دورية أكاديمية
أعرض في EDS

Dual glucagon-like peptide-1 and glucagon receptor agonism reduces energy intake in type 2 diabetes with obesity.

التفاصيل البيبلوغرافية
العنوان: Dual glucagon-like peptide-1 and glucagon receptor agonism reduces energy intake in type 2 diabetes with obesity.
المؤلفون: Golubic R; Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.; Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK., Kennet J; Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK., Parker V; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Robertson D; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Luo D; Statistics, Biometrics Oncology, Oncology R&D, AstraZeneca, Gaithersburg, Maryland, USA., Hansen L; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA., Jermutus L; Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Ambery P; Late Clinical Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Ryaboshapkina M; Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Surakala M; R&D IT, AstraZeneca, Cambridge, UK., Laker RC; Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA., Venables M; MRC Epidemiology Unit, University of Cambridge, Cambridge, UK., Koulman A; MRC Epidemiology Unit, University of Cambridge, Cambridge, UK., Park A; Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK., Evans M; Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
المصدر: Diabetes, obesity & metabolism [Diabetes Obes Metab] 2024 Jul; Vol. 26 (7), pp. 2634-2644. Date of Electronic Publication: 2024 Apr 01.
نوع المنشور: Journal Article; Randomized Controlled Trial; Clinical Trial, Phase II
اللغة: English
بيانات الدورية: Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 100883645 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1463-1326 (Electronic) Linking ISSN: 14628902 NLM ISO Abbreviation: Diabetes Obes Metab Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Oxford : Wiley-Blackwell, c1999-
مواضيع طبية MeSH: Diabetes Mellitus, Type 2*/drug therapy , Diabetes Mellitus, Type 2*/complications , Obesity*/drug therapy , Obesity*/complications , Energy Intake*/drug effects , Weight Loss*/drug effects , Energy Metabolism*/drug effects, Humans ; Male ; Female ; Middle Aged ; Double-Blind Method ; Adult ; Hypoglycemic Agents/therapeutic use ; Hypoglycemic Agents/pharmacology ; Receptors, Glucagon/agonists ; Glucagon-Like Peptide 1/agonists ; Single-Blind Method ; Aged ; Glucagon-Like Peptide-1 Receptor/agonists ; Treatment Outcome ; Peptides
مستخلص: Aims: To establish which components of energy balance mediate the clinically significant weight loss demonstrated with use of cotadutide, a glucagon-like peptide-1 (GLP-1)/glucagon receptor dual agonist, in early-phase studies.
Materials and Methods: We conducted a phase 2a, single-centre, randomized, placebo-controlled trial in overweight and obese adults with type 2 diabetes. Following a 16-day single-blind placebo run-in, participants were randomized 2:1 to double-blind 42-day subcutaneous treatment with cotadutide (100-300 μg daily) or placebo. The primary outcome was percentage weight change. Secondary outcomes included change in energy intake (EI) and energy expenditure (EE).
Results: A total of 12 participants (63%) in the cotadutide group and seven (78%) in the placebo group completed the study. The mean (90% confidence interval [CI]) weight change was -4.0% (-4.9%, -3.1%) and -1.4% (-2.7%, -0.1%) for the cotadutide and placebo groups, respectively (p = 0.011). EI was lower with cotadutide versus placebo (-41.3% [-66.7, -15.9]; p = 0.011). Difference in EE (per kJ/kg lean body mass) for cotadutide versus placebo was 1.0% (90% CI -8.4, 10.4; p = 0.784), assessed by doubly labelled water, and -6.5% (90% CI -9.3, -3.7; p < 0.001), assessed by indirect calorimetry.
Conclusion: Weight loss with cotadutide is primarily driven by reduced EI, with relatively small compensatory changes in EE.
(© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)
References: Rinella ME, Lazarus JV, Ratziu V, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023;78(6):1966‐1986.
Chen L, Magliano DJ, Zimmet PZ. The worldwide epidemiology of type 2 diabetes mellitus – present and future perspectives. Nat Rev Endocrinol. 2011;8(4):228‐236.
Dieleman JL, Baral R, Birger M, et al. US Spending on Personal Health Care and Public Health, 1996‐2013. JAMA. 2016;316(24):2627‐2646.
GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390(10100):1211‐1259.
