Objective To evaluate the cardiovascular protective effects and adverse reaction of sodium-glucose cotransporter 2 (SGLT2) inhibitors in type 2 diabetes mellitus (T2DM) patients with severe renal insufficiency. Methods We searched three public databases, including Medline, Embase and Cochrane Library, to collect randomized controlled trials on SGLT2 inhibitors in patients with diabetic nephropathy from the inception to August 2021. Results A total of six RCTs were included, including 3679 diabetic patients with severe renal insufficiency. The meta-analysis showed that SGLT2 inhibitor had significantly reduced the risk of hospitalization (HR=0.74, 95% CI=0.55-0.99, P=0.04) and stroke (HR=0.75, 95% CI=0.60-0.93, P=0.008) due to heart failure in comparison with placebo group. The incidence of cardiovascular death (HR=0.89, 95% CI=0.60-1.30, P=0.54) and all-cause death (HR=0.84, 95% CI=0.56-1.28, P=0.43) in the SGLT2 inhibitor group was similar to that in placebo group. As for side effects, there was no significant difference in total adverse events (RR=1.00, 95% CI=0.94-1.07, P=0.96), fracture (RR=2.34, 95% CI=0.52-10.51, P=0.27), urinary tract infection (RR=1.22, 95% CI=0.64-2.35, P=0.54), hypotension (RR=1.32, 95% CI=0.59-2.95, P=0.49), reproductive tract infection (RR=0.67, 95% CI=0.15-2.93, P=0.6) and acute kidney injury (RR=0.96, 95% CI=0.41-2.26, P=0.93) between groups. Conclusion For T2DM patients with severe renal insufficiency, the administration of SGLT2 inhibitors is capable of reducing the risks of hospitalization and stroke due to heart failure, without increasing the risk of adverse events. SGLT2 inhibitors may have a protective and relatively safe effect on their cardiovascular outcomes. Future clinical trials are needed to support the impact of SGLT2 inhibitors on cardiovascular benefits in T2DM patients.