High baseline FGF21 levels are associated with poor glucose-lowering efficacy of exenatide in patients with type 2 diabetes



To investigate the association between fibroblast growth factor 21 (FGF21) levels and glycemic response to exenatide in patients with type 2 diabetes.


The exploratory analysis of a multi-center trial included 190 patients with type 2 diabetes inadequately controlled by monotherapy or combination therapy of metformin and insulin secretagogues. All participants received exenatide twice daily as an add-on therapy for 16 weeks. Serum FGF21 and other information at the baseline and end of follow-ups were obtained. Linear regression analysis was used to determine the correlations between baseline FGF21 levels and HbA1c reduction from baseline after the treatment.


After 16 weeks of treatment with exenatide, a decline in the HbA1c levels from baseline was associated with higher baseline FGF21 levels among all participants (r = 0.193, P = 0.008) and in subgroup of the participants receiving background metformin monotherapy (r = 0.231, P = 0.034). Compared with patients in the lowest FGF21 quartile, patients in the highest FGF21 quartile showed a significantly weakened decline in HbA1c levels from baseline among all participants (β = − 0.16 [95% Cl − 0.31 to − 0.01], P < 0.05) and in subgroup of the participants receiving background metformin monotherapy (β = − 0.23 [95% Cl − 0.43 to − 0.03], P < 0.05), after adjusting for the confounding factors, including age, sex, and baseline HbA1c levels.


The high baseline FGF21 levels are associated with poor glycemic responses to exenatide in patients with type 2 diabetes. Therefore, FGF21 could be used as a biomarker for predicting the efficacy of exenatide treatment.

Trial registration

ChiCTR-IPR-15006558, date registered May 27, 2015.

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

Fig. 1

Availability of data and materials

The datasets generated during the current study are available from the corresponding authors upon reasonable request.



Fibroblast growth factor 21


Glucagon-like peptide-1 receptor agonist


Glycated hemoglobin A1c


  1. 1.

    DeFronzo RA, Ferrannini E, Groop L, Henry RR, Herman WH, Holst JJ et al (2015) Type 2 diabetes mellitus. Nat Rev Dis Primers 1:15019

    Article  Google Scholar 

  2. 2.

    Ji LN, Lu JM, Guo XH, Yang WY, Weng JP, Jia WP et al (2013) Glycemic control among patients in China with type 2 diabetes mellitus receiving oral drugs or injectables. BMC Publ Health 13:602

    CAS  Article  Google Scholar 

  3. 3.

    Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N et al (2019) Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9(th) edition. Diabetes Res Clin Pract 157:107843

    Article  Google Scholar 

  4. 4.

    Palmer SC, Mavridis D, Nicolucci A, Johnson DW, Tonelli M, Craig JC et al (2016) Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: a meta-analysis. JAMA 316:313–324

    CAS  Article  Google Scholar 

  5. 5.

    American Diabetes Association (2020) Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2020. Diabetes Care 43(Suppl 1):S98–S110

    Article  Google Scholar 

  6. 6.

    Drucker DJ, Nauck MA (2006) The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368:1696–1705

    CAS  Article  Google Scholar 

  7. 7.

    Esposito K, Mosca C, Brancario C, Chiodini P, Ceriello A, Giugliano D (2011) GLP-1 receptor agonists and HbA1c target of < 7% in type 2 diabetes: meta-analysis of randomized controlled trials. Curr Med Res Opin 27:1519–1528

    CAS  Article  Google Scholar 

  8. 8.

    Gimeno RE, Moller DE (2014) FGF21-based pharmacotherapy–potential utility for metabolic disorders. Trends Endocrinol Metab 25:303–311

    CAS  Article  Google Scholar 

  9. 9.

    Liu J, Yang K, Yang J, Xiao W, Le Y, Yu F et al (2019) Liver-derived fibroblast growth factor 21 mediates effects of glucagon-like peptide-1 in attenuating hepatic glucose output. EBioMedicine 41:73–84

    Article  Google Scholar 

  10. 10.

