Concomitant Use of Oral Anticoagulants with Oral Dipeptidyl Peptidase-4 Inhibitors and Serious Bleeding Events

Overview

Journal Clin Pharmacol Ther

Publisher Wiley

Specialty Pharmacology

Date 2024 Sep 12

PMID 39262110

Authors

Thanh Phuong Pham Nguyen

Charles E Leonard

Colleen M Brensinger

Warren B Bilker

Sophie P Chung

John R Horn

Kacie Bogar

Todd A Miano

Sean Hennessy

Affiliations

Soon will be listed here.

Abstract

In a prior screening study, saxagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4i), was found to have an increased rate of serious bleeding when used concomitantly with several oral anticoagulants (OACs). We aimed to confirm or refute the associations between concomitant use of individual OACs and DPP-4is and serious bleeding in a large US database, using self-controlled case series (SCCS) and case-crossover (CCO) designs. The study population was eligible Medicare beneficiaries co-exposed to a DPP-4i (precipitant) and either an OAC (object drug) or lisinopril (negative control object drug) in 2016-2020. For the SCCS, we used conditional Poisson regression to estimate adjusted rate ratios (RRs) between each co-exposure (vs. not) and serious bleeding and divided the RR by the adjusted RR for the corresponding lisinopril + precipitant pair to obtain ratios of RRs (RRRs). For the CCO, we estimated the adjusted odds ratios (ORs) of exposure to the precipitant in the focal window vs. referent window using multivariable conditional logistic regression and divided the ORs in the object drug-exposed cases over the ORs in negative object drug-exposed cases to obtain the ratios of ORs (RORs). The adjusted RRRs for serious bleeding ranged from 0.32 (0.05-1.91) for apixaban/lisinopril + saxagliptin to 3.49 (1.29-9.48) for warfarin/lisinopril + linagliptin. The adjusted RORs ranged from 0.01 (0.00-0.20) for rivaroxaban/lisinopril + saxagliptin to 2.99 (0.74-12.11) for apixaban/lisinopril + linagliptin. While we could not confirm previously identified signals because of statistical imprecision, several numerically elevated estimates still warrant caution in concomitant use and further examination.

References

Gupta A, Verma A, Kailashiya J, Singh S, Kumar N . Sitagliptin: anti-platelet effect in diabetes and healthy volunteers. Platelets. 2012; 23(8):565-70. DOI: 10.3109/09537104.2012.721907. View

Carnicelli A, Hong H, Connolly S, Eikelboom J, Giugliano R, Morrow D . Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation: Patient-Level Network Meta-Analyses of Randomized Clinical Trials With Interaction Testing by Age and Sex. Circulation. 2022; 145(4):242-255. PMC: 8800560. DOI: 10.1161/CIRCULATIONAHA.121.056355. View

Nusca A, Tuccinardi D, Pieralice S, Giannone S, Carpenito M, Monte L . Platelet Effects of Anti-diabetic Therapies: New Perspectives in the Management of Patients with Diabetes and Cardiovascular Disease. Front Pharmacol. 2021; 12:670155. PMC: 8149960. DOI: 10.3389/fphar.2021.670155. View

Mueck W, Stampfuss J, Kubitza D, Becka M . Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet. 2013; 53(1):1-16. PMC: 3889701. DOI: 10.1007/s40262-013-0100-7. View

Cadarette S, MacLure M, Delaney J, Whitaker H, Hayes K, Wang S . Control yourself: ISPE-endorsed guidance in the application of self-controlled study designs in pharmacoepidemiology. Pharmacoepidemiol Drug Saf. 2021; 30(6):671-684. PMC: 8251635. DOI: 10.1002/pds.5227. View

Pham Nguyen T, Brensinger C, Bilker W, Hennessy S, Leonard C . Evaluation of serious bleeding signals during concomitant use of clopidogrel and hypnotic drugs. Biomed Pharmacother. 2021; 139:111559. PMC: 8187300. DOI: 10.1016/j.biopha.2021.111559. View

Kim N, Yu T, Lee D . The nonglycemic actions of dipeptidyl peptidase-4 inhibitors. Biomed Res Int. 2014; 2014:368703. PMC: 4129137. DOI: 10.1155/2014/368703. View

Budnitz D, Lovegrove M, Shehab N, Richards C . Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med. 2011; 365(21):2002-12. DOI: 10.1056/NEJMsa1103053. View

Bykov K, Schneeweiss S, Glynn R, Mittleman M, Gagne J . A Case-Crossover-Based Screening Approach to Identifying Clinically Relevant Drug-Drug Interactions in Electronic Healthcare Data. Clin Pharmacol Ther. 2019; 106(1):238-244. DOI: 10.1002/cpt.1376. View

10.

