Glucagon-like receptor agonists and next-generation incretin-based medications: metabolic, cardiovascular, and renal benefits.

# Glucagon-like receptor agonists and next-generation incretin-based medications: metabolic, cardiovascular, and renal benefits *The Lancet 2026* Review GLP-1 receptor agonists and next-generation incretin-based medications: metabolic, cardiovascular, and renal benefits Michael A Nauck, Katherine R Tuttle, Matthias H Tschöp, Matthias Blüher Lancet 2026; 407: 892–908 GLP-1 receptor agonists were initially developed to treat type 2 diabetes and have had a transformative eect on its therapy, and are highly eective for glycaemic control, with the added benefit of bodyweight reduction and a low risk Published Online January 14, 2026 of causing hypoglycaemia. GLP-1 receptor agonists reduce risks for major adverse cardiovascular events (eg, non-fatal https://doi.org/10.1016/ myocardial infarction, stroke, and cardiovascular death), and the risk of admission to or treatment within hospital for S0140-6736(25)02105-1 heart failure. These drugs reduce albuminuria and slow the decline in estimated glomerular filtration rate over time, This online publication has therefore delaying or preventing kidney failure. Furthermore, GLP-1 receptor agonists (eg, liraglutide and semaglutide) been corrected. The corrected and the dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor co-agonist tirzepatide have been version first appeared at thelancet.com on approved for treatment of obesity, with clinical trials establishing benefits for various obesity-related conditions: March 12, 2026 prevention of type 2 diabetes; risk for major adverse cardiovascular events; heart failure, especially with preserved Diabetes, Endocrinology, ejection fraction; regression of steatosis and prevention of fibrosis in steatotic liver disease; and symptomatic Metabolism Section, Medical improvements in obstructive sleep apnoea and knee osteoarthritis. Current developments include the exploration of Department 1, St Josef- novel indications (eg, neurodegenerative diseases and substance use disorders) with suggestive evidence of ecacy, Hospital, Katholisches Klinikum Bochum gGmbH, and the development of small-molecule GLP-1 receptor agonists for oral treatment to improve convenience. Dual (ie, Ruhr University Bochum, GLP-1–glucagon and GLP-1–amylin) and triple (ie, GIP–GLP-1–glucagon) receptor agonists activating multiple Bochum, Germany receptors promise greater ecacy than mono-agonists, especially for weight loss. However, some clinical development (Prof M A Nauck MD); Institute programmes have a high burden of adverse gastrointestinal events, and dose-escalation regimens should be optimised for Clinical Chemistry and Laboratory Medicine, to reach acceptable tolerability. University Medicine Greifswald, Greifswald, Introduction clinical trials, and the elucidation of their mechanisms Germany (Prof M A Nauck); Incretin-based medications, developed based on the of action. We provide a forecast for potential novel Providence Inland Northwest Health, Division of Nephrology therapeutic potential of GLP-1, have evolved to become indications, with respect to current and future drug and Kidney Research Institute, highly eective and widely recommended medications developments aiming at improved ecacy and safety. University of Washington to treat type 2 diabetes and obesity complicated by Although incretin hormones have a role in the action of School of Medicine, Spokane, comorbidities. This Review highlights the history of inhibitors of dipeptidyl peptidase-4 (DPP-4), we use the WA, USA (Prof K R Tuttle MD); Division of Metabolic Diseases, their development, the establishment of robust clinical term incretin-based medications exclusively for agonists Technische Universität benefits and safety in well defined patient populations in acting selectively on GLP-1 receptors (ie, mono-agonists) München, Helmholtz Diabetes or on GLP-1 and other receptors (ie, dual or triple Center, Helmholtz Zentrum München, Munich, Germany agonists). (Prof M H Tschöp MD); Ludwig- Search strategy and selection criteria Maximilians-Universität Discovering the therapeutic potential of GLP-1 München (LMU Munich), Literature for this Review was gathered by searching PubMed GLP-1 is one of two gut-derived incretin hormones. GLP-1 Munich, Germany (for papers published in English, German, and French, from (Prof M H Tschöp); Helmholtz database inception to Oct 13, 2025) to identify clinical trials and its primary amino acid sequence were predicted Institute for Metabolic, Obesity based on the gene sequence of animal and human with titles that included the drugs exenatide, efpeglenatide, and Vascular Research proglucagon.1 In 1987, the GLP-1 peptide structure was (HI-MAG) of the Helmholtz ecnoglutide, lixisenatide, liraglutide, dulaglutide, albiglutide, identified in gut extracts, and insulinotropic actions were Zentrum München, University semaglutide (for subcutaneous and oral use), tirzepatide, of Leipzig and University orforglipron, danuglipron, survodutide, mazdutide, shown,2,3 indicating an incretin role.4 Additional Hospital Leipzig, Leipzig, milestones in incretin research, eventually leading to the cagrilintide, CagriSema, or retatrutide; dual and triple Germany (Prof M Blüher MD) development of incretin-based medications, are shown in agonists; therapeutic effects on glycaemic control (ie, Correspondence to: figure 1 (further literature is available in appendix p 3). A through glycated haemoglobin or plasma glucose), Professor Michael A Nauck, meta-analysis of head-to-head trials comparing eects of Diabetes, Endocrinology, bodyweight reduction, cardiovascular (ie, atherosclerotic Metabolism Section, Medical cardiovascular disease or heart failure) outcomes, and renal GLP-1 receptor agonists and the dual glucose-dependent Department 1, Katholisches insulinotropic polypeptide (GIP)–GLP-1 receptor agonist outcomes; adverse events in individuals with type 2 diabetes; Klinikum Bochum gGmbH, tirzepatide to basal insulin treatment in type 2 diabetes is St Josef Hospital, Ruhr-University prevention of progression from prediabetes to type 2 shown in the appendix (p 4). The primary endpoint for Bochum, 44791 Bochum, diabetes; treatment of heart failure with preserved ejection Germany fraction, metabolic dysfunction-associated steatotic liver these trials was a reduction in glycated haemoglobin michael.nauck@rub.de (HbA ). These data show superior ecacy for recently disease, obstructive sleep apnoea syndrome, or osteoarthritis; 1c See Online for appendix and adverse events in people with overweight or obesity. All developed, incretin-based medications over basal insulin, and a