# GLP-1 & Incretin Therapies Domain: Advanced Medicine · 230 papers indexed · newest 2026-10-27 Semaglutide, tirzepatide and next-generation incretin agonists; obesity, diabetes, cardiovascular, renal, liver and neuropsychiatric outcomes. Key concepts: GLP-1 ## Research dossier (premium) **GLP-1 & Incretin Therapies: State of the Field (October 2026)** (v1, updated 2026-10-29; 5,487 words, 100 sources, 36 evidence-mapped claims) Covers semaglutide, tirzepatide, the new oral GLP-1 agonists and next-generation triple-agonist and amylin-combination drugs, with their effects on weight, diabetes, cardiovascular, kidney, heart-failure, liver, sleep-apnea, joint and brain outcomes as of October 2026. The central takeaway: the field has moved from proving weight loss to proving organ protection. Placebo-adjusted mean weight loss at the top doses of pivotal trials in adults without diabetes now ranges from about 9 percentage points (oral orforglipron) to about 21 (retatrutide, not yet approved), and the main open questions are durability after stopping, lean-mass and rare safety signals, cost and access, and how much of the benefit is independent of weight loss. - Preview (free): https://space-kitty.com/api/v1/dossiers/glp1-metabolic/preview - Full dossier ($0.20 via x402): https://space-kitty.com/api/v1/dossiers/glp1-metabolic - Research pack ($0.20): https://space-kitty.com/api/v1/topics/glp1-metabolic/pack ## Most influential - **[Once-Weekly Semaglutide in Adults with Overweight or Obesity](https://space-kitty.com/papers/doi:10.1056/nejmoa2032183)**. John P.H. Wilding, Rachel Louise Batterham, Salvatore Calanna et al. · 2021 · New England Journal of Medicine (doi:10.1056/nejmoa2032183 · 5,188 citations). Source: - **[Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes](https://space-kitty.com/papers/doi:10.1056/nejmoa2307563)**. Abraham Michael Lincoff, Kirstine Brown‐Frandsen, Helen Martina Colhoun et al. · 2023 · New England Journal of Medicine (doi:10.1056/nejmoa2307563 · 3,220 citations). Source: - **[Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity](https://space-kitty.com/papers/doi:10.1056/nejmoa2306963)**. Mikhail Kosiborod, Steen Zabell Abildstrom, Barry A. Borlaug et al. · 2023 · New England Journal of Medicine (doi:10.1056/nejmoa2306963 · 1,661 citations). Source: - **[Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension](https://space-kitty.com/papers/doi:10.1111/dom.14725)**. John P.H. Wilding, Rachel Louise Batterham, Melanie Jane Davies et al. · 2022 · Diabetes Obesity and Metabolism (doi:10.1111/dom.14725 · 1,120 citations). Source: > 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 e… > _Abstract excerpt by John P.H. Wilding et al., CC-BY, https://doi.org/10.1111/dom.14725; truncated._ - **[Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity](https://space-kitty.com/papers/doi:10.1001/jama.2021.3224)**. Domenica Rubino, Niclas Abrahamsson, Melanie Jane Davies et al. · 2021 · JAMA (doi:10.1001/jama.2021.3224 · 1,443 citations). Source: - **[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](https://space-kitty.com/papers/doi:10.1016/s0140-6736(21)00213-0)**. Melanie Jane Davies, Louise Færch, Ole Kleist Jeppesen et al. · 2021 · The Lancet (doi:10.1016/s0140-6736(21)00213-0 · 1,419 citations). Source: - **[Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial](https://space-kitty.com/papers/doi:10.1038/s41591-022-02026-4)**. William Timothy Garvey, Rachel Louise Batterham, Meena Bhatta et al. · 2022 · Nature Medicine (doi:10.1038/s41591-022-02026-4 · 867 citations). Source: > 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… > _Abstract excerpt by William Timothy Garvey et al., CC-BY, https://doi.org/10.1038/s41591-022-02026-4; truncated._ - **[Tirzepatide as Compared with Semaglutide for the Treatment of