Overview of available treatment and new drug action points in obesity pharmacology. Will GIP, glucagon, amylin replace GLP-1?
DOI:
https://doi.org/10.56782/pps.361Keywords:
Obesity, GLP-1, GIP, glucagon, amylinAbstract
Nearly 50% of the world's population struggles with excess body weight. Elevated BMI contributed to about 5 million deaths from non-communicable diseases in 2019 and is a defined negative predictor of numerous diseases, mainly on the cardiovascular side. The purpose of this article is to characterize possible new drug breakthrough points for obesity therapy and also to describe already available approaches. Pubmed and clinical trials databes was searched using obesity, GLP-1, GIP, glucagon, amylin as the key words. To date, five drugs have been registered in the European Union for the treatment of obesity. Of these, Glucagon-like peptide-1 agonists administered by subcutaneous injection are the most effective. In order to further increase the effectiveness of overweight therapy, research is underway to combine different mechanisms of action in a single preparation. Promising directions are substances that activate receptors for glucagon and amylin, which may represent new points of action in the treatment of obesity. A preparation combining agonism of glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide and glucagon receptors - retatrutide - showed a significant weight reduction effect of 24% over 48 weeks. However, further studies including comparative analyses are needed to reliably assess their efficacy and safety.
Downloads
References
1. World Health Organization. Obesity and Overweight. Available online: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight (accessed on 7 January 2025).
2. Narodowy Fundusz Zdrowia. Otyłość i jej konsekwencje. Available online: https://ezdrowie.gov.pl/19636 (accessed on 7 January 2025).
3. Murray, C.J.L.; Aravkin, A.Y.; Zheng, P.; et al. Global burden of 87 risk factors in 204 countries and territories, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet 2020, 396, 1223–1249. doi: 10.1016/S0140-6736(20)30752-2 DOI: https://doi.org/10.1016/S0140-6736(20)30752-2
4. Narodowy Fundusz Zdrowia. Europejski Dzień Walki z Otyłością. Nowy raport NFZ – Otyłość i jej konsekwencje. Available online: https://www.nfz.gov.pl/aktualnosci/aktualnosci-centrali/europejski-dzien-walki-z-otyloscia-nowy-raport-nfz-otylosc-i-jej-konsekwencje%2C8611.htm (accessed on 7 January 2025).
5. Barczyk, A.; Kutkowska-Kaźmierczak, A.; Castañeda, J.; Obersztyn, E. Childhood obesity—epidemiology, pathogenesis, complications and treatment. Dev. Period Med. 2017, 21, 186–202. doi: 10.34763/devperiodmed.20172103.186202
6. The European Medicines Agency. Available online: https://www.ema.europa.eu/en/search (accessed on 6 January 2025).
7. Torgerson, J.S.; Hauptman, J.; Boldrin, M.N.; Sjöström, L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: A randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 2004, 27, 155–161. doi: 10.2337/diacare.27.1.155 DOI: https://doi.org/10.2337/diacare.27.1.155
8. Liu, Y.; Han, F.; Xia, Z.; et al. The effects of bupropion alone and combined with naltrexone on weight loss: A systematic review and meta-regression analysis of randomized controlled trials. Diabetol. Metab. Syndr. 2024, 16, Art. No: 93. doi: 10.1186/s13098-024-01319-7 DOI: https://doi.org/10.1186/s13098-024-01319-7
