{"topic":"glp1-metabolic","sort":"top","limit":25,"offset":0,"count":25,"papers":[{"id":"doi:10.1056/nejmoa2032183","kind":"article","title":"Once-Weekly Semaglutide in Adults with Overweight or Obesity","authors":["John P.H. Wilding","Rachel Louise Batterham","Salvatore Calanna","Melanie Jane Davies","Luc F. Van Gaal","Ildiko Lingvay","Barbara M. McGowan","Julio Rosenstock","Marie Thi Dao Tran","Thomas A. Wadden","Sean Wharton","Koutaro Yokote","Niels Zeuthen","Robert F. Kushner"],"author_count":14,"year":2021,"published":"2021-02-10","venue":"New England Journal of Medicine","cited_by":5188,"doi":"10.1056/nejmoa2032183","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1056/nejmoa2032183","archive_url":"https://space-kitty.com/papers/doi:10.1056/nejmoa2032183","updated":null,"pmid":"33567185","pmcid":null,"openalex_id":"W3127371223","pdf_url":"https://discovery.ucl.ac.uk/10127569/1/nejmoa2032183.pdf","abstract":null,"abstract_license":null,"license":null,"is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Pharmacology and Obesity Treatment"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1056/nejmoa2307563","kind":"article","title":"Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes","authors":["Abraham Michael Lincoff","Kirstine Brown‐Frandsen","Helen Martina Colhoun","John Eric Deanfield","Scott S. Emerson","Sille Esbjerg","Søren Hardt‐Lindberg","G. Kees Hovingh","Steven E. Kahn","Robert F. Kushner","Ildiko Lingvay","Tuğçe Kalaycı Oral","Marie Mide Michelsen","Jorge Plutzky","Christoffer Wenzel Tornøe","Donna H. Ryan"],"author_count":16,"year":2023,"published":"2023-11-11","venue":"New England Journal of Medicine","cited_by":3220,"doi":"10.1056/nejmoa2307563","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1056/nejmoa2307563","archive_url":"https://space-kitty.com/papers/doi:10.1056/nejmoa2307563","updated":null,"pmid":"37952131","pmcid":null,"openalex_id":"W4388592674","pdf_url":"https://discovery.ucl.ac.uk/10184940/1/nejmoa2307563.pdf","abstract":null,"abstract_license":null,"license":null,"is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Diabetes Treatment and Management"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1056/nejmoa2306963","kind":"article","title":"Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity","authors":["Mikhail Kosiborod","Steen Zabell Abildstrom","Barry A. Borlaug","Javed Butler","Søren Rasmussen","Melanie Jane Davies","G. Kees Hovingh","Dalane W. Kitzman","Marie L.S. Lindegaard","Daniél V. Møller","Sanjiv Jayendra Shah","Marianne Bach Treppendahl","Subodh Verma","Walter P. Abhayaratna","Fozia Zahir Ahmed","Vijay Chopra","Justin Adrian Ezekowitz","Michael L.X. Fu","Hiroshi Ito","Małgorzata Lelonek","Vojtěch Melenovský","Béla Péter Merkely","Julio E. Núñez","Eduardo Roque Perna","Morten Schou"],"author_count":31,"year":2023,"published":"2023-08-25","venue":"New England Journal of Medicine","cited_by":1661,"doi":"10.1056/nejmoa2306963","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1056/nejmoa2306963","archive_url":"https://space-kitty.com/papers/doi:10.1056/nejmoa2306963","updated":null,"pmid":"37622681","pmcid":null,"openalex_id":"W4386154055","pdf_url":"https://www.nejm.org/doi/pdf/10.1056/NEJMoa2306963","abstract":null,"abstract_license":null,"license":"other-oa","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Heart Failure Treatment and Management"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1111/dom.14725","kind":"article","title":"Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension","authors":["John P.H. Wilding","Rachel Louise Batterham","Melanie Jane Davies","Luc F. Van Gaal","Kristian Kandler","Katerina Konakli","Ildiko Lingvay","Barbara M. McGowan","Tuğçe Kalaycı Oral","Julio Rosenstock","Thomas A. Wadden","Sean Wharton","Koutaro Yokote","Robert F. Kushner","STEP 1 Study Group"],"author_count":15,"year":2022,"published":"2022-04-19","venue":"Diabetes Obesity and Metabolism","cited_by":1120,"doi":"10.1111/dom.14725","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1111/dom.14725","archive_url":"https://space-kitty.com/papers/doi:10.1111/dom.14725","updated":null,"pmid":"35441470","pmcid":"PMC9542252","openalex_id":"W4224218205","pdf_url":"https://europepmc.org/articles/PMC9542252/pdf","abstract":"AIM: To explore changes in body weight and cardiometabolic risk factors after treatment withdrawal in the STEP 1 trial extension. MATERIALS AND METHODS: with ≥ 1 weight-related co-morbidity) without diabetes to 68 weeks of once-weekly subcutaneous semaglutide 2.4 mg (including 16 weeks of dose escalation) or placebo, as an adjunct to lifestyle intervention. At week 68, treatments (including lifestyle intervention) were discontinued. An off-treatment extension assessed for a further year a representative subset of participants who had completed 68 weeks of treatment. This subset comprised all eligible participants from any site in Canada, Germany and the UK, and sites in the United States and Japan with the highest main phase recruitment. All analyses in the extension were exploratory. RESULTS: Extension analyses included 327 participants. From week 0 to week 68, mean weight loss was 17.3% (SD: 9.3%) with semaglutide and 2.0% (SD: 6.1%) with placebo. Following treatment withdrawal, semaglutide and placebo participants regained 11.6 (SD: 7.7) and 1.9 (SD: 4.8) percentage points of lost weight, respectively, by week 120, resulting in net losses of 5.6% (SD: 8.9%) and 0.1% (SD: 5.8%), respectively, from week 0 to week 120. Cardiometabolic improvements seen from week 0 to week 68 with semaglutide reverted towards baseline at week 120 for most variables. CONCLUSIONS: One year after withdrawal of once-weekly subcutaneous semaglutide 2.4 mg and lifestyle intervention, participants regained two-thirds of their prior weight loss, with similar changes in cardiometabolic variables. Findings confirm the chronicity of obesity and suggest ongoing treatment is required to maintain improvements in weight and health.