Kutoh Eiji, Murayama Teruma, Wada Asuka, Hirate Mitsuru
Department of Clinical Research, Biomedical Center, Tokyo, 1320034, Japan.
Division of Diabetes and Endocrinology, Department of Internal Medicine, Gyoda General Hospital, Saitama, Japan.
Drugs R D. 2016 Dec;16(4):369-376. doi: 10.1007/s40268-016-0149-5.
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.
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.
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]).
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).
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.
钠-葡萄糖协同转运蛋白2抑制剂已被证明可减轻体重。然而，关于体重减轻是否会影响血糖和非血糖参数，人们知之甚少。
本研究旨在探讨初治2型糖尿病（T2DM）患者接受依帕列净单药治疗时体重变化与代谢参数变化之间的联系。
受试者接受依帕列净单药治疗，剂量为25 - 50mg/天，持续3个月（n = 33）。然后将他们分为两组：L组（“体重减轻组”；n = 17）包括体重减轻的患者（体重指数[BMI]变化[Δ]≤ -0.75，p < 0.00001），N组（“体重未减轻组”；n = 16）包括体重未减轻的患者（ΔBMI > -0.75，无统计学意义[NS]）。
在这两组中，糖化血红蛋白（HbA）水平均有相似程度的降低（L组：9.76 - 8.02%，p < 0.00001；N组：10.07 - 8.36%，p < 0.0005）。两组的稳态模型评估（HOMA）-B水平均升高，组间存在差异（p < 0.05；L组和N组分别升高38.91%和96.83%）。然而，一些参数呈现出不同的调节模式。例如，在L组中，HOMA-R水平降低（-20.18%，p < 0.04），尿酸（UA）水平降低（-8.91%，p < 0.02）。HOMA-R变化与空腹血糖（FBG）水平变化之间存在相关性（R = 0.557，p < 0.02）。游离脂肪酸（FFA）水平无显著升高，非高密度脂蛋白胆固醇（non-HDL-C）或低密度脂蛋白胆固醇（LDL-C）水平降低。在N组中，观察到FFA水平降低（-17.07%，p < 0.05），ΔHOMA-B与ΔFBG之间（R = -0.4781，p < 0.05）以及ΔFFA与ΔHOMA-B水平之间（R = -0.4305，p < 0.05）存在负相关。non-HDL-C和LDL-C水平无显著升高。L组和N组在non-HDL-C和LDL-C水平变化方面存在组间差异（均p < 0.05）。
这些结果表明，依帕列净可能根据体重变化具有不同的双重降糖机制。体重减轻的受试者胰岛素抵抗程度降低。相反，在体重未减轻的受试者中，依帕列净降低脂毒性（FFA水平），从而激活β细胞功能。两种情况下观察到相似的降糖疗效。与体重未减轻的患者相比，体重减轻的患者使用依帕列净与心血管危险因素相关的代谢参数水平改善有关，包括UA以及致动脉粥样硬化血脂水平（non-HDL-C和LDL-C）。