greatly reduced risk for hypo glycaemia, occurring authors had collected relevant literature on these and similar mainly in participants taking sulfonylureas.5 More details topics since 1987, independent from a formal literature regarding the development of GLP-1 receptor agonists, search. their glucose-lowering and bodyweight-lowering actions, 892 Review and typical adverse events are described in the appendix Key messages (pp 2–3). • Currently available GLP-1 receptor agonists, and a dual glucose-dependent Rationale for developing dual or triple agonists insulinotropic polypeptide–GLP-1 agonist, are highly efficacious and safe therapies for activating receptors for gastroenteropancreatic treatment of hyperglycaemia in people with type 2 diabetes. hormones • Some of these agents also induce substantial weight loss for people with overweight The development of dual and triple agonists was based on or obesity (with and without type 2 diabetes). technical advances enabling the synthesis of peptides • Cardiovascular outcomes trials have established cardiovascular safety of GLP-1 combining amino acid sequences from various peptide receptor agonists; some agents within this class (eg, liraglutide, semaglutide, hormones, with the resulting hybrid being able to interact dulaglutide, and tirzepatide) reduce the risk of major adverse cardiovascular events in with two or more relevant receptors. The rationale to people with type 2 diabetes, or in those with obesity with atherosclerotic address glucagon receptor activity was anchored in studies cardiovascular disease (ie, semaglutide). of obese rodents, which showed that long-acting glucagon • A placebo-controlled, dedicated kidney outcomes trial of semaglutide, a GLP-1 agonists decrease bodyweight and improve glucose control receptor agonist, showed reduced risks for loss of kidney function, kidney failure, and via mechanisms that include suppression of energy intake, cardiovascular death, leading to approval for its treatment of chronic kidney disease in elevation of energy expenditure, stimulation of lipolysis, people with type 2 diabetes. and lipid use.6,7 GLP-1–glucagon receptor co-agonists were • Obesity-associated conditions, such as progression to type 2 diabetes, metabolic the first dual agonists explored in animals.8 Other dysfunction-associated steatotic liver disease, heart failure with preserved ejection prominent examples include GIP–GLP-1 receptor fraction, obstructive sleep apnoea, and knee osteoarthritis, benefit from treatment co-agonists, which yielded stronger suppression of energy with GLP-1-based medications, with symptomatic relief and improved prognoses. intake and, consequently, greater weight loss compared • Novel safety concerns, such as non-arteritic ischaemic optic neuritis and critical with selective GLP-1 receptor agonists.9 The additional reduction in muscle mass accompanying weight loss induced by incretin-based reduction in bodyweight versus that seen with selective medications, should be addressed but do not seem to affect the overal risk–benefit GLP-1 receptor agonists was independent of GLP-1 relationship. receptors,10 and mediated by GIP receptor signalling in • Incretin-based medications are being studied for novel indications (eg, GABAergic neurons of the CNS.11 Tirzepatide was neurodegenerative diseases and substance use disorders), with prelimary evidence for developed successfully based on this dual mechanism of preventing dementia and improving Parkinson’s disease. A role in reducing abuse of action. The concept of unimolecular, incretin-based alcohol and other substances is less clear. polyagonism was expanded in 2015 with the introduction • Next-generation medications, built on existing incretin-based medications, could of the first GIP–GLP-1–glucagon receptor triple agonist.12 provide greater efficay (ie, in glycaemic control and bodyweight reduction) and are This development was based on the assumption that any being studied in large-scale phase 3 trials to establish their clinical benefit and safety. risk of hyperglycaemia through stimulation of glucagon • When aiming to achieve greater effectiveness, measures should be taken to reduce receptors would be counteracted by the glucose-lowering adverse events and assure acceptable tolerability (eg, by slowed dose escalation upon eect of the incretin co-agonist. Consistent with this treatment initiation). assumption, the triple receptor agonist outperformed GIP–GLP-1 receptor co-agonists to yield greater weight loss and further improvements in glucose control in animal the treatment of type 2 diabetes or obesity. Open experiments, with documented contributions of agonism questions regarding the role of GIP receptor agonism in at each receptor, as verified in mice with individual genetic the mechanism of action of tirzepatide for improved or pharmacological receptor inhibition and deletion.12 glycaemic control and bodyweight reduction are Receptors for gastroenterop ancreatic peptide hormones discussed in the appendix (p 6). with therapeutic potential, and their possible mechanisms of action leading to weight reduction and improvements in Incretin-based medications and cardiovascular glycaemic control, are listed in the appendix (p 6). disease Cardiovascular outcomes trials (CVOTs) have studied Trizepatide, a first dual receptor agonist the eects of incretin-based medications reported in Tirzepatide is currently the only dual agonist specifically populations with type 2 diabetes and in people with targeting GIP and GLP-1 receptors that has been overweight or obesity with pre-existing atherosclerotic approved to treat type 2 diabetes and obesity.13 When cardiovascular disease (ASCVD; figure 2).28 compared with the most eective selective GLP-1 receptor agonist (ie, subcutaneous semaglutide), Reduction of major adverse cardiovascular events in tirzepatide provides greater improvements in glycaemic people with type 2 diabetes control in type 2 diabetes.14 Tirzepatide also leads to CVOTs were required by the US Food and Drug greater weight loss than semaglutide for people with Administration between 2008 and 2020 to prove the type 2 diabetes14 and than liraglutide for people with safety of novel glucose-lowering medications. Most obesity.15 GLP-1 receptor agonists and tirzepatide are the CVOTs (appendix pp 7–8) have shown significant currently available incretin-based medications for both reductions in major adverse cardio vascular events Review pain-free walking distance in people with type 2 History of incretin-based therapy for type 2 diabetes and clinical obesity diabetes and peripheral artery disease.34 Year or era Discoveries, findings, and insights 1964–67 Qualitative description of