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Pharmacology and Obesity Treatment"],"details":null,"provenance":"openalex+europepmc","attribution":"Abstract of \"Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension\" by John P.H. Wilding, Rachel Louise Batterham, Melanie Jane Davies et al., https://doi.org/10.1111/dom.14725, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1001/jama.2021.3224","kind":"article","title":"Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity","authors":["Domenica Rubino","Niclas Abrahamsson","Melanie Jane Davies","Dan Hesse","Frank L. Greenway","Camilla Jensen","Ildiko Lingvay","Ofri Mosenzon","Julio Rosenstock","Miguel A. Rubio","Gottfried Rudofsky","Sayeh Tadayon","Thomas A. Wadden","Dror Dicker","STEP 4 Investigators","M. Friberg","Anders Mikael Sjödin","Gabriella Segal","Muhammad Sabbah","Yael Sofer","Victor Vishlitzky","Eelco W. Meesters","Mirelle Serlie","Arianne C. van Bon","Helena Cardoso"],"author_count":88,"year":2021,"published":"2021-03-23","venue":"JAMA","cited_by":1443,"doi":"10.1001/jama.2021.3224","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1001/jama.2021.3224","archive_url":"https://space-kitty.com/papers/doi:10.1001/jama.2021.3224","updated":null,"pmid":"33755728","pmcid":null,"openalex_id":"W3138431202","pdf_url":"https://jamanetwork.com/journals/jama/articlepdf/2777886/jama_rubino_2021_oi_210023_1618250221.55359.pdf","abstract":null,"abstract_license":null,"license":null,"is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Pharmacology and Obesity Treatment"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1016/s0140-6736(21)00213-0","kind":"article","title":"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","authors":["Melanie Jane Davies","Louise Færch","Ole Kleist Jeppesen","Arash Pakseresht","Sue D. Pedersen","Leigh Perreault","Julio Rosenstock","Iichiro Shimomura","Adie Viljoen","Thomas A. Wadden","Ildiko Lingvay"],"author_count":11,"year":2021,"published":"2021-03-01","venue":"The Lancet","cited_by":1419,"doi":"10.1016/s0140-6736(21)00213-0","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1016/s0140-6736(21)00213-0","archive_url":"https://space-kitty.com/papers/doi:10.1016/s0140-6736(21)00213-0","updated":null,"pmid":"33667417","pmcid":null,"openalex_id":"W3133746780","pdf_url":null,"abstract":null,"abstract_license":null,"license":"cc-by-nc-nd","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Pharmacology and Obesity Treatment"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1038/s41591-022-02026-4","kind":"article","title":"Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial","authors":["William Timothy Garvey","Rachel Louise Batterham","Meena Bhatta","Silvio Buscemi","Louise N. Christensen","Juan P. Frías","Esteban Jódar","Kristian Kandler","Georgia Rigas","Thomas A. Wadden","Sean Wharton","the STEP 5 Study Group"],"author_count":12,"year":2022,"published":"2022-10-01","venue":"Nature Medicine","cited_by":867,"doi":"10.1038/s41591-022-02026-4","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41591-022-02026-4","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41591-022-02026-4","updated":null,"pmid":"36216945","pmcid":"PMC9556320","openalex_id":"W4304080455","pdf_url":"https://www.nature.com/articles/s41591-022-02026-4.pdf","abstract":"Abstract The STEP 5 trial assessed the efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg versus placebo (both plus behavioral intervention) for long-term treatment of adults with obesity, or overweight with at least one weight-related comorbidity, without diabetes. The co-primary endpoints were the percentage change in body weight and achievement of weight loss of ≥5% at week 104. Efficacy was assessed among all randomized participants regardless of treatment discontinuation or rescue intervention. From 5 October 2018 to 1 February 2019, 304 participants were randomly assigned to semaglutide 2.4 mg (n = 152) or placebo (n = 152), 92.8% of whom completed the trial (attended the end-of-trial safety visit). Most participants were female (236 (77.6%)) and white (283 (93.1%)), with a mean (s.d.) age of 47.3 (11.0) years, body mass index of 38.5 (6.9) kg m–2 and weight of 106.0 (22.0) kg. The mean change in body weight from baseline to week 104 was −15.2% in the semaglutide group (n = 152) versus −2.6% with placebo (n = 152), for an estimated treatment difference of −12.6 %-points (95% confidence interval, −15.3 to −9.8; P < 0.0001). More participants in the semaglutide group than in the placebo group achieved weight loss ≥5% from baseline at week 104 (77.1% versus 34.4%; P < 0.0001). Gastrointestinal adverse events, mostly mild-to-moderate, were reported more often with semaglutide than with placebo (82.2% versus 53.9%). In summary, in adults with overweight (with at least one weight-related comorbidity) or obesity, semaglutide treatment led to substantial, sustained weight loss over 104 weeks versus placebo. NCT03693430","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Pharmacology and Obesity Treatment"],"details":null,"provenance":"openalex+europepmc","attribution":"Abstract of \"Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial\" by William Timothy Garvey, Rachel Louise Batterham, Meena Bhatta et al., https://doi.org/10.1038/s41591-022-02026-4, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1056/nejmoa2416394","kind":"article","title":"Tirzepatide as Compared with Semaglutide for the Treatment of Obesity","authors":["Louis J. Aronne","Deborah Bade Horn","Carel Wynand le Roux","Wayne Ho","Beverly L. Falcón","Elisa Gomez Valderas","Sagar Das","Clare J. Lee","Leonard C. Glass","Çağrı Şenyücel","Julia P. Dunn"],"author_count":11,"year":2025,"published":"2025-05-11","venue":"New England Journal of Medicine","cited_by":626,"doi":"10.1056/nejmoa2416394","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1056/nejmoa2416394","archive_url":"https://space-kitty.com/papers/doi:10.1056/nejmoa2416394","updated":null,"pmid":"40353578","pmcid":null,"openalex_id":"W4410277932","pdf_url":null,"abstract":null,"abstract_license":null,"license":"cc-by-nc-nd","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Pharmacology and Obesity Treatment"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1001/jama.2021.1831","kind":"article","title":"Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity","authors":["Thomas A. Wadden","Timothy Silleck Bailey","Liana K. Billings","Melanie Jane Davies","Juan P. Frías","Anna Koroleva","Ildiko Lingvay","Patrick Mahlen O'Neil","Domenica Rubino","Dorthe Charlotte Skovgaard","Signe Olrik Rytter Wallenstein","William Timothy Garvey","STEP 3 Investigators"],"author_count":13,"year":2021,"published":"2021-02-24","venue":"JAMA","cited_by":1113,"doi":"10.1001/jama.2021.1831","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1001/jama.2021.1831","archive_url":"https://space-kitty.com/papers/doi:10.1001/jama.2021.1831","updated":null,"pmid":"33625476","pmcid":null,"openalex_id":"W3129305070","pdf_url":"https://jamanetwork.com/journals/jama/articlepdf/2777025/jama_wadden_2021_oi_210014_1618250237.04792.pdf","abstract":null,"abstract_license":null,"license":null,"is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Pharmacology