Obesity](https://space-kitty.com/papers/doi:10.1056/nejmoa2416394)**. Louis J. Aronne, Deborah Bade Horn, Carel Wynand le Roux et al. · 2025 · New England Journal of Medicine (doi:10.1056/nejmoa2416394 · 626 citations). Source: - **[Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity](https://space-kitty.com/papers/doi:10.1001/jama.2021.1831)**. Thomas A. Wadden, Timothy Silleck Bailey, Liana K. Billings et al. · 2021 · JAMA (doi:10.1001/jama.2021.1831 · 1,113 citations). Source: - **[Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes](https://space-kitty.com/papers/doi:10.1056/nejmoa2313917)**. Mikhail Kosiborod, Mark Colquhoun Petrie, Barry A. Borlaug et al. · 2024 · New England Journal of Medicine (doi:10.1056/nejmoa2313917 · 753 citations). Source: - **[The Discovery and Development of Liraglutide and Semaglutide](https://space-kitty.com/papers/doi:10.3389/fendo.2019.00155)**. Lotte Bjerre Knudsen, Jesper F. Lau · 2019 · Frontiers in Endocrinology (doi:10.3389/fendo.2019.00155 · 969 citations). Source: > 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 investigat… > _Abstract excerpt by Lotte Bjerre Knudsen et al., CC-BY, https://doi.org/10.3389/fendo.2019.00155; truncated._ - **[Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes](https://space-kitty.com/papers/doi:10.1001/jama.2021.23619)**. Domenica M. Rubino, Frank L. Greenway, Usman Khalid et al. · 2022 · JAMA (doi:10.1001/jama.2021.23619 · 994 citations). Source: - **[Obesity Management in Adults](https://space-kitty.com/papers/doi:10.1001/jama.2023.19897)**. Arielle Elmaleh-Sachs, Jessica L. Schwartz, Carolyn T. Bramante et al. · 2023 · JAMA (doi:10.1001/jama.2023.19897 · 756 citations). Source: - **[Discontinuation and Reinitiation of Dual-Labeled GLP-1 Receptor Agonists Among US Adults With Overweight or Obesity](https://space-kitty.com/papers/doi:10.1001/jamanetworkopen.2024.57349)**. Patricia J. Rodriguez, Vincent Zhang, Samuel Gratzl et al. · 2025 · JAMA Network Open (doi:10.1001/jamanetworkopen.2024.57349 · 370 citations). Source: > 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,… > _Abstract excerpt by Patricia J. Rodriguez et al., CC-BY, https://doi.org/10.1001/jamanetworkopen.2024.57349; truncated._ - **[Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial](https://space-kitty.com/papers/doi:10.1038/s41591-024-02996-7)**. Donna H. Ryan, Ildiko Lingvay, John Eric Deanfield et al. · 2024 · Nature Medicine (doi:10.1038/s41591-024-02996-7 · 346 citations). Source: > 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 circum… > _Abstract excerpt by Donna H. Ryan et al., CC-BY, https://doi.org/10.1038/s41591-024-02996-7; truncated._ ## Newest - **[GLP-1-Based Therapy in Type 1 Diabetes: Balancing Efficacy, Safety, and Patient Selection](https://space-kitty.com/papers/doi:10.1111/dom.71428)**. Rossatto T, de Andrade Oliveira R, Cardoso AM · 2026 · Diabetes, obesity & metabolism (doi:10.1111/dom.71428). Source: - **[Retatrutide Once Weekly for Treatment of Obstructive Sleep Apnea](https://space-kitty.com/papers/doi:10.1056/nejmoa2611477)**. Ronald R. Grunstein, Virend Kristen Somers, Ali Azarbarzin et al. · 2026 · New England Journal of Medicine (doi:10.1056/nejmoa2611477). Source: - **[A Study of EloraTZP in Adult Participants With Obesity Without Type 2 Diabetes](https://space-kitty.com/papers/nct:NCT07881432)**. Eli Lilly and Company · 2026 · ClinicalTrials.gov (NCT07881432). Source: - **[Efficacy and safety of orforglipron in adults with body mass index of 27 to less than 30 kg/m2 and adiposity-related complications: A post hoc analysis of the ATTAIN-1 trial](https://space-kitty.com/papers/pmc:PMC13697276)**. Almandoz J, Miras A, Blüher M et al. · 2026 · Obesity pillars. Source: - **[12-month weight-loss trajectories and predictors of response to tirzepatide under