Background: The association between pancreatic ductal adenocarcinoma (PDAC) and type 2 diabetes mellitus (DM2) has long been evaluated. Indeed, DM2 can be both an epiphenomenon of PDAC and a risk factor. However, the data on the influence of DM2 and concomitant drug therapy in the progression of pancreatic neoplasms are conflicting. The present study aimed to investigate the correlation between overall survival (OS) and antidiabetic drugs in patients with metastatic pancreatic ductal adenocarcinoma and DM2. Methods: Data from 232 patients were collected retrospectively from 2014 to 2021. 174 from the Department of Medical Oncology of the University Hospital of Cagliari and 58 from the Department of Medical Oncology, AOU Ospedali Riuniti of Ancona. All patients had stage IV disease and received gemcitabine plus nab-paclitaxel first-line chemotherapy. Statistical analysis was performed with the MedCalc package. We aimed to evaluate the correlation between DM2, anti-diabetic medications (ADMs) and median overall survival (mOS). Survival distribution was assessed by Kaplan-Meier curves. Finally, multivariate analysis was performed, taking into consideration the following prognostic factors: sex, ECOG-PS, LDH, Ca19.9, and metastatic sites. Results: The median age was 69 y.o. (range 40-84 y.o.), 127 (54,7%) were male. All patients received first-line treatment with gemcitabine plus nab-paclitaxel. 138 (59,4%) patients were not affected by DM2, 94/232 (40,6%) were affected by DM2. Among DM2 patients, 57 (%) were insulin-treated and 37 (%) were metformin-treated. DM2 patients showed a statistically significant higher median overall survival (26 versus 11 months, 95% CI, p = 0,0002). Furthermore, among DM2 patients insulin-treated and metformin-treated showed a mOS of 21 months and 33 months, respectively (95% CI, p = 0.0002). Finally, multivariate analysis showed that treated-DM2 is an independent prognostic factor (p = 0.03). Conclusions: The results of our study showed a correlation between DM2 on treatment (with insulin or metformin) and higher mOSin patients with metastatic PDAC. However, the limitations due to retrospective data collection must be considered. The mechanisms underlying these findings could be explained by maintaining optimal insulin concentration and good glycemic control during treatments, or by the activity of anti-diabetic medication in neoplastic tissues. However, further studies in this setting are needed.