the incretin effect Reduction of MACE in people with overweight or 1970–73 Discovery of GIP as the first well characterised incretin hormone obesity and ASCVD 1985–87 Loss of insulinotropic activity of GIP in type 2 diabetes, questioning its therapeutic potential The SELECT trial recruited people with BMIs of at least 1987 Truncated GLP-1 isolated and functionally characterised as an incretin hormone 1992–93 GLP-1 stimulates insulin secretion and substantially lowers glucose concentrations in 27 kg m² who had established cardiovascular disease, but type 2 diabetes not type 2 diabetes (HbA <6·5% [48 mmol/mol]). The 1c 1992–98 GLP-1 reduces appetite and ad libitum food (energy) intake primary endpoint—MACE—was reduced, with a HR of 2003–today Development and approval of GLP-1 receptor agonists for the treatment of type 2 diabetes 0·80 (95% CI 0·72–0·90),28 indicating a separation 2007–today Development and approval of GLP-1 receptor agonists for the treatment of obesity between the cardiovascular benefits and glucose-lowering 2016–today Cardiovascular outcomes trials report beneficial effects of GLP-1 receptor agonists on eects provided by semaglutide. Furthermore, reductions cardiovascular and renal outcomes in hospitalisation or urgent medical visits for heart 2013–near future Development of the concept of dual and triple hormone receptor agonists with increased efficacy for improving glycaemic control and bodyweight reduction failure (18%), all-cause mortality (19%), coronary 2022–24 Tirzepatide approved as the first dual (GIP–GLP-1) receptor agonist for the treatment of revascularisation (23%), and a kidney composite type 2 diabetes and obesity (mechanism of action still only partially understood) endpoint (22%; appendix p 9) had upper bounds of 2022–27 (projected) Development and approval of small-molecule (orally absorbed) GLP-1 receptor agonists 95% CIs of below 1·0, but cannot be considered 2024–30 (projected) Development (and approval) of: Glucagon–GLP-1 dual receptor agonists significant according to the hierarchical statistical testing Amylin–GLP-1 dual receptor agonists or combinations used. GIP–GLP-1–glucagon triple receptor agonists GLP-1 receptor agonist–GIP receptor antagonistic antibody Mechanisms of ASCVD benefits with GLP-1 receptor Figure 1: Milestones in research related to the pathophysiology of the incretin hormones GIP and GLP-1 as agonists parent compounds for incretin-based medications for treatment of type 2 diabetes and clinical obesity GLP-1 and GLP-1 receptor agonists improve fasting plasma Relevant literature is available in the appendix (p 3). Predictions regarding approvals of drugs currently under glucose and HbA , but also systolic blood pressure, development are subject to uncertainty. GIP=glucose-dependent insulinotropic polypeptide. 1c atherogenic lipoproteins (ie, LDL cholesterol, VLDL cholesterol, triglycerides, and chylomicrons), inflammation (MACE; comprising non-fatal myocardial infarction, (eg, high-sensitivity C-reactive protein and interleukin-6) non-fatal stroke, and cardiovascular death) in people and bodyweight.35–37 Exploratory mediation analysis based with type 2 diabetes, with hazard ratios (HRs) ranging on the LEADER and REWIND trials suggested a role from 0·88 (95% CI 0·79–0·99; REWIND; dulaglutide22) for reductions in HbA and albuminuria as potential 1c to 0·73 (0·58–0·92; AMPLITUDE-O; efpeglenatide24), mediators of cardiovascular benefits.38,39 In addition, GLP-1 indicating a relative risk reduction of between 12% and and GLP-1 receptor agonists cause a multitude of eects 27% (figure 2A). The ELIXA,17 EXSCEL (ie, exenatide within blood vessels, including on endothelial cells and 2 mg per week subcutaneously),20 PIONEER 6 (oral nitrous oxide production (ie, vasodilation); on monocytes, semaglutide),23 and FREEDOM CVOT25 trials did not macrophages, and foam cells (reducing their secretion of show significant reductions in MACE, probably because inflammatory cytokines); on smooth muscle cells of insucient exposure over a 24 h period29 (for the (reducing their proliferation); and by reducing the activity ELIXA trial), a high proportion of participants of matrix metalloproteinases (and thus potentially discontinuing treatment in the EXSCEL trial,20 and low preventing the digestion of the fibrous caps that seal numbers of MACE events accrued in the PIONEER 6 atherosclerotic plaques),35–37,40 which could explain the and FREEDOM CVOT trials.23,25 Systematic reviews and prevention of ischaemic cardiovascular events. meta-analyses of CVOTs with GLP-1 receptor agonists in people with type 2 diabetes showed reductions in the Incretin-based medications and chronic kidney risk for MACE by 13–14%, myocardial infarction by disease 10–14%, stroke by 13–17%, cardiovascular death by Kidney outcomes in people with type 2 diabetes (with 13–14%, all-cause death by 12%, and hospitalisation for or without chronic kidney disease at baseline) heart failure by 11–14%.16,30,31 Findings from the most Clinical trials with incretin-based medications have recent and comprehensive meta-analysis are displayed reported meaningful improvements in kidney outcomes. in figure 2B.16 Relative risk reductions were similar in In people with type 2 diabetes with or without chronic subgroups based on gender, and with or without kidney disease (CKD), GLP-1 receptor agonists (eg, ASCVD at baseline. Some of these findings have been liraglutide, semaglutide, dulaglutide, and efpeglenatide) confirmed in real-world studies (appendix p 8). and the GIP–GLP-1 receptor agonist tirzepatide reduced Tirzepatide, as well as showing some preliminary albuminuria and slowed declines in estimated evidence of cardiovascular safety,32 was found to be non- glomerular filtration rates (eGFR; appendix p 10). Major inferior to dulaglutide in reducing MACE, which kidney outcomes consisting of eGFR decline, kidney implies superiority over putative placebo.33 In addition, failure, and death from kidney-related causes (sometimes semaglutide was recently shown to increase the including progression to macroalbuminuria; appendix 894 Review Lixisenatide Liraglutide Semaglutide (subcutaneous) Exenatide once weekly Dulaglutide Semaglutide (oral) Efpeglenatide Exenatide (osmotic minipump) ELIXA p=0·81 LEADER p=0·01 SUSTAIN-6 p=0·016 EXSCEL p=0·061 HARMONY-Outcomes p=0·0006 REWIND p=0·026 PIONEER-6 p=0·17 AMPLITUDE-O p=0·0069 FREEDOM CVOT NR FLOW p=0·029 SOUL p=0·0055 p 10) were reduced (figure 3).24,41–46In the SUSTAIN-6 slope dierence 1·16 mL/min per 1·73 m², 0·86–1·47), trial, participants with type 2 diabetes were also more MACE (HR 0·82, 0·68–0·98), and all-cause mortality likely to remit to a lower risk category in the Kidney (HR 0·80, 