Nahra R, Wang T, Gadde KM, et al. Effects of Cotadutide on Metabolic and Hepatic Parameters in Adults With Overweight or Obesity and Type 2 Diabetes: A 54‐Week Randomized Phase 2b Study. Diabetes Care. 2021;44(6):1433‐1442.
García‐Compeán D, Kumar R, Cueto‐Aguilera ÁND, Maldonado‐Garza HJ, Villarreal‐Pérez JZ. Body weight loss and glycemic control on the outcomes of patients with NAFLD. The role of new antidiabetic agents. Ann Hepatol. 2023;28(4):100751.
Look ARG, Wing RR. Long‐term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: four‐year results of the Look AHEAD trial. Arch Intern Med. 2010;170(17):1566‐1575.
Empagliflozin (Jardiance) for diabetes. Med Lett Drugs Ther. 2014;56(1453):99‐100.
American Diabetes Association Professional Practice Committee. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2022. Diabetes Care. 2021;45(Supplement_1):S125‐S143.
Htike ZZ, Zaccardi F, Papamargaritis D, Webb DR, Khunti K, Davies MJ. Efficacy and safety of glucagon‐like peptide‐1 receptor agonists in type 2 diabetes: A systematic review and mixed‐treatment comparison analysis. Diabetes Obes Metab. 2017;19(4):524‐536.
Andreadis P, Karagiannis T, Malandris K, et al. Semaglutide for type 2 diabetes mellitus: A systematic review and meta‐analysis. Diabetes Obes Metab. 2018;20(9):2255‐2263.
van Can J, Sloth B, Jensen CB, Flint A, Blaak EE, Saris WH. Effects of the once‐daily GLP‐1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non‐diabetic adults. Int J Obes (Lond). 2014;38(6):784‐793.
Leibel RL, Rosenbaum M, Hirsch J. Changes in energy expenditure resulting from altered body weight. N Engl J Med. 1995;332(10):621‐628.
Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. New Engl J Med. 2022;387(3):205‐216.
Salem V, Izzi‐Engbeaya C, Coello C, et al. Glucagon increases energy expenditure independently of brown adipose tissue activation in humans. Diabetes Obes Metab. 2016;18(1):72‐81.
Tan TM, Field BC, McCullough KA, et al. Coadministration of glucagon‐like peptide‐1 during glucagon infusion in humans results in increased energy expenditure and amelioration of hyperglycemia. Diabetes. 2013;62(4):1131‐1138.
Chakravarthy M, Parsons S, Lassman ME, et al. Effects of 13‐Hour Hyperglucagonemia on Energy Expenditure and Hepatic Glucose Production in Humans. Diabetes. 2017;66(1):36‐44.
Whytock KL, Carnero EA, Vega RB, et al. Prolonged Glucagon Infusion Does Not Affect Energy Expenditure in Individuals with Overweight/Obesity: A Randomized Trial. Obesity (Silver Spring). 2021;29(6):1003‐1013.
Leong KS, Walker AB, Martin I, Wile D, Wilding J, MacFarlane IA. An audit of 500 subcutaneous glucagon stimulation tests to assess growth hormone and ACTH secretion in patients with hypothalamic‐pituitary disease. Clin Endocrinol (Oxf). 2001;54(4):463‐468.
Janssen Research & Development. A Study to Evaluate the Safety and Efficacy of JNJ‐64565111 in Severely Obese Participants With Type 2 Diabetes Mellitus. National Library of Medicine (US). 2020. https://clinicaltrials.gov/ct2/show/results/NCT03586830; accessed 10 Dec 2022.
Gregg EW, Lin J, Bardenheier B, et al. Impact of Intensive Lifestyle Intervention on Disability‐Free Life Expectancy: The Look AHEAD Study. Diabetes Care. 2018;41(5):1040‐1048.
Hope DCD, Vincent ML, Tan TMM. Striking the Balance: GLP‐1/Glucagon Co‐Agonism as a Treatment Strategy for Obesity. Front Endocrinol (Lausanne). 2021;12:735019.
Friedrichsen M, Endahl L, Kreiner FF, et al. Glucagon/GLP‐1 receptor co‐agonist NNC9204‐1177 reduced body weight in adults with overweight or obesity but was associated with safety issues. medRxiv. 2022; 2022.06.02.22275920.