and Obesity Treatment"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1056/nejmoa2313917","kind":"article","title":"Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes","authors":["Mikhail Kosiborod","Mark Colquhoun Petrie","Barry A. Borlaug","Javed Butler","Melanie Jane Davies","G. Kees Hovingh","Dalane W. Kitzman","Daniél V. Møller","Marianne Bach Treppendahl","Subodh Verma","Thomas Jensen","Karoline Liisberg","Marie L.S. Lindegaard","Walter P. Abhayaratna","Fozia Zahir Ahmed","Tuvia Ben Gal","Vijay Chopra","Justin Adrian Ezekowitz","Michael L.X. Fu","Hiroshi Ito","Małgorzata Lelonek","Vojtěch Melenovský","Béla Péter Merkely","Julio E. Núñez","Eduardo Roque Perna"],"author_count":32,"year":2024,"published":"2024-03-28","venue":"New England Journal of Medicine","cited_by":753,"doi":"10.1056/nejmoa2313917","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1056/nejmoa2313917","archive_url":"https://space-kitty.com/papers/doi:10.1056/nejmoa2313917","updated":null,"pmid":"38587233","pmcid":null,"openalex_id":"W4393255879","pdf_url":null,"abstract":null,"abstract_license":null,"license":"other-oa","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Heart Failure Treatment and Management"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.3389/fendo.2019.00155","kind":"review","title":"The Discovery and Development of Liraglutide and Semaglutide","authors":["Lotte Bjerre Knudsen","Jesper F. Lau"],"author_count":2,"year":2019,"published":"2019-04-12","venue":"Frontiers in Endocrinology","cited_by":969,"doi":"10.3389/fendo.2019.00155","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.3389/fendo.2019.00155","archive_url":"https://space-kitty.com/papers/doi:10.3389/fendo.2019.00155","updated":null,"pmid":"31031702","pmcid":"PMC6474072","openalex_id":"W2924479779","pdf_url":"https://www.frontiersin.org/articles/10.3389/fendo.2019.00155/pdf","abstract":"The discovery of glucagon-like peptide-1 (GLP-1), an incretin hormone with important effects on glycemic control and body weight regulation, led to efforts to extend its half-life and make it therapeutically effective in people with type 2 diabetes (T2D). The development of short- and then long-acting GLP-1 receptor agonists (GLP-1RAs) followed. Our article charts the discovery and development of the long-acting GLP-1 analogs liraglutide and, subsequently, semaglutide. We examine the chemistry employed in designing liraglutide and semaglutide, the human and non-human studies used to investigate their cellular targets and pharmacological effects, and ongoing investigations into new applications and formulations of these drugs. Reversible binding to albumin was used for the systemic protraction of liraglutide and semaglutide, with optimal fatty acid and linker combinations identified to maximize albumin binding while maintaining GLP-1 receptor (GLP-1R) potency. GLP-1RAs mediate their effects via this receptor, which is expressed in the pancreas, gastrointestinal tract, heart, lungs, kidneys, and brain. GLP-1Rs in the pancreas and brain have been shown to account for the respective improvements in glycemic control and body weight that are evident with liraglutide and semaglutide. Both liraglutide and semaglutide also positively affect cardiovascular (CV) outcomes in individuals with T2D, although the precise mechanism is still being explored. Significant weight loss, through an effect to reduce energy intake, led to the approval of liraglutide (3.0 mg) for the treatment of obesity, an indication currently under investigation with semaglutide. Other ongoing investigations with semaglutide include the treatment of non-alcoholic fatty liver disease (NASH) and its use in an oral formulation for the treatment of T2D. In summary, rational design has led to the development of two long-acting GLP-1 analogs, liraglutide and semaglutide, that have made a vast contribution to the management of T2D in terms of improvements in glycemic control, body weight, blood pressure, lipids, beta-cell function, and CV outcomes. Furthermore, the development of an oral formulation for semaglutide may provide individuals with additional benefits in relation to treatment adherence. In addition to T2D, liraglutide is used in the treatment of obesity, while semaglutide is currently under investigation for use in obesity and NASH.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Diabetes Treatment and Management"],"details":null,"provenance":"openalex+europepmc","attribution":"Abstract of \"The Discovery and Development of Liraglutide and Semaglutide\" by Lotte Bjerre Knudsen, Jesper F. Lau, https://doi.org/10.3389/fendo.2019.00155, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1001/jama.2021.23619","kind":"article","title":"Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes","authors":["Domenica M. Rubino","Frank L. Greenway","Usman Khalid","Patrick M. O’Neil","Julio Rosenstock","Rasmus Sørrig","Thomas A. Wadden","Alicja Wizert","William Timothy Garvey","STEP 8 Investigators","Carlos Arauz-Pacheco","Kevin Cannon","H. Jackson Downey","David Fitz-Patrick","Jeffrey Geohas","Gregg Gerety","John Gilbert","Priscilla Hollander","Eric Klein","Karen Laufer","Philip O'Donnell","Paul Rosenblit","Phillip D. Toth"],"author_count":23,"year":2022,"published":"2022-01-11","venue":"JAMA","cited_by":994,"doi":"10.1001/jama.2021.23619","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1001/jama.2021.23619","archive_url":"https://space-kitty.com/papers/doi:10.1001/jama.2021.23619","updated":null,"pmid":"35015037","pmcid":null,"openalex_id":"W4205651374","pdf_url":"https://jamanetwork.com/journals/jama/articlepdf/2787907/jama_rubino_2022_oi_210142_1641310203.77797.pdf","abstract":null,"abstract_license":null,"license":null,"is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Pharmacology and Obesity Treatment"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1001/jama.2023.19897","kind":"review","title":"Obesity Management in Adults","authors":["Arielle Elmaleh-Sachs","Jessica L. Schwartz","Carolyn T. Bramante","Jacinda Mawson Nicklas","Kimberly Anne Gudzune","Melanie R