0·67–0·95) in hierarchical testing of Disease: Improving Global Outcomes (KDIGO) risk confirmatory secondary outcomes compared with classification (HR 1·69, 95% CI 1·32–2·16) and less likely placebo.26 Benefits regarding composite renal endpoints to progress to a higher KDIGO risk category (HR 0·71, (appendix p 9) have been confirmed in systematic 0·59–0·86) with semaglutide treatment compared with analyses and meta-analyses, including the aforemen- placebo.47 In post-hoc analyses of clinical trials in people tioned clinical studies.16,31 with type 2 diabetes, tirzepatide consistently lowered albuminuria and stabilised eGFR compared with active Kidney outcomes in people with overweight or obesity comparators or insulin for glycaemic control, or with The SELECT trial, a CVOT of subcutaneous semaglutide placebo.48,49 The FLOW trial was a dedicated kidney (2·4 mg once weekly) versus placebo in people with outcome trial conducted in participants with type 2 overweight or obesity with an established diagnosis of diabetes and established CKD.26 Treatment with ASCVD, found a 22% lower relative risk (HR 0·78, injectable semaglutide 1 mg once weekly reduced the 95% CI 0·63–0·96) for a composite kidney outcome (ie, relative risk for the composite primary outcome (ie, onset of macroalbuminuria, >50% eGFR decline, eGFR ≥50% eGFR decline, eGFR <15 mL/min per 1·73 m², <15 mL/min per 1·73m², dialysis or transplant, or death dialysis or transplant, or death due to kidney disease or due to kidney disease).28,50 As only 21% of participants in cardiovascular disease) by 24% compared with placebo the SELECT trial had an eGFR of less than 60 mL/min (HR 0·76, 0·66–0·88).26 Furthermore, semaglutide also per 1·73m² or a urinary albumin-to-creatinine ratio of at significantly reduced the rate of eGFR decline (annual least 30 mg/g at baseline, these data suggest that CKD setebaid epyT A Individual studies B Meta-analysis ytisebO htiw DVCSA Number needed to treat 3-point MACE 63 Myocardial infarction 141 Stroke 234 Cardiovascular death 139 All-cause death 102 Hospitalisation 199 for heart failure 0 0·2 0·4 0·6 0·7 0·8 0·9 1·0 Hazard ratio (±95% CI) C SELECT p<0·001 0 0·2 0·4 0·6 0·8 1·0 1·2 1·4 1·6 1·8 Hazard ratio for MACE (±95% CI) Figure 2: Results for reductions in MACE from individual cardiovascular outcomes studies (A and C) and for various outcomes from a meta-analysis of cardiovascular outcomes studies (B) in populations with type 2 diabetes and overweight or obesity with ASCVD The hazard ratios (for active treatment vs placebo, with 95% CIs) are shown. Results of a recent meta-analysis16 summarising all cardiovascular outcomes trials in populations with type 2 diabetes are shown for the primary endpoint (MACE), the components of MACE (ie, fatal and non-fatal myocardial infarction or stroke and cardiovascular death), all-cause mortality, and hospitalisation for heart failure. Original results were taken from the primary publications: ELIXA,17 LEADER,18 SUSTAIN-6,19 EXSCEL,20 HARMONY-Outcomes,21 REWIND,22 PIONEER-6,23 AMPLITUDE-O,24 FREEDOM CVOT,25 FLOW,26 SOUL,27 and SELECT.28 In the LEADER, SUSTAIN-6, and PIONEER-6 trials, CKD with an estimated glomerular filtration rate of less than 60 mL/min per 1·73 m² body surface was taken as an equivalent of established cardiovascular disease. The meta-analysis16 disregarded ELIXA’s results because of the absence of any effects of lixisenatide. ASCVD=atherosclerotic cardiovascular disease. MACE=major adverse cardiovascular event. NR=not reported. Review HR 0·45 (0·20–0·97) p=NR HR 0·68 13 Placebo (0·57–0·79) Liraglutide 1·8 mg once daily HR 0·79 p<0·001 12 Semaglutide (subcutaneous) (0·41–1·519) 1·0 mg/week p=NR Dulaglutide 0·75 mg/week Dulaglutide 1·5 mg/week Efpeglenatide 4 or 6 mg/week 10 Oral semaglutide 14 mg/day 8 HR 0·64 (0·46–0·88) p=0·005 HR 0·79 6 (0·66–0·94) HR 0·85 p=NR (0·57–0·79) p=NR HR 0·78 3 (0·67–0·92) p=0·003 HR 0·86 2 (0·66–1·10) p=NR 0 LEADER SUSTAIN-6 AWARD-7 REWIND AMPLITUDE-O FLOW SOUL Proportion of people 11·3 NR 78·0 35·0 48·4 96·9 NR with increased urine albumin-to-creatinine ratio (%) Proportion of people 23·1 28.5 94·8 22·2 31·2 79·9 29·2 with an estimated glomerular filtration rate <60 mL/min per 1·73 m² body surface Figure 3: Effect of GLP-1 receptor agonists on composite kidney outcomes in cardiovascular and kidney outcomes trials in populations with type 2 diabetes HRs (vs placebo) are shown with 95% CIs and p values indicating the significance of the difference to placebo treatment. Original results were taken from the primary publications: LEADER,20,41 SUSTAIN-6,19 AWARD-7,42,43 REWIND,622,44 AMPLITUDE-O,24 and FLOW.26 Results from the FLOW trial regarding a composite of kidney-specific components of the primary outcome (excluding cardiovascular death) are depicted for better comparability with other studies. This was not the primary outcome of that study. In the LEADER, SUSTAIN-6, and SOUL trials, chronic kidney disease with an estimated glomerular filtration rate of less than 60 mL/min per 1·73 m² body surface was taken as an equivalent of established cardiovascular disease. The ELIXA,17 EXSCEL,20 HARMONY-Outcomes,21 PIONEER-6,23 and SELECT28 trials (for people with obesity with established atherosclerotic cardiovascular disease at baseline) did not report these outcomes. Details of the components of composite kidney outcomes in the individual trials are available in the appendix (p 9). In most trials, the primary outcome included cardiovascular death; in this figure, only kidney- specific composite outcomes are depicted. HR=hazard ratio. NR=not reported. could be prevented by a GLP-1 receptor agonist. Moreover, Additionally, no relationship between changes in in people with obesity and heart failure without type 2 bodyweight and eGFR was observed in clinical trials of diabetes, tirzepatide treatment versus placebo was dulaglutide and semaglutide (selective GLP-1 receptor associated with a slight increase in eGFR, with a agonists) or tirzepatide (dual GIP–GLP-1 receptor concomitant reduction in albuminuria over 52 weeks.51 agonist) in study populations with type 2 diabetes or obesity with and without CKD.53–55 Direct protective Mechanisms of GLP-1 receptor agonists in CKD eects on the kidney by GLP-1 receptor agonists acting In a mediation analysis for kidney outcomes (ie, through other mechanisms are therefore probable. macroalbuminuria, doubling of serum creatinine, eGFR GLP-1 receptors are expressed in the kidney,56 primarily <45 mL/min per 1·73 m², or kidney failure) from CVOTs in endothelial cells and vascular smooth muscle cells of of liraglutide and semaglutide in type 2 diabetes, lower the juxtaglomerular apparatus.57 Non-intrinsic kidney levels of