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Risk for Hospitalized Heart Failure Among New Users of Saxagliptin, Sitagliptin, and Other Antihyperglycemic Drugs: A
Insights
This study found no increased risk of hospitalized heart failure (hHF) with saxagliptin or sitagliptin compared to other diabetes medications. These dipeptidyl peptidase-4 (DPP-4) inhibitors appear safe for managing type 2 diabetes.
Area of Science:
- Cardiovascular Medicine
- Endocrinology
- Pharmacology
Background:
- Conflicting results from postmarketing trials created uncertainty regarding the risk of hospitalized heart failure (hHF) associated with dipeptidyl peptidase-4 (DPP-4) inhibitors.
- Antihyperglycemic agents, including DPP-4 inhibitors, are widely used for type 2 diabetes management, necessitating clear safety profiles.
- The U.S. Food and Drug Administration (FDA) has monitored the cardiovascular safety of these medications.
Purpose of the Study:
- To investigate the association between saxagliptin and sitagliptin use and the risk of hospitalized heart failure (hHF).
- To compare the hHF risk of saxagliptin and sitagliptin against other common antihyperglycemic agents.
- To provide evidence-based safety information for clinicians and patients regarding DPP-4 inhibitors.
Main Methods:
- A population-based, retrospective, new-user cohort study was conducted using data from 18 health insurance and health system partners in the Mini-Sentinel program.
- Patients aged 18 years or older with type 2 diabetes initiating therapy with saxagliptin, sitagliptin, pioglitazone, second-generation sulfonylureas, or long-acting insulin between 2006 and 2013 were included.
- Hospitalized heart failure (hHF) was identified using specific International Classification of Diseases, Ninth Revision, Clinical Modification codes as the principal discharge diagnosis. Analyses included disease risk score (DRS)-stratified and propensity score-matched approaches.
Main Results:
- The study included 78,553 saxagliptin users and 298,124 sitagliptin users, with an average follow-up of 7-9 months.
- The risk for hHF was not found to be higher with DPP-4 inhibitors (saxagliptin or sitagliptin) compared to pioglitazone, sulfonylureas, or long-acting insulin.
- Hazard ratios consistently showed no increased risk for hHF across various comparisons and subgroups, including those with and without prior cardiovascular disease.
Conclusions:
- In this large cohort, users of saxagliptin or sitagliptin did not exhibit an elevated risk for hospitalized heart failure when compared to users of other selected antihyperglycemic agents.
- The findings suggest that saxagliptin and sitagliptin are associated with a similar risk of hHF as other common diabetes treatments.
- Limitations include potential residual confounding and the relatively short follow-up period, warranting continued surveillance.
Background:
Recent postmarketing trials produced conflicting results about the risk for hospitalized heart failure (hHF) associated with dipeptidyl peptidase-4 (DPP-4) inhibitors, creating uncertainty about the safety of these antihyperglycemic agents.
Objective:
To examine the associations of hHF with saxagliptin and sitagliptin.
Design:
Population-based, retrospective, new-user cohort study.
Setting:
18 health insurance and health system data partners in the U.S. Food and Drug Administration's Mini-Sentinel program.
Patients:
Patients aged 18 years or older with type 2 diabetes who initiated therapy with saxagliptin, sitagliptin, pioglitazone, second-generation sulfonylureas, or long-acting insulin products from 2006 to 2013.
Measurements:
Hospitalized HF, identified by International Classification of Diseases, Ninth Revision, Clinical Modification codes 402.x1, 404.x1, 404.x3, and 428.xx recorded as the principal discharge diagnosis.
Results:
78 553 saxagliptin users and 298 124 sitagliptin users contributed an average of 7 to 9 months of follow-up data to 1 or more pairwise comparisons. The risk for hHF was not higher with DPP-4 inhibitors than with the other study drugs. The hazard ratios from the disease risk score (DRS)-stratified analyses were 0.83 (95% CI, 0.70 to 0.99) for saxagliptin versus sitagliptin, 0.63 (CI, 0.47 to 0.85) for saxagliptin versus pioglitazone, 0.69 (CI, 0.54 to 0.87) for saxagliptin versus sulfonylureas, and 0.61 (CI, 0.50 to 0.73) for saxagliptin versus insulin. The DRS-stratified hazard ratios were 0.74 (CI, 0.64 to 0.85) for sitagliptin versus pioglitazone, 0.86 (CI, 0.77 to 0.95) for sitagliptin versus sulfonylureas, and 0.71 (CI, 0.64 to 0.78) for sitagliptin versus insulin. Results from the 1:1 propensity score-matched analyses were similar. Results were also similar in subgroups of patients with and without prior cardiovascular disease and in a subgroup defined by the 2 highest DRS deciles.
Limitation:
Residual confounding and short follow-up.
Conclusion:
In this large cohort study, a higher risk for hHF was not observed in users of saxagliptin or sitagliptin compared with other selected antihyperglycemic agents.
Primary Funding Source:
U.S. Food and Drug Administration.
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