Jay"],"author_count":6,"year":2023,"published":"2023-11-28","venue":"JAMA","cited_by":756,"doi":"10.1001/jama.2023.19897","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1001/jama.2023.19897","archive_url":"https://space-kitty.com/papers/doi:10.1001/jama.2023.19897","updated":null,"pmid":"38015216","pmcid":null,"openalex_id":"W4389082549","pdf_url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC11325826/pdf/nihms-2013936.pdf","abstract":null,"abstract_license":null,"license":null,"is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Obesity, Physical Activity, Diet"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1001/jamanetworkopen.2024.57349","kind":"article","title":"Discontinuation and Reinitiation of Dual-Labeled GLP-1 Receptor Agonists Among US Adults With Overweight or Obesity","authors":["Patricia J. Rodriguez","Vincent Zhang","Samuel Gratzl","Duy Do","Brianna M Goodwin Cartwright","Charlotte Baker","Ty J. Gluckman","Nicholas L Stucky","Ezekiel Emanuel"],"author_count":9,"year":2025,"published":"2025-01-31","venue":"JAMA Network Open","cited_by":370,"doi":"10.1001/jamanetworkopen.2024.57349","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1001/jamanetworkopen.2024.57349","archive_url":"https://space-kitty.com/papers/doi:10.1001/jamanetworkopen.2024.57349","updated":null,"pmid":"39888616","pmcid":"PMC11786232","openalex_id":"W4407010133","pdf_url":"https://jamanetwork.com/journals/jamanetworkopen/articlepdf/2829779/rodriguez_2025_oi_241605_1737666970.3467.pdf","abstract":"Importance: Adherence to glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is important for their effectiveness. Discontinuation and reinitiation patterns are not well understood. Objective: To describe rates of and factors associated with discontinuation and subsequent reinitiation of GLP-1 RAs among adults with overweight or obesity. Design, Setting, and Participants: In this retrospective cohort study, 125 474 adults with overweight or obesity newly initiated treatment with a dual-labeled GLP-1 RA (liraglutide, semaglutide, or tirzepatide) between January 1, 2018, and December 31, 2023, with a baseline body mass index of 27 or more, an available weight measurement within 60 days before initiation, and regular care in the year before initiation were identified using electronic health record data from a collective of US health care systems. Patients were followed up for up to 2 years to assess discontinuation and for 2 additional years to assess reinitiation. Exposure: Patients were stratified by presence of type 2 diabetes at baseline. Main Outcomes and Measures: Proportions of patients discontinuing and reinitiating GLP-1 RA were estimated from Kaplan-Meier models. Associations of sociodemographic characteristics, health factors, weight changes, and gastrointestinal adverse events with discontinuation and reinitiation outcomes were modeled using time-varying Cox proportional hazards regression models. All analyses were conducted separately for patients with and patients without type 2 diabetes. Results: In this cohort study of 125 474 adults (mean [SD] age, 54.4 [13.1] years; 82 063 women [65.4%]), 76 524 (61.0%) had type 2 diabetes. One-year discontinuation was significantly higher for patients without type 2 diabetes (64.8% [95% CI, 64.4%-65.2%]) compared with those with type 2 diabetes (46.5% [95% CI, 46.2%-46.9%]). Higher weight loss (1% reduction in weight from baseline was associated with a 3.1% [95% CI, 2.9%-3.2%] lower hazard of discontinuation for patients with type 2 diabetes and a 3.3% [95% CI, 3.2%-3.5%] lower hazard of discontinuation for patients without type 2 diabetes) and higher income (type 2 diabetes only; >$80 000: hazard ratio [HR], 0.72 [95% CI, 0.69-0.76]) were significantly associated with lower rates of discontinuation, while moderate or severe incident gastrointestinal adverse events were associated with a higher hazard of discontinuation (with type 2 diabetes: HR, 1.38 [95% CI, 1.31-1.45]; without type 2 diabetes: HR, 1.19 [95% CI, 1.12-1.27]). Of 41 792 patients who discontinued and had a discontinuation weight measurement available, 1-year reinitiation was lower for those without type 2 diabetes (36.3% [95% CI, 35.6%-37.0%]) compared with those with type 2 diabetes (47.3% [95% CI, 46.6%-48.0%]). Weight regain of 1% from discontinuation was significantly associated with increased hazards of reinitiation of 2.3% (95% CI, 1.9%-2.8%) for patients with type 2 diabetes and 2.8% (95% CI, 2.4%-3.2%) for patients without type 2 diabetes. Conclusions and Relevance: In this cohort study, most patients with overweight or obesity discontinued GLP-1 RA therapy within 1 year, but those without type 2 diabetes had higher discontinuation rates and lower reinitiation rates. Inequities in access and adherence to effective treatments have the potential to exacerbate disparities in obesity.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Pharmacology and Obesity Treatment"],"details":null,"provenance":"openalex+europepmc","attribution":"Abstract of \"Discontinuation and Reinitiation of Dual-Labeled GLP-1 Receptor Agonists Among US Adults With Overweight or Obesity\" by Patricia J. Rodriguez, Vincent Zhang, Samuel Gratzl et al., https://doi.org/10.1001/jamanetworkopen.2024.57349, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1038/s41591-024-02996-7","kind":"article","title":"Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial","authors":["Donna H. Ryan","Ildiko Lingvay","John Eric Deanfield","Steven E. Kahn","Eric Barros","Bartolome G. Burguera","Helen Martina Colhoun","Cíntia Cercato","Dror Dicker","Deborah Bade Horn","G. Kees Hovingh","Ole Kleist Jeppesen","Alexander D. Kokkinos","Abraham Michael Lincoff","Sebastian M. Meyhöfer","Tuğçe Kalaycı Oral","Jorge Plutzky","André P. van Beek","John P.H. Wilding","Robert F. Kushner"],"author_count":20,"year":2024,"published":"2024-05-13","venue":"Nature Medicine","cited_by":346,"doi":"10.1038/s41591-024-02996-7","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41591-024-02996-7","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41591-024-02996-7","updated":null,"pmid":"38740993","pmcid":"PMC11271387","openalex_id":"W4396850943","pdf_url":"https://www.nature.com/articles/s41591-024-02996-7.pdf","abstract":"Abstract In the SELECT cardiovascular outcomes trial, semaglutide showed a 20% reduction in major adverse cardiovascular events in 17,604 adults with preexisting cardiovascular disease, overweight or obesity, without diabetes. Here in this prespecified analysis, we examined effects of semaglutide on weight and anthropometric outcomes, safety and tolerability by baseline body mass index (BMI). In patients treated with semaglutide, weight loss continued over 65 weeks and