Elevated circulating hepatokine follistatin (FST) is associated with increased risk of type 2 diabetes (T2D) by inducing adipose tissue insulin resistance and adipocyte lipolysis. In this post-hoc analysis, we explored effects of the GIP/GLP-1 receptor agonist tirzepatide (TZP 5, 10, and 15 mg) and insulin glargine on plasma FST levels at weeks 24 and 52 in adults with T2D and high cardiovascular risk (SURPASS-4, n=1624). At baseline, higher concentration of FST was correlated with higher HbA1c and reduced HOMA-B. The adjusted hazard ratio (HR) for achieving HbA1c<5.7% by 15 mg TZP in the highest quartile of baseline plasma FST (Q4) vs. the lowest quartile (Q1) was 2.39 (CI: 1.14-5.03, p<0.05) in 24 weeks and 2.03 (CI: 1.12-3.70, p<0.05) in 52 weeks. TZP dose dependently reduced FST at 52 weeks (4.69; 4.49; 4.11 ng/ml for 5, 10, 15 mg TZP, p<0.001); and 15 mg TZP reduced FST at 24 and 52 weeks (baseline 5.14; 24 week 4.03; 52 week 4.11 ng/ml, p<0.001). Change from baseline FST correlated with HbA1c and BMI reduction and HOMA-B increase, with stronger associations on higher TZP dose. These post-hoc data show that TZP treatment reduces plasma FST, and TZP is more effective for reaching HbA1c<5.7% in T2D individuals with higher baseline FST levels. Further understanding of link between TZP outcomes and FST, including related role of FST in β-cell, hepatocyte and/or adipocyte function associated with TZP treatment, remain to be elucidated.
Q. Zou: None. G. Engström: Stock/Shareholder; AstraZeneca. J. Pan: None. J. Zhang: None. E.J. Perisho: Research Support; Eli Lilly and Company. Y. Lin: Stock/Shareholder; Eli Lilly and Company, Pfizer Inc., AstraZeneca. R. Wiese: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. J.M. Wilson: Employee; Eli Lilly and Company. I. Pavo: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. R. Gao: None. K.L. Duffin: Employee; Eli Lilly and Company. Y. De Marinis: None.
Crafoord Foundation (Crafoordska stiftelsen) grant to Y.D.M.
