A Randomized Controlled Trial of Dapagliflozin Plus Once-Weekly Exenatide Versus Placebo in Individuals with Obesity and Without Diabetes: Metabolic Effects and Markers Associated with Bodyweight Loss
| العنوان: | A Randomized Controlled Trial of Dapagliflozin Plus Once-Weekly Exenatide Versus Placebo in Individuals with Obesity and Without Diabetes: Metabolic Effects and Markers Associated with Bodyweight Loss |
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| المؤلفون: | Maria J. Pereira, Per Lundkvist, Prasad G. Kamble, Julian G. Martins, C. David Sjöström, Jan W. Eriksson, Volker Schnecke, Eva Johnsson, Anna Walentinsson, Joey Lau |
| المصدر: | Diabetes Therapy |
| بيانات النشر: | Springer Science and Business Media LLC, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Weight loss, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, 030209 endocrinology & metabolism, Endocrinology and Diabetes, Placebo, Glucagon, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Diabetes mellitus, Internal medicine, Internal Medicine, Medicine, Obesity, Dapagliflozin, Original Research, Single-nucleotide polymorphism, business.industry, Insulin, medicine.disease, Lipid metabolism, 030104 developmental biology, Endocrinology, chemistry, Endokrinologi och diabetes, Exenatide, Blood sugar regulation, medicine.symptom, business, medicine.drug |
| الوصف: | Introduction 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. Methods In the primary trial, adults with obesity and without diabetes [n = 50; 18–70 years; body mass index (BMI) 30–45 kg/m2] 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. Results 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. Conclusions 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. Funding AstraZeneca Electronic supplementary material The online version of this article (10.1007/s13300-018-0449-6) contains supplementary material, which is available to authorized users. |
| وصف الملف: | application/pdf |
| تدمد: | 1869-6961 1869-6953 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::48097aa873ae8a0a1fc42e567463db27Test https://doi.org/10.1007/s13300-018-0449-6Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....48097aa873ae8a0a1fc42e567463db27 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 18696961 18696953 |
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