was sustained for up to 4 years. At 208 weeks, semaglutide was associated with mean reduction in weight (−10.2%), waist circumference (−7.7 cm) and waist-to-height ratio (−6.9%) versus placebo (−1.5%, −1.3 cm and −1.0%, respectively; P < 0.0001 for all comparisons versus placebo). Clinically meaningful weight loss occurred in both sexes and all races, body sizes and regions. Semaglutide was associated with fewer serious adverse events. For each BMI category (<30, 30 to <35, 35 to <40 and ≥40 kg m − 2 ) there were lower rates (events per 100 years of observation) of serious adverse events with semaglutide (43.23, 43.54, 51.07 and 47.06 for semaglutide and 50.48, 49.66, 52.73 and 60.85 for placebo). Semaglutide was associated with increased rates of trial product discontinuation. Discontinuations increased as BMI class decreased. In SELECT, at 208 weeks, semaglutide produced clinically significant weight loss and improvements in anthropometric measurements versus placebo. Weight loss was sustained over 4 years. ClinicalTrials.gov identifier: NCT03574597 .","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Pharmacology and Obesity Treatment"],"details":null,"provenance":"openalex+europepmc","attribution":"Abstract of \"Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial\" by Donna H. Ryan, Ildiko Lingvay, John Eric Deanfield et al., https://doi.org/10.1038/s41591-024-02996-7, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1038/s41591-023-02597-w","kind":"article","title":"Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial","authors":["Wadden TA","Chao AM","Machineni S","Kushner R","Ard J","Srivastava G","Halpern B","Zhang S","Chen J","Bunck MC","Ahmad NN","Forrester T"],"author_count":12,"year":2023,"published":"2023-10-15","venue":"Nature medicine","cited_by":364,"doi":"10.1038/s41591-023-02597-w","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41591-023-02597-w","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41591-023-02597-w","updated":null,"pmid":"37840095","pmcid":"PMC10667099","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC10667099/pdf","abstract":"The effects of tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, on weight reduction after successful intensive lifestyle intervention are unknown. This double-blind, placebo-controlled trial randomized (1:1) adults with body mass index ≥30 or ≥27 kg/m 2 and at least one obesity-related complication (excluding diabetes), who achieved ≥5.0% weight reduction after a 12-week intensive lifestyle intervention, to tirzepatide maximum tolerated dose (10 or 15 mg) or placebo once weekly for 72 weeks (n = 579). The treatment regimen estimand assessed effects regardless of treatment adherence in the intention-to-treat population. The coprimary endpoint of additional mean per cent weight change from randomization to week 72 was met with changes of -18.4% (standard error (s.e.) 0.7) with tirzepatide and 2.5% (s.e. 1.0) with placebo (estimated treatment difference -20.8 percentage points (95% confidence interval (CI) -23.2%, -18.5%; P < 0.001). The coprimary endpoint of the percentage of participants achieving additional weight reduction ≥5% was met with 87.5% (s.e. 2.2) with tirzepatide and 16.5% (s.e. 3.0) with placebo achieving this threshold (odds ratio 34.6%; 95% CI 19.2%, 62.6%; P < 0.001). The most common adverse events with tirzepatide were gastrointestinal, with most being mild to moderate in severity. Tirzepatide provided substantial additional reduction in body weight in participants who had achieved ≥5.0% weight reduction with intensive lifestyle intervention. ClinicalTrials.gov registration: NCT04657016 .","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial\" by Wadden TA, Chao AM, Machineni S et al., https://doi.org/10.1038/s41591-023-02597-w, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1021/acs.jmedchem.5b00726","kind":"article","title":"Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide","authors":["Jesper F. Lau","Paw Bloch","Lauge Schäffer","Ingrid Pettersson","Jane C. Spetzler","Jacob Kofoed","Kjeld Madsen","Lotte Bjerre Knudsen","James McGuire","Dorte B. Steensgaard","Holger M. Strauss","Dorte Xenia Gram","Sanne Møller Knudsen","Flemming Seier Nielsen","Peter Thygesen","Steffen Reedtz‐Runge","Thomas Kruse"],"author_count":17,"year":2015,"published":"2015-08-26","venue":"Journal of Medicinal Chemistry","cited_by":1104,"doi":"10.1021/acs.jmedchem.5b00726","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1021/acs.jmedchem.5b00726","archive_url":"https://space-kitty.com/papers/doi:10.1021/acs.jmedchem.5b00726","updated":null,"pmid":"26308095","pmcid":null,"openalex_id":"W2162140339","pdf_url":null,"abstract":null,"abstract_license":null,"license":null,"is_open_access":false,"retracted":false,"peer_reviewed":null,"categories":["Diabetes Treatment and Management"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1016/s0140-6736(24)01498-3","kind":"article","title":"Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial","authors":["John Eric Deanfield","Subodh Verma","Benjamin M. Scirica","Steven E. Kahn","Scott S. Emerson","Donna H. Ryan","Ildiko Lingvay","Helen Martina Colhoun","Jorge Plutzky","Mikhail Kosiborod","G. Kees Hovingh","Søren Hardt-Lindberg","Ofir Frenkel","Peter Weeke","Søren Rasmussen","Assen Goudev","Chim Choy Lang","Miguel Urina‐Triana","Mikko Pietilä","A Michael Lincoff","Mitsunori Abe","Rajpal K Abhaichand","Walter P Abhayaratna","Atul Abhyankar","Imran B Zainal Abidin"],"author_count":100,"year":2024,"published":"2024-08-01","venue":"The Lancet","cited_by":278,"doi":"10.1016/s0140-6736(24)01498-3","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1016/s0140-6736(24)01498-3","archive_url":"https://space-kitty.com/papers/doi:10.1016/s0140-6736(24)01498-3","updated":null,"pmid":"39181597","pmcid":null,"openalex_id":"W4401815221","pdf_url":null,"abstract":"Background Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure. Methods The SELECT trial was a randomised, double-blind, multicentre, placebo-controlled, event-driven phase 3 trial in 41 countries. Adults aged 45 years and older, with a BMI of 27 kg/m 2 or greater and established cardiovascular disease were eligible for the study. Patients were randomly assigned (1:1) with a block size of four using an interactive web response system in a double-blind manner to escalating doses of once-weekly subcutaneous semaglutide over 16 weeks to a target dose of 2·4 mg, or placebo. In a prespecified analysis, we examined the effect of semaglutide compared with placebo in patients with and without a history of heart failure at enrolment, subclassified as heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, or unclassified heart failure. Endpoints comprised MACE (a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); a composite heart failure outcome (cardiovascular death or hospitalisation or urgent hospital visit for heart failure); cardiovascular death; and all-cause death. The study is registered with ClinicalTrials.gov, NCT03574597. Findings Between Oct 31, 2018, and March 31, 2021, 17 604 patients with a mean age of 61·6 years (SD 8·9) and a mean BMI of 33·4 kg/m 2 (5·0) were randomly assigned to receive semaglutide (8803 [50·0%] patients) or placebo (8801 [50·0%] patients). 