9. Watanabe, J.H.; Kwon, J.; Nan, B.; Reikes, A. Trends in glucagon-like peptide 1 receptor agonist use, 2014 to 2022. J. Am. Pharm. Assoc. 2024, 64, 133–138. doi: 10.1016/j.japh.2023.10.002 DOI: https://doi.org/10.1016/j.japh.2023.10.002
10. Ranganath, L.R. The entero-insular axis: Implications for human metabolism. Clin. Chem. Lab. Med. 2008, 46, 43–56. doi: 10.1515/CCLM.2008.008 DOI: https://doi.org/10.1515/CCLM.2008.008
11. Wu, T.; Ma, J.; Bound, M.J.; et al. Effects of sitagliptin on glycemia, incretin hormones, and antropyloroduodenal motility in response to intraduodenal glucose infusion in healthy lean and obese humans and patients with type 2 diabetes treated with or without metformin. Diabetes 2014, 63, 2776–2787. doi: 10.2337/db13-1627 DOI: https://doi.org/10.2337/db13-1627
12. Ma, J.; Checklin, H.L.; Wishart, J.M.; et al. A randomised trial of enteric-coated nutrient pellets to stimulate gastrointestinal peptide release and lower glycaemia in type 2 diabetes. Diabetologia 2013, 56, 1236–1242. doi: 10.1007/s00125-013-2876-2 DOI: https://doi.org/10.1007/s00125-013-2876-2
13. Perano, S.J.; Couper, J.J.; Horowitz, M.; et al. Pancreatic enzyme supplementation improves the incretin hormone response and attenuates postprandial glycemia in adolescents with cystic fibrosis: A randomized crossover trial. J. Clin. Endocrinol. Metab. 2014, 99, 2486–2493. doi: 10.1210/jc.2013-4417 DOI: https://doi.org/10.1210/jc.2013-4417
14. Lu, W.J.; Yang, Q.; Sun, W.; Woods, S.C.; D'Alessio, D.; Tso, P. The regulation of the lymphatic secretion of glucagon-like peptide-1 (GLP-1) by intestinal absorption of fat and carbohydrate. Am. J. Physiol. Gastrointest. Liver Physiol. 2007, 293, G963–G971. doi: 10.1152/ajpgi.00146.2007 DOI: https://doi.org/10.1152/ajpgi.00146.2007
15. Kuhre, R.E.; Gribble, F.M.; Hartmann, B.; et al. Fructose stimulates GLP-1 but not GIP secretion in mice, rats, and humans. Am. J. Physiol. Gastrointest. Liver Physiol. 2014, 306, G622–G630. doi: 10.1152/ajpgi.00372.2013 DOI: https://doi.org/10.1152/ajpgi.00372.2013
16. Kahles, F.; Meyer, C.; Möllmann, J.; et al. GLP-1 secretion is increased by inflammatory stimuli in an IL-6-dependent manner, leading to hyperinsulinemia and blood glucose lowering. Diabetes 2014, 63, 3221–3229. doi: 10.2337/db14-0100 DOI: https://doi.org/10.2337/db14-0100
17. Lindgren, O.; Mari, A.; Deacon, C.F.; et al. Differential islet and incretin hormone responses in morning versus afternoon after standardized meal in healthy men. J. Clin. Endocrinol. Metab. 2009, 94, 2887–2892. doi: 10.1210/jc.2009-0366 DOI: https://doi.org/10.1210/jc.2009-0366
18. Plamboeck, A.; Veedfald, S.; Deacon, C.F.; et al. Characterisation of oral and i.v. glucose handling in truncally vagotomised subjects with pyloroplasty. Eur. J. Endocrinol. 2013, 169, 187–201. doi: 10.1530/EJE-13-0264 DOI: https://doi.org/10.1530/EJE-13-0264
19. Vilsbøll, T.; Agersø, H.; Lauritsen, T.; et al. The elimination rates of intact GIP as well as its primary metabolite, GIP 3-42, are similar in type 2 diabetic patients and healthy subjects. Regul. Pept. 2006, 137, 168–172. doi: 10.1016/j.regpep.2006.07.007 DOI: https://doi.org/10.1016/j.regpep.2006.07.007
