The incidence rates of common adverse events, with the use of SGLT2i, namely genital mycotic infections and volume depletion, were similar with both drugs. One surprise was the almost twofold increased risk for lower extremity amputations (LEA) with canagliflozin (HR 1.97; 95% CI 1.41–2.75,
p < 0.001), unlike empagliflozin. Further, the percentage of subjects with prior amputation in two arms (canagliflozin and placebo arm) of CANVAS was similar. Amputations in CANVAS were observed more often in men, and in those with history of prior amputation, neuropathy or peripheral vascular disease [
4]. Further the amputation risk was not different between 100 and 300 mg doses of canagliflozin. The amputation events were not systematically captured in EMPA-REG; hence, it was not possible to extrapolate the same risk with empagliflozin. However, a total of 131 patients in EMPA-REG had LEA, but the incidence was similar between placebo and empagliflozin (0.2% each) groups [
3]. Further, the US FDA Adverse Event Reporting System (FAERS) analysis exhibited a higher frequency of LEA (including any amputation and toe amputation) with canagliflozin with a proportional reporting ratio (PRR) of 5.33 (95% CI 4.04–7.04,
p < 0.0001), 0.25 with dapagliflozin, and 2.37 with empagliflozin compared to non-SGLT2i agents for diabetes indication [
19]. The risk of LEA with canagliflozin was more compared to with non-SGLT2i, despite that many patients with non-SGLT2i were receiving insulin, a marker of advanced vascular disease, which itself is a risk factor for LEA. What drives the increased risk of LEA with canagliflozin needs to be explored. A possible mechanism may be hemoconcentration due to osmotic diuresis as profound diuresis was observed more often with canagliflozin than placebo [34.5 vs 13.3,
p < 0.001 (event rate/1000 patient-year)] and more severe volume depletion with canagliflozin than empagliflozin (HR 1.44 vs 0.99 with canagliflozin and empagliflozin, respectively) [
3,
4].
Another eye-opener was a 23% increased risk for low-trauma fracture (predominantly in upper limb and ribs) with canagliflozin (HR 1.23, 95% CI 0.99–1.52) [
4]. The fracture rates were reported to be similar in both empagliflozin and placebo arms (3.8% versus 3.9%), though the fractures were not systematically captured in the EMPA-REG trial [
20]. Further, the fractures observed in the two studies were independent of baseline bone mineral density (BMD). The possible explanations for increased risk of fracture risk include increase in serum phosphate and consequent secondary hyperparathyroidism, postural fall due to volume depletion (HR 1.03 with empagliflozin and HR 1.44 with canagliflozin) [
21], decrease in estrogen secretion subsequent to weight loss (predominantly fat), and possible decrease in BMD [
22]. However, both EMPA-REG and CANVAS were not powerful enough to detect significant differences in either amputation or fracture among the studied population.