Sodium-Glucose Co-Transporter 2 Inhibitors and Fracture Risk

Abstract

Patients with type 2 diabetes mellitus (T2DM) appear to have increased risk for fractures. In this context, the finding that canagliflozin, a sodiumglucose co-transporter-2 (SGLT) inhibitor, increased the risk for fracture compared with placebo in the Canagliflozin Cardiovascular Assessment Study (CANVAS), a large randomized controlled trial (RCT) in patients with established cardiovascular disease or multiple cardiovascular risk factors, created concern. In the present review, we summarize the data regarding the association between SGLT2 inhibitors and fracture risk in patients with T2DM. In contrast to the findings reported in CANVAS, canagliflozin did not affect the risk of fracture in a more recent, large RCT in patients with diabetic nephropathy. In addition, empagliflozin and dapagliflozin, other members of this class, also do not appear to affect the incidence of fracture. Moreover, there is no clear pathogenetic mechanism through which SGLT2 inhibitors increase the risk for fractures. Therefore, available data are inconclusive to attribute to these drugs a direct responsibility for bone fractures.

Renoprotective mechanisms of sodium‐glucose co‐transporter 2 (SGLT2) inhibitors against the progression of diabetic kidney disease

“…This observation was consistent across all groups of eGFR, ranging from 30 to <90 ml per minute per 1.73 m 2 (Jardine et al, 2020). Intriguingly, the use of dapagliflozin and empagliflozin does not increase the incidence of fractures (Erythropoulou‐Kaltsidou et al, 2020) or amputations (Scheen, 2020) in patients. An expert panel overview concluded that an increased amputation risk in patients was related only to canagliflozin use (not with other SGTL2‐Is) and hence, not generalizable to SGLT2‐Is class (Katsiki et al, 2019).…”

Cardiovascular benefits from SGLT2 inhibition in type 2 diabetes mellitus patients is not impaired with phosphate flux related to pharmacotherapy

“…FGF23 is known to be provoked by increased phosphate, and the latter also provokes PTH excretion. Therefore, by proxy, SGLT2i by increasing phosphate, increase both FGF23 and PTH[ 120 , 121 ]. Within this small study, FGF23 levels peaked roughly 12 h after phosphate reached its maximus, consistent with physiologic studies of FGF23 expression[ 122 ].…”

“…FGF23 acts on the proximal tubule, inhibiting NPT2, a cotransporter of sodium and phosphate (which may further explain why natriuresis is not the predominant mechanism of urinary loss within SGLT2i administration after phosphate levels subsequently reach clinically relevant concentrations)[ 123 ]. Interestingly, FGF23 suppresses 1-α-hydroxylation of Vitamin D to activate it , while PTH promotes 1-α-hydroxylation resulting in a mismatch of calcium reabsorption[ 121 ]. The dynamics of this small-scale Canagliflozin study that measured FGF23, PTH, and 1,25-dihydroxyvitamin D levels on a daily basis implied that early FGF23 expression resulted in a transient hypocalcemia.…”

Basic and Clinical Pharmaco-Therapeutics of SGLT2 Inhibitors: A Contemporary Update

“…Canagliflozin and ertugliflozin have demonstrated increased risk of lower limb amputations, whereas bone fracture risk has been specifically observed with canagliflozin in the clinically indicated range of eGFR [66,67]. Several plausible mechanisms for these adverse reactions have been proposed, and are reviewed elsewhere [68,69]. The CRE-DENCE study was designed with specific measures to minimize the risk of lower limb amputations; this study did not demonstrate significantly increased risk of lower limb amputations with canagliflozin [5].…”