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Neither saxagliptin nor alogliptin was associated with increased – or decreased – rates of major adverse cardiovascular events in high-risk patients with type 2 diabetes mellitus in separate randomized, double-blind, placebo-controlled trials.
The findings with respect to these recently approved antidiabetic therapies – members of the same class of selective dipeptidyl peptidase–4 (DDP-4) inhibitors – provide clinicians with important information to help guide treatment decision-making for patients with type 2 diabetes and cardiovascular risk, the authors concluded.
Both studies were mandated by the Food and Drug Administration, which in 2008 began requiring all diabetes therapies to demonstrate cardiovascular safety after concerns were raised in 2007 about a link between rosiglitazone (Avandia) and an increased risk of myocardial infarction. The results were reported at the annual congress of the European Society of Cardiology, and were simultaneously published online Sept. 2 in the New England Journal of Medicine.
SAVOR-TIMI 53
SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) randomized 16,492 patients with type 2 diabetes and a history of established cardiovascular disease or multiple risk factors for vascular disease to either saxagliptin, doses ranging from 2.5 to 5 mg daily, or placebo.
The primary endpoint – a composite of cardiovascular death, myocardial infarction, or ischemic stroke – occurred at similar rates in 613 patients randomized to receive saxagliptin treatment and 609 patients randomized to receive placebo (7.3% and 7.2%, respectively) at a median follow-up of 2.1 years, Dr. Benjamin M. Scirica of Brigham and Women’s Hospital and Harvard Medical School, Boston, and his colleagues reported on behalf of the SAVOR-TIMI 53 Steering Committee and Investigators.
A major secondary endpoint – a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure – also occurred at similar rates in the treatment and placebo groups (12.8% and 12.4%, respectively), they reported (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMoa1307684]).
However, more patients in the treatment group than in the placebo group were hospitalized for heart failure (3.5% vs. 2.8%), they noted, adding that this was an unexpected finding that merits further study.
The findings demonstrate that DPP-4 inhibition with saxagliptin neither increases nor decreases the rate of ischemic events over a median 2-year period, although longer duration of treatment may have different effects.
"Together with ongoing trials of other DPP-4 inhibitors and novel antihyperglycemic agents, these data will provide a more rigorous and robust evidence base than is currently available to guide the future care of patients with diabetes," they concluded.
EXAMINE
Similarly, the EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial showed that the primary endpoint – a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke – did not occur significantly more often at a median follow-up of 18 months in 2,679 patients randomized to receive treatment, compared with 2,701 patients randomized to receive placebo (11.3% vs. 11.8%, respectively), Dr. William B. White of the University of Connecticut School of Medicine, Farmington, and his colleagues reported on behalf of the EXAMINE investigators.
Patients included in this noninferiority study had type 2 diabetes and a recent acute myocardial infarction or unstable angina requiring hospitalization, who received standard-of-care treatment for diabetes and cardiovascular risk factors throughout the study period. Alogliptin doses ranged from 6.25 to 25 mg daily on the basis of the patients’ estimated glomerular filtration rate at baseline.
"The alogliptin and placebo groups did not differ significantly with respect to the incidence of serious adverse events (33.6% and 35.5%, respectively)," the investigators wrote (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMoa1305889]).
In this group of patients at very high cardiovascular event risk, alogliptin did not increase or decrease cardiovascular morbidity or mortality over a median 18-month period; the findings do not rule out longer-term risks with respect to cardiovascular endpoints, they noted.
"These data can be used to help guide clinicians in choosing among the many available antidiabetic agents when treating patients with type 2 diabetes and very high cardiovascular risk," they concluded.
The SAVOR-TIMI 53 trial was supported by AstraZeneca and Bristol-Myers Squibb. The EXAMINE trial was supported by Takeda Development Center Americas. Multiple authors for both studies reported disclosures. Details are provided with the full text of each article at NEJM.org.
The findings of the SAVOR-TIMI 53 and EXAMINE trials show the relative safety of saxagliptin and alogliptin in terms of cardiovascular risk, but it is disappointing that neither the use of intensive glycemic control nor the use of these diabetes medications is associated with any suggestion of cardiovascular benefit.