Foerster K, Hermann S, Mikus G, Haefeli W . Drug-Drug Interactions with Direct Oral Anticoagulants. Clin Pharmacokinet. 2020; 59(8):967-980. PMC: 7403169. DOI: 10.1007/s40262-020-00879-x. View

11.

Lemesle G, Meurice T, Tricot O, Lamblin N, Bauters C . Association of Diabetic Status and Glycemic Control With Ischemic and Bleeding Outcomes in Patients With Stable Coronary Artery Disease: The 5-Year CORONOR Registry. J Am Heart Assoc. 2018; 7(10). PMC: 6015307. DOI: 10.1161/JAHA.117.008354. View

12.

Lane S, Al-Zubiedi S, Hatch E, Matthews I, Jorgensen A, Deloukas P . The population pharmacokinetics of R- and S-warfarin: effect of genetic and clinical factors. Br J Clin Pharmacol. 2011; 73(1):66-76. PMC: 3248257. DOI: 10.1111/j.1365-2125.2011.04051.x. View

13.

Wright D, Herman G, Maes A, Liu Q, Johnson-Levonas A, Wagner J . Multiple doses of sitagliptin, a selective DPP-4 inhibitor, do not meaningfully alter pharmacokinetics and pharmacodynamics of warfarin. J Clin Pharmacol. 2009; 49(10):1157-67. DOI: 10.1177/0091270009341653. View

14.

Johnson J . Warfarin pharmacogenetics: a rising tide for its clinical value. Circulation. 2012; 125(16):1964-6. PMC: 3337679. DOI: 10.1161/CIRCULATIONAHA.112.100628. View

15.

Graefe-Mody E, Brand T, Ring A, Withopf B, Stangier J, Iovino M . Effect of linagliptin on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers. Int J Clin Pharmacol Ther. 2011; 49(5):300-10. DOI: 10.5414/cp201507. View

16.

Maeda K, Hisaka A, Ito K, Ohno Y, Ishiguro A, Sato R . Classification of drugs for evaluating drug interaction in drug development and clinical management. Drug Metab Pharmacokinet. 2021; 41:100414. DOI: 10.1016/j.dmpk.2021.100414. View

17.

Camm A, Sabbour H, Schnell O, Summaria F, Verma A . Managing thrombotic risk in patients with diabetes. Cardiovasc Diabetol. 2022; 21(1):160. PMC: 9396895. DOI: 10.1186/s12933-022-01581-x. View

18.

Bykov K, Franklin J, Li H, Gagne J . Comparison of Self-controlled Designs for Evaluating Outcomes of Drug-Drug Interactions: Simulation Study. Epidemiology. 2019; 30(6):861-866. PMC: 6768702. DOI: 10.1097/EDE.0000000000001087. View

19.

Steven S, Jurk K, Kopp M, Kroller-Schon S, Mikhed Y, Schwierczek K . Glucagon-like peptide-1 receptor signalling reduces microvascular thrombosis, nitro-oxidative stress and platelet activation in endotoxaemic mice. Br J Pharmacol. 2016; 174(12):1620-1632. PMC: 5446582. DOI: 10.1111/bph.13549. View

20.

Bykov K, Li H, Kim S, Vine S, Lo Re 3rd V, Gagne J . Drug-Drug Interaction Surveillance Study: Comparing Self-Controlled Designs in Five Empirical Examples in Real-World Data. Clin Pharmacol Ther. 2020; 109(5):1353-1360. PMC: 8058240. DOI: 10.1002/cpt.2119. View