Abstract Background and purpose Diabetes mellitus (DM) is common in heart failure with preserved ejection fraction (HFpEF). Patients with DM and HF with reduced ejection fraction have higher levels of prognostic biomarkers relative to non-diabetics. We sought to examine differences in biomarkers at baseline and over time in patients with HFpEF with and without DM (non-DM). Methods The Americas cohort of the TOPCAT trial included 248 subjects with baseline measurements of serum biomarkers and follow-up measures 12 months later. Subjects were identified as non-DM or DM at baseline. Baseline values were compared using non-parametric tests and 12-month changes were compared via linear regression after log-transformation and adjustment for baseline biomarker value, age, gender, randomization strata, and randomized treatment. Results At baseline, DM patients had significantly lower eGFR and higher hsCRP, PIIINP, TIMP1, and Gal-3 levels versus non-DM patients (Table). In addition, there was a significantly larger increase over time in levels of hs-TnT, a marker of myocyte death, in DM vs. non-DM patients (p=0.016). Baseline and 12-Month Biomarkers Baseline % Change at 12 Months Non-DM (n=132) DM (n=116) p Non-DM (n=110) DM (n=94) p eGFR (mL/min/1.73m2) 67 [57, 77] 57 [46, 73] 0.003 −14% (−17, −10) −14% (−18, −10) 0.34 hsCRP (mg/L) 2.4 [1.1, 5.6] 3.1 [1.6, 7.5] 0.046 1% (−5, 3) −11% (−27, 7) 0.54 NT-proBNP (pg/mL) 624 [338, 1235] 629 [278, 1429] 0.80 −2% (−12, 10) −5% (−21, 13) 0.48 hs-TNT (ng/mL) 5.7 [3.1, 12.4] 7.1 [3.7, 14.2] 0.17 −1% (−14, 13) 11% (−3, 27) 0.016 Soluble ST2 (ng/mL) 28 [22, 32] 28 [21, 35] 0.36 −1% (−7, 5) −4% (−9, 2) 0.60 Aldosterone (ng/L) 149 [120, 202] 142 [113, 174] 0.09 17% (9, 26) 23% (14, 33) 0.76 PICP (ng/mL) 137 [101, 169] 127 [102, 155] 0.29 5% (−5, 17) 1% (−9, 12) 0.07 CITP (ng/mL) 1.6 [1.0, 2.8] 1.6 [0.9, 3.0] 0.93 −25% (−37, 10) −23% (−36, −8) 0.87 PIIINP (ng/mL) 23 [16, 30] 28 [21, 36] <0.001 5% (−4, 15) 5% (−3, 14) 0.12 TIMP-1 (ng/mL) 188 [170, 212] 212 [183, 245] <0.001 −1% (−4, 2) −2% (−5, 2) 0.59 Galectin-3 (ng/mL) 20 [16, 23] 22 [18, 28] <0.001 6% (3, 10) 9% (4, 14) 0.52 eGFR, estimated glomerular filtration rate; hsCRP, high-sensitivity CRP; NT-proBNP, N-terminal pro-B-type natriuretic peptide; hs-TnT, high-sensitivity troponin T; PICP, pro-collagen type I carboxy-terminal peptide; CITP, collage type I; PIIINP=pro-collagen type III amino-terminal peptide; TIMP-1=tissue inhibitor of MMP-1. Conclusions In comparison to patients without DM, those with DM had poorer renal function and higher baseline levels of markers of myocardial stretch, myocyte death, and pro-fibrotic biomarkers. Further, hs-TnT increased over 12 months only in patients with DM.