These studies were required by the Food and Drug Administration to assess cardiovascular safety – a requirement for all new diabetes drugs that came in the wake of recently debunked concerns raised in 2007 regarding the safety of rosiglitazone. Perhaps the recent experience with rosiglitazone will allow the FDA to become more targeted in its adjudication of the cardiovascular safety of new diabetes drugs, focusing the considerable resources needed to rule out a cardiovascular concern only on drugs with clinical or preclinical justification for the expenditure.
Regardless, based on the SAVOR-TIMI 53 and EXAMINE findings, the use of glycated hemoglobin as a valid surrogate for assessing cardiovascular risk or benefit of diabetes therapy is not supported.
The optimal approach to the reduction of cardiovascular risk in diabetes should focus on aggressive management of the standard cardiovascular risk factors rather than on intensive glycemic control.
Dr. William R. Hiatt of the University of Colorado in Aurora, Dr. Sanjay Kaul of Cedars-Sinai Medical Center in Los Angeles, and Dr. Robert J. Smith of Brown University in Providence, R.I., made these comments in an editorial that accompanied the published versions of the SAVOR and EXAMINE reports (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMp1309610]). All reported having disclosures, and Dr. Hiatt served on the FDA advisory committee that reviewed rosiglitazone. Details are available with the full text of the editorial at NEJM.org.
The findings of the SAVOR-TIMI 53 and EXAMINE trials show the relative safety of saxagliptin and alogliptin in terms of cardiovascular risk, but it is disappointing that neither the use of intensive glycemic control nor the use of these diabetes medications is associated with any suggestion of cardiovascular benefit.
These studies were required by the Food and Drug Administration to assess cardiovascular safety – a requirement for all new diabetes drugs that came in the wake of recently debunked concerns raised in 2007 regarding the safety of rosiglitazone. Perhaps the recent experience with rosiglitazone will allow the FDA to become more targeted in its adjudication of the cardiovascular safety of new diabetes drugs, focusing the considerable resources needed to rule out a cardiovascular concern only on drugs with clinical or preclinical justification for the expenditure.
Regardless, based on the SAVOR-TIMI 53 and EXAMINE findings, the use of glycated hemoglobin as a valid surrogate for assessing cardiovascular risk or benefit of diabetes therapy is not supported.
The optimal approach to the reduction of cardiovascular risk in diabetes should focus on aggressive management of the standard cardiovascular risk factors rather than on intensive glycemic control.
Dr. William R. Hiatt of the University of Colorado in Aurora, Dr. Sanjay Kaul of Cedars-Sinai Medical Center in Los Angeles, and Dr. Robert J. Smith of Brown University in Providence, R.I., made these comments in an editorial that accompanied the published versions of the SAVOR and EXAMINE reports (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMp1309610]). All reported having disclosures, and Dr. Hiatt served on the FDA advisory committee that reviewed rosiglitazone. Details are available with the full text of the editorial at NEJM.org.
The findings of the SAVOR-TIMI 53 and EXAMINE trials show the relative safety of saxagliptin and alogliptin in terms of cardiovascular risk, but it is disappointing that neither the use of intensive glycemic control nor the use of these diabetes medications is associated with any suggestion of cardiovascular benefit.
These studies were required by the Food and Drug Administration to assess cardiovascular safety – a requirement for all new diabetes drugs that came in the wake of recently debunked concerns raised in 2007 regarding the safety of rosiglitazone. Perhaps the recent experience with rosiglitazone will allow the FDA to become more targeted in its adjudication of the cardiovascular safety of new diabetes drugs, focusing the considerable resources needed to rule out a cardiovascular concern only on drugs with clinical or preclinical justification for the expenditure.
Regardless, based on the SAVOR-TIMI 53 and EXAMINE findings, the use of glycated hemoglobin as a valid surrogate for assessing cardiovascular risk or benefit of diabetes therapy is not supported.
The optimal approach to the reduction of cardiovascular risk in diabetes should focus on aggressive management of the standard cardiovascular risk factors rather than on intensive glycemic control.
Dr. William R. Hiatt of the University of Colorado in Aurora, Dr. Sanjay Kaul of Cedars-Sinai Medical Center in Los Angeles, and Dr. Robert J. Smith of Brown University in Providence, R.I., made these comments in an editorial that accompanied the published versions of the SAVOR and EXAMINE reports (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMp1309610]). All reported having disclosures, and Dr. Hiatt served on the FDA advisory committee that reviewed rosiglitazone. Details are available with the full text of the editorial at NEJM.org.
