Distinct Glucose-Lowering Mechanisms of Ipragliflozin Depending on Body Weight Changes.

Background: Sodium-glucose co-transporter 2 inhibitors have been shown to reduce body weight. However, little is known about whether a reduction in body weight affects glycemic and non-glycemic parameters.

Objectives: The aim of this study was to investigate the link between the changes in body weight and those in metabolic parameters in drug-naïve subjects with type 2 diabetes mellitus (T2DM) receiving ipragliflozin monotherapy.

Methods: Subjects received ipragliflozin monotherapy 25-50 mg/day for 3 months (n = 33). They were then divided into two groups: group L ('lost'; n = 17) comprised patients who lost weight (change [Δ] in body mass index [BMI] ≤ -0.75, p < 0.00001), and group N ('neutral'; n = 16) comprised patients who did not lose weight (ΔBMI > -0.75, not significant [NS]).

Results: In these two groups, similar reductions were observed in glycated hemoglobin (HbA) levels (group L: 9.76-8.02%, p < 0.00001; group N: 10.07-8.36%, p < 0.0005). Homeostasis model assessment (HOMA)-B levels increased in both groups, with inter-group differences (p < 0.05; +38.91 vs. +96.83% in group L and N, respectively). However, some parameters showed distinct regulatory patterns. For instance, in group L, reductions were observed in HOMA-R (-20.18%, p < 0.04) and uric acid (UA; -8.91%, p < 0.02) levels. Correlations were seen between the change in HOMA-R and those in fasting blood glucose (FBG) levels (R = 0.557, p < 0.02). Non-significant increases in free fatty acid (FFA) levels and decreases in non-high-density lipoprotein cholesterol (non-HDL-C) or low-density lipoprotein cholesterol (LDL-C) levels were also noted. In group N, reductions in FFA levels (-17.07%, p < 0.05) were observed, and negative correlations were seen between ΔHOMA-B and ΔFBG (R = -0.4781, p < 0.05) and between Δ FFA and Δ HOMA-B levels (R = -0.4305, p < 0.05). Non-significant increases in non-HDL-C and LDL-C levels were also noted. Inter-group differences existed between group L and group N in the changes in non-HDL-C and LDL-C levels (both p < 0.05).

Conclusions: These results indicate that ipragliflozin may possess distinct dual glucose-lowering mechanisms depending on body weight changes. Degrees of insulin resistance decrease in subjects who lose weight. Conversely, ipragliflozin reduces lipotoxicity (FFA levels), thereby activating beta-cell function, in subjects who do not lose weight. Similar glycemic efficacies were observed in both cases. In patients who lost weight, ipragliflozin was associated with improvements in the levels of metabolic parameters related to cardiovascular risk factors, including UA and atherogenic lipid levels (non-HDL-C and LDL-C) compared with those who did not lose weight.