Diabetes secondary to total pancreaticoduodenectomy (TP) is challenging to manage due to high glycemic variability and risk of hypoglycemia, in a frail population. We report the case of four patients with no prior diabetes who underwent TP. Three of four patients needed artificial nutritional support. Hybrid closed-loop (HCL) insulin therapy was initiated within 12 weeks of surgery. After 90 days of HCL treatment, continuous glucose measurement showed a 70.4 ± 11.8 % time in range (versus 43 ± 6.5 % before HCL); 0.2 ± 0.2 % time below range (versus 0.6 ± 0.5 % before HCL); 23.8 ± 9.1 % time above range 180–250 mg/dl (versus 22.9 ± 6.1 % before HCL); 4.2 ± 2.5 % time above range > 250 mg/dl (versus 33.8 ± 3.9 % before HCL). The glucose management indicator improved from 8.5 ± 0.6 % to 6.9 ± 0.6 %. There was no severe hypoglycemia or need for unplanned medical attention. Early post-operative use of HCL allowed our patients to achieve safely optimal glycemic control after TP.