4286 (24·3%) of 17 604 patients had a history of investigator-defined heart failure at enrolment: 2273 (53·0%) of 4286 patients had heart failure with preserved ejection fraction, 1347 (31·4%) had heart failure with reduced ejection fraction, and 666 (15·5%) had unclassified heart failure. Baseline characteristics were similar between patients with and without heart failure. Patients with heart failure had a higher incidence of clinical events. Semaglutide improved all outcome measures in patients with heart failure at random assignment compared with those without heart failure (hazard ratio [HR] 0·72, 95% CI 0·60–0·87 for MACE; 0·79, 0·64–0·98 for the heart failure composite endpoint; 0·76, 0·59–0·97 for cardiovascular death; and 0·81, 0·66–1·00 for all-cause death; all p interaction >0·19). Treatment with semaglutide resulted in improved outcomes in both the heart failure with reduced ejection fraction (HR 0·65, 95% CI 0·49–0·87 for MACE; 0·79, 0·58–1·08 for the composite heart failure endpoint) and heart failure with preserved ejection fraction groups (0·69, 0·51–0·91 for MACE; 0·75, 0·52–1·07 for the composite heart failure endpoint), although patients with heart failure with reduced ejection fraction had higher absolute event rates than those with heart failure with preserved ejection fraction. For MACE and the heart failure composite, there were no significant differences in benefits across baseline age, sex, BMI, New York Heart Association status, and diuretic use. Serious adverse events were less frequent with semaglutide versus placebo, regardless of heart failure subtype. Interpretation In patients with atherosclerotic cardiovascular diease and overweight or obesity, treatment with semaglutide 2·4 mg reduced MACE and composite heart failure endpoints compared with placebo in those with and without clinical heart failure, regardless of heart failure subtype. Our findings could facilitate prescribing and result in improved clinical outcomes for this patient group. Funding Novo Nordisk.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Heart Failure Treatment and Management"],"details":null,"provenance":"openalex+europepmc","attribution":"Abstract of \"Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial\" by John Eric Deanfield, Subodh Verma, Benjamin M. Scirica et al., https://doi.org/10.1016/s0140-6736(24)01498-3, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1056/nejmoa2208601","kind":"article","title":"Once-Weekly Semaglutide in Adolescents with Obesity","authors":["Daniel Weghuber","Timothy Geoffrey Barrett","Margarita Barrientos Pérez","Inge Gies","Dan Hesse","Ole Kleist Jeppesen","Aaron S. Kelly","Lucy D. Mastrandrea","Rasmus Sørrig","Silva A Arslanian"],"author_count":10,"year":2022,"published":"2022-11-02","venue":"New England Journal of Medicine","cited_by":727,"doi":"10.1056/nejmoa2208601","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1056/nejmoa2208601","archive_url":"https://space-kitty.com/papers/doi:10.1056/nejmoa2208601","updated":null,"pmid":"36322838","pmcid":null,"openalex_id":"W4308053954","pdf_url":"https://www.nejm.org/doi/pdf/10.1056/NEJMoa2208601?articleTools=true","abstract":null,"abstract_license":null,"license":null,"is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Pharmacology and Obesity Treatment"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1001/jamapsychiatry.2024.4789","kind":"article","title":"Once-Weekly Semaglutide in Adults With Alcohol Use Disorder: A Randomized Clinical Trial","authors":["Hendershot CS","Bremmer MP","Paladino MB","Kostantinis G","Gilmore TA","Sullivan NR","Tow AC","Dermody SS","Prince MA","Jordan R","McKee SA","Fletcher PJ","Claus ED","Klein KR"],"author_count":14,"year":2025,"published":"2025-04-01","venue":"JAMA psychiatry","cited_by":213,"doi":"10.1001/jamapsychiatry.2024.4789","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1001/jamapsychiatry.2024.4789","archive_url":"https://space-kitty.com/papers/doi:10.1001/jamapsychiatry.2024.4789","updated":null,"pmid":"39937469","pmcid":"PMC11822619","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC11822619/pdf","abstract":"Importance Preclinical, observational, and pharmacoepidemiology evidence indicates that glucagon-like peptide 1 receptor agonists (GLP-1RAs) may reduce alcohol intake. Randomized trials are needed to determine the clinical significance of these findings. Objective To evaluate the effects of once-weekly subcutaneous semaglutide on alcohol consumption and craving in adults with alcohol use disorder (AUD). Design, setting, and participants This was a phase 2, double-blind, randomized, parallel-arm trial involving 9 weeks of outpatient treatment. Enrollment occurred at an academic medical center in the US from September 2022 to February 2024. Of 504 potential participants assessed, 48 non-treatment-seeking participants with AUD were randomized. Intervention Participants received semaglutide (0.25 mg/week for 4 weeks, 0.5 mg/week for 4 weeks, and 1.0 mg for 1 week) or placebo at weekly clinic visits. Main outcomes and measures The primary outcome was laboratory alcohol self-administration, measured at pretreatment and posttreatment (0.5 mg/week). Secondary and exploratory outcomes, including prospective changes in alcohol consumption and craving, were assessed at outpatient visits. Results Forty-eight participants (34 [71%] female; mean [SD] age, 39.9 [10.6] years) were randomized. Low-dose semaglutide reduced the amount of alcohol consumed during a posttreatment laboratory self-administration task, with evidence of medium to large effect sizes for grams of alcohol consumed (β, -0.48; 95% CI, -0.85 to -0.11; P = .01) and peak breath alcohol concentration (β, -0.46; 95% CI, -0.87 to -0.06; P = .03). Semaglutide treatment did not affect average drinks per calendar day or number of drinking days, but significantly reduced drinks per drinking day (β, -0.41; 95% CI, -0.73 to -0.09; P = .04) and weekly alcohol craving (β, -0.39; 95% CI, -0.73 to -0.06; P = .01), also predicting greater reductions in heavy drinking over time relative to placebo (β, 0.84; 95% CI, 0.71 to 0.99; P = .04). A significant treatment-by-time interaction indicated that semaglutide treatment predicted greater relative reductions in cigarettes per day in a subsample of individuals with current cigarette use (β, -0.10; 95% CI, -0.16 to -0.03; P = .005). Conclusions and relevance These findings provide initial prospective evidence that low-dose semaglutide can reduce craving and some drinking outcomes, justifying larger clinical trials to evaluate GLP-1RAs for alcohol use disorder. Trial registration ClinicalTrials.gov Identifier: NCT05520775.