Predictors of poor response to urate-lowering therapy in patients with gout and hyperuricemia: a post-hoc analysis of a multicenter randomized trial

Abstract

Introduction

Clinical guidelines have recommended a target of serum uric acid (SUA) level below 6.0 mg/dL for the urate-lowering therapy (ULT) of gout patients, but there are still a high proportion of patients failing to achieve the therapeutic target above. This study aimed to identify possible predictors of poor response to ULT in gout patients.

Methods

We performed a post-hoc analysis of a multicenter randomized double-blind trial which assessed the efficacy of febuxostat in patients with hyperuricemia (serum urate level ≥ 8.0 mg/dL) and gout. Demographic characters and baseline data including SUA levels were collected. Poor response to ULT was defined as average SUA after ULT was more than 6.0 mg/dL. Factors associated with poor response to ULT in gout patients were analyzed, and multivariate logistic regression analysis was also carried out to find out those independent predictors.

Results

A total of 370 patients were enrolled in this post-hoc analysis. Compared with those with good response to ULT, patients with poor response to ULT had younger age (P < 0.001), higher proportion of obesity (P = 0.003), higher proportion of statins use (P = 0.019), higher body mass index (BMI) (P < 0.001), higher baseline SUA (P < 0.001), higher proportion of males (P = 0.001), higher alanine transaminase (P < 0.001), higher aspartate transaminase (P = 0.017), higher total cholesterol (P = 0.005), higher triglyceride (P = 0.042), and higher low density lipoprotein (P = 0.037). Multivariate logistic regression analysis showed that younger age (odds ratio (OR) = 0.965, 95% CI 0.943–0.987, P = 0.002), higher BMI (OR = 1.133, 95% CI 1.049–1.224, P = 0.001), higher baseline SUA (OR = 1.006, 95% CI 1.002–1.009, P = 0.001), and no application of febuxostat therapy (OR = 0.41, 95% CI 0.25–0.68, P < 0.001) were independent predictors of poor response to ULT in patients with gout.

Conclusion

In patients with gout and hyperuricemia, younger age, higher BMI, and higher baseline SUA are predictors of poor response to ULT. These findings could help physicians better identify patients who may fail in ULT and give individualized treatment precisely.

Trial registration

The trial was registered at chinadrugtrials.org.cn in 2012 (CTR20130172).

Key Points
• A post-hoc analysis of a multicenter randomized double-blind trial which assessed the efficacy of febuxostat in patients with hyperuricemia and gout was performed.
• Multivariate logistic regression analysis showed that younger age, higher BMI, and higher baseline SUA are predictors of poor response to urate-lowering therapy.

This is a preview of subscription content, access via your institution.

Fig. 1

Abbreviations

ACR:

American College of Rheumatology

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

BMI:

Body mass index

BUN:

Blood urea nitrogen

Cr:

Creatinine

DBP:

Diastolic blood pressure

EULAR:

European League Against Rheumatism

FBG:

Fasting blood glucose

LDL:

Low density lipoprotein

OR:

Odds ratio

SBP:

Systolic blood pressure

SUA:

Serum uric acid

T2DM:

Type 2 diabetes mellitus

TBIL:

Total bilirubin

TC:

Total cholesterol

TG:

Triglyceride

ULT:

Urate-lowering therapy

References

  1. 1.

    Dalbeth N, Merriman TR, Stamp LK (2016) Gout. Lancet 388(10055):2039–2052. https://doi.org/10.1016/S0140-6736(16)00346-9

    CAS  Article  Google Scholar 

  2. 2.

    Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, Pillinger MH, Merill J, Lee S, Prakash S, Kaldas M, Gogia M, Perez-Ruiz F, Taylor W, Liote F, Choi H, Singh JA, Dalbeth N, Kaplan S, Niyyar V, Jones D, Yarows SA, Roessler B, Kerr G, King C, Levy G, Furst DE, Edwards NL, Mandell B, Schumacher HR, Robbins M, Wenger N, Terkeltaub R, American College of R (2012) 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res 64(10):1431–1446. https://doi.org/10.1002/acr.21772

    CAS  Article  Google Scholar 

  3. 3.

