User login
SILVER SPRING, MD.– Results of a large postmarketing study evaluating the cardiovascular safety of saxagliptin in a high-risk population provided reassuring evidence about the drug’s overall cardiovascular risk, although a signal for heart failure hospitalizations associated with the drug was a concern, according to a Food and Drug Administration advisory panel.
At a meeting on April 14, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13-1, with one abstention, that the results of the SAVOR (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus) trial showed that the use of saxagliptin in patients with type 2 diabetes had an acceptable cardiovascular risk profile. However, the panelists were concerned about the signal for an increased risk of hospitalizations for heart failure associated with saxagliptin in the study, which they agreed should be studied further. Nearly all of the panelists also voted that the safety data, including the heart failure finding and an imbalance in all-cause mortality among those on saxagliptin arm of the study, be added to the drug’s prescribing information.
Approved in 2009, saxagliptin, a dipeptidyl peptidase–4 (DPP4) inhibitor, is indicated “as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings” and is marketed as Onglyza by AstraZeneca. A fixed-dose combination of saxagliptin with extended-release metformin (Kombiglyze XR) was approved in 2010. The FDA panel votes apply to both products.
The FDA is requiring that manufacturers conduct CV outcomes trials for all type 2 diabetes drugs in patients at high risk for cardiovascular disease (CVD), and in December 2008, issued a guidance document for industry, outlining the requirements for these studies, which included showing that the CVD risk, based on a major adverse cardiovascular event (MACE) endpoint, is not increased by more than 30% compared to placebo.
AstraZeneca conducted SAVOR, a prospective, randomized, double-blind, placebo-controlled study of nearly 16,500 people with type 2 diabetes, who had or were at risk of CVD, comparing saxagliptin to placebo, on top of standard treatment (N. Engl. J. Med. 2013;369:1317-26). After a median follow-up of about 2 years, the incidence of MACE (a composite of cardiovascular death, nonfatal MI, and nonfatal ischemic stroke) was identical in both groups, at 7.4%, with a hazard ratio of 1.0, meeting the FDA criteria for cardiovascular safety as outlined in the guidance, according to the company. Saxagliptin was not superior to placebo in reducing the MACE events, another primary objective of the study.
Unexpectedly, hospitalization for heart failure (HF), a component of the secondary composite endpoint, was increased among those treated with saxagliptin (hazard ratio, 1.27). There was also a “numerical imbalance” in all-cause mortality between groups, with 17 deaths in the saxagliptin patients vs. 11 in the placebo group (HR, 1.11).
However, deaths caused by heart failure were balanced between those on saxagliptin and those on placebo, and no possible mechanism for the HF finding could be identified, according to AstraZeneca, which is planning a mechanistic study to evaluate the effects of saxagliptin on volume, neurohormonal changes, and cardiac function. The company has proposed that the HF finding be addressed by adding this information to the prescribing information.
The cardiovascular safety results were reassuring, said Dr. Morris Schambelan, a panelist and professor emeritus of medicine in the division of endocrinology at the University of California, San Francisco, but like others on the committee, added that he believes the heart failure signal was real and that providing clinicians with information in the drug’s label to help predict those at higher risk in would be helpful.
Several panelists were somewhat concerned about the all-cause mortality finding, which is a strong endpoint, and therefore cannot be ruled out, they said. But they also pointed out that follow-up was relatively short for a drug that is used long term and that the results should be applied cautiously to patients at lower risk than were those enrolled in the trial.
The FDA usually follows the recommendations of its advisory panel members. Panelists had no relevant disclosures.
CV outcomes trials for other approved DPP4 inhibitors approved for type 2 diabetes – sitagliptin (Januvia) and linagliptin (Tradjenta) – are ongoing. The panel review of the CV outcomes trial for another DPP4 inhibitor approved, alogliptin (Nesina), followed the meeting on saxagliptin.
SILVER SPRING, MD.– Results of a large postmarketing study evaluating the cardiovascular safety of saxagliptin in a high-risk population provided reassuring evidence about the drug’s overall cardiovascular risk, although a signal for heart failure hospitalizations associated with the drug was a concern, according to a Food and Drug Administration advisory panel.
At a meeting on April 14, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13-1, with one abstention, that the results of the SAVOR (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus) trial showed that the use of saxagliptin in patients with type 2 diabetes had an acceptable cardiovascular risk profile. However, the panelists were concerned about the signal for an increased risk of hospitalizations for heart failure associated with saxagliptin in the study, which they agreed should be studied further. Nearly all of the panelists also voted that the safety data, including the heart failure finding and an imbalance in all-cause mortality among those on saxagliptin arm of the study, be added to the drug’s prescribing information.
Approved in 2009, saxagliptin, a dipeptidyl peptidase–4 (DPP4) inhibitor, is indicated “as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings” and is marketed as Onglyza by AstraZeneca. A fixed-dose combination of saxagliptin with extended-release metformin (Kombiglyze XR) was approved in 2010. The FDA panel votes apply to both products.
The FDA is requiring that manufacturers conduct CV outcomes trials for all type 2 diabetes drugs in patients at high risk for cardiovascular disease (CVD), and in December 2008, issued a guidance document for industry, outlining the requirements for these studies, which included showing that the CVD risk, based on a major adverse cardiovascular event (MACE) endpoint, is not increased by more than 30% compared to placebo.
AstraZeneca conducted SAVOR, a prospective, randomized, double-blind, placebo-controlled study of nearly 16,500 people with type 2 diabetes, who had or were at risk of CVD, comparing saxagliptin to placebo, on top of standard treatment (N. Engl. J. Med. 2013;369:1317-26). After a median follow-up of about 2 years, the incidence of MACE (a composite of cardiovascular death, nonfatal MI, and nonfatal ischemic stroke) was identical in both groups, at 7.4%, with a hazard ratio of 1.0, meeting the FDA criteria for cardiovascular safety as outlined in the guidance, according to the company. Saxagliptin was not superior to placebo in reducing the MACE events, another primary objective of the study.
