GLP-1 & Incretin Therapies
Semaglutide, tirzepatide and next-generation incretin agonists; obesity, diabetes, cardiovascular, renal, liver and neuropsychiatric outcomes.
GLP-1 & Incretin Therapies: State of the Field (October 2026)
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.
Most influential
- Once-Weekly Semaglutide in Adults with Overweight or ObesityArticle5,188 citationsdoi:10.1056/nejmoa2032183
- Semaglutide and Cardiovascular Outcomes in Obesity without DiabetesArticle3,220 citationsdoi:10.1056/nejmoa2307563
- Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and ObesityArticle1,661 citationsdoi:10.1056/nejmoa2306963
- Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension
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. …
Abstract excerpt by John P.H. Wilding et al., CC-BY, https://doi.org/10.1111/dom.14725; truncated.
Article1,120 citationsdoi:10.1111/dom.14725 - Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or ObesityArticle1,443 citationsdoi:10.1001/jama.2021.3224
- 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 trialArticle1,419 citationsdoi:10.1016/s0140-6736(21)00213-0
- Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial
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 achiev…
Abstract excerpt by William Timothy Garvey et al., CC-BY, https://doi.org/10.1038/s41591-022-02026-4; truncated.
Article867 citationsdoi:10.1038/s41591-022-02026-4 - Tirzepatide as Compared with Semaglutide for the Treatment of ObesityArticle626 citationsdoi:10.1056/nejmoa2416394
- Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or ObesityArticle1,113 citationsdoi:10.1001/jama.2021.1831
- Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 DiabetesArticle753 citationsdoi:10.1056/nejmoa2313917
- The Discovery and Development of Liraglutide and Semaglutide
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 …
Abstract excerpt by Lotte Bjerre Knudsen et al., CC-BY, https://doi.org/10.3389/fendo.2019.00155; truncated.
Review969 citationsdoi:10.3389/fendo.2019.00155 - Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without DiabetesArticle994 citationsdoi:10.1001/jama.2021.23619
- Obesity Management in AdultsReview756 citationsdoi:10.1001/jama.2023.19897
- Discontinuation and Reinitiation of Dual-Labeled GLP-1 Receptor Agonists Among US Adults With Overweight or Obesity
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, a…
Abstract excerpt by Patricia J. Rodriguez et al., CC-BY, https://doi.org/10.1001/jamanetworkopen.2024.57349; truncated.
Article370 citationsdoi:10.1001/jamanetworkopen.2024.57349 - Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial
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…
Abstract excerpt by Donna H. Ryan et al., CC-BY, https://doi.org/10.1038/s41591-024-02996-7; truncated.
Article346 citationsdoi:10.1038/s41591-024-02996-7
Newest work
- GLP-1-Based Therapy in Type 1 Diabetes: Balancing Efficacy, Safety, and Patient SelectionReviewdoi:10.1111/dom.71428
- Retatrutide Once Weekly for Treatment of Obstructive Sleep ApneaArticledoi:10.1056/nejmoa2611477
- A Study of EloraTZP in Adult Participants With Obesity Without Type 2 DiabetesClinical trialNCT07881432
- 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 trialArticle
- 12-month weight-loss trajectories and predictors of response to tirzepatide under individualized dosing: A multicenter real-world studyArticledoi:10.1016/j.obpill.2026.100344
- Cutaneous Adverse Events Associated with Semaglutide, Liraglutide and Tirzepatide: A Systematic ReviewReviewdoi:10.3390/medsci14060652
- GLP-1 receptor biology and the therapeutic role of incretin-based agonists in metabolic diseasesReviewdoi:10.1016/j.ejphar.2026.179406
- Tirzepatide alleviates hepatic steatosis and inflammation in MASLD partly through suppression of macrophage Dectin-1/Syk/NF-κB signalingArticledoi:10.1016/j.ejphar.2026.179418
- Maridebart Cafraglutide Versus Semaglutide in Participants With Type 2 DiabetesClinical trialNCT07866066
- The Conventional Cost-Effectiveness and Distributional Cost-Effectiveness of Semaglutide for Obesity TreatmentArticledoi:10.1002/oby.70311
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)Clinical trialNCT07481747
- The Effect of Retatrutide Once Weekly on Cardiovascular Outcomes and Kidney Outcomes in Adults Living With Obesity (TRIUMPH-Outcomes)Clinical trialNCT06383390
- A Study of Tirzepatide (LY3298176) on the Reduction on Morbidity and Mortality in Adults With ObesityClinical trialNCT05556512
- Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or ObesityClinical trialNCT03574597
- 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 WeightClinical trialNCT07564414
- A Research Study to See How Well CagriSema Helps People With Excess Body Weight Lose WeightClinical trialNCT05567796
- A Study of Orforglipron (LY3502970) in Adult Participants With Obesity or Overweight With Weight-Related ComorbiditiesClinical trialNCT05869903
- A Study of EloraTZP in Adult Participants With Obesity Without Type 2 DiabetesClinical trialNCT07881432