    Elfishawi MM, Zleik N, Kvrgic Z, Michet CJ Jr, Crowson CS, Matteson EL, Bongartz T (2018) The rising incidence of gout and the increasing burden of comorbidities: a population-based study over 20 years. J Rheumatol 45(4):574–579. https://doi.org/10.3899/jrheum.170806

    Article  PubMed  Google Scholar 

  4. 4.

    Zobbe K, Prieto-Alhambra D, Cordtz R, Hojgaard P, Hindrup JS, Kristensen LE, Dreyer L (2018) Secular trends in the incidence and prevalence of gout in Denmark from 1995 to 2015: a nationwide register-based study. Rheumatology. 58:836–839. https://doi.org/10.1093/rheumatology/key390

    Article  Google Scholar 

  5. 5.

    Zhu Y, Pandya BJ, Choi HK (2011) Prevalence of gout and hyperuricemia in the US general population: the national health and nutrition examination survey 2007-2008. Arthritis Rheum 63(10):3136–3141. https://doi.org/10.1002/art.30520

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Lim SY, Lu N, Oza A, Fisher M, Rai SK, Menendez ME, Choi HK (2016) Trends in gout and rheumatoid arthritis hospitalizations in the United States, 1993-2011. Jama 315(21):2345–2347. https://doi.org/10.1001/jama.2016.3517

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Xiaofeng Z, Yaolong C (2017) 2016 China guidelines for management of gout. Chin J Intern Med 55(11):892–899. https://doi.org/10.3760/cma.j.issn.0578-1426.2016.11.019

    Article  Google Scholar 

  8. 8.

    Roddy E, Mallen CD, Doherty M (2013) Gout. BMJ 347:f5648. https://doi.org/10.1136/bmj.f5648

    Article  PubMed  Google Scholar 

  9. 9.

    Wood R, Fermer S, Ramachandran S, Baumgartner S, Morlock R (2016) Patients with gout treated with conventional urate-lowering therapy: association with disease control, health-related quality of life, and work productivity. J Rheumatol 43(10):1897–1903. https://doi.org/10.3899/jrheum.151199

    Article  PubMed  Google Scholar 

  10. 10.

    Shiozawa A, Buysman EK, Korrer S (2017) Serum uric acid levels and the risk of flares among gout patients in a US managed care setting. Curr Med Res Opin 33(1):117–124. https://doi.org/10.1080/03007995.2016.1239193

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Schlesinger N, Dalbeth N, Perez-Ruiz F (2009) Gout–what are the treatment options? Expert Opin Pharmacother 10(8):1319–1328. https://doi.org/10.1517/14656560902950742

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Richette P, Doherty M, Pascual E, Barskova V, Becce F, Castaneda-Sanabria J, Coyfish M, Guillo S, Jansen TL, Janssens H, Liote F, Mallen C, Nuki G, Perez-Ruiz F, Pimentao J, Punzi L, Pywell T, So A, Tausche AK, Uhlig T, Zavada J, Zhang W, Tubach F, Bardin T (2017) 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis 76(1):29–42. https://doi.org/10.1136/annrheumdis-2016-209707

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Juraschek SP, Kovell LC, Miller ER 3rd, Gelber AC (2015) Gout, urate-lowering therapy, and uric acid levels among adults in the United States. Arthritis Care Res 67(4):588–592. https://doi.org/10.1002/acr.22469

    CAS  Article  Google Scholar 

  14. 14.

