Two Glucose-Lowering Mechanisms of Canagliflozin Depending on Body Weight Changes in Drug-Naïve Subjects with Type 2 Diabetes

Abstract

Abstract Objectives The aim of this study was to investigate the relations between the changes in body weight and those of glycemic and non-glycemic parameters in drug-naïve subjects with type 2 diabetes mellitus (T2DM) treated with canagliflozin monotherapy. Methods Subjects received 50–100 mg/day canagliflozin monotherapy for 3 months (n = 36), and were then divided into two groups: (1) those who lost weight [changes in (Δ)BMI ≤ − 0.45, p − 0.45, p = non-significant: Group N(eutral), n = 16]. At 3 months, the levels of glycemic and non-glycemic parameters were compared with those at baseline. Results Significant reductions of BMI levels (− 2.1%, p < 0.00001) were observed for the overall subjects. At baseline, fasting blood glucose (FBG) and HbA1c levels were significantly higher, and homeostasis model assessment-B (HOMA-B) levels were significantly lower in Group N versus Group L. Similar reductions of HbA1c (Group L: 9.54 ± 2.58% to 7.54 ± 1.27%, p < 0.05; Group N: 11.23 ± 2.27% to 9.19 ± 1.64%, p < 0.0002) and homeostasis model assessment-R (HOMA-R; Group L: − 32.3%, p < 0.005; Group N: − 36.5%, p < 0.02) levels were seen in these two groups. However, other parameters showed distinct regulatory patterns. (1) Group L: significant reductions in uric acid (UA) levels (− 6.9%, p < 0.02) were observed. Significant correlations between the changes in FBG and HOMA-R (R = 0.458, p < 0.05) were seen. (2) Group N: significant increases in HOMA-B (+ 69.4%, p < 0.007) and reductions in free fatty acid (FFA; − 25.8%, p < 0.02) levels were observed. Significant negative or positive correlations between the changes in (Δ)FBG and ΔHOMA-B (R = − 0.557, p < 0.03), and between ΔFBG and ΔHOMA-R (R = 0.458, p < 0.05) were seen. Conclusions These results indicate that (1) body weight changes with canagliflozin were not associated with its glycemic efficacy; and (2) distinct glucose-lowering pathways may exist with canagliflozin, reducing insulin resistance in those who lose weight and enhancing β-cell function, as well as reducing insulin resistance, possibly via the decreased FFA levels, in those who do not lose weight.