Evaluation of Fractures, Bone Mineral Density (BMD), and Bone Biomarkers in Patients with Type 2 Diabetes Mellitus (T2DM) Receiving Ertugliflozin

Ertugliflozin (ERTU) is an SGLT2 inhibitor for the treatment of T2DM. The risk of fracture was assessed in adults with T2DM receiving ERTU relative to placebo (PBO) or active comparator in pooled analyses of 7 randomized, double-blind, Phase 3 trials. Patients (N=4859) received ERTU 5 mg (n=1716), ERTU 15 mg (n=1693) or non-ERTU (PBO, glimepiride or sitagliptin; n=1450) for up to 2 years (years). Mean age was 57.8 years, 25.8% were ≥65 years old and 51.8% were male. Mean eGFR was 85.3 mL/min/1.73 m². Mean duration of T2DM was 7.9 years and mean A1C was 8.2%. In an add-on to metformin study (VERTIS MET; N=621 [41.1% postmenopausal {PM} women]; ERTU 5 mg n=207; ERTU 15 mg n=205; PBO n=209) BMD was measured at the lumbar spine, femoral neck, total hip and distal forearm through 2 years. Biomarkers of bone metabolism were also measured.

In pooled analyses, the incidence of adjudication-confirmed fractures was similar across groups (ERTU 5 mg 0.5%; ERTU 15 mg 0.5%; non-ERTU 0.6%). At week 26 serum calcium did not change when compared across groups but there were small mean increases in serum magnesium (0.13 mEq/L vs. -0.02 mEq/L) and phosphate (0.23 mg/dL vs. 0.04 mg/dL) for all ERTU vs. PBO. In VERTIS MET at week 104, overall and in the PM subgroup (n=255), ERTU had no impact on BMD, except at the total hip where small reductions in BMD were observed (-0.84% overall; -1.17% PM) for ERTU 15 mg vs. PBO. At week 104 there were no meaningful differences from baseline in procollagen type 1 N-terminal propeptide (P1NP; ERTU 5 mg 10.1%; ERTU 15 mg 24.2%; PBO 19.4%) or parathyroid hormone (ERTU 5 mg 8.2%; ERTU 15 mg 5.5%; PBO 10.1%) across groups. A small non-sustained increase in serum C-terminal telopeptide of type 1 collagen (CTX) was noted at week 26 and 52 with ERTU vs. PBO, which attenuated at week 104 (ERTU 5 mg 26.9%; ERTU 15 mg 32.5%; PBO 19.3%).

In conclusion, there was no increased risk of fracture and no clinically meaningful change in BMD or bone biomarkers in patients with T2DM receiving ERTU.