20. Nauck, M.; Stöckmann, F.; Ebert, R.; Creutzfeldt, W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 1986, 29, 46–52. doi: 10.1007/BF02427280 DOI: https://doi.org/10.1007/BF02427280
21. Secher, A.; Jelsing, J.; Baquero, A.F.; et al. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J. Clin. Invest. 2014, 124, 4473–4488. doi: 10.1172/JCI75276 DOI: https://doi.org/10.1172/JCI75276
22. van Bloemendaal, L.; IJzerman, R.G.; Ten Kulve, J.S.; et al. GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans. Diabetes 2014, 63, 4186–4196. doi: 10.2337/db14-0849 DOI: https://doi.org/10.2337/db14-0849
23. Marso, S.P.; Bain, S.C.; Consoli, A.; et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 2016, 375, 1834–1844. doi: 10.1056/NEJMoa1607141 DOI: https://doi.org/10.1056/NEJMoa1607141
24. Gerstein, H.C.; Abella, M.; et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019, 394, 121–130. doi: 10.1016/S0140-6736(19)31149-3 DOI: https://doi.org/10.1016/S0140-6736(19)31149-3
25. Yaribeygi, H.; Farrokhi, F.R.; Abdalla, M.A.; et al. The effects of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors on blood pressure and cardiovascular complications in diabetes. J. Diabetes Res. 2021, 2021, 6518221. doi: 10.1155/2021/6518221 DOI: https://doi.org/10.1155/2021/6518221
26. Mann, J.F.E.; Ørsted, D.D.; Brown-Frandsen, K.; et al. Liraglutide and renal outcomes in type 2 diabetes. N. Engl. J. Med. 2017, 377, 839–848. doi: 10.1056/NEJMoa1616011 DOI: https://doi.org/10.1056/NEJMoa1616011
27. Yildirim Simsir, I.; Soyaltin, U.E.; Cetinkalp, S. Glucagon like peptide-1 (GLP-1) likes Alzheimer's disease. Diabetes Metab. Syndr. 2018, 12, 469–475. doi: 10.1016/j.dsx.2018.03.002 DOI: https://doi.org/10.1016/j.dsx.2018.03.002
28. Nevola, R.; Epifani, R.; Imbriani, S.; et al. GLP-1 receptor agonists in non-alcoholic fatty liver disease: Current evidence and future perspectives. Int. J. Mol. Sci. 2023, 24, Art. No: 1703. doi: 10.3390/ijms24021703 DOI: https://doi.org/10.3390/ijms24021703
29. Zhang, Q.; Delessa, C.T.; Augustin, R.; et al. The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling. Cell Metab. 2021, 33, 833–844.e5. doi: 10.1016/j.cmet.2021.01.015 DOI: https://doi.org/10.1016/j.cmet.2021.01.015
30. Song, D.H.; Getty-Kaushik, L.; Tseng, E.; Simon, J.; Corkey, B.E.; Wolfe, M.M. Glucose-dependent insulinotropic polypeptide enhances adipocyte development and glucose uptake in part through Akt activation. Gastroenterology 2007, 133, 1796–1805. doi: 10.1053/j.gastro.2007.09.005 DOI: https://doi.org/10.1053/j.gastro.2007.09.005
31. Kim, S.J.; Nian, C.; McIntosh, C.H. GIP increases human adipocyte LPL expression through CREB and TORC2-mediated trans-activation of the LPL gene. J. Lipid Res. 2010, 51, 3145–3157. doi: 10.1194/jlr.M006841 DOI: https://doi.org/10.1194/jlr.M006841
32. Novikoff, A.; Müller, T.D. Pharmacological advances in incretin-based polyagonism: What we know and what we don't. Physiology (Bethesda) 2024, 39, 142–156. doi: 10.1152/physiol.00032.2023 DOI: https://doi.org/10.1152/physiol.00032.2023
33. Helsted, M.M.; Gasbjerg, L.S.; Lanng, A.R.; et al. The role of endogenous GIP and GLP-1 in postprandial bone homeostasis. Bone 2020, 140, Art. No: 115553. doi: 10.1016/j.bone.2020.115553 DOI: https://doi.org/10.1016/j.bone.2020.115553
