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

Abstract

BackgroundSodium-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.ObjectivesThe 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.MethodsSubjects 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]).ResultsIn these two groups, similar reductions were observed in glycated hemoglobin (HbA1c) 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).ConclusionsThese 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.

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

“…Interestingly, similar glycemic efficacies were seen in subjects with (Group L) or without (Group N) body weight reductions (Table 4a, b). This result implicates that the glycemic efficacy of canagliflozin is not linked to the reductions of body weight as shown with another SGLT-2 inhibitor [5]. However, those who lose weight with canagliflozin may have more advantages than those who do not with respect to some of the non-glycemic parameters, including UA and TG (Table 4a).…”

“…Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are new oral hypoglycemic drugs for type 2 diabetes mellitus (T2DM) that increase glucose excretion into the urine [1–3]. Consistent with this mechanism of action, one of the most beneficial non-glycemic properties of SGLT-2 inhibitors is their effect on body weight [4]; however, it is frequently experienced by physicians and patients that body weight reductions of SGLT-2 inhibitors are not always linked to their glycemic efficacies as previously proposed [5].…”

“…With the simple mechanism of excreting glucose into the urine, SGLT-2 inhibitors, including canagliflozin, were shown to ameliorate glucotoxicity [9], thereby ameliorating β-cell function and enhancing insulin sensitivity [6, 7]. Furthermore, it was preliminarily reported that ipragliflozin, another SGLT-2 inhibitor, could downregulate free fatty acid (FFA) levels in certain populations, thereby affecting β-cell function and/or insulin sensitivity [5].…”

Efficacy and safety of ipragliflozin as an add‐on therapy to sitagliptin and metformin in Korean patients with inadequately controlled type 2 diabetes mellitus: A randomized controlled trial

“…Previous studies of ipragliflozin monotherapy and ipragliflozin add-on to metformin have shown improvements in insulin resistance and β-cell function at the EOT. 14,21 In a study in which patients were treated with ipragliflozin monotherapy, significant reductions in HOMA-IR levels and significant increases in HOMA-β levels from baseline were observed at the end of the 12-week treatment. 21 In another study in patients whose T2DM was inadequately controlled by metformin, addition of ipragliflozin resulted in significant decrease in HOMA-IR levels compared with placebo after 24 weeks of treatment.…”

“…14,21 In a study in which patients were treated with ipragliflozin monotherapy, significant reductions in HOMA-IR levels and significant increases in HOMA-β levels from baseline were observed at the end of the 12-week treatment. 21 In another study in patients whose T2DM was inadequately controlled by metformin, addition of ipragliflozin resulted in significant decrease in HOMA-IR levels compared with placebo after 24 weeks of treatment. 14 Other studies of SGLT2 inhibitors also reported a significant decrease in insulin resistance and a significant increase in β-cell function at the EOT.…”