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Original Research |

Risk for Hospitalized Heart Failure Among New Users of Saxagliptin, Sitagliptin, and Other Antihyperglycemic Drugs: A Retrospective Cohort StudyRisk for Hospitalized Heart Failure in New Users of Antihyperglycemic Drugs

Sengwee Toh, ScD; Christian Hampp, PhD; Marsha E. Reichman, PhD; David J. Graham, MD, MPH; Suchitra Balakrishnan, MD, PhD; Frank Pucino, PharmD, MPH; Jack Hamilton, AB; Samuel Lendle, PhD; Aarthi Iyer, JD, MPH; Malcolm Rucker, MS; Madelyn Pimentel, BA; Neesha Nathwani, BS; Marie R. Griffin, MD, MPH; Nancy J. Brown, MD; and Bruce H. Fireman, MA
[+] Article, Author, and Disclosure Information

This article was published at www.annals.org on 26 April 2016.


From Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts; U.S. Food and Drug Administration, Silver Spring, Maryland; Vanderbilt University and VA Tennessee Valley Health Care System, Nashville, Tennessee; and Kaiser Permanente Northern California, Oakland, California.

Note: Dr. Toh had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Disclaimer: The views expressed are those of the authors and do not necessarily represent the views of the FDA or the U.S. government.

Acknowledgment: The authors thank all of the data partners that participated in this study: Aetna, Anthem, Group Health Research Institute, Harvard Pilgrim Health Care Institute, HealthPartners Institute for Education and Research, Henry Ford Health System, Humana, Kaiser Permanente Colorado, Kaiser Permanente Georgia, Kaiser Permanente Hawaii, Kaiser Permanente Mid-Atlantic, Kaiser Permanente Northern California, Kaiser Permanente Northwest, Lovelace Clinic Foundation, Marshfield Clinic Research Foundation, Meyers Primary Care Institute, OptumInsight, and Vanderbilt University Medical Center.

Financial Support: By the FDA through the U.S. Department of Health and Human Services (contract HHSF223200910006I, HHSF22301004T, and HHSF22301007T).

Disclosures: Dr. Toh reports grants from the U.S. Food and Drug Administration during the conduct of the study. Mr. Hamilton reports grants from the U.S. Food and Drug Administration during the conduct of the study. Dr. Lendle reports grants from the U.S. Food and Drug Administration during the conduct of the study. Dr. Iyer reports grants from the U.S. Food and Drug Administration during the conduct of the study. Mr. Rucker reports grants from the U.S. Food and Drug Administration during the conduct of the study. Ms. Pimentel reports grants from the U.S. Food and Drug Administration during the conduct of the study. Ms. Nathwani reports grants from the U.S. Food and Drug Administration during the conduct of the study. Dr. Griffin reports grants from the U.S. Food and Drug Administration and Harvard Pilgrim Health Care during the conduct of the study. Dr. Brown reports personal fees from Novartis Pharmaceuticals outside the submitted work. Mr. Fireman reports grants from the U.S. Food and Drug Administration during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-2568.

Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.

Reproducible Research Statement:Study protocol: The overall protocol that includes the heart failure analysis is available at www.mini-sentinel.org/work_products/Assessments/Mini-Sentinel_AMI-and-Anti-Diabetic-Agents_Protocol.pdf. Statistical code: Available from Dr. Toh (e-mail, Darren_Toh@harvardpilgrim.org). Data set: Not available.

Requests for Single Reprints: Sengwee Toh, ScD, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, 401 Park Drive, Suite 401, Boston, MA 02215; e-mail, darren_toh@harvardpilgrim.org.

Current Author Addresses: Drs. Toh and Iyer, Mr. Rucker, Ms. Pimentel, and Ms. Nathwani: Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, 401 Park Drive, Suite 401, Boston, MA 02215.

Dr. Hampp: Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, White Oak CDER Office Building 22, Room 2441, 10903 New Hampshire Avenue, Silver Spring, MD 20993.

Dr. Reichman: Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, White Oak CDER Office Building 22, Room 3462, 10903 New Hampshire Avenue, Silver Spring, MD 20993.

Dr. Graham: Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, White Oak CDER Office Building 22, Room 4314, 10903 New Hampshire Avenue, Silver Spring, MD 20993.

Dr. Balakrishnan: Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, White Oak CDER Office Building 22, Room 3145, 10903 New Hampshire Avenue, Silver Spring, MD 20993.

Dr. Pucino: Office of New Drugs, Center for Drug Evaluation and Safety, U.S. Food and Drug Administration, White Oak CDER Office Building 22, Room 3204, 10903 New Hampshire Avenue, Silver Spring, MD 20993.

Mr. Hamilton, Dr. Lendle, and Mr. Fireman: Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA 94612.

Dr. Griffin: Department of Health Policy, Vanderbilt University Medical Center, Village at Vanderbilt, Suite 2600, 1500 21st Avenue South, Nashville, TN 37212.

Dr. Brown: Vanderbilt University School of Medicine, D-3100 Medical Center North, Nashville, TN 37232.

Author Contributions: Conception and design: S. Toh, C. Hampp, M.E. Reichman, D.J. Graham, S. Balakrishnan, F. Pucino, B.H. Fireman.

Analysis and interpretation of the data: S. Toh, C. Hampp, M.E. Reichman, D.J. Graham, S. Balakrishnan, F. Pucino, S. Lendle, N. Nathwani, B.H. Fireman.

Drafting of the article: S. Toh, S. Balakrishnan, M. Pimentel, B.H. Fireman.

Critical revision of the article for important intellectual content: S. Toh, C. Hampp, M.E. Reichman, D.J. Graham, S. Balakrishnan, F. Pucino, M.R. Griffin, N.J. Brown, B.H. Fireman.

Final approval of the article: S. Toh, C. Hampp, M.E. Reichman, D.J. Graham, S. Balakrishnan, F. Pucino, J. Hamilton, S. Lendle, A. Iyer, M. Rucker, M. Pimentel, N. Nathwani, M.R. Griffin, N.J. Brown, B.H. Fireman.

Provision of study materials or patients: S. Toh, M.R. Griffin.

Statistical expertise: S. Toh, M.E. Reichman, S. Lendle, B.H. Fireman.

Obtaining of funding: S. Toh, B.H. Fireman.

Administrative, technical, or logistic support: S. Toh, M.E. Reichman, J. Hamilton, A. Iyer, M. Rucker, M. Pimentel.

Collection and assembly of data: S. Toh, J. Hamilton, A. Iyer, M. Pimentel, M.R. Griffin.


Ann Intern Med. 2016;164(11):705-714. doi:10.7326/M15-2568
© 2016 American College of Physicians
Text Size: A A A

This article has been corrected. The original version (PDF) is appended to this article as a Supplement.

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.

Figures

Grahic Jump Location
Figure 1.

Study design for each of the 7 pairwise comparisons.

AMI = acute myocardial infarction; HF = heart failure.

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Grahic Jump Location
Appendix Figure.

DRS-stratified analysis.

DRS = disease risk score; hHF = hospitalized heart failure.

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Grahic Jump Location
Figure 2.

Hazard ratios and 95% CIs for hospitalized heart failure, by study drug and analysis.

Hazard ratio <1 indicates a lower risk for hospitalized heart failure among users of saxagliptin (left) or sitagliptin (right). DRS = disease risk score; PSM = propensity score matching.

Grahic Jump Location

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