    Nonogaki K, Hazama M, Satoh N (2014) Liraglutide suppresses obesity and hyperglycemia associated with increases in hepatic fibroblast growth factor 21 production in KKAy mice. Biomed Res Int 2014:751930

    Article  Google Scholar 

  11. 11.

    Bobbert T, Schwarz F, Fischer-Rosinsky A, Pfeiffer AF, Mohlig M, Mai K et al (2013) Fibroblast growth factor 21 predicts the metabolic syndrome and type 2 diabetes in Caucasians. Diabetes Care 36:145–149

    CAS  Article  Google Scholar 

  12. 12.

    Chen C, Cheung BM, Tso AW, Wang Y, Law LS, Ong KL et al (2011) High plasma level of fibroblast growth factor 21 is an independent predictor of type 2 diabetes: a 5.4-year population-based prospective study in Chinese subjects. Diabetes Care 34:2113–2115

    CAS  Article  Google Scholar 

  13. 13.

    Yang J, Xiao W, Guo L, Li Q, Zhong L, Yang J et al (2020) Efficacy and safety of generic exenatide injection in Chinese patients with type 2 diabetes: a multicenter, randomized, controlled, non-inferiority trial. Acta Diabetol 57:991–1000

    CAS  Article  Google Scholar 

  14. 14.

    Defronzo RA (2009) Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 58:773–795

    CAS  Article  Google Scholar 

  15. 15.

    Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA et al (2016) Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 375:311–322

    CAS  Article  Google Scholar 

  16. 16.

    Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA et al (2016) Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 375:1834–1844

    CAS  Article  Google Scholar 

  17. 17.

    Jones AG, McDonald TJ, Shields BM, Hill AV, Hyde CJ, Knight BA et al (2016) Markers of beta-cell failure predict poor glycemic response to GLP-1 receptor agonist therapy in type 2 diabetes. Diabetes Care 39:250–257

    CAS  PubMed  Google Scholar 

  18. 18.

    Hu Y, Liu J, Zhang H, Xu Y, Hong T, Wang G (2016) Exenatide treatment decreases fasting fibroblast growth factor 21 levels in patients with newly diagnosed type 2 diabetes mellitus. Diabetes Metab 42:358–363

    CAS  Article  Google Scholar 

  19. 19.

    Yang M, Zhang L, Wang C, Liu H, Boden G, Yang G et al (2012) Liraglutide increases FGF-21 activity and insulin sensitivity in high fat diet and adiponectin knockdown induced insulin resistance. PLoS ONE 7:e48392

    CAS  Article  Google Scholar 

  20. 20.

    Jaiswal M, Martin CL, Brown MB, Callaghan B, Albers JW, Feldman EL et al (2015) Effects of exenatide on measures of diabetic neuropathy in subjects with type 2 diabetes: results from an 18-month proof-of-concept open-label randomized study. J Diabetes Compl 29:1287–1294

    Article  Google Scholar 

  21. 21.

    Rosenstock J, Fonseca VA, Gross JL, Ratner RE, Ahren B, Chow FC et al (2014) Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro. Diabetes Care 37:2317–2325

    CAS  Article  Google Scholar 

  22. 22.

    Nauck MA, Stewart MW, Perkins C, Jones-Leone A, Yang F, Perry C et al (2016) Efficacy and safety of once-weekly GLP-1 receptor agonist albiglutide (HARMONY 2): 52 week primary endpoint results from a randomised, placebo-controlled trial in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetologia 59:266–274

    CAS  Article  Google Scholar 

  23. 23.

    Buse JB, Bergenstal RM, Glass LC, Heilmann CR, Lewis MS, Kwan AY et al (2011) Use of twice-daily exenatide in basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med 154:103–112

    Article  Google Scholar 

  24. 24.

    Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD et al (2004) Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 27:2628–2635

    CAS  Article  Google Scholar 

  25. 25.

    Cheng X, Zhu B, Jiang F, Fan H (2011) Serum FGF-21 levels in type 2 diabetic patients. Endocr Res 36:142–148

    CAS  Article  Google Scholar 

  26. 26.