individualized dosing: A multicenter real-world study](https://space-kitty.com/papers/doi:10.1016/j.obpill.2026.100344)**. Angelopoulos N, Fousteris E, Zianni D et al. · 2026 · Obesity pillars (doi:10.1016/j.obpill.2026.100344). Source: - **[Cutaneous Adverse Events Associated with Semaglutide, Liraglutide and Tirzepatide: A Systematic Review](https://space-kitty.com/papers/doi:10.3390/medsci14060652)**. Gupta AK, Teasell EM, Magalhães RF et al. · 2026 · Medical sciences (Basel, Switzerland) (doi:10.3390/medsci14060652). Source: - **[GLP-1 receptor biology and the therapeutic role of incretin-based agonists in metabolic diseases](https://space-kitty.com/papers/doi:10.1016/j.ejphar.2026.179406)**. Koceva E, Moll GN · 2026 · European journal of pharmacology (doi:10.1016/j.ejphar.2026.179406). Source: - **[Tirzepatide alleviates hepatic steatosis and inflammation in MASLD partly through suppression of macrophage Dectin-1/Syk/NF-κB signaling](https://space-kitty.com/papers/doi:10.1016/j.ejphar.2026.179418)**. He Y, Ma T, Xing H et al. · 2026 · European journal of pharmacology (doi:10.1016/j.ejphar.2026.179418). Source: - **[Maridebart Cafraglutide Versus Semaglutide in Participants With Type 2 Diabetes](https://space-kitty.com/papers/nct:NCT07866066)**. Amgen · 2026 · ClinicalTrials.gov (NCT07866066). Source: - **[The Conventional Cost-Effectiveness and Distributional Cost-Effectiveness of Semaglutide for Obesity Treatment](https://space-kitty.com/papers/doi:10.1002/oby.70311)**. Kulkarni NS, Hutton D, Rhyan C et al. · 2026 · Obesity (Silver Spring, Md.) (doi:10.1002/oby.70311). Source: ## Clinical trials - **[Efficacy and Safety of Tirzepatide Once Weekly Versus Placebo in Participants Who Are Either Obese or Overweight With Weight-Related Comorbidities (SURMOUNT-1)](https://space-kitty.com/papers/nct:NCT07481747)**. Hudson Biotech · 2026 · ClinicalTrials.gov (NCT07481747). Source: - **[The Effect of Retatrutide Once Weekly on Cardiovascular Outcomes and Kidney Outcomes in Adults Living With Obesity (TRIUMPH-Outcomes)](https://space-kitty.com/papers/nct:NCT06383390)**. Eli Lilly and Company · 2024 · ClinicalTrials.gov (NCT06383390). Source: - **[A Study of Tirzepatide (LY3298176) on the Reduction on Morbidity and Mortality in Adults With Obesity](https://space-kitty.com/papers/nct:NCT05556512)**. Eli Lilly and Company · 2022 · ClinicalTrials.gov (NCT05556512). Source: - **[Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity](https://space-kitty.com/papers/nct:NCT03574597)**. Novo Nordisk A/S · 2018 · ClinicalTrials.gov (NCT03574597). Source: - **[A Research Study to Look at How Two Different Doses of CagriSema and One Dose of Semaglutide Help People Living With Obesity With or Without Type 2 Diabetes Lose Weight](https://space-kitty.com/papers/nct:NCT07564414)**. Novo Nordisk A/S · 2026 · ClinicalTrials.gov (NCT07564414). Source: - **[A Research Study to See How Well CagriSema Helps People With Excess Body Weight Lose Weight](https://space-kitty.com/papers/nct:NCT05567796)**. Novo Nordisk A/S · 2022 · ClinicalTrials.gov (NCT05567796). Source: - **[A Study of Orforglipron (LY3502970) in Adult Participants With Obesity or Overweight With Weight-Related Comorbidities](https://space-kitty.com/papers/nct:NCT05869903)**. Eli Lilly and Company · 2023 · ClinicalTrials.gov (NCT05869903). Source: - **[A Study of EloraTZP in Adult Participants With Obesity Without Type 2 Diabetes](https://space-kitty.com/papers/nct:NCT07881432)**. Eli Lilly and Company · 2026 · ClinicalTrials.gov (NCT07881432). Source: --- Space Kitty Archive · https://space-kitty.com · API: https://space-kitty.com/api/v1 · MCP: https://space-kitty.com/mcp · Premium: $0.20/request via x402 (Base Sepolia (testnet)). Metadata: arXiv (CC0), OpenAlex (CC0), Europe PMC (CC BY/CC0 works), ClinicalTrials.gov.