FDA Warns of Heart-Failure Risk With Two Diabetes Drugs
Miriam E Tucker
April 05, 2016
(updated April 6) The US Food and Drug Administration (FDA) has issued a new alert about the potential for increased risk for heart failure in patients taking the type 2 diabetes drugs saxagliptin (Onglyza, AstraZeneca) and alogliptin (Nesina, Takeda).
The FDA announced that new warnings will be added to the labels of the two dipeptidyl peptidase–4 (DPP-4) inhibitor drugs, cautioning that they may increase the risk for heart failure, particularly in patients who already have cardiovascular or kidney disease.
"Healthcare professionals should consider discontinuing medications containing saxagliptin and alogliptin in patients who develop heart failure and monitor their diabetes control," an FDA statement notes. "If a patient's blood sugar level is not well-controlled with their current treatment, other diabetes medicines may be required."
Combination products containing the two agents are also affected, including saxagliptin and metformin extended release (Kombiglyze XR, AstraZeneca ), alogliptin and metformin (Kazano, Takeda), and alogliptin and pioglitazone (Oseni, Takeda).
The move follows an FDA internal safety review of two large cardiovascular-outcomes trials of patients with cardiovascular disease and a recommendation for the label revision by the FDA's Endocrinologic and Metabolic Drugs Advisory Committee during an April 2015 hearing.
At that meeting, the panel expressed greater concern about heart failure for saxagliptin than for alogliptin, but because the mechanism is not clear and the two belong to the same class, the majority opted to recommend the warning on both labels.
However, in the interim, a third large cardiovascular-outcomes trial with another DPP-4 inhibitor, sitagliptin (Januvia, Merck), the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), showed no signal of heart failure at all in type 2 diabetes patients who received the drug.
SAVOR and EXAMINE, Compared With TECOS
Results of the two studies that prompted the FDA safety review — Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) and Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) — were first presented at the European Society of Cardiology (ESC) meeting in 2013 and later published in the New England Journal of Medicine.
In the saxagliptin trial, which included 16,492 patients with type 2 diabetes and established cardiovascular disease or who were at high risk for cardiovascular disease, there was no overall risk for cardiovascular events, but there was a 27% increase (3.5% vs 2.8%) in the rate of the first event of hospitalization for heart failure and a potential increased risk for all-cause mortality. Risk factors included a history of heart failure or kidney impairment.
In EXAMINE, which included a total of 5380 patients, 3.9% of patients receiving drug were hospitalized for heart failure vs 3.3% of patients receiving placebo. Although the difference was not statistically significant (hazard ratio, 1.19), heart failure was not an end point of the study.
The TECOS results with sitagliptin, the DPP-4 inhibitor that has been on the market for longest, were first presented at the ADA meeting last year and simultaneously published in the New England Journal of Medicine; the absence of any heart-failure signal was confirmed with a deeper dive into the results presented at the ESC meeting in September 2015.
Miriam E Tucker
April 05, 2016
(updated April 6) The US Food and Drug Administration (FDA) has issued a new alert about the potential for increased risk for heart failure in patients taking the type 2 diabetes drugs saxagliptin (Onglyza, AstraZeneca) and alogliptin (Nesina, Takeda).
The FDA announced that new warnings will be added to the labels of the two dipeptidyl peptidase–4 (DPP-4) inhibitor drugs, cautioning that they may increase the risk for heart failure, particularly in patients who already have cardiovascular or kidney disease.
"Healthcare professionals should consider discontinuing medications containing saxagliptin and alogliptin in patients who develop heart failure and monitor their diabetes control," an FDA statement notes. "If a patient's blood sugar level is not well-controlled with their current treatment, other diabetes medicines may be required."
Combination products containing the two agents are also affected, including saxagliptin and metformin extended release (Kombiglyze XR, AstraZeneca ), alogliptin and metformin (Kazano, Takeda), and alogliptin and pioglitazone (Oseni, Takeda).
The move follows an FDA internal safety review of two large cardiovascular-outcomes trials of patients with cardiovascular disease and a recommendation for the label revision by the FDA's Endocrinologic and Metabolic Drugs Advisory Committee during an April 2015 hearing.
At that meeting, the panel expressed greater concern about heart failure for saxagliptin than for alogliptin, but because the mechanism is not clear and the two belong to the same class, the majority opted to recommend the warning on both labels.
However, in the interim, a third large cardiovascular-outcomes trial with another DPP-4 inhibitor, sitagliptin (Januvia, Merck), the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), showed no signal of heart failure at all in type 2 diabetes patients who received the drug.
SAVOR and EXAMINE, Compared With TECOS
Results of the two studies that prompted the FDA safety review — Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) and Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) — were first presented at the European Society of Cardiology (ESC) meeting in 2013 and later published in the New England Journal of Medicine.
In the saxagliptin trial, which included 16,492 patients with type 2 diabetes and established cardiovascular disease or who were at high risk for cardiovascular disease, there was no overall risk for cardiovascular events, but there was a 27% increase (3.5% vs 2.8%) in the rate of the first event of hospitalization for heart failure and a potential increased risk for all-cause mortality. Risk factors included a history of heart failure or kidney impairment.
In EXAMINE, which included a total of 5380 patients, 3.9% of patients receiving drug were hospitalized for heart failure vs 3.3% of patients receiving placebo. Although the difference was not statistically significant (hazard ratio, 1.19), heart failure was not an end point of the study.
The TECOS results with sitagliptin, the DPP-4 inhibitor that has been on the market for longest, were first presented at the ADA meeting last year and simultaneously published in the New England Journal of Medicine; the absence of any heart-failure signal was confirmed with a deeper dive into the results presented at the ESC meeting in September 2015.
