A Randomized Controlled Trial on the Effect of Luseogliflozin on Bone Microarchitecture Evaluated Using HR-pQCT in Elderly Type 2 Diabetes

Abstract

Introduction: Bone fragility is a critical issue in the treatment of elderly people with type 2 diabetes (T2D). In the Canagliflozin Cardiovascular Assessment Study, the subjects with T2D who were treated with canagliflozin showed a significant increase in fracture events compared to a placebo group as early as 12 weeks post-initiation. In addition, it has been unclear whether sodium-glucose co-transporter 2 (SGLT2) inhibitors promote bone fragility. We used high-resolution peripheral quantitative computed tomography (HR-pQCT) to prospectively evaluate the short-term effect of the SGLT2 inhibitor luseogliflozin on bone strength and microarchitecture in elderly people with T2D.

Methods: This was a single-center, randomized, open-label, active-controlled pilot trial for ≥ 60-year-old Japanese individuals with T2D without osteoporosis. A total of 22 subjects (seven women and 15 men) were randomly assigned to a Lusefi group (added luseogliflozin 2.5 mg) or a control group (added metformin 500 mg) and treated for 48 weeks. We used the second-generation HR-pQCT (Xtreme CT II®, Scanco Medical, Brüttisellen, Switzerland) before and 48 weeks after the treatment to evaluate the subjects' bone microarchitecture and estimate their bone strength.

Results: Twenty subjects (Lusefi group, n = 9; control group, n = 11) completed the study, with no fracture events. As the primary outcome, the 48-week changes in the bone strength (stiffness and failure load) estimated by micro-finite element analysis were not significantly different between the groups. As the secondary outcome, the changes in all of the cortical/trabecular microarchitectural parameters at the radius and tibia from baseline to 48 weeks were not significantly different between the groups.

Conclusions: In the pilot trial, we observed no negative effect of 48-week luseogliflozin treatment on bone microarchitecture or bone strength in elderly people with T2D.

Trial registration: UMIN-CTR no. 000036202 and jRCT 071180061.

Keywords: Bone microarchitecture; HR-pQCT; High-resolution peripheral quantitative computed tomography; Luseogliflozin; SGLT2 inhibitor; Type 2 diabetes.

Fig. 1

Image samples of distal radius (A–F) of a patient with type 2 diabetes allocated in the Lusefi group scanned by second-generation HR-pQCT (Xtreme CT II^®, Scanco Medical, Brüttisellen, Switzerland). A Three-dimensional imaging of distal radius, B the cortical compartments, C the trabecular compartments, D distribution of cortical porosity, E cross-sectional image of distal radius, F magnification of cortical bone with porous and construction of trabecule

Fig. 2

Summary of the study design and the randomized subjects. AE adverse event, α-GI alpha glucosidase inhibitor, BMD bone mineral density, DPP4i dipeptidyl peptidase-4 inhibitor, DXA dual-energy X-ray absorptiometry, HbA1c glycosylated hemoglobin, SD standard deviation

Fig. 3

Results of HR-pQCT values in the Lusefi group and the control group. A The µFE-estimated bone strength (stiffness and failure load) at baseline (week 0) and week 48, and the comparisons between the 48-week changes in the Lusefi group and those in the control group. B The cortical/trabecular microarchitectural values at baseline (week 0) and week 48, and the comparisons between the 48-week changes in the Lusefi group and those in the control group. Red marks: the Lusefi group (L). Blue marks: the control group (C). Red (blue) bars and bold horizontal lines indicate interquartile ranges and medians. Black diamonds within each bar indicate means. Ct.Ar cortical area, Ct.Pm cortical perimeter, Ct.Po cortical porosity, Ct.PoDm cortical pore diameter, Ct.Th cortical thickness, Ct.vBMD cortical volumetric bone mineral density, NS not significant, Tb.1/N.SD inhomogeneity of trabecular network, Tb.Ar trabecular area, Tb.BV/TV trabecular bone volume fraction, Tb.N trabecular number, Tb.Th trabecular thickness, Tb.Sp trabecular separation, Tb.vBMD trabecular volumetric bone mineral density, Wk week. §p < 0.05 vs. baseline (week 0) in each group

Fig. 4

Changes in physical/biochemical data and bone metabolic markers from baseline (week 0) in the Lusefi and control groups. A Changes in physical and biochemical data from baseline (week 0) to 12, 24, 36, and 48 weeks after treatment with the study drugs. B Changes in bone metabolic markers from baseline (week 0) to week 48. Red marks: the Lusefi group (L). Blue marks: the control group (C). Red (blue) bars and bold horizontal lines indicate interquartile ranges and medians. 1,25OHD 1,25-dihydroxyvitamin D, 25OHD 25-hydoroxyvitamin D, ALT alanine aminotransferase, AST aspartate aminotransferase, BAP bone alkaline phosphatase, BMI body mass index, BUN blood urea nitrogen, Ca calcium, Cl chloride, Cr creatinine, DBP diastolic blood pressure, DKK1 dickkopf-related protein 1, FECa fractional excretion of calcium, FENa fractional excretion of sodium, FEP fractional excretion of phosphate, GGT gamma-glutamyl transpeptidase, HbA1c glycosylated hemoglobin, HDL-C high-density lipoprotein cholesterol, K potassium, LDL-C low-density lipoprotein cholesterol, Mg magnesium, Na sodium, P phosphate, P1NP procollagen type 1 N-terminal propeptide, PTH parathyroid hormone, RBC red blood cells, SBP systolic blood pressure, TG triglyceride, TRACP-5b tartrate-resistant acid phosphatase 5b, ucOC undercarboxylated osteocalcin. *p < 0.05 vs. baseline (week 0) in each group; †p < 0.05 vs. the control group