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Empagliflozin and Risk of Incident Gout: Analysis from the EMPagliflozin Comparative Effectiveness and SafEty (EMPRISE) Cohort Study

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Abstract

Background

Hyperuricemia is frequently observed in patients with type 2 diabetes (T2D) and is associated with increased risk of gout and cardiovascular disease (CVD). Empagliflozin lowers serum urate levels by enhancing its urinary excretion.

Objective

To compare initiators of empagliflozin vs dipeptidyl peptidase-4 inhibitor (DPP4i) and initiators of empagliflozin vs glucagon-like peptide-1 receptor agonist (GLP-1RA) with respect to the risk of incident gout events.

Design and Participants

Using three claims-based datasets from 08/2014 to 09/2019, we generated two cohorts (cohort 1: empagliflozin vs DPP4i; cohort 2: empagliflozin vs GLP-1RA) of adult patients with T2D and without prior history of gout or gout-specific medication dispensing separately in each dataset. To assess the risk of incident gout, we estimated hazard ratios (HR) and rate differences (RD) per 1000 person-years (PY) with their 95% confidence intervals (CI) before and after 1:1 propensity score (PS) matching adjusting for 141 baseline covariates.

Key Results

We identified 102,262 pairs of 1:1 propensity score-matched adults in cohort 1 and 131,216 pairs in cohort 2. Over a mean follow-up period of 8 months on treatment, the risk of gout was lower in patients initiating empagliflozin compared to DPP4i (HR = 0.69: 95% CI (0.60–0.79); RD =  − 2.27: 95% CI (− 3.08, 1.46)) or GLP-1RA (HR = 0.83: 95% CI (0.73–0.94); RD =  − 0.99: 95% CI (− 1.66, − 0.32)). Results were consistent across subgroups (sex, age, body mass index, chronic kidney disease, heart failure, cardiovascular disease, and concurrent diuretic use) and sensitivity analyses.

Conclusions

Among adults with T2D, the initiation of empagliflozin vs a DPP4i or GLP-1RA was associated with lower risk of incident gout, complementing results from a post hoc analysis of the EMPA-REG OUTCOME trial and previously published observational research focusing on the sodium-glucose co-transporter-2 inhibitor class in more narrowly defined study populations.

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Data Availability

A data use agreement is required for each of the data sources. Our data use agreements do not permit us to share patient-level source data or data derivatives with individuals and institutions not covered under the data use agreements. The databases used in this study are accessible to other researchers by contacting the data providers and acquiring data use agreements/licenses.

References

  1. Cowie MR, Fisher M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat Rev Cardiol. 2020;17(12):761–772. https://doi.org/10.1038/s41569-020-0406-8.

    Article  CAS  PubMed  Google Scholar 

  2. Hsia DS, Grove O, Cefalu WT. An update on sodium-glucose co-transporter-2 inhibitors for the treatment of diabetes mellitus. Curr Opin Endocrinol Diabetes Obes. 2017;24(1):73–79. https://doi.org/10.1097/med.0000000000000311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Verma S. Potential mechanisms of sodium-glucose co-transporter 2 inhibitor-related cardiovascular benefits. Am J Cardiol. 2019;124:S36–S44. https://doi.org/10.1016/j.amjcard.2019.10.028.

    Article  CAS  PubMed  Google Scholar 

  4. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995–2008. https://doi.org/10.1056/NEJMoa1911303.

    Article  CAS  PubMed  Google Scholar 

  5. Perkovic V, de Zeeuw D, Mahaffey KW, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol. 2018;6(9):691–704. https://doi.org/10.1016/s2213-8587(18)30141-4.

    Article  CAS  PubMed  Google Scholar 

  6. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295–2306. https://doi.org/10.1056/NEJMoa1811744.

    Article  CAS  PubMed  Google Scholar 

  7. Zhao Y, Xu L, Tian D, et al. Effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid level: a meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2018;20(2):458–462. https://doi.org/10.1111/dom.13101.

    Article  CAS  PubMed  Google Scholar 

  8. Ferreira JP, Inzucchi SE, Mattheus M, et al. Empagliflozin and uric acid metabolism in diabetes: a post hoc analysis of the EMPA-REG OUTCOME trial. Diabetes Obes Metab. 2022;24(1):135–141. https://doi.org/10.1111/dom.14559.