glycaemia or blood pressure only moderately cells could also contribute to CKD progression. mediated 10–25% of these benefits, indicating direct Macrophages and T lymphocytes are important drivers of action on the kidney by these GLP-1 receptor agonists.52 inflammation and fibrosis within the kidney.37,58,59 896 )noitavresbo fo sraey-nosrep rep( tniopdne etisopmoc laner a gnihcaer rof etaR Clinical trial Review Activation of GLP-1 receptors on these immune cells Disease or condition Proven clinical benefits of GLP-1 receptor agonists Tirzepatide converts them to less-inflammatory or anti-inflammatory phenotypes.58 Mouse and rat models show that GLP-1 Type 2 diabetes • HbA 1c ↓, FPG ↓, bodyweight↓, waist circumference↓ √ ASCVD • Risk for MACE* ↓ √ receptor agonists suppress signals through pro- • ASCVD at baseline: robust evidence, substantial absolute risk reduction inflammatory pathways (eg, the receptor for advanced • No ASCVD at baseline: Less robust evidence, smaller absolute risk glycation end products and Toll-like receptors), possibly reduction involving GLP-1 actions in the CNS and resulting in CKD • Albuminuria and eGFR decline over time ↓ ? • Composite kidney outcomes representing kidney function loss of 40% immunomodulation via parasympathetic and opioid or 50%, kidney failure ↓ eerent activity.60–61 Accordingly, GLP-1 receptor agonists HFpEF or HFrEF • Heart failure-related endpoints ↓(eg, hospital admission or urgent ? reduce kidney inflammation and fibrosis in mouse and (NYHA class 2–4) treatment for heart failure, cardiovascular death) rat models of CKD with or without diabetes.60–61 In Symptomatic PVD • Maximum walking distance↑ ? humans with type 2 diabetes and CKD, dulaglutide • Pain-free walking distance↑ reduced pro-fibrotic biomarkers in blood and urine.63 In a Obesity • Bodyweight↓, waist circumference↓, blood pressure↓, triglycerides↓ √ mouse model of sepsis, liraglutide decreased lung injury Prediabetes • Progression to manifest diabetes mellitus ↓ √ and reduced the death rate,62 suggesting that resistance to severe illness could be another potential mechanistic ASCVD • Risk for MACE↓ ? link to improved overall survival, as observed in the HFpEF • KCCQ clinical summary score ↑(heart failure-related symptoms↓) √ FLOW trial.26 • 6-min walking distance↑ √ • Heart failure-related hospital admission (urgent treatment) ↓ √ Incretin-based medications for bodyweight MASLD • Resolution of MASLD↑ √ reduction in obesity • Progression of liver fibrosis↓ ? Based on the experience of participants with type 2 OSAS • Apnoea–hypopnoea index↓ √ diabetes in clinical trials, GLP-1 receptor agonists Knee osteoarthritis • Pain, stiffness, and physical function (WOMAC) index↓ ? liraglutide and semaglutide (subcutaneous) and the dual agonist tirzepatide have been studied in people Figure 4: Proven clinical benefits related to GLP-1 receptor agonists and the GIP–GLP-1 receptor co-agonist with overweight (BMI 25·0–29·9 kg/m²) and obesity tirzepatide in people with type 2 diabetes or obesity Details of clinical trials supporting the conclusions presented in this figure are in the appendix (p 12). (BMI ≥30·0 kg/m²). Higher doses of selective GLP-1 ASCVD=atherosclerotic cardiovascular disease. CKD=chronic kidney disease. eGFR=estimated glomerular filtration rate. receptor agonists are used for treatment of overweight FPG=fasting plasma glucose. GIP=glucose-dependent insulinotropic polypeptide. HbA=glycated haemoglobin. 1c or obesity than those for treatment of type 2 diabetes HFpEF=heart failure with preserved ejection fraction. HFrEF=heart failure with reduced ejection fraction. KCCQ=Kansas (eg, 3 mg/day instead of 1·8 mg/day for liraglutide and City Cardiomyopathy Questionnaire. MACE=major adverse cardiovascular events. MASLD=metabolic dysfunction- associated steatotic liver disease. NYHA=New York Heart Association. OSAS=obstructive sleep apnoea syndrome. 2·4 mg/week instead of 1·0 mg/week for semaglutide). PVD=peripheral vascular disease. WOMAC Index=Western Ontario and McMaster Universities Osteoarthritis Index. Tirzepatide 5, 10, and 15 mg/week are approved doses *Composite endpoint comprised of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. for treatment of type 2 diabetes, overweight, or obesity. If treatment with incretin-based medications is Incretin-based medications and benefits for discontinued, bodyweight will increase at approximately obesity-associated conditions the velocity as it had been lost with treatment.64–66 The Clinical obesity has been defined as “a systemic illness extent of bodyweight reduction is highly variable directly and specifically caused by excess adiposity”, between individuals,64,67–69 and some participants gained “causing illness by altering the function of various weight even with the highest dose of tirzepatide.69 organs, not only those involved in metabolic Clinical trials have yielded consistent results regarding regulations”.72 Excess body fat—including the their eect sizes for bodyweight reduction for each pathophysiologically important visceral adipose tissue— agent studied (see appendix p 11). In the STEP-8 trial,70 could therefore lead to prediabetes and progression to semaglutide 2·4 mg/week led to greater weight loss (a type 2 diabetes, metabolic dysfunction-associated 15·8% reduction) compared with liraglutide 3·0 mg steatotic liver disease (MASLD) with fibrosis, CKD, once daily (a 6·4% reduction); in the SURMOUNT-5 ASCVD, obesity-associated heart failure with preserved trial,15 tirzepatide 15 mg caused significantly higher ejection fraction, obstructive sleep apnoea syndrome weight reduction (20·2%) compared with semaglutide (OSAS), and symptomatic knee osteoarthritis.73 2·4 mg (13·7%). Weight loss is generally more Symptomatic improvements can be achieved with pronounced in people with overweight or obesity bodyweight reductions of 5–15% for most of these without type 2 diabetes, perhaps due to reduced conditions.74 Therapeutic eects of incretin-based glucosuria and fewer calories being lost.71 Similar medications in such conditions are presented in figure 4 dierences in eectiveness are found when looking at and the appendix (pp 12–13). reductions in waist circumference, systolic blood pressure, and serum triglycerides, with dierences in Progression to type 2 diabetes eect sizes reflecting the dierences in weight loss in Liraglutide, semaglutide (subcutaneous), and tirzepatide response to liraglutide, semaglutide, and tirzepatide have shown the potential to slow the progression from treatment.15,70 prediabetes to type 2 diabetes by 66–93% compared with Review placebo.65,75,76 After wash-out periods (of 12–28 weeks), the without worsening of MASLD after 72 weeks of