Unexpectedly, hospitalization for heart failure (HF), a component of the secondary composite endpoint, was increased among those treated with saxagliptin (hazard ratio, 1.27). There was also a “numerical imbalance” in all-cause mortality between groups, with 17 deaths in the saxagliptin patients vs. 11 in the placebo group (HR, 1.11).
However, deaths caused by heart failure were balanced between those on saxagliptin and those on placebo, and no possible mechanism for the HF finding could be identified, according to AstraZeneca, which is planning a mechanistic study to evaluate the effects of saxagliptin on volume, neurohormonal changes, and cardiac function. The company has proposed that the HF finding be addressed by adding this information to the prescribing information.
The cardiovascular safety results were reassuring, said Dr. Morris Schambelan, a panelist and professor emeritus of medicine in the division of endocrinology at the University of California, San Francisco, but like others on the committee, added that he believes the heart failure signal was real and that providing clinicians with information in the drug’s label to help predict those at higher risk in would be helpful.
Several panelists were somewhat concerned about the all-cause mortality finding, which is a strong endpoint, and therefore cannot be ruled out, they said. But they also pointed out that follow-up was relatively short for a drug that is used long term and that the results should be applied cautiously to patients at lower risk than were those enrolled in the trial.
The FDA usually follows the recommendations of its advisory panel members. Panelists had no relevant disclosures.
CV outcomes trials for other approved DPP4 inhibitors approved for type 2 diabetes – sitagliptin (Januvia) and linagliptin (Tradjenta) – are ongoing. The panel review of the CV outcomes trial for another DPP4 inhibitor approved, alogliptin (Nesina), followed the meeting on saxagliptin.
SILVER SPRING, MD.– Results of a large postmarketing study evaluating the cardiovascular safety of saxagliptin in a high-risk population provided reassuring evidence about the drug’s overall cardiovascular risk, although a signal for heart failure hospitalizations associated with the drug was a concern, according to a Food and Drug Administration advisory panel.
At a meeting on April 14, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13-1, with one abstention, that the results of the SAVOR (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus) trial showed that the use of saxagliptin in patients with type 2 diabetes had an acceptable cardiovascular risk profile. However, the panelists were concerned about the signal for an increased risk of hospitalizations for heart failure associated with saxagliptin in the study, which they agreed should be studied further. Nearly all of the panelists also voted that the safety data, including the heart failure finding and an imbalance in all-cause mortality among those on saxagliptin arm of the study, be added to the drug’s prescribing information.
Approved in 2009, saxagliptin, a dipeptidyl peptidase–4 (DPP4) inhibitor, is indicated “as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings” and is marketed as Onglyza by AstraZeneca. A fixed-dose combination of saxagliptin with extended-release metformin (Kombiglyze XR) was approved in 2010. The FDA panel votes apply to both products.
The FDA is requiring that manufacturers conduct CV outcomes trials for all type 2 diabetes drugs in patients at high risk for cardiovascular disease (CVD), and in December 2008, issued a guidance document for industry, outlining the requirements for these studies, which included showing that the CVD risk, based on a major adverse cardiovascular event (MACE) endpoint, is not increased by more than 30% compared to placebo.
AstraZeneca conducted SAVOR, a prospective, randomized, double-blind, placebo-controlled study of nearly 16,500 people with type 2 diabetes, who had or were at risk of CVD, comparing saxagliptin to placebo, on top of standard treatment (N. Engl. J. Med. 2013;369:1317-26). After a median follow-up of about 2 years, the incidence of MACE (a composite of cardiovascular death, nonfatal MI, and nonfatal ischemic stroke) was identical in both groups, at 7.4%, with a hazard ratio of 1.0, meeting the FDA criteria for cardiovascular safety as outlined in the guidance, according to the company. Saxagliptin was not superior to placebo in reducing the MACE events, another primary objective of the study.
Unexpectedly, hospitalization for heart failure (HF), a component of the secondary composite endpoint, was increased among those treated with saxagliptin (hazard ratio, 1.27). There was also a “numerical imbalance” in all-cause mortality between groups, with 17 deaths in the saxagliptin patients vs. 11 in the placebo group (HR, 1.11).
However, deaths caused by heart failure were balanced between those on saxagliptin and those on placebo, and no possible mechanism for the HF finding could be identified, according to AstraZeneca, which is planning a mechanistic study to evaluate the effects of saxagliptin on volume, neurohormonal changes, and cardiac function. The company has proposed that the HF finding be addressed by adding this information to the prescribing information.
The cardiovascular safety results were reassuring, said Dr. Morris Schambelan, a panelist and professor emeritus of medicine in the division of endocrinology at the University of California, San Francisco, but like others on the committee, added that he believes the heart failure signal was real and that providing clinicians with information in the drug’s label to help predict those at higher risk in would be helpful.
Several panelists were somewhat concerned about the all-cause mortality finding, which is a strong endpoint, and therefore cannot be ruled out, they said. But they also pointed out that follow-up was relatively short for a drug that is used long term and that the results should be applied cautiously to patients at lower risk than were those enrolled in the trial.
The FDA usually follows the recommendations of its advisory panel members. Panelists had no relevant disclosures.
CV outcomes trials for other approved DPP4 inhibitors approved for type 2 diabetes – sitagliptin (Januvia) and linagliptin (Tradjenta) – are ongoing. The panel review of the CV outcomes trial for another DPP4 inhibitor approved, alogliptin (Nesina), followed the meeting on saxagliptin.
AT AN FDA ADVISORY COMMITTEE MEETING