    Schumacher HR Jr, Becker MA, Wortmann RL, Macdonald PA, Hunt B, Streit J, Lademacher C, Joseph-Ridge N (2008) Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum 59(11):1540–1548. https://doi.org/10.1002/art.24209

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Luo H, Fang WG, Zuo XX, Wu R, Li XX, Chen JW, Zhou JG, Yang J, Song H, Duan XJ, Lin XF, Zeng XW, Zeng H (2018) The clinical characteristics, diagnosis and treatment of patients with gout in China. Zhonghua Nei Ke Za Zhi 57(1):27–31. https://doi.org/10.3760/cma.j.issn.0578-1426.2018.01.005

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Graham GG, Stocker SL, Kannangara DRW, Day RO (2018) Predicting response or non-response to urate-lowering therapy in patients with gout. Curr Rheumatol Rep 20(8):47. https://doi.org/10.1007/s11926-018-0760-2

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Neogi T, Jansen TL, Dalbeth N, Fransen J, Schumacher HR, Berendsen D, Brown M, Choi H, Edwards NL, Janssens HJ, Liote F, Naden RP, Nuki G, Ogdie A, Perez-Ruiz F, Saag K, Singh JA, Sundy JS, Tausche AK, Vaquez-Mellado J, Yarows SA, Taylor WJ (2015) 2015 Gout classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 74(10):1789–1798. https://doi.org/10.1136/annrheumdis-2015-208237

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Endocrinology CSo (2013) Chinese expert consensus on hyperuricemia and gout treatment. Chin J Endocrinol Metab 29(11):913–920

    Google Scholar 

  19. 19.

    Sheer R, Null KD, Szymanski KA, Sudharshan L, Banovic J, Pasquale MK (2017) Predictors of reaching a serum uric acid goal in patients with gout and treated with febuxostat. Clinicoecon Outcomes Res 9:629–639. https://doi.org/10.2147/CEOR.S139939

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Hatoum H, Khanna D, Lin SJ, Akhras KS, Shiozawa A, Khanna P (2014) Achieving serum urate goal: a comparative effectiveness study between allopurinol and febuxostat. Postgrad Med 126(2):65–75. https://doi.org/10.3810/pgm.2014.03.2741

    Article  PubMed  Google Scholar 

  21. 21.

    Fei Y, Cong Y, Wei T, Guifeng S, Linli D, Shaoxian H, Yikai Y, Ting Y (2017) Analysis of factors influencing the therapeutic effect of lowering uric acid in patients with gout. Chin J Rheumatol 21(2):110–113

    Google Scholar 

  22. 22.

    Choi HK, Atkinson K, Karlson EW, Curhan G (2005) Obesity, weight change, hypertension, diuretic use, and risk of gout in men: the health professionals follow-up study. Arch Intern Med 165(7):742–748. https://doi.org/10.1001/archinte.165.7.742

    Article  PubMed  Google Scholar 

  23. 23.

    Zhou J, Wang Y, Lian F, Chen D, Qiu Q, Xu H, Liang L, Yang X (2017) Physical exercises and weight loss in obese patients help to improve uric acid. Oncotarget 8(55):94893–94899. https://doi.org/10.18632/oncotarget.22046

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Cheung KJ, Tzameli I, Pissios P, Rovira I, Gavrilova O, Ohtsubo T, Chen Z, Finkel T, Flier JS, Friedman JM (2007) Xanthine oxidoreductase is a regulator of adipogenesis and PPARgamma activity. Cell Metab 5(2):115–128. https://doi.org/10.1016/j.cmet.2007.01.005

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Scheepers L, van Onna M, Stehouwer CDA, Singh JA, Arts ICW, Boonen A (2018) Medication adherence among patients with gout: a systematic review and meta-analysis. Semin Arthritis Rheum 47(5):689–702. https://doi.org/10.1016/j.semarthrit.2017.09.007

    Article  PubMed  Google Scholar 

  26. 26.

    Morlock R, Chevalier P, Horne L, Nuevo J, Storgard C, Aiyer L, Hines DM, Ansolabehere X, Nyberg F (2016) Disease control, health resource use, healthcare costs, and predictors in gout patients in the United States, the United Kingdom, Germany, and France: a retrospective analysis. Rheumatol Ther 3(1):53–75. https://doi.org/10.1007/s40744-016-0033-3

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Winckler K, Obe G, Madle S, Kocher-Becker U, Kocher W, Nau H (1987) Cyclophosphamide: interstrain differences in the production of mutagenic metabolites by S9-fractions from liver and kidney in different mutagenicity test systems in vitro and in the teratogenic response in vivo between CBA and C 57 BL mice. Teratog Carcinog Mutagen 7(4):399–409

    CAS  Article  Google Scholar 

  28. 28.