Neither saxagliptin nor alogliptin was associated with increased – or decreased – rates of major adverse cardiovascular events in high-risk patients with type 2 diabetes mellitus in separate randomized, double-blind, placebo-controlled trials.
The findings with respect to these recently approved antidiabetic therapies – members of the same class of selective dipeptidyl peptidase–4 (DDP-4) inhibitors – provide clinicians with important information to help guide treatment decision-making for patients with type 2 diabetes and cardiovascular risk, the authors concluded.
Both studies were mandated by the Food and Drug Administration, which in 2008 began requiring all diabetes therapies to demonstrate cardiovascular safety after concerns were raised in 2007 about a link between rosiglitazone (Avandia) and an increased risk of myocardial infarction. The results were reported at the annual congress of the European Society of Cardiology, and were simultaneously published online Sept. 2 in the New England Journal of Medicine.
SAVOR-TIMI 53
SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) randomized 16,492 patients with type 2 diabetes and a history of established cardiovascular disease or multiple risk factors for vascular disease to either saxagliptin, doses ranging from 2.5 to 5 mg daily, or placebo.
The primary endpoint – a composite of cardiovascular death, myocardial infarction, or ischemic stroke – occurred at similar rates in 613 patients randomized to receive saxagliptin treatment and 609 patients randomized to receive placebo (7.3% and 7.2%, respectively) at a median follow-up of 2.1 years, Dr. Benjamin M. Scirica of Brigham and Women’s Hospital and Harvard Medical School, Boston, and his colleagues reported on behalf of the SAVOR-TIMI 53 Steering Committee and Investigators.
A major secondary endpoint – a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure – also occurred at similar rates in the treatment and placebo groups (12.8% and 12.4%, respectively), they reported (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMoa1307684]).
However, more patients in the treatment group than in the placebo group were hospitalized for heart failure (3.5% vs. 2.8%), they noted, adding that this was an unexpected finding that merits further study.
The findings demonstrate that DPP-4 inhibition with saxagliptin neither increases nor decreases the rate of ischemic events over a median 2-year period, although longer duration of treatment may have different effects.
"Together with ongoing trials of other DPP-4 inhibitors and novel antihyperglycemic agents, these data will provide a more rigorous and robust evidence base than is currently available to guide the future care of patients with diabetes," they concluded.
EXAMINE
Similarly, the EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial showed that the primary endpoint – a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke – did not occur significantly more often at a median follow-up of 18 months in 2,679 patients randomized to receive treatment, compared with 2,701 patients randomized to receive placebo (11.3% vs. 11.8%, respectively), Dr. William B. White of the University of Connecticut School of Medicine, Farmington, and his colleagues reported on behalf of the EXAMINE investigators.
Patients included in this noninferiority study had type 2 diabetes and a recent acute myocardial infarction or unstable angina requiring hospitalization, who received standard-of-care treatment for diabetes and cardiovascular risk factors throughout the study period. Alogliptin doses ranged from 6.25 to 25 mg daily on the basis of the patients’ estimated glomerular filtration rate at baseline.
"The alogliptin and placebo groups did not differ significantly with respect to the incidence of serious adverse events (33.6% and 35.5%, respectively)," the investigators wrote (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMoa1305889]).
In this group of patients at very high cardiovascular event risk, alogliptin did not increase or decrease cardiovascular morbidity or mortality over a median 18-month period; the findings do not rule out longer-term risks with respect to cardiovascular endpoints, they noted.
"These data can be used to help guide clinicians in choosing among the many available antidiabetic agents when treating patients with type 2 diabetes and very high cardiovascular risk," they concluded.
The SAVOR-TIMI 53 trial was supported by AstraZeneca and Bristol-Myers Squibb. The EXAMINE trial was supported by Takeda Development Center Americas. Multiple authors for both studies reported disclosures. Details are provided with the full text of each article at NEJM.org.
Neither saxagliptin nor alogliptin was associated with increased – or decreased – rates of major adverse cardiovascular events in high-risk patients with type 2 diabetes mellitus in separate randomized, double-blind, placebo-controlled trials.
The findings with respect to these recently approved antidiabetic therapies – members of the same class of selective dipeptidyl peptidase–4 (DDP-4) inhibitors – provide clinicians with important information to help guide treatment decision-making for patients with type 2 diabetes and cardiovascular risk, the authors concluded.
