Fifty articles comprising 18 randomized controlled trials (RCTs), 16 observational studies, and 16 meta-analyses on the safety and effectiveness of sodium-glucose cotransporter 2 inhibitors were evaluated in the current review. Only one-fourth of the cohorts of recent trials had peripheral arterial disease (PAD), whereas this subgroup was at high risk for amputations. Despite a remarkable heterogeneity of RCTs, only 2 trials on canagliflozin suggested excess amputation rates, whereas several observational studies generated conflicting conclusions and remained short on possible explanations. Preliminary evidence from observational research suggested that patients with PAD may even benefit from SGLT-2 inhibitor treatment due to lower observed heart failure hospitalization rates.