treatment eects were at least partly maintained. with semaglutide.84 Semaglutide has been approved for the treatment of MASLD based on these results.85 Obesity-associated heart failure Similarly, approval for tirzepatide to treat MASLD has Heart failure with preserved ejection fraction (ie, been announced to be applied for.86 Therefore, incretin- impaired diastolic ventricular filling) is closely based medications for the treatment of MASLD could be associated with obesity. Until recently, no specific made available, supplementing resmetirom as the only treatment was available. Clinical trials have approved medication in the USA and Europe.87 been conducted for semaglutide (in people with obesity with77 or without78 type 2 diabetes) and tirzepatide (in Obstructive sleep apnoea non-diabetic people79). Co-primary endpoints in the The risk for OSAS rises with increasing adiposity, and its semaglutide trials were a change in the Kansas City successful treatment requires substantial reductions in Cardiomyopathy Questionnaire Clinical Summary bodyweight. Liraglutide (3 mg/day) reduced hypopnoea Score (KCCQ-CSS; an assessment of physical and/or apnoea events over 32 weeks of treatment.88 functioning related to heart failure) and reductions in Tirzepatide reduced hypopnoea and/or apnoea events bodyweight. The SUMMIT trial (for tirzepatide) used significantly in populations either using or not using time to cardiovascular death or worsening heart failure positive airway pressure therapy (PAPT); in 50·2% of events over 104 weeks and a change in KCCQ-CSS from people using PAPT, and in 42·2% of those not using baseline to 52 weeks.79 Additional outcomes were PAPT, the apnoea–hypopnoea index was reduced to the changes in the 6-min walking test and bodyweight. range where PAPT would no longer appear necessary for Improvements in the KCCQ-CSS were described treatment of OSAS. The US Food and Drug (appendix pp 12–13) and bodyweight was reduced Administration has approved OSAS as a new indication (appendix p 11). The 6-min walking distance improved for tirzepatide. more with either drug than with placebo treatment. More importantly, a prespecified pooled analysis of the Knee osteoarthritis two semaglutide trials showed a reduction in time to Semaglutide (2·4 mg/week) has been shown to cause first heart failure event (ie, an event requiring symptomatic improvement related to moderate knee hospitalisation or an urgent medical visit; HR 0·27, osteoarthritis as well as bodyweight reduction.89 95% CI 0·12–0·56).80 Likewise, the SUMMIT trial (for tirzepatide) showed a reduction in events regarding Safety and tolerability issues of current concerns time to cardiovascular death or worsening heart failure Optic nerve and retinal disorders have been found to be over 104 weeks (HR 0·62, 0·41–0·95),79 indicating associated with the use of potent GLP-1 receptor agonists improvements in various clinically relevant parameters. (ie, semaglutide) and the dual agonist tirzepatide, such as The same parameters in clinical trials of semaglutide, non-arteritic ischaemic optic neuropathy, papilloedema, tirzepatide, and SGLT2 inhibitors in heart failure with macular oedema, retinal detachment, retinal haemor- preserved ejection fraction are indirectly compared in rhage, retinal tear, vitreous detachment, and vitreous the appendix (p 14). haemorrhage.90,91 Although such an association has not been confirmed by other studies,92,93 a small proportion of Metabolic dysfunction-associated steatotic liver disease people with type 2 diabetes treated with potent incretin- MASLD is a common complication of obesity that can based medications could be aected (~0·05% over progress to liver fibrosis, cirrhosis, and hepatocellular 2 years).90 Whether or not this association is related to the carcinoma. Studies have been published for liraglutide potent glucose-lowering ability of semaglutide or (1·8 mg/day),81 daily injections of semaglutide tirzepatide, potentially leading to a reduced glucose (0·1–0·4 mg/day; subcutaneous),82 and tirzepatide uptake into neural or retinal tissues after adapting to (5–15 mg/week).83 A particular focus of these studies was hyperglycaemia, requires further research. on the prevention of progression, and potential Because GLP-1 receptor agonists and the dual regression of fibrosis (appendix pp 12–13). The primary agonist tirzepatide support major bodyweight reduction, outcome for all three studies was resolution of fatty liver including a reduction in lean body mass (of which ~50% disease without worsening of fibrosis, and significant is muscle mass), there is concern that this could also lead improvements were noted. In addition, liraglutide led to to a critical reduction in muscle mass and, consequently, fewer participants with a worsening fibrosis stage,81 to related functional impairments.94 Older people with semaglutide showed a trend for improvements in fibrosis sarcopenia before starting such treatment could be at stage,82 and tirzepatide led to an increased proportion of particular risk.95 Concerns are mainly based on inferences participants reaching an improvement in fibrosis by at from the numerical reduction in muscle mass observed least one stage.83 A recent study reported significant with incretin-based weight-loss medications. We are not eects on the resolution of MASLD without worsening aware of any systematic assessment of functional of fibrosis, but also significant improvements in fibrosis impairments (eg, inability to rise from a sitting to a 898 Review standing position) arising from use of incretin-based once weekly) increased abstinence by 70%.109 Results medications. Furthermore, whether a somewhat reduced regarding alcohol use also range from no significant muscle mass is functionally appropriate after major overall eect on heavy drinking days—except for a weight loss (eg, 15% bodyweight reduction), is unclear. In subgroup with BMIs greater than 30 kg/m² with exenatide addition, although incretin-based medications once weekly110—to a 29% reduction in alcohol consumption numerically reduce muscle mass, they could also improve with dulaglutide111 and a reduced rate of alcohol muscle quality by reducing intramuscular fat infiltration, intoxication with diverse GLP-1 receptor agonists.112 A as shown with tirzepatide.96 Further research is needed recent clinical trial with once-weekly semaglutide before the importance of this risk can be estimated,94 and (1 mg/week) reported reduced alcohol self-administration pharmacological treatments are being developed to and lower peak breath alcohol concentrations compared address the preservation of muscle mass during treatment with placebo, but no change in average drinks per day, the