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Once-Weekly Semaglutide in Adults With Alcohol Use Disorder: A Randomized Clinical Trial\" by Hendershot CS, Bremmer MP, Paladino MB et al., https://doi.org/10.1001/jamapsychiatry.2024.4789, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1038/s41366-024-01473-y","kind":"review","title":"What is the pipeline for future medications for obesity?","authors":["Eka Melson","Uzma Ashraf","Dimitris Papamargaritis","Melanie Jane Davies"],"author_count":4,"year":2024,"published":"2024-02-01","venue":"International Journal of Obesity","cited_by":332,"doi":"10.1038/s41366-024-01473-y","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41366-024-01473-y","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41366-024-01473-y","updated":null,"pmid":"38302593","pmcid":"PMC11971045","openalex_id":"W4391440666","pdf_url":"https://www.nature.com/articles/s41366-024-01473-y.pdf","abstract":"Obesity is a chronic disease associated with increased risk of obesity-related complications and mortality. Our better understanding of the weight regulation mechanisms and the role of gut-brain axis on appetite has led to the development of safe and effective entero-pancreatic hormone-based treatments for obesity such as glucagon-like peptide-1 (GLP-1) receptor agonists (RA). Semaglutide 2.4 mg once weekly, a subcutaneously administered GLP-1 RA approved for obesity treatment in 2021, results in 15-17% mean weight loss (WL) with evidence of cardioprotection. Oral GLP-1 RA are also under development and early data shows similar WL efficacy to semaglutide 2.4 mg. Looking to the next generation of obesity treatments, combinations of GLP-1 with other entero-pancreatic hormones with complementary actions and/or synergistic potential (such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, and amylin) are under investigation to enhance the WL and cardiometabolic benefits of GLP-1 RA. Tirzepatide, a dual GLP-1/GIP receptor agonist has been approved for glycaemic control in type 2 diabetes as well as for obesity management leading in up to 22.5% WL in phase 3 obesity trials. Other combinations of entero-pancreatic hormones including cagrisema (GLP-1/amylin RA) and the triple agonist retatrutide (GLP-1/GIP/glucagon RA) have also progressed to phase 3 trials as obesity treatments and early data suggests that may lead to even greater WL than tirzepatide. Additionally, agents with different mechanisms of action to entero-pancreatic hormones (e.g. bimagrumab) may improve the body composition during WL and are in early phase clinical trials. We are in a new era for obesity pharmacotherapy where combinations of entero-pancreatic hormones approach the WL achieved with bariatric surgery. In this review, we present the efficacy and safety data for the pipeline of obesity pharmacotherapies with a focus on entero-pancreatic hormone-based treatments and we consider the clinical implications and challenges that the new era in obesity management may bring.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Pharmacology and Obesity Treatment"],"details":null,"provenance":"openalex+europepmc","attribution":"Abstract of \"What is the pipeline for future medications for obesity?\" by Eka Melson, Uzma Ashraf, Dimitris Papamargaritis et al., https://doi.org/10.1038/s41366-024-01473-y, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1186/s12933-022-01604-7","kind":"review","title":"Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction","authors":["Michael Albrecht Nauck","David A. D’Alessio"],"author_count":2,"year":2022,"published":"2022-09-01","venue":"Cardiovascular Diabetology","cited_by":405,"doi":"10.1186/s12933-022-01604-7","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1186/s12933-022-01604-7","archive_url":"https://space-kitty.com/papers/doi:10.1186/s12933-022-01604-7","updated":null,"pmid":"36050763","pmcid":"PMC9438179","openalex_id":"W4294069033","pdf_url":"https://cardiab.biomedcentral.com/counter/pdf/10.1186/s12933-022-01604-7","abstract":"and body weight than the selective GLP-1 RA semaglutide (1.0 mg per week), and titrated basal insulin. Adverse events related to tirzepatide were similar to what has been reported for selective GLP-1RA, mainly nausea, vomiting, diarrhoea, and constipation, that were more common at higher doses. Cardiovascular events have been adjudicated across the whole study program, and MACE-4 (nonfatal myocardial infarction, non-fatal stroke, cardiovascular death and hospital admission for angina) events tended to be reduced over up to a 2 year-period, albeit with low numbers of events. For none of the cardiovascular events analysed (MACE-4, or its components) was a hazard ratio > 1.0 vs. pooled comparators found in a meta-analysis covering the whole clinical trial program, and the upper bounds of the confidence intervals for MACE were < 1.3, fulfilling conventional definitions of cardiovascular safety. Tirzepatide was found to improve insulin sensitivity and insulin secretory responses to a greater extent than semaglutide, and this was associated with lower prandial insulin and glucagon concentrations. Both drugs caused similar reductions in appetite, although tirzepatide caused greater weight loss. While the clinical effects of tirzepatide have been very encouraging, important questions remain as to the mechanism of action. While GIP reduces food intake and body weight in rodents, these effects have not been demonstrated in humans. Moreover, it remains to be shown that GIPR agonism can improve insulin secretion in type 2 diabetic patients who have been noted in