    Harrold LR, Andrade SE, Briesacher BA, Raebel MA, Fouayzi H, Yood RA, Ockene IS (2009) Adherence with urate-lowering therapies for the treatment of gout. Arthritis Res Ther 11(2):R46. https://doi.org/10.1186/ar2659

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Riedel AA, Nelson M, Joseph-Ridge N, Wallace K, MacDonald P, Becker M (2004) Compliance with allopurinol therapy among managed care enrollees with gout: a retrospective analysis of administrative claims. J Rheumatol 31(8):1575–1581

    PubMed  Google Scholar 

  30. 30.

    Janssen CA, Oude Voshaar MAH, Vonkeman HE, Krol M, van de Laar M (2018) A retrospective analysis of medication prescription records for determining the levels of compliance and persistence to urate-lowering therapy for the treatment of gout and hyperuricemia in the Netherlands. Clin Rheumatol 37(8):2291–2296. https://doi.org/10.1007/s10067-018-4127-x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    McGowan B, Bennett K, Silke C, Whelan B (2016) Adherence and persistence to urate-lowering therapies in the Irish setting. Clin Rheumatol 35(3):715–721. https://doi.org/10.1007/s10067-014-2823-8

    Article  PubMed  Google Scholar 

  32. 32.

    Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Eustace D, Palo WA, Streit J, Joseph-Ridge N (2005) Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 353(23):2450–2461. https://doi.org/10.1056/NEJMoa050373

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Altan A, Shiozawa A, Bancroft T, Singh JA (2015) A real-world study of switching from allopurinol to febuxostat in a health plan database. J Clin Rheumatol 21(8):411–418. https://doi.org/10.1097/RHU.0000000000000322

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Takano Y, Hase-Aoki K, Horiuchi H, Zhao L, Kasahara Y, Kondo S, Becker MA (2005) Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase. Life Sci 76(16):1835–1847. https://doi.org/10.1016/j.lfs.2004.10.031

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    White WB, Saag KG, Becker MA, Borer JS, Gorelick PB, Whelton A, Hunt B, Castillo M, Gunawardhana L, Investigators C (2018) Cardiovascular safety of febuxostat or allopurinol in patients with gout. N Engl J Med 378(13):1200–1210. https://doi.org/10.1056/NEJMoa1710895

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Derosa G, Maffioli P, Reiner Z, Simental-Mendia LE, Sahebkar A (2016) Impact of statin therapy on plasma uric acid concentrations: a systematic review and meta-analysis. Drugs 76(9):947–956. https://doi.org/10.1007/s40265-016-0591-2

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Milionis HJ, Kakafika AI, Tsouli SG, Athyros VG, Bairaktari ET, Seferiadis KI, Elisaf MS (2004) Effects of statin treatment on uric acid homeostasis in patients with primary hyperlipidemia. Am Heart J 148(4):635–640. https://doi.org/10.1016/j.ahj.2004.04.005

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Dr. Robin Wang for advice regarding statistical analysis of data.

Author information

Affiliations

Authors

Contributions

All authors contributed to the study conception and design, data collection, analysis of the data, interpretation of the results, and drafting of the manuscript. All authors revised the manuscript and approved the final version.

Corresponding author

Correspondence to Zhongchao Wang.

Ethics declarations

Disclosures

None.

Ethical standards

This clinical trial conformed to principles of the Declaration of Helsinki and the Good Clinical Practice of China and was approved by the Drug Clinical Trial Ethics Committee, Shandong Provincial Hospital. All participants provided written informed consent.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(XLSX 12 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Mu, Z., Wang, W., Wang, J. et al. Predictors of poor response to urate-lowering therapy in patients with gout and hyperuricemia: a post-hoc analysis of a multicenter randomized trial. Clin Rheumatol 38, 3511–3519 (2019). https://doi.org/10.1007/s10067-019-04737-5

Download citation

Keywords

  • Gout
  • Predictors
  • Treatment outcomes
  • Urate-lowering therapy