34. Bollag, R.J.; Zhong, Q.; Phillips, P.; et al. Osteoblast-derived cells express functional glucose-dependent insulinotropic peptide receptors. Endocrinology 2000, 141, 1228–1235. doi: 10.1210/endo.141.3.7366 DOI: https://doi.org/10.1210/en.141.3.1228
35. Helsted, M.M.; Gasbjerg, L.S.; Lanng, A.R.; et al. The role of endogenous GIP and GLP-1 in postprandial bone homeostasis. Bone 2020, 140, Art. No: 115553. doi: 10.1016/j.bone.2020.115553 DOI: https://doi.org/10.1016/j.bone.2020.115553
36. Styrkarsdottir, U.; Tragante, V.; Stefansdottir, L.; et al. Obesity variants in the GIPR gene are not associated with risk of fracture or bone mineral density. J. Clin. Endocrinol. Metab. 2024, 109, e1608–e1615. doi: 10.1210/clinem/dgad734 DOI: https://doi.org/10.1210/clinem/dgad734
37. Fujii, H.; Tamamori-Adachi, M.; Uchida, K.; et al. Marked cortisol production by intracrine ACTH in GIP-treated cultured adrenal cells in which the GIP receptor was exogenously introduced. PLoS One 2014, 9, Art. No: e110543. doi: 10.1371/journal.pone.0110543 DOI: https://doi.org/10.1371/journal.pone.0110543
38. Bergmann, N.C.; Lund, A.; Gasbjerg, L.S.; et al. Effects of combined GIP and GLP-1 infusion on energy intake, appetite and energy expenditure in overweight/obese individuals: A randomised, crossover study. Diabetologia 2019, 62, 665–675. doi: 10.1007/s00125-018-4810-0 DOI: https://doi.org/10.1007/s00125-018-4810-0
39. Krarup, T.; Saurbrey, N.; Moody, A.J.; Kühl, C.; Madsbad, S. Effect of porcine gastric inhibitory polypeptide on beta-cell function in type I and type II diabetes mellitus. Metabolism 1987, 36, 677–682. doi: 10.1016/0026-0495(87)90153-3 DOI: https://doi.org/10.1016/0026-0495(87)90153-3
40. Davies, M.J.; Bergenstal, R.; Bode, B.; et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: The SCALE Diabetes randomized clinical trial. JAMA 2015, 314, 687–699. doi: 10.1001/jama.2015.9676 DOI: https://doi.org/10.1001/jama.2015.9676
41. Davies, M.; Færch, L.; Jeppesen, O.K.; et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): A randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet 2021, 397, 971–984. doi: 10.1016/S0140-6736(21)00213-0 DOI: https://doi.org/10.1016/S0140-6736(21)00213-0
42. Watanabe, J.H.; Kwon, J.; Nan, B.; Reikes, A. Trends in glucagon-like peptide 1 receptor agonist use, 2014 to 2022. J. Am. Pharm. Assoc. 2024, 64, 133–138. doi: 10.1016/j.japh.2023.10.002 DOI: https://doi.org/10.1016/j.japh.2023.10.002
43. Aroda, V.R.; Bauer, R.; Christiansen, E.; et al. Efficacy and safety of oral semaglutide by subgroups of patient characteristics in the PIONEER phase 3 programme. Diabetes Obes. Metab. 2022, 24, 1338–1350. doi: 10.1111/dom.14710 DOI: https://doi.org/10.1111/dom.14710
44. Dutta, D.; Surana, V.; Singla, R.; Aggarwal, S.; Sharma, M. Efficacy and safety of novel twincretin tirzepatide, a dual GIP and GLP-1 receptor agonist in the management of type-2 diabetes: A Cochrane meta-analysis. Indian J. Endocrinol. Metab. 2021, 25, 475–489. doi: 10.4103/ijem.ijem_423_21 DOI: https://doi.org/10.4103/ijem.ijem_423_21
45. Dutta, D.; Nagendra, L.; Anne, B.; Kumar, M.; Sharma, M.; Kamrul-Hasan, A.B.M. Orforglipron, a novel non-peptide oral daily GLP-1 receptor agonist as an anti-obesity medicine: A systematic review and meta-analysis. Obes. Sci. Pract. 2024, 10, e743. doi: 10.1002/osp4.743. DOI: https://doi.org/10.1002/osp4.743
