**Conflict of interest**

*Type 2 Diabetes - From Pathophysiology to Modern Management*

could not be replicated in other trials of canagliflozin [118].

In CANVAS study, patients treated with canagliflozin had about six additional cases of bone fracture compared to those receiving placebo. However, such an effect

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

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 m2

Empagliflozin however did not show any clear evidence of increase fracture rates in

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

Pending further evidence, the US FDA has revised the label of canagliflozin with

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

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

SGLT2-I are a unique emerging class of OAH agents that has addressed fundamental aspects of the unmet needs that challenge physicians treating T2DM patients, such as increased risk of hypoglycemia and weight gain that are usually noticed with other agents such as insulin. On the contrary, SGLT2-I therapy in T2DM is associated with very low risk of hypoglycemia and also promotes weight loss. Moreover, SGLT2-I have been shown to reduce the risk of MACE, all-cause mortality, and hospitalization for heart failure. They have additional renal protective properties besides reducing SBP. In fact, their mode of action through prevention of glucose reabsorption in the kidney makes them work independently from the pancreas, bypassing the problem of progressive beta cell failure that happens in most patients with T2DM over time, and this gives them longer durability. They can be used regardless of duration of disease and can be used as monotherapy as well as in combination as they have been shown to complement actions of other OAH agents including insulin. Considering their unique mechanism of action, they may be useful in impaired glucose tolerance and prediabetes also. The major side effects drawbacks of SGLT2-I is the increased rate of GMI. Another important side effect of SGLT2-I is EKA in T2DM patients during stress and following surgery as

) [104].

*6.6.4 Effect on bone health*

people with T2DM [119].

extrinsic to bone health [28].

new warning in September 2015.

contraindicated in severe chronic kidney disease.

*6.4.5 Restrictions of application*

due to glucuronidation.

**7. Conclusion**

turnover [118].

**88**

Authors declare that there is no conflict of interest. No fund or grant was received in any form for this work.
