Pereira Maria J, Lundkvist Per, Kamble Prasad G, Lau Joey, Martins Julian G, Sjöström C David, Schnecke Volker, Walentinsson Anna, Johnsson Eva, Eriksson Jan W
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
Diabetes Ther. 2018 Aug;9(4):1511-1532. doi: 10.1007/s13300-018-0449-6. Epub 2018 Jun 13.
The sodium-glucose cotransporter 2 inhibitor dapagliflozin and the glucagon-like peptide-1 (GLP-1) receptor agonist exenatide reduce bodyweight via differing and complementary mechanisms. This post hoc analysis investigated the metabolic effects and baseline associations with bodyweight loss on coadministration of dapagliflozin and exenatide once weekly (QW) among adults with obesity and without diabetes.
In the primary trial, adults with obesity and without diabetes [n = 50; 18-70 years; body mass index (BMI) 30-45 kg/m] were randomized to double-blind oral dapagliflozin 10 mg (DAPA) once daily plus subcutaneous long-acting exenatide 2 mg QW (ExQW) or placebo over 24 weeks, followed by an open-label extension from 24-52 weeks during which all participants received active treatment. Primary results have been published previously. This analysis evaluated: (1) the effects of DAPA + ExQW on changes in substrates [free fatty acids (FFAs), glycerol, beta-OH-butyrate, and glucose], hormones (glucagon and insulin), and insulin secretion [insulinogenic index (IGI)] via an oral glucose tolerance test (OGTT) and (2) associations between bodyweight loss and baseline characteristics (e.g., BMI), single-nucleotide polymorphisms (SNPs) associated with the GLP-1 pathway, and markers of glucose regulation.
Compared with placebo at 24 weeks, 2-h FFAs post-OGTT increased (mean difference, +20.4 μmol/l; P < 0.05), and fasting glucose, 2-h glucose post-OGTT, and glucose area under the concentration-time curve (AUC) decreased with DAPA + ExQW [mean differences, -0.68 mmol/l [P < 0.001], -2.20 mmol/l (P < 0.01), and -306 mmol/l min (P < 0.001), respectively]. Glucagon, glycerol, beta-OH-butyrate, and IGI did not differ by treatment group at 24 weeks. Over 52 weeks, DAPA + ExQW decreased fasting insulin, 2-h post-OGTT insulin, and insulin AUC. Among DAPA + ExQW-treated participants, for each copy of the SNP variant rs10010131 A allele (gene WFS1), bodyweight decreased by 2.4 kg (P < 0.05). Lower BMI and a lower IGI were also associated with greater bodyweight loss with DAPA + ExQW.
Metabolic effects with DAPA + ExQW included less FFA suppression versus placebo during the OGTT, suggesting compensatory lipid mobilization for energy production when glucose availability was reduced because of glucosuria. The expected increase in glucagon with DAPA did not occur with DAPA + ExQW coadministration. Bodyweight loss with DAPA + ExQW was associated with the SNP variant rs10010131 A allele, lower baseline adiposity (BMI), and lower baseline insulin secretion (IGI). These findings require further validation.
AstraZeneca.
钠-葡萄糖协同转运蛋白2抑制剂达格列净和胰高血糖素样肽-1（GLP-1）受体激动剂艾塞那肽通过不同且互补的机制减轻体重。这项事后分析研究了达格列净和艾塞那肽每周一次（QW）联合给药对肥胖且无糖尿病的成年人的代谢影响以及与体重减轻的基线关联。
在一项主要试验中，将肥胖且无糖尿病的成年人（n = 50；年龄18 - 70岁；体重指数（BMI）30 - 45 kg/m²）随机分为两组，一组接受每日一次口服10 mg达格列净（DAPA）加每周一次皮下注射2 mg长效艾塞那肽（ExQW），另一组接受安慰剂，为期24周，随后进行24至52周的开放标签延长期，在此期间所有参与者均接受活性治疗。主要结果已在之前发表。本分析评估了：（1）通过口服葡萄糖耐量试验（OGTT）评估DAPA + ExQW对底物[游离脂肪酸（FFA）、甘油、β-羟基丁酸和葡萄糖]、激素（胰高血糖素和胰岛素）以及胰岛素分泌[胰岛素生成指数（IGI）]变化的影响；（2）体重减轻与基线特征（如BMI）、与GLP-1途径相关的单核苷酸多态性（SNP）以及葡萄糖调节标志物之间的关联。
与24周时的安慰剂相比，OGTT后2小时FFA升高（平均差值，+20.4 μmol/l；P < 0.05），而DAPA + ExQW使空腹血糖、OGTT后2小时血糖以及浓度-时间曲线下葡萄糖面积（AUC）降低[平均差值分别为 -0.68 mmol/l（P < 0.001）、-2.20 mmol/l（P < 0.01）和 -306 mmol/l·min（P < 0.001）]。24周时，胰高血糖素、甘油、β-羟基丁酸和IGI在治疗组之间无差异。在52周期间，DAPA + ExQW降低了空腹胰岛素、OGTT后2小时胰岛素以及胰岛素AUC。在接受DAPA + ExQW治疗的参与者中，对于SNP变体rs10010131 A等位基因（基因WFS1）的每一个拷贝，体重下降2.4 kg（P < 0.05）。较低的BMI和较低的IGI也与DAPA + ExQW导致的更大体重减轻相关。
DAPA + ExQW的代谢作用包括在OGTT期间与安慰剂相比对FFA的抑制作用较小，这表明由于糖尿导致葡萄糖可用性降低时，为能量产生进行了代偿性脂质动员。DAPA与ExQW联合给药时，未出现预期的胰高血糖素升高。DAPA + ExQW导致的体重减轻与SNP变体rs10010131 A等位基因、较低的基线肥胖程度（BMI）和较低的基线胰岛素分泌（IGI）相关。这些发现需要进一步验证。
阿斯利康公司。