Boland ML, Laker RC, Mather K, et al. Resolution of NASH and hepatic fibrosis by the GLP‐1R/GcgR dual‐agonist Cotadutide via modulating mitochondrial function and lipogenesis. Nat Metab. 2020;2(5):413‐431.
Ambery P, Parker VE, Stumvoll M, et al. MEDI0382, a GLP‐1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double‐blind, ascending dose and phase 2a study. Lancet. 2018;391(10140):2607‐2618.
Parker VER, Robertson D, Wang T, et al. Efficacy, Safety, and Mechanistic Insights of Cotadutide, a Dual Receptor Glucagon‐Like Peptide‐1 and Glucagon Agonist. J Clin Endocrinol Metab. 2020;105(3):803‐820.
Penick SB, Hinkle LE Jr. Depression of food intake induced in healthy subjects by glucagon. N Engl J Med. 1961;264:893‐897.
Calles‐Escandon J. Insulin dissociates hepatic glucose cycling and glucagon‐induced thermogenesis in man. Metabolism. 1994;43(8):1000‐1005.
Nair KS. Hyperglucagonemia increases resting metabolic rate in man during insulin deficiency. J Clin Endocrinol Metab. 1987;64(5):896‐901.
Cegla J, Troke RC, Jones B, et al. Coinfusion of low‐dose GLP‐1 and glucagon in man results in a reduction in food intake. Diabetes. 2014;63(11):3711‐3720.
De Block CEM, Dirinck E, Verhaegen A, Van Gaal LF. Efficacy and safety of high‐dose glucagon‐like peptide‐1, glucagon‐like peptide‐1/glucose‐dependent insulinotropic peptide, and glucagon‐like peptide‐1/glucagon receptor agonists in type 2 diabetes. Diabetes Obes Metab. 2022;24(5):788‐805.
Selley E, Kun S, Szijarto IA, Kertesz M, Wittmann I, Molnar GA. Vasodilator Effect of Glucagon: Receptorial Crosstalk Among Glucagon, GLP‐1, and Receptor for Glucagon and GLP‐1. Horm Metab Res. 2016;48(7):476‐483.
Muller TD, Finan B, Clemmensen C, DiMarchi RD, Tschop MH. The new biology and pharmacology of glucagon. Physiol Rev. 2017;97(2):721‐766.
Henderson SJ, Konkar A, Hornigold DC, et al. Robust anti‐obesity and metabolic effects of a dual GLP‐1/glucagon receptor peptide agonist in rodents and non‐human primates. Diabetes Obes Metab. 2016;18(12):1176‐1190.
Ambery PD, Klammt S, Posch MG, et al. MEDI0382, a GLP‐1/glucagon receptor dual agonist, meets safety and tolerability endpoints in a single‐dose, healthy‐subject, randomized, Phase 1 study. Br J Clin Pharmacol. 2018;84(10):2325‐2335.
Laursen DRT, Paludan‐Muller AS, Hrobjartsson A. Randomized clinical trials with run‐in periods: frequency, characteristics and reporting. Clin Epidemiol. 2019;11:169‐184.
Basolo A, Burkholder J, Osgood K, et al. Exenatide has a pronounced effect on energy intake but not energy expenditure in non‐diabetic subjects with obesity: A randomized, double‐blind, placebo‐controlled trial. Metabolism. 2018;85:116‐125.
Blundell J, Finlayson G, Axelsen M, et al. Effects of once‐weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity. Diabetes Obes Metab. 2017;19(9):1242‐1251.
Janssen LGM, Nahon KJ, Bracke KFM, et al. Twelve weeks of exenatide treatment increases [(18)F]fluorodeoxyglucose uptake by brown adipose tissue without affecting oxidative resting energy expenditure in nondiabetic males. Metabolism. 2020;106:154167.
Krieger JP, Santos da Conceicao EP, Sanchez‐Watts G, et al. Glucagon‐like peptide‐1 regulates brown adipose tissue thermogenesis via the gut‐brain axis in rats. Am J Physiol Regul Integr Comp Physiol. 2018;315(4):R708‐R720.
Kleinert M, Sachs S, Habegger KM, Hofmann SM, Muller TD. Glucagon Regulation of Energy Expenditure. Int J Mol Sci. 2019;20(21):5407.
