PMID- 27798769 OWN - NLM STAT- MEDLINE DCOM- 20180215 LR - 20210109 IS - 1179-6901 (Electronic) IS - 1174-5886 (Print) IS - 1174-5886 (Linking) VI - 16 IP - 4 DP - 2016 Dec TI - Distinct Glucose-Lowering Mechanisms of Ipragliflozin Depending on Body Weight Changes. PG - 369-376 AB - 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-naive 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 [Delta] in body mass index [BMI] -0.75, not significant [NS]). RESULTS: In these two groups, similar reductions were observed in glycated hemoglobin (HbA(1c)) 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 DeltaHOMA-B and DeltaFBG (R = -0.4781, p < 0.05) and between Delta FFA and Delta 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. FAU - Kutoh, Eiji AU - Kutoh E AD - Department of Clinical Research, Biomedical Center, Tokyo, 1320034, Japan. ekuto@excite.com. AD - Division of Diabetes and Endocrinology, Department of Internal Medicine, Gyoda General Hospital, Saitama, Japan. ekuto@excite.com. AD - Division of Diabetes and Metabolism, Department of Internal Medicine, Higashitotsuka Memorial Hospital, Yokohama, Japan. ekuto@excite.com. FAU - Murayama, Teruma AU - Murayama T AD - Department of Clinical Research, Biomedical Center, Tokyo, 1320034, Japan. FAU - Wada, Asuka AU - Wada A AD - Division of Diabetes and Endocrinology, Department of Internal Medicine, Gyoda General Hospital, Saitama, Japan. FAU - Hirate, Mitsuru AU - Hirate M AD - Department of Clinical Research, Biomedical Center, Tokyo, 1320034, Japan. LA - eng PT - Journal Article PT - Observational Study PL - New Zealand TA - Drugs R D JT - Drugs in R&D JID - 100883647 RN - 0 (Blood Glucose) RN - 0 (Glucosides) RN - 0 (Thiophenes) RN - 3N2N8OOR7X (ipragliflozin) SB - IM MH - Blood Glucose/*drug effects/metabolism MH - Body Weight/*drug effects MH - Diabetes Mellitus, Type 2/diagnosis/*drug therapy/metabolism MH - Dose-Response Relationship, Drug MH - Female MH - Glucosides/administration & dosage/chemistry/*pharmacology MH - Homeostasis/drug effects MH - Humans MH - Insulin Resistance MH - Insulin-Secreting Cells/drug effects/metabolism MH - Male MH - Middle Aged MH - Thiophenes/administration & dosage/chemistry/*pharmacology PMC - PMC5114207 COIS- Eiji Kutoh, Teruma Murayama, Asuka Wada, and Mitsuru Hirate have no conflicts of interests that are directly relevant to the content of this manuscript. Ethical Approval All subjects provided informed consent. The studies were conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation Good Clinical Practice (ICH GCP) guidelines. Author Contributions EK participated in the design of the study and data acquisition, performed the statistical analysis, and drafted the manuscript. TM, MH, and AW made substantial contributions to the conception and design of the study and helped draft the manuscript. All authors read and approved the final manuscript. Funding No sources of funding were used to conduct this study or prepare this manuscript. EDAT- 2016/11/01 06:00 MHDA- 2018/02/16 06:00 PMCR- 2016/10/31 CRDT- 2016/11/01 06:00 PHST- 2016/11/01 06:00 [pubmed] PHST- 2018/02/16 06:00 [medline] PHST- 2016/11/01 06:00 [entrez] PHST- 2016/10/31 00:00 [pmc-release] AID - 10.1007/s40268-016-0149-5 [pii] AID - 149 [pii] AID - 10.1007/s40268-016-0149-5 [doi] PST - ppublish SO - Drugs R D. 2016 Dec;16(4):369-376. doi: 10.1007/s40268-016-0149-5.