46. Lingvay, I.; Cheng, A.Y.; Levine, J.A.; et al. Achievement of glycaemic targets with weight loss and without hypoglycaemia in type 2 diabetes with the once-weekly GIP and GLP-1 receptor agonist tirzepatide: A post hoc analysis of the SURPASS-1 to -5 studies. Diabetes Obes. Metab. 2023, 25, 965–974. doi: 10.1111/dom.14943 DOI: https://doi.org/10.1111/dom.14943
47. Miyawaki, K.; Yamada, Y.; Ban, N.; et al. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat. Med. 2002, 8, 738–742. doi: 10.1038/nm727 DOI: https://doi.org/10.1038/nm727
48. Flatt, P.R.; Bailey, C.J.; Kwasowski, P.; Swanston-Flatt, S.K.; Marks, V. Abnormalities of GIP in spontaneous syndromes of obesity and diabetes in mice. Diabetes 1983, 32, 433–435. doi: 10.2337/diab.32.5.433 DOI: https://doi.org/10.2337/diabetes.32.5.433
49. Bailey, C.J.; Flatt, P.R.; Kwasowski, P.; Powell, C.J.; Marks, V. Immunoreactive gastric inhibitory polypeptide and K cell hyperplasia in obese hyperglycaemic (ob/ob) mice fed high fat and high carbohydrate cafeteria diets. Acta Endocrinol. 1986, 112, 224–229. doi: 10.1530/acta.0.1120224 DOI: https://doi.org/10.1530/acta.0.1120224
50. Irwin, N.; McClean, P.L.; Patterson, S.; Hunter, K.; Flatt, P.R. Active immunisation against gastric inhibitory polypeptide (GIP) improves blood glucose control in an animal model of obesity-diabetes. Biol. Chem. 2009, 390, 75–80. doi: 10.1515/BC.2009.002 DOI: https://doi.org/10.1515/BC.2009.002
51. Killion, E.A.; Wang, J.; Yie, J.; et al. Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models. Sci. Transl. Med. 2018, 10, Art. No: eaat3392. doi: 10.1126/scitranslmed.aat3392 DOI: https://doi.org/10.1126/scitranslmed.aat3392
52. Jensen, M.H.; Sanni, S.J.; Riber, D.; Holst, J.J.; Rosenkilde, M.M.; Sparre-Ulrich, A.H. AT-7687, a novel GIPR peptide antagonist, combined with a GLP-1 agonist, leads to enhanced weight loss and metabolic improvements in cynomolgus monkeys. Mol. Metab. 2024, 88, Art. No: 102006. doi: 10.1016/j.molmet.2024.102006 DOI: https://doi.org/10.1016/j.molmet.2024.102006
53. Campbell, J.E. Targeting the GIPR for obesity: To agonize or antagonize? Potential mechanisms. Mol. Metab. 2021, 46, Art. No: 101139. doi: 10.1016/j.molmet.2020.101139 DOI: https://doi.org/10.1016/j.molmet.2020.101139
54. Wang, Y.Z.; Yang, D.H.; Wang, M.W. Signaling profiles in HEK 293T cells co-expressing GLP-1 and GIP receptors. Acta Pharmacol. Sin. 2022, 43, 1453–1460. doi: 10.1038/s41401-021-00758-6 DOI: https://doi.org/10.1038/s41401-021-00758-6
55. Teff, K.L.; Engelman, K. Oral sensory stimulation improves glucose tolerance in humans: Effects on insulin, C-peptide, and glucagon. Am. J. Physiol. 1996, 270, R1371–R1379. doi: 10.1152/ajpregu.1996.270.6.R1371 DOI: https://doi.org/10.1152/ajpregu.1996.270.6.R1371
56. Ambery, P.; Parker, V.E.; 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, 2607–2618. doi: 10.1016/S0140-6736(18)30726-8 DOI: https://doi.org/10.1016/S0140-6736(18)30726-8
57. Pocai, A.; Carrington, P.E.; Adams, J.R.; et al. Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes 2009, 58, 2258–2266. doi: 10.2337/db09-0278 DOI: https://doi.org/10.2337/db09-0278
