Scopus: Evaluating, in patients with multiple comorbidities and drug resistance, impact of triple therapy with iSGLT-2 (Dapaglifozin or Empaglifozin) in association with metformin and insulin (Group A) versus GLP1-RA (Semaglutide sc or Dulaglutide) in association to metformin and insulin (Group B) on indices of renal function, cardiovascular risk, insulin requirement and liver fibrosis (Fib-4). Materials and methods: We selected the patients who came under observation in the last year due to therapeutic failure, randomizing them one by one to group A or group B. The parameters evaluated at baseline were insulin requirements, LDL values, HbA1c values, the eGFR calculated according to CKD-EPI and the Body Mass Index (BMI) and Fib-4 as a non-invasive index of liver fibrosis. These parameters were re-evaluated at the next follow-up after approximately six months. Results: 91 patients were selected, including 55 males and 36 females, and 47 patients were assigned to Group A and the remaining 44 to Group B. At the time of enrollment, the patients in group A took an average dose of Metformin of 1855 mg/day, while those in group B took 1961 mg/day (p-value not significant). In all the parameters evaluated in the two populations, no significant differences were found at time zero. In Group A, at the sixth month of follow-up, the only parameter with a significant reduction was HbA1c (p=0.016). In Group B, however, BMI and HbA1c reduced significantly (p<0.0001), while the change in LDL bordered on statistical significance (p=0.054). The study showed how group B undergoes a significant reduction in LDL concentration and insulin requirements compared to group A (p=0.027). Fib-4 decreased at the sixth month only in GROUP B with a significant difference between the two populations examined. Conclusions: The triple therapy with GLP1-RA (Semaglutide sc or Dulaglutide) resulted in a significant reduction in LDL, BMI, HbA1c values, agreeing with the effect known in the literature of GLP1-RAs, this effect is also confirmed by the lower insulin requirement of this group at six months. Instead, triple therapy with SGLT2-i (Dapaglifozin or Empaglifozin) only led to a reduction in HbA1c values. From these preliminary data, it seems that liver fibrosis benefits from treatment with GLP1-RA even in patients with drug-resistant diabetes mellitus.