    Article  CAS  PubMed  Google Scholar 

  9. Li J, Woodward M, Perkovic V, et al. Mediators of the effects of canagliflozin on heart failure in patients with type 2 diabetes. JACC Heart Fail. 2020;8(1):57–66. https://doi.org/10.1016/j.jchf.2019.08.004.

    Article  PubMed  Google Scholar 

  10. Li J, Neal B, Perkovic V, et al. Mediators of the effects of canagliflozin on kidney protection in patients with type 2 diabetes. Kidney Int. 2020;98(3):769–777. https://doi.org/10.1016/j.kint.2020.04.051.

    Article  CAS  PubMed  Google Scholar 

  11. Dehghan A, van Hoek M, Sijbrands EJ, Hofman A, Witteman JC. High serum uric acid as a novel risk factor for type 2 diabetes. Diabetes Care. 2008;31(2):361–362. https://doi.org/10.2337/dc07-1276.

    Article  CAS  PubMed  Google Scholar 

  12. Madero M, Sarnak MJ, Wang X, et al. Uric acid and long-term outcomes in CKD. Am J Kidney Dis. 2009;53(5):796–803. https://doi.org/10.1053/j.ajkd.2008.12.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Johnson RJ, Nakagawa T, Jalal D, Sanchez-Lozada LG, Kang DH, Ritz E. Uric acid and chronic kidney disease: which is chasing which? Nephrol Dial Transplant. 2013;28(9):2221–2228. https://doi.org/10.1093/ndt/gft029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dehlin M, Jacobsson L, Roddy E. Global epidemiology of gout: prevalence, incidence, treatment patterns and risk factors. Nat Rev Rheumatol. 2020;16(7):380–390. https://doi.org/10.1038/s41584-020-0441-1.

    Article  PubMed  Google Scholar 

  15. Safiri S, Kolahi AA, Cross M, et al. Prevalence, incidence, and years lived with disability due to gout and its attributable risk factors for 195 countries and territories 1990–2017: a systematic analysis of the global burden of disease study 2017. Arthritis Rheumatol. 72(11):1916–1927. https://doi.org/10.1002/art.41404.

  16. White WB, Saag KG, Becker MA, et al. Cardiovascular safety of febuxostat or allopurinol in patients with gout. N Engl J Med. 2018;378(13):1200–1210. https://doi.org/10.1056/NEJMoa1710895.

    Article  CAS  PubMed  Google Scholar 

  17. Patorno E, Najafzadeh M, Pawar A, et al. The EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) study programme: design and exposure accrual for an evaluation of empagliflozin in routine clinical care. Endocrinol Diabetes Metab. 2020;3(1):e00103. https://doi.org/10.1002/edm2.103.

    Article  PubMed  Google Scholar 

  18. Association AD. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2021. Diabetes Care. 2020;44(Supplement_1):S111–S124. https://doi.org/10.2337/dc21-S009.

  19. Tonneijck L, Muskiet MHA, Smits MM, et al. Effect of immediate and prolonged GLP-1 receptor agonist administration on uric acid and kidney clearance: post-hoc analyses of four clinical trials. Diabetes Obes Metab. 2018;20(5):1235–1245. https://doi.org/10.1111/dom.13223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bethel MA, Patel RA, Merrill P, et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol. 2018;6(2):105–113. https://doi.org/10.1016/S2213-8587(17)30412-6.

    Article  PubMed  Google Scholar 

  21. MacFarlane LA, Liu CC, Solomon DH, Kim SC. Validation of claims-based algorithms for gout flares. Pharmacoepidemiol Drug Saf. 2016;25(7):820-6. https://doi.org/10.1002/pds.4044.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Dehlin M, Stasinopoulou K, Jacobsson L. Validity of gout diagnosis in Swedish primary and secondary care - a validation study. BMC Musculoskelet Disord. 2015;16(1):149. https://doi.org/10.1186/s12891-015-0614-2.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Fralick M, Chen SK, Patorno E, Kim SC. Assessing the risk for gout with sodium-glucose cotransporter-2 inhibitors in patients with type 2 diabetes: a population-based cohort study. Ann Intern Med. 2020;172(3):186–194. https://doi.org/10.7326/M19-2610.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Delgado C, Baweja M, Crews DC, et al. A unifying approach for GFR estimation: recommendations of the NKF-ASN Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease. J Am Soc Nephrol. 2021;32(12):2994–3015. https://doi.org/10.1681/ASN.2021070988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Rubin DB. Estimating causal effects from large data sets using propensity scores. Ann Intern Med. 1997;127(8 Pt 2):757–763. https://doi.org/10.7326/0003-4819-127-8_part_2-199710151-00064.

