Distinct Atherosclerotic Cardiovascular Disease Events Current evidence suggests that SGLT2-is reduce the risk of MI but do not reduce the risk of unstable angina, stroke, TIA, arterial revascularization, and PAD (Table 2). MI and angina pectoris. Analyzing 40 trials with approximately 60,000 participants, an umbrella review showed that SGLT2-i users have a 14% lower risk of incident MI compared to controls (HR, 0.86; 95%CI, 0.78–0.94) (Zhu et al., 2020). These results were consistent with another meta-analysis of RCTs in patients with diabetes (Zheng et al., 2018). However, the aforementioned meta-analyses did not show differences in the risk of unstable angina between SGLT2-i users and controls (Zheng et al., 2018; Zhu et al., 2020). Stroke and TIA. Several meta-analyses and reviews reported that SGLT2-is, including canagliflozin, dapagliflozin, and empagliflozin, do not affect the risk of stroke (Milonas and Tziomalos, 2018; Zheng et al., 2018; Sinha and Ghosal, 2019b; Sinha and Ghosal, 2019a; Zhu et al., 2020). In line, the empagliflozin and placebo arms in the EMPA-REG OUTCOME trial did not differ in the risk of TIA (Zinman et al., 2015). Further investigations evaluating the role of SGLT2-is in ischemic stroke are needed. Arterial revascularization. A limited number of studies have investigated the likelihood of arterial revascularization among SGLT2-i users. In the EMPA-REG OUTCOME trial on empagliflozin and in the DECLARE-TIMI 58 trial on dapagliflozin, the administration of SGLT2-is did not affect the risks of coronary revascularization or lower extremity revascularization, respectively (Zinman et al., 2015; Bonaca et al., 2020). PAD. There is inconsistent evidence regarding the role of SGLT2-is on PAD risk and subsequent lower limb amputations. Patients with diabetes are already at high risk of PAD, and SGLT2-is can presumably increase the risk of PAD even further via promoting glucosuria, volume depletion, and haemoconcentration (Shah et al., 2012). The CANVAS Program found increased risk of lower extremity amputations in the canagliflozin group compared to the placebo (HR, 1.97; 95%CI, 1.41–2.75) (Neal et al., 2017). However, the effects of canagliflozin on PAD may not be generalizable to other SGLT2-i compounds. In meta-analyses, dapagliflozin and empagliflozin were not associated with increased risk of amputations (Dicembrini et al., 2019; Heyward et al., 2020; Huang and Lee, 2020). Further studies are warranted to compare the risk of PAD between users of canagliflozin and users of other SGLT2-i compounds.