58. Vajda, E.G.; Logan, D.; Lasseter, K.; et al. Pharmacokinetics and pharmacodynamics of single and multiple doses of the glucagon receptor antagonist LGD-6972 in healthy subjects and subjects with type 2 diabetes mellitus. Diabetes Obes. Metab. 2017, 19, 24–32. doi: 10.1111/dom.12752 DOI: https://doi.org/10.1111/dom.12752
59. Guan, H.P.; Yang, X.; Lu, K.; et al. Glucagon receptor antagonism induces increased cholesterol absorption. J. Lipid Res. 2015, 56, 2183–2195. doi: 10.1194/jlr.M060897 DOI: https://doi.org/10.1194/jlr.M060897
60. Kazierad, D.J.; Chidsey, K.; Somayaji, V.R.; Bergman, A.J.; Calle, R.A. Efficacy and safety of the glucagon receptor antagonist PF-06291874: A 12-week, randomized, dose-response study in patients with type 2 diabetes mellitus on background metformin therapy. Diabetes Obes. Metab. 2018, 20, 2608–2616. doi: 10.1111/dom.13440 DOI: https://doi.org/10.1111/dom.13440
61. Okamoto, H.; Kim, J.; Aglione, J.; et al. Glucagon receptor blockade with a human antibody normalizes blood glucose in diabetic mice and monkeys. Endocrinology 2015, 156, 2781–2794. doi: 10.1210/en.2015-1011 DOI: https://doi.org/10.1210/en.2015-1011
62. Jastreboff, A.M.; Kaplan, L.M.; Frías, J.P.; et al. Triple-hormone-receptor agonist retatrutide for obesity—A phase 2 trial. N. Engl. J. Med. 2023, 389, 514–526. doi: 10.1056/NEJMoa2301972 DOI: https://doi.org/10.1056/NEJMoa2301972
63. Nahra, R.; Wang, T.; Gadde, K.M.; 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, 1433–1442. doi: 10.2337/dc20-2151 DOI: https://doi.org/10.2337/dc20-2151
64. Pharmaceutical Technology. AZ to terminate once-daily cotadutide program to focus on weekly GLP-1RA co-agonist. Available online: www.pharmaceutical-technology.com/analyst-comment/az-terminate-cotadutide-coagonist (accessed on 9 January 2025).
65. Lutz, T.A. Creating the amylin story. Appetite 2022, 172, Art. No: 105965. doi: 10.1016/j.appet.2022.105965 DOI: https://doi.org/10.1016/j.appet.2022.105965
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Barbara Szostak, Monika Kułaga, Anna Kasprzak, Monika Grzybek, Diana Mazur-Lesińska, Sylwia Wielgosz-Biała, Krzysztof Tyszkiewicz, Borys Łozowski, Małgorzata Kasprzak, Barbara Wilczyńska
This work is licensed under a Creative Commons Attribution 4.0 International License.
For all articles published in Prospects in Pharmaceutical Sciences copyright is retained by the authors. The journal publishes articles in the Open Access policy, within the CC BY 4.0 licence.
This is a human-readable summary of (and not a substitute for) the license. Disclaimer.
You are free to:
Share — copy and redistribute the material in any medium or format
Adapt — remix, transform, and build upon the material for any purpose, even commercially.
The licensor cannot revoke these freedoms as long as you follow the license terms.
Under the following terms:
Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.
Notices:
You do not have to comply with the license for elements of the material in the public domain or where your use is permitted by an applicable exception or limitation.
No warranties are given. The license may not give you all of the permissions necessary for your intended use. For example, other rights such as publicity, privacy, or moral rights may limit how you use the material.
How to Cite
