*6.6.3 SGLT2 inhibitors and risk of limb amputations*

Canagliflozin significantly reduced the risk of CV events by 14% but increased the risk of lower limb amputation in patients with T2DM and high CVD risk (hazard ratio 1.97) versus placebo as seen in CANVAS trial [114].

In the EMAP REG trial using empagliflozin, in T2DM patient with established CVD, the rate of lower limb amputation was similar to placebo group [88].

Recently in DECLARE-TIMI 58 trial, the rate of amputation was similar between the dapagliflozin- and placebo-treated patient (hazard ratio 1.09) [97].

In a recent report, canagliflozin, but not dapagliflozin or empagliflozin, was associated with a higher risk of amputation in a pharmacovigilance analysis using the US FDA Adverse Event Reporting System [117].

Presently the evidence may not be enough to explain a precise causal relationship between canagliflozin and amputation. Neither the underlying mechanisms are currently known, nor do we know whether it is specifically related to canagliflozin. As amputation carries a negative impact on patient's clinical course, understanding predisposing factors and mechanisms of amputation will be crucial to maximize the benefits of SGLT2 inhibitors in clinical practice [117].

### *6.6.4 Effect on bone health*

In CANVAS study, patients treated with canagliflozin had about six additional cases of bone fracture compared to those receiving placebo. However, such an effect could not be replicated in other trials of canagliflozin [118].

Canagliflozin is associated with a small but statistically significant decrease in total hip bone mineral density (BMD) but no statistically significant change in BMD at other sites and without any meaningful changes in most biomarkers of bone turnover [118].

No significant changes in bone density or increase in rate of fracture were observed with dapagliflozin in patients with DM and normal or mildly impaired renal function, but more fractures were observed in dapagliflozin-treated patients with moderate renal impairment (eGFR ≤30–60 mL/min/1.73 m<sup>2</sup> ) [104]. Empagliflozin however did not show any clear evidence of increase fracture rates in people with T2DM [119].

Furthermore, the absence of SGLT2 in bone or bone marrow makes direct causeeffect hypothesis unlikely. It is known that SGLT2-I induce osmotic diuresis leading to volume depletion which may increase the susceptibility to falls. An increase in fall-related fractures cannot be ruled out as a possible explanation. The exact reason and mechanism are unknown at this time and may possibly be related to factors extrinsic to bone health [28].

Pending further evidence, the US FDA has revised the label of canagliflozin with new warning in September 2015.

#### *6.4.5 Restrictions of application*

SGLT2-I are prescribed as once daily oral pill due to their long elimination halflife. They are metabolized in the liver, and inactive metabolites are formed mainly due to glucuronidation.

They are also eliminated partially by renal excretion of parent drugs. Thus, dose adjustment is needed in patients with hepatic and/or renal disorders. They are contraindicated in severe chronic kidney disease.
