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.
ChiCTR-IPR-15006558, date registered May 27, 2015.
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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
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
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
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
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
American Diabetes Association (2020) Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2020. Diabetes Care 43(Suppl 1):S98–S110
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
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
Gimeno RE, Moller DE (2014) FGF21-based pharmacotherapy–potential utility for metabolic disorders. Trends Endocrinol Metab 25:303–311
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Cheng X, Zhu B, Jiang F, Fan H (2011) Serum FGF-21 levels in type 2 diabetic patients. Endocr Res 36:142–148
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
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
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
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
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
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
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
Baggio LL, Drucker DJ (2007) Biology of incretins: GLP-1 and GIP. Gastroenterology 132:2131–2157
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).
Conflict of interest
The authors declare that there is no duality of interest associated with this manuscript.
The research protocol was approved by the Medical Ethics Committee of Peking University Third Hospital.
All participants provided written informed consent before enrollment in this study.
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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
- Fibroblast growth factor 21
- Glucagon-like peptide-1 receptor agonist
- Therapeutic efficacy
- Type 2 diabetes