    Mraz M, Bartlova M, Lacinova Z, Michalsky D, Kasalicky M, Haluzikova D et al (2009) Serum concentrations and tissue expression of a novel endocrine regulator fibroblast growth factor-21 in patients with type 2 diabetes and obesity. Clin Endocrinol (Oxf) 71:369–375

    CAS  Article  Google Scholar 

  27. 27.

    Reinehr T, Woelfle J, Wunsch R, Roth CL (2012) Fibroblast growth factor 21 (FGF-21) and its relation to obesity, metabolic syndrome, and nonalcoholic fatty liver in children: a longitudinal analysis. J Clin Endocrinol Metab 97:2143–2150

    CAS  Article  Google Scholar 

  28. 28.

    Wang D, Zhu W, Li J, An C, Wang Z (2013) Serum concentrations of fibroblast growth factors 19 and 21 in women with gestational diabetes mellitus: association with insulin resistance, adiponectin, and polycystic ovary syndrome history. PLoS ONE 8:e81190

    Article  Google Scholar 

  29. 29.

    Stein S, Stepan H, Kratzsch J, Verlohren M, Verlohren HJ, Drynda K et al (2010) Serum fibroblast growth factor 21 levels in gestational diabetes mellitus in relation to insulin resistance and dyslipidemia. Metabolism 59:33–37

    CAS  Article  Google Scholar 

  30. 30.

    Dekker NM, Barrett HL, Kubala MH, Scholz RK, Denny KJ, Woodruff TM et al (2014) Increased placental expression of fibroblast growth factor 21 in gestational diabetes mellitus. J Clin Endocrinol Metab 99:E591–598

    Article  Google Scholar 

  31. 31.

    Dushay J, Chui PC, Gopalakrishnan GS, Varela-Rey M, Crawley M, Fisher FM et al (2010) Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology 139:456–463

    CAS  Article  Google Scholar 

  32. 32.

    Mutanen A, Heikkila P, Lohi J, Raivio T, Jalanko H, Pakarinen MP (2014) Serum FGF21 increases with hepatic fat accumulation in pediatric onset intestinal failure. J Hepatol 60:183–190

    CAS  Article  Google Scholar 

  33. 33.

    Baggio LL, Drucker DJ (2007) Biology of incretins: GLP-1 and GIP. Gastroenterology 132:2131–2157

    CAS  Article  Google Scholar 

Download references


We sincerely thank all the investigators from Beijing Hospital; PLA Rocket Forces Characteristic Medical Center; Beijing Tiantan Hospital, Capital Medical University; Beijing Tongren Hospital, Capital Medical University; The First Hospital of Shanxi Medical University; People’s Hospital of Hainan Province; and Peking University Third Hospital. We also thank all the patients whose participation made this study possible.


This study was supported by research grants from National Key Research and Development Program of China (2018YFC1313900), the National Natural Science Foundation of China (81830022, 81800730, 81670701 and 91749101), and the Capital’s Funds for Health Improvement and Research (2020-3-40914).

Author information




KY performed the experiments, analyzed the data, and drafted the manuscript. HW, RW, WX, QT, and CW performed the experiments. JY helped supervise the project, performed the experiments, and edited the manuscript. TH designed the study, supervised the project, and edited the manuscript. TH is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Corresponding authors

Correspondence to Jin Yang or Tianpei Hong.

Ethics declarations

Conflict of interest

The authors declare that there is no duality of interest associated with this manuscript.

Ethical approval

The research protocol was approved by the Medical Ethics Committee of Peking University Third Hospital.

Informed consent

All participants provided written informed consent before enrollment in this study.

Additional information

Publisher's Note

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

Managed by Antonio Secchi.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 74 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yang, K., Wang, H., Wei, R. et al. High baseline FGF21 levels are associated with poor glucose-lowering efficacy of exenatide in patients with type 2 diabetes. Acta Diabetol (2021). https://doi.org/10.1007/s00592-020-01660-z

Download citation


  • Fibroblast growth factor 21
  • Glucagon-like peptide-1 receptor agonist
  • Therapeutic efficacy
  • Type 2 diabetes