Background: Two classes of drugs, SGLT2i and GLP-1 RA, have revolutionized the management of type 2 diabetes mellitus (T2DM) from glycemic control to overall cardiorenal risk reduction. Though there was strong evidence from randomized controlled trials, there are still some aspects of their effectiveness in the real world that are not understood completely, such as their efficacy with combination therapy and outcomes in advanced chronic kidney disease (CKD). Methods: This systematic review followed PRISMA 2020 guidelines. A detailed literature review was carried out on PubMed/MEDLINE, Web of Science and Scopus for the articles published over a past 5 years. Studies were included if they involved adult patients with T2DM treated with SGLT2i, GLP-1 RA or both, and if they measured major adverse cardiovascular events (MACE) or renal events. Eleven observational studies (mainly retrospective cohort, with more than 700,000 patients) fulfilled the inclusion criteria. The ROBINS-I tool was used to assess the risk of bias. Results: Combination therapy with the two drugs showed additive cardiorenal benefit: A reduction in risk of MACE by 30% compared to GLP-1 RA (HR 0.70; 95% CI: 0.49–0.99) and by 29% compared to SGLT2i (HR 0.71; 95% CI: 0.52–0.98). Adding GLP-1 RA to SGLT2i was associated with a 27% lower risk of major adverse kidney events (HR 0.73; 95% CI: 0.69–0.77) and a 39% lower risk of end-stage kidney disease (HR 0.61; 95% CI: 0.47–0.78). SGLT2i was more renal protective in advanced CKD (stage 4–5), but both classes of drugs retained cardiovascular benefits. Significant increased mortality (HR up to 1.97) and cardiovascular events were seen with treatment discontinuation ≥180 days. Conclusion: SGLT2i and GLP-1 RA are consistently linked to better MACE and renal outcomes in T2DM patients and combination therapy provides additional protection. The results were very strongly in favor of the current guideline recommendations for these agents in high cardiorenal-risk patients. Studies aimed to assess combination therapy versus monotherapy in dedicated randomized controlled trials, especially in non-diabetic and advanced CKD populations are warranted.