with GLP-1 receptor agonists.97 number of drinking days, or weekly alcohol cravings.113 Other safety and tolerability issues associated with For opioid dependence, exenatide reduced oxycodone established incretin-based medications are presented in intake,114 but not morphine intake,115 and liraglutide the appendix (pp 18–19). Putative reasons for underusing reduced heroin intake116 in rodents, indicating some incretin-based medications and for poor adherence to and heterogeneity regarding the type of opioid drug. In an persistence with treatment, which are potentially related observational study based on a database of electronic to safety concerns, are also available (appendix p 19). health records, the risk of opioid overdose was reduced by 42–68% with semaglutide versus other glucose- New indications for established GLP-1 receptor lowering medication classes.117 Although animal studies agonists suggest an interference of GLP-1 receptor agonists with Neurodegenerative diseases and substance use disorders cocaine self-administration,118 this was not confirmed in a Novel fields of use appear possible for GLP-1 receptor clinical trial with short-term exenatide administration.119 agonists and tirzepatide based on recent exploratory Various clinical trials in the area of neurodegenerative research. GLP-1 is involved in cognitive brain function and diseases and substance abuse disorders are underway to learning,98 and the GLP-1 receptor agonist liraglutide potentially support the use of GLP-1 receptor agonists for interferes with cognitive decline in individuals with type 2 such conditions (appendix pp 16–17). diabetes.99 Therefore, therapeutic actions in neuro- degenerative diseases, such as Alzheimer’s dementia and Next-generation incretin-based medications for Parkinson’s disease, have been explored both in animal easier use or increased efficacy models and in clinical trials (appendix pp 16–17). A recent Over the past 10–15 years, the armamentarium of meta-analysis reported significant reductions in the incretin-based medications has greatly increased. One incidence of all-cause dementia with GLP-1 receptor focus of research was the development of small agonists, but not with SGLT2 inhibitors, with no significant molecules, readily absorbed from the gastrointestinal dierences for Alzheimer’s or vascular forms of tract, which can oer oral therapy to activate GLP-1 and dementia.100 A dedicated prospective study (ie, the EVOKE other receptors. Another focus was the development of For the dedicated prospective study, NCT04777396), however, found no significant peptides that can specifically interact with more than study see https://clinicaltrials. dierences in disease progression between treatment with one receptor. Tirzepatide is currently the only approved gov/study/NCT04777396 semaglutide or placebo.1101 agent of this type. Three clinical trials consistently describe a slowed decline in motor function when using the short-acting Oral small-molecule GLP-1 receptor agonists GLP-1 receptor agonists exenatide and lixisenatide in Small-molecule, orally bioavailable, synthetic non- people with Parkinson’s disease;102–104 however, this decline peptide GLP-1 receptor agonists can provide an eective was not confirmed in a study using exenatide once pharmacotherapy as an alternative to peptide-based weekly105 or in another recent trial of NLY01, a brain- GLP-1 receptor agonists, without a need for injection.120,121 penetrant, pegylated exenatide.106 Less definite infor mation Orforglipron is such a molecule (table). The ecacy and is available regarding other neurodegenerative diseases safety of orforglipron have been investigated in phase 3 (eg, Huntington’s disease107). Because GLP-1 interacts with clinical trials in people with overweight or obesity130,141 and neurons in brain areas involved in the homeostatic and early type 2 diabetes.122 hedonic regulation of food intake, the role of GLP-1 In adults with overweight or obesity, plus at least synthesised in the CNS, and of GLP-1 receptor agonists one weight-related coexisting condition, but without administered peripherally, in interference with substance type 2 diabetes, the maximum reduction in weight at use disorders has been a focus of research in recent week 72 was 11·2% with orforglipron 36 mg/day versus years.108 Varying results have been reported for the role 2·1 % with placebo.130 Orforglipron is further under of GLP-1 and GLP-1 receptor agonists in inducing or investigation as a potential treatment for obesity in the maintaining abstinence from nicotine use (appendix phase 3 ATTAIN programme. The ATTAIN-2 study pp 16–17), but the GLP-1 receptor agonist exenatide (given reported a placebo-subtracted bodyweight reduction by Review up to 7·1% (95% CI 6·1–8·2).142 In people with type 2 bodyweight reduction of up to 5·9% (4·4–7·4) versus diabetes, the maximum reduction in HbA with baseline.122 Gastrointestinal tolerability has been 1c orforglipron was 1·1% (0·8–1·3) or 12 (9–14) mmol/mol improved since a previous phase 2 trial143 by prolonging for 36 mg per day (placebo-corrected), along with a the dose-escalation period (up to 20 weeks), but remained Compound or Dose range and Reduction in Reduction in HbA , Other prominent findings Reference Ongoing clinical trials 1c preparation duration bodyweight, percentage points vs (ClinicalTrials.gov) percentage of baseline value baseline value (95% CI; placebo- (95% CI; placebo- subtracted) subtracted) Type 2 diabetes Small-molecule, Orforglipron 3–36 mg once daily vs Up to 5·9% (4·4–7·4) Up to 1·07% Low drug discontinuation due to Rosenstock NCT06045221 oral GLP-1 receptor placebo over with 36 mg/day (0·81–1·33) with adverse events (<5·7%); weight et al (2025)122 (vs semaglutide) agonist 40 weeks highest dose plateau not reached (ACHIEVE-1) Biased GLP-1 Ecnoglutide 0·4–1·2 mg/week over Up to 2·8% Up to 1·8% (1·4–2·3; Low burden of nausea and Zhu et al NCT05680155 receptor agonist 20 weeks (–3·6 to 1·9) highest dose) vomiting or drug discontinuation (2024)123 (vs placebo) (reduced β-arrestin recruitment) Biased GLP-1 Ecnoglutide 0·6 or 1·2 mg/week Up to 5·7 ± 0·3% Up to 1·8 ± 0·05% Low drug discontinuation due to He et al NA receptor agonist over 52 weeks (SEM); change vs (SEM); change vs adverse events (up to 4%) (2025)124 (reduced β-arrestin dulaglutide dulaglutide recruitment) 1·5 mg/week –3·0% 1·5 mg/week 0·25% (– 3·7 to –2·2) (–0·40 to –0·11) Dual glucagon– Survodutide 0·3–2·7 mg/week; Up to 7·5% (95% CI Up to 1·7 % (1·5–1·9) High drug discontinuation due to Blüher et al NCT06066528 (focus GLP-1 receptor 1·2–1·8 mg once every not reported) vs placebo (0·2%) adverse events (up to 30%); (2023)125 on weight reduction) agonist 