    Article  CAS  PubMed  Google Scholar 

  26. Ripollone JE, Huybrechts KF, Rothman KJ, Ferguson RE, Franklin JM. Implications of the propensity score matching paradox in pharmacoepidemiology. Am J Epidemiol. 2018;187(9):1951–1961. https://doi.org/10.1093/aje/kwy078.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Petrie JR, Guzik TJ, Touyz RM. Diabetes, hypertension, and cardiovascular disease: clinical insights and vascular mechanisms. Can J Cardiol. 2018;34(5):575–584. https://doi.org/10.1016/j.cjca.2017.12.005.

    Article  PubMed  Google Scholar 

  28. Suijk DLS, van Baar MJB, van Bommel EJM, et al. SGLT2 inhibition and uric acid excretion in patients with type 2 diabetes and normal kidney function. Clin J Am Soc Nephrol. 2022;17(5):663–671. https://doi.org/10.2215/CJN.11480821.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Doehner W, Anker SD, Butler J, et al. Uric acid and sodium-glucose cotransporter-2 inhibition with empagliflozin in heart failure with reduced ejection fraction: the EMPEROR-reduced trial. Eur Heart J. 2022;43(36):3435–3446. https://doi.org/10.1093/eurheartj/ehac320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Li J, Badve SV, Zhou Z, et al. The effects of canagliflozin on gout in type 2 diabetes: a post-hoc analysis of the CANVAS Program. Lancet Rheumatol. 2019;1(4):e220–e228. https://doi.org/10.1016/S2665-9913(19)30078-5.

    Article  PubMed  Google Scholar 

  31. McCormick N, Yokose C, Wei J, et al. Comparative effectiveness of sodium-glucose cotransporter-2 inhibitors for recurrent gout flares and gout-primary emergency department visits and hospitalizations : a general population cohort study. Ann Intern Med. 2023. https://doi.org/10.7326/M23-0724.

    Article  PubMed  Google Scholar 

  32. Chung MC, Hung PH, Hsiao PJ, et al. Association of sodium-glucose transport protein 2 inhibitor use for type 2 diabetes and incidence of gout in taiwan. JAMA Netw Open. 2021;4(11):e2135353. https://doi.org/10.1001/jamanetworkopen.2021.35353.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Loree JM, Anand S, Dasari A, et al. Disparity of race reporting and representation in clinical trials leading to cancer drug approvals from 2008 to 2018. JAMA Oncol. 2019;5(10):e191870. https://doi.org/10.1001/jamaoncol.2019.1870.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Kennedy-Martin T, Curtis S, Faries D, Robinson S, Johnston J. A literature review on the representativeness of randomized controlled trial samples and implications for the external validity of trial results. Trials. 2015;16:495. https://doi.org/10.1186/s13063-015-1023-4.

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This study was supported by a research grant 116283 to the Brigham and Women’s Hospital from Boehringer Ingelheim. The authors had full control of the design and conduct of the study and interpretation of the study’s findings.

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Authors and Affiliations

Authors

Contributions

All authors were involved in the study conception and design. HT and EP conducted the statistical analyses. All authors were involved in the interpretation of results. KMW and HT wrote the first draft of the manuscript, and all authors edited, reviewed, and approved the final version of the manuscript. EP obtained funding for the study. JP and EP supervised the study and HT and EP are the guarantor of this work. All authors approved the final version of the manuscript and agree to be accountable for the accuracy of the work.

Corresponding author

Correspondence to Elisabetta Patorno MD, DrPH.

Ethics declarations

Conflict of Interest:

HT, KW, LZ, and JP have no conflicts of interest to disclose.

EP was supported by research grants from the Patient Centered Outcomes Research Institute (DB-2020C2-20326) and the Food and Drug Administration (5U01FD007213), not related to the topic of this work.

DW reports serving on Data Monitoring Committees for Novo Nordisk.

LK is an employee of Eli Lilly and Company and owns stock in Eli Lilly and Company.

NS and LS are employees of Boehringer-Ingelheim.

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Helen Tesfaye, and Katherine M. Wang are co-first authors.

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Tesfaye, H., Wang, K.M., Zabotka, L.E. et al. Empagliflozin and Risk of Incident Gout: Analysis from the EMPagliflozin Comparative Effectiveness and SafEty (EMPRISE) Cohort Study. J GEN INTERN MED (2024). https://doi.org/10.1007/s11606-024-08793-9

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