Scott R, Minnion J, Tan T, Bloom SR. Oxyntomodulin analogue increases energy expenditure via the glucagon receptor. Peptides. 2018;104:70‐77.
Lockie SH, Heppner KM, Chaudhary N, et al. Direct control of brown adipose tissue thermogenesis by central nervous system glucagon‐like peptide‐1 receptor signaling. Diabetes. 2012;61(11):2753‐2762.
Ma T, Huo S, Xu B, et al. A novel long‐acting oxyntomodulin analogue eliminates diabetes and obesity in mice. Eur J Med Chem. 2020;203:112496.
Pocai A. Action and therapeutic potential of oxyntomodulin. Mol Metab. 2014;3(3):241‐251.
Cohen MA, Ellis SM, Le Roux CW, et al. Oxyntomodulin suppresses appetite and reduces food intake in humans. J Clin Endocrinol Metab. 2003;88(10):4696‐4701.
Wynne K, Park AJ, Small CJ, et al. Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: a double‐blind, randomized, controlled trial. Diabetes. 2005;54(8):2390‐2395.
Flint A, Kapitza C, Zdravkovic M. The once‐daily human GLP‐1 analogue liraglutide impacts appetite and energy intake in patients with type 2 diabetes after short‐term treatment. Diabetes Obes Metab. 2013;15(10):958‐962.
Corbin KD, Carnero EA, Allerton TD, et al. Glucagon‐like peptide‐1/glucagon receptor agonism associates with reduced metabolic adaptation and higher fat oxidation: A randomized trial. Obesity (Silver Spring). 2023;31(2):350‐362.
Wynne K, Park AJ, Small CJ, et al. Oxyntomodulin increases energy expenditure in addition to decreasing energy intake in overweight and obese humans: a randomised controlled trial. Int J Obes (Lond). 2006;30(12):1729‐1736.
Bagger JI, Holst JJ, Hartmann B, Andersen B, Knop FK, Vilsboll T. Effect of Oxyntomodulin, Glucagon, GLP‐1, and Combined Glucagon +GLP‐1 Infusion on Food Intake, Appetite, and Resting Energy Expenditure. J Clin Endocrinol Metab. 2015;100(12):4541‐4552.
Klein S, Jahoor F, Baba H, Townsend CM Jr, Shepherd M, Wolfe RR. In vivo assessment of the metabolic alterations in glucagonoma syndrome. Metabolism. 1992;41(11):1171‐1175.
Greenway FL. Physiological adaptations to weight loss and factors favouring weight regain. Int J Obes (Lond). 2015;39(8):1188‐1196.
Prentice AM, Goldberg GR, Jebb SA, Black AE, Murgatroyd PR, Diaz EO. Physiological responses to slimming. Proc Nutr Soc. 1991;50(2):441‐458.
Yates T, Sargeant JA, King JA, et al. Initiation of New Glucose‐Lowering Therapies May Act to Reduce Physical Activity Levels: Pooled Analysis From Three Randomized Trials. Diabetes Care. 2022;45(11):2749‐2752.
Meier JJ, Rosenstock J, Hincelin‐Mery A, et al. Contrasting Effects of Lixisenatide and Liraglutide on Postprandial Glycemic Control, Gastric Emptying, and Safety Parameters in Patients With Type 2 Diabetes on Optimized Insulin Glargine With or Without Metformin: A randomized, American Diabetes Association Professional Practice Committee. Diabetes Care. 2015;38(7):1263‐1273.
معلومات مُعتمدة: AstraZeneca
فهرسة مساهمة: Keywords: clinical trial; drug development; energy regulation; incretin physiology; weight control
المشرفين على المادة: QL6A9B13HW (cotadutide)
0 (Hypoglycemic Agents)
0 (Receptors, Glucagon)
89750-14-1 (Glucagon-Like Peptide 1)
0 (Glucagon-Like Peptide-1 Receptor)
0 (Peptides)
تواريخ الأحداث: Date Created: 20240402 Date Completed: 20240604 Latest Revision: 20240604
رمز التحديث: 20240604
DOI: 10.1111/dom.15579
PMID: 38562018
قاعدة البيانات: MEDLINE
الوصف
تدمد:1463-1326
DOI:10.1111/dom.15579