previous studies to be unresponsive to GIP. Certainly, the apparent advantage of tirzepatide, a dual incretin agonist, over GLP-1RA will spark renewed interest in the therapeutic potential of GIP in type 2 diabetes, obesity and related co-morbidities.","abstract_license":"CC-BY (publisher license, via OpenAlex)","license":"cc-by","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":["Diabetes Treatment and Management"],"details":null,"provenance":"openalex+europepmc","attribution":"Abstract of \"Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction\" by Michael Albrecht Nauck, David A. D’Alessio, https://doi.org/10.1186/s12933-022-01604-7, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1172/jci.insight.140532","kind":"article","title":"Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist","authors":["Willard FS","Douros JD","Gabe MB","Showalter AD","Wainscott DB","Suter TM","Capozzi ME","van der Velden WJ","Stutsman C","Cardona GR","Urva S","Emmerson PJ","Holst JJ","D'Alessio DA","Coghlan MP","Rosenkilde MM","Campbell JE","Sloop KW"],"author_count":18,"year":2020,"published":"2020-09-03","venue":"JCI insight","cited_by":414,"doi":"10.1172/jci.insight.140532","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1172/jci.insight.140532","archive_url":"https://space-kitty.com/papers/doi:10.1172/jci.insight.140532","updated":null,"pmid":"32730231","pmcid":"PMC7526454","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC7526454/pdf","abstract":"Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, and nonalcoholic steatohepatitis. Early phase trials in T2DM indicate that tirzepatide improves clinical outcomes beyond those achieved by a selective GLP-1 receptor agonist. Therefore, we hypothesized that the integrated potency and signaling properties of tirzepatide provide a unique pharmacological profile tailored for improving broad metabolic control. Here, we establish methodology for calculating occupancy of each receptor for clinically efficacious doses of the drug. This analysis reveals a greater degree of engagement of tirzepatide for the GIP receptor than the GLP-1 receptor, corroborating an imbalanced mechanism of action. Pharmacologically, signaling studies demonstrate that tirzepatide mimics the actions of native GIP at the GIP receptor but shows bias at the GLP-1 receptor to favor cAMP generation over β-arrestin recruitment, coincident with a weaker ability to drive GLP-1 receptor internalization compared with GLP-1. Experiments in primary islets reveal β-arrestin1 limits the insulin response to GLP-1, but not GIP or tirzepatide, suggesting that the biased agonism of tirzepatide enhances insulin secretion. Imbalance toward GIP receptor, combined with distinct signaling properties at the GLP-1 receptor, together may account for the promising efficacy of this investigational agent.","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist\" by Willard FS, Douros JD, Gabe MB et al., https://doi.org/10.1172/jci.insight.140532, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."},{"id":"doi:10.1016/s0140-6736(18)31773-2","kind":"article","title":"Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial","authors":["Patrick Mahlen O'Neil","Andreas L. Birkenfeld","Barbara M. McGowan","Ofri Mosenzon","Sue D. Pedersen","Sean Wharton","Charlotte Giwercman Carson","Cecilie Heerdegen Jepsen","Maria Kabisch","John P.H. Wilding"],"author_count":10,"year":2018,"published":"2018-08-01","venue":"The Lancet","cited_by":813,"doi":"10.1016/s0140-6736(18)31773-2","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1016/s0140-6736(18)31773-2","archive_url":"https://space-kitty.com/papers/doi:10.1016/s0140-6736(18)31773-2","updated":null,"pmid":"30122305","pmcid":null,"openalex_id":"W2885588864","pdf_url":null,"abstract":null,"abstract_license":null,"license":null,"is_open_access":false,"retracted":false,"peer_reviewed":null,"categories":["Pharmacology and Obesity Treatment"],"details":null,"provenance":"openalex","attribution":"Metadata and citation counts: OpenAlex (CC0)."},{"id":"doi:10.1038/s41591-024-03018-2","kind":"article","title":"Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial","authors":["Sanyal AJ","Kaplan LM","Frias JP","Brouwers B","Wu Q","Thomas MK","Harris C","Schloot NC","Du Y","Mather KJ","Haupt A","Hartman ML"],"author_count":12,"year":2024,"published":"2024-06-10","venue":"Nature medicine","cited_by":228,"doi":"10.1038/s41591-024-03018-2","arxiv_id":null,"nct_id":null,"source_url":"https://doi.org/10.1038/s41591-024-03018-2","archive_url":"https://space-kitty.com/papers/doi:10.1038/s41591-024-03018-2","updated":null,"pmid":"38858523","pmcid":"PMC11271400","openalex_id":null,"pdf_url":"https://europepmc.org/articles/PMC11271400/pdf","abstract":"Retatrutide is a novel triple agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 and glucagon receptors. A 48-week phase 2 obesity study demonstrated weight reductions of 22.8% and 24.2% with retatrutide 8 and 12 mg, respectively. The primary objective of this substudy was to assess mean relative change from baseline in liver fat (LF) at 24 weeks in participants from that study with metabolic dysfunction-associated steatotic liver disease and ≥10% of LF. Here, in this randomized, double-blind, placebo-controlled trial, participants (n = 98) were randomly assigned to 48 weeks of once-weekly subcutaneous retatrutide (1, 4, 8 or 12 mg dose) or placebo. The mean relative change from baseline in LF at 24 weeks was -42.9% (1 mg), -57.0% (4 mg), -81.4% (8 mg), -82.4% (12 mg) and +0.3% (placebo) (all P < 0.001 versus placebo). At 24 weeks, normal LF (<5%) was achieved by 27% (1 mg), 52% (4 mg), 79% (8 mg), 86% (12 mg) and 0% (placebo) of participants. LF reductions were significantly related to changes in body weight, abdominal fat and metabolic measures associated with improved insulin sensitivity and lipid metabolism. The ClinicalTrials.gov registration is NCT04881760 .","abstract_license":"CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)","license":"CC-BY","is_open_access":true,"retracted":false,"peer_reviewed":null,"categories":[],"details":null,"provenance":"europepmc","attribution":"Abstract of \"Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial\" by Sanyal AJ, Kaplan LM, Frias JP et al., https://doi.org/10.1038/s41591-024-03018-2, used under its Creative Commons Attribution license (CC-BY); markup removed, otherwise unmodified."}],"next":"https://space-kitty.com/api/v1/topics/glp1-metabolic/papers?sort=top&limit=25&offset=25"}