held in Las Vegas, by Dr. Afshin Salsali, an endocrinologist and executive director, diabetes and metabolism, at Boehringer Ingelheim Pharmaceuticals, the manufacturer of the drug.

Since hypertension is common among patients with type 2 diabetes and is associated with diabetes-related complications, a treatment approach that includes control of blood pressure and hyperglycemia might reduce the risk of cardiovascular complications and mortality in these patients, Dr. Salsali said in an interview before the meeting.

In the phase III randomized, controlled study, 823 patients were treated with either 10 mg of empagliflozin (276 patients), 25 mg of empagliflozin (276), or placebo (271), once a day for 12 weeks. At baseline, the patients’ mean seated systolic and diastolic blood pressures were 130-159 mm Hg and 80-99 mm Hg, respectively; their mean age was 60 years; and their mean body mass index was about 33 kg/m², in the obese category.

The two primary endpoints were changes from baseline in hemoglobin A_1c and mean 24-hour systolic blood pressure as measured by ambulatory blood pressure monitoring, at week 12.

At 12 weeks, the mean reductions in HbA_1c from baseline over placebo were 0.62% for those on the 10-mg dose and 0.65% among those on the 25-mg dose, both significant differences. The reductions in mean 24-hour systolic blood pressure were also significant, compared with placebo: They were 3.44 mm Hg with the 10-mg dose and 4.16 mm Hg with the 25-mg dose, according to Dr. Salsali.

In addition, the mean reductions from baseline in 24-hour diastolic blood pressure were significant at week 12, compared with placebo, a secondary endpoint. Those reductions were 1.36 mm Hg for patients on the 10-mg dose and 1.72 mm Hg for those on the 25-mg dose.

About half of the patients in each group reported adverse events. "Events consistent with volume depletion" were reported in one patient on the 10-mg dose of empagliflozin and one in the placebo group.

This study is unique because it utilized the gold standard for monitoring blood pressure to evaluate the effects of the drug on blood pressure, Dr. Salsali said.

Currently, empagliflozin is approved only in Australia, and it is under review in the United States and Europe. In March, Boehringer Ingelheim and Eli Lilly announced that the Food and Drug Administration had issued a complete response letter stating that deficiencies at a site where empagliflozin would be manufactured needed to be resolved before approval. But the FDA has not requested that any new clinical trials be completed for approval, according to the statement issued by Boehringer Ingelheim.

In March, the drug was recommended for approval by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency for treating adults with type 2 diabetes.

In January, the FDA approved the SGLT2 inhibitor dapagliflozin for the treatment of type 2 diabetes. The first drug in this class to be approved in the United States was canagliflozin (Invokana), approved in March 2013. These agents, taken orally, work by inhibiting SGLT2 that is expressed in the kidney, reducing renal glucose reabsorption, increasing urinary excretion of glucose, and reducing plasma glucose levels.

The study was sponsored by Boehringer Ingelheim; Eli Lilly was a collaborator. Dr. Salsali is an employee of Boehringer Ingelheim USA. Other authors of the study included employees of Boehringer Ingelheim, including Boehringer Ingelheim Finland.

[email protected]