Both studies were mandated by the Food and Drug Administration, which in 2008 began requiring all diabetes therapies to demonstrate cardiovascular safety after concerns were raised in 2007 about a link between rosiglitazone (Avandia) and an increased risk of myocardial infarction. The results were reported at the annual congress of the European Society of Cardiology, and were simultaneously published online Sept. 2 in the New England Journal of Medicine.
SAVOR-TIMI 53
SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) randomized 16,492 patients with type 2 diabetes and a history of established cardiovascular disease or multiple risk factors for vascular disease to either saxagliptin, doses ranging from 2.5 to 5 mg daily, or placebo.
The primary endpoint – a composite of cardiovascular death, myocardial infarction, or ischemic stroke – occurred at similar rates in 613 patients randomized to receive saxagliptin treatment and 609 patients randomized to receive placebo (7.3% and 7.2%, respectively) at a median follow-up of 2.1 years, Dr. Benjamin M. Scirica of Brigham and Women’s Hospital and Harvard Medical School, Boston, and his colleagues reported on behalf of the SAVOR-TIMI 53 Steering Committee and Investigators.
A major secondary endpoint – a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure – also occurred at similar rates in the treatment and placebo groups (12.8% and 12.4%, respectively), they reported (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMoa1307684]).
However, more patients in the treatment group than in the placebo group were hospitalized for heart failure (3.5% vs. 2.8%), they noted, adding that this was an unexpected finding that merits further study.
The findings demonstrate that DPP-4 inhibition with saxagliptin neither increases nor decreases the rate of ischemic events over a median 2-year period, although longer duration of treatment may have different effects.
"Together with ongoing trials of other DPP-4 inhibitors and novel antihyperglycemic agents, these data will provide a more rigorous and robust evidence base than is currently available to guide the future care of patients with diabetes," they concluded.
EXAMINE
Similarly, the EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial showed that the primary endpoint – a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke – did not occur significantly more often at a median follow-up of 18 months in 2,679 patients randomized to receive treatment, compared with 2,701 patients randomized to receive placebo (11.3% vs. 11.8%, respectively), Dr. William B. White of the University of Connecticut School of Medicine, Farmington, and his colleagues reported on behalf of the EXAMINE investigators.
Patients included in this noninferiority study had type 2 diabetes and a recent acute myocardial infarction or unstable angina requiring hospitalization, who received standard-of-care treatment for diabetes and cardiovascular risk factors throughout the study period. Alogliptin doses ranged from 6.25 to 25 mg daily on the basis of the patients’ estimated glomerular filtration rate at baseline.
"The alogliptin and placebo groups did not differ significantly with respect to the incidence of serious adverse events (33.6% and 35.5%, respectively)," the investigators wrote (N. Engl. J. Med. 2013 Sept. 2 [doi: 10.1056/NEJMoa1305889]).
In this group of patients at very high cardiovascular event risk, alogliptin did not increase or decrease cardiovascular morbidity or mortality over a median 18-month period; the findings do not rule out longer-term risks with respect to cardiovascular endpoints, they noted.
"These data can be used to help guide clinicians in choosing among the many available antidiabetic agents when treating patients with type 2 diabetes and very high cardiovascular risk," they concluded.
The SAVOR-TIMI 53 trial was supported by AstraZeneca and Bristol-Myers Squibb. The EXAMINE trial was supported by Takeda Development Center Americas. Multiple authors for both studies reported disclosures. Details are provided with the full text of each article at NEJM.org.
FROM THE ESC CONGRESS 2013
Major finding: Percentage of treatment group vs. placebo group patients reaching a composite cardiovascular endpoint in SAVOR-TIMI 53: 7.3% vs. 7.2%, and in EXAMINE: 11.3% vs. 11.8%.
Data source: Separate randomized, placebo-controlled trials – SAVOR-TIMI 53, involving 16,492 patients, and EXAMINE, involving 5,380 patients.
Disclosures: The SAVOR-TIMI 53 trial was supported by AstraZeneca and Bristol-Myers Squibb. The EXAMINE trial was supported by Takeda Development Center Americas. Multiple authors for both studies reported disclosures. Details are provided with the full text of each article at NEJM.org.
