Abstract Body (Do not enter title and authors here): Hospitalizations for worsening heart failure (WHF) remain high despite the efficacy of SGLT2 inhibitors such as Empagliflozin (Empa). Urocortin-2 (UCN-2) peptide which is part of the corticotropin-releasing factor (CRF) family, is a paracrine CRF2 receptor agonist that protects heart and kidney function in various HF models and in HF patients. UCN-2 is unstable, therefore a long-acting analog COR-1167 was synthesized as a daily injectable therapeutic peptide. We explored the effect of COR-1167 plus Empa, or Empa versus control ZSF-1 rats with WHF. Two groups of female rats (36 weeks old) were fed chow (control) or chow containing Empa (10 mg/kg/day) for 28 days. On Day 0, WHF was triggered by dosing saline p.o. that was repeated on Day 13. On Day 0.5 until Day 21, Empa treated rats were injected s.c. daily with vehicle (Empa) or with COR-1167 (3 μg/kg; Empa+COR3). A third control ZSF-1 group continued in parallel. Echocardiography (Days -8, 0, 1 and 14), kidney function (Day 7), treadmill distance (Day 8), direct cardiovascular function and kidney histology (Day 21) were assessed. Oral saline depressed cardiac output (CO) in control and Empa treated rats on Day 1 (82±5, 87±8 mL/min) and Day 14 (74±3, 87±4 mL/min) versus control rats on Days -8 and 0 (119±7, 114±7 mL/min), while the Empa+COR3 group improved their CO on Days 1 and 14 (111±6, 107±5 mL/min: P<0.05). Empa+COR3 versus Empa, increased treadmill distance (Day 8: 246±70, 181±49 m; P=0.054), decreased Tau (Day 21: 10.8±0.9, 12.2±1.2 ms; P<0.05) and left ventricular end diastolic pressure volume relationship (Day 21: 2.3±0.9, 3.8±0.5 mm Hg/RVU; P<0.05). Urine sodium, glucose and volume were lower in control ZSF-1 rats (Day 7: 999±155 mmol, 2.6±0.4 mmol, 13±2 mL) versus Empa (1328±315 mmol, 2222±292 mmol, 32±6 mL; P<0.05). Comparing Empa+COR3 to Empa, demonstrated increased urine sodium (Day 7: 1546±183, 1328±215 mmol; P<0.05), urine creatinine (2088±312, 1772±290 mmol; P<0.05) while plasma KIM-1 decreased (Day 21: 550±69, 441±53 pg/mL; P<0.05). Histology scoring showed that Empa+COR3 reduced glomerulosclerosis compared to Empa (Day 21: 0.95±0.28, 1.90±0.20 arbitrary unit; P<0.05). On a background of volume overload and Empa treatment, daily s.c. delivery of COR-1167 maintained CO, rapidly ameliorated decompensation and deteriorating heart and kidney function in ZSF-1 rats. Chronic CRF2 agonism with COR-1167 is a potential new therapy to treat patients with WHF and preserved ejection fraction.