2 weeks over weight plateau not reached 16 weeks Dual glucagon– Mazdutide 3–6 mg/week over Up to 5·7% (3·9–7·6) Up to 1·7% (1·3–2·1) No treatment discontinuation Zhang et al NA GLP-1 receptor 20 weeks with 6 mg/week with 3 mg/week due to adverse events (2024)126 agonist Amylin–GLP-1 Cagrilintide– Cagrilintide 10·4% (9·5–11·2) 1·4% (1·2–1·6) Improved physical function Davies et al NCT06323161 (vs receptor agonist semaglutide 2·4 mg/week; (according to IWQOL-Lite-CT and (2025)127 once-daily insulin); NCT combination semaglutide SF-36v2 scores); drug (REDEFINE-2) 06323174 (vs diet and 2·4 mg/week for discontinuation due to adverse exercise) 68 weeks events 8·4%; weight plateau reached Triple GIP–GLP-1– Retatrutide 0·5–12 mg/week over Up to 13·9% Up to 1·9% (1·3–2·4) High drug discontinuation due to Rosenstock NCT06260722 glucagon receptor 36 weeks (10·7–17·1) with with highest dose; adverse events (up to 17%); et al (2023)128 (vs semaglutide); co-agonist highest dose efficacy estimand weight plateau not reached NCT06354660 (not controlled on diet and exercise) GLP-1 receptor Maridebart 140–420 mg every Up to 12·3% (9·2–15·3) Up to 1·5% (1·0–1·9) Nausea in up to 59%, vomiting in Jastreboff et al NCT06660173 (adults); agonist–GIP cafraglutide 4 weeks for 52 weeks up to 75%, drug discontinuation (2025)129 NCT06858878 (with receptor due to adverse events up to 19%; obesity or overweight) antagonistic bodyweight plateau not reached antibody Obesity and overweight Small-molecule, Orforglipron 6–36 mg once daily vs Up to 9·1% (8·1–10·1) Up to 0·3% (several High drug discontinuation rate Wharton et al NCT05869903 (obesity oral GLP-1 receptor placebo over 72 weeks doses; SEM 0·0%) (up to 24%), up to 7% due to (2025)130 with weight-related agonist gastrointestinal adverse events; comorbidities); weight plateau reached after NCT06649045 ~52 weeks (obstructive sleep apnoea syndrome) Biased GLP-1 Ecnoglutide 1·2–2·4 mg/week over Up to 13·3% Up to 0·4% (0·3–0·4) Low drug discontinuation due to Ji et al NCT07143227 (in receptor agonist 40 weeks (11·3–15·3) adverse events (up to 3%); weight (2025)131 adolescents) (reduced β-arrestin plateau not reached recruitment) Glucagon–GLP-1 Survodutide 0·6–4·8 mg Up to 12·1% (9·2–15·0) Up to 0·25% (95% CI High drug discontinuation due to Le Roux et al NCT06066515 (focus receptor co-agonist once weekly over with highest dose not reported) with adverse events (up to 29%); (2024)132 on weight loss); 46 weeks highest dose weight plateau not reached NCT06077864 (SYNCHRONIZE; cardiovascular outcomes trial) (Table continues on next page) 900 Review Compound or Dose range and Reduction in Reduction in HbA, Other prominent findings Reference Ongoing clinical trials 1c preparation duration bodyweight, percentage points vs (ClinicalTrials.gov) percentage of baseline value baseline value (95% CI; placebo- (95% CI; placebo- subtracted) subtracted) (Continued from previous page) Glucagon–GLP-1 Mazdutide 3–6 mg/week over Up to 12·3% Up to 0·4% Few participants discontinued Ji et al NCT06519656 receptor co-agonist 24 weeks; 4 or 6 mg (10·5–14·1); up to (0·33–0·47); values treatment due to adverse events (2023);133 (polycystic ovary over 48 weeks 13·0% (14·3–11·7) not reported for 4 or 6 (up to 6·6% with 6 mg/week); Ji et al syndrome) mg over 48 weeks despite nausea in up to 50·5%, (2025)134 vomiting in up to 43·1%, and diarrhoea in up to 38·6%, only 1·5% (for 4 mg) and 0·5% (for 6 mg) discontinued drug because of adverse events Amylin–GLP-1 Cagrilintide– Cagrilintide 17·3% (16·6–18·1) vs 0·4% (not more than Improved physical function Garvey et al NCT06131372 receptor agonist semaglutide 2·4 mg/week; placebo; 5·5% the effect of (based on IWQOL-Lite-CT and (2025)135 (vs semaglutide, combination semaglutide (4·3–6·7) vs semaglutide alone) SF-36v2 scores); drug (REDIFINE-1) cagrilintide, and 2·4 mg/week for semaglutide alone discontinuation due to adverse placebo for chronic 68 weeks events 5·9%; weight plateau not kidney disease in people reached with type 2 diabetes and obesity; NCT06131437 (vs tirzepatide) Amylin–GLP-1 Amycretin Amycretin 11·7% (6·1–17·3) with 0·1% (–0·4 to 0·1) with High risk for nausea (up to 82%), Dahl et al NA receptor co-agonist (subcutaneous) 1·25–60 mg 1·25 mg/week; 1·25 mg/week; vomiting (up to 60%), and drug (2025)136 once weekly 23·2% (15·6–30·8) 0·5% (–1·0 to 0·0) with discontinuation (up to 35%), also (phase 1) with 60 mg/week 60 mg/week with placebo treatment (nausea up to 94%, vomiting up to 60%) Amylin–GLP-1 Amycretin Amycretin two 25 mg Up to 11·8% 0·3% (SD 0·3) with High risk for nausea (up to 94%), Gasiorek et al NA receptor co-agonist (oral) tablets, one 50 mg (9·0–14·6) with two two 50 mg tablets per vomiting (up to 56%), but low (2025)137 tablet, or two 50 mg 50 mg tablets per day day risk for drug discontinuation (up (phase 1) tablets daily for to 6%), all low with placebo 12 weeks treatment (nausea 8%, vomiting 8%) Triple GIP–GLP-1– Retatrutide 1–12 mg/week over Up to 22·1% Up to 0·5% (0·3–0·6) High drug discontinuation due to Jastreboff et al NCT06662383 glucagon receptor 48 weeks (primary (19·3–24·9) with with 8 mg (initial dose adverse events (up to 16% with (2023)138 (vs tirzepatide); co-agonist endpoint for 12 mg/week 2 mg)/week 12 mg/week); discontinuation for NCT06383390 bodyweight: any reason up to 23·5% (with 4 (TRIUMPH-Dual 24 weeks) mg/week); weight plateau not primary outcomes: reached cardiovascular and kidney) GLP-1 receptor Maridebart 140–420 mg every Up to 16·2% Up to 0·3% Nausea in up to 87%, vomiting in Jastreboff et al NCT06858839 agonist–GIP cafraglutide 4 weeks for 52 weeks (13·5–18·9) up to 87%, drug discontinuation (2025)129 (without type 2 receptor due to adverse events up to 29%; (phase 2) diabetes); antagonistic gastrointestinaI adverse events NCT07037433 antibody and drug discontinuation (cardiovascular somewhat improved by slower outcomes); dose escalation; bodyweight NCT06352892 plateau not reached (Chinese patients); NCT06987695 (Japanese patients) MASLD (with fibrosis stage F1–F3) Dual glucagon– Survodutide 2·4–6·0 mg/week Up to 12·1% (95% CI 0·7% points (95% CI More improvement in MASH Sanyal et al NCT06632457 GLP-1 receptor over 48 weeks not reported) not reported); 39% of with no worsening of fibrosis, (2024)139 (LIVERAGE [cirrhosis]) agonists participants with reduction in liver fat by ≥30%, type 2 diabetes numerically more improvement of fibrosis with active treatment MASLD Triple GIP–GLP-1– Retatrutide 1–12 mg/week over Up to 25·9% (SEM 2·4) NA Reduction in hepatic fat fraction Sanyal et al NA glucagon receptor 48 weeks by <86·0%; no histology available (2024)140 co-agonist to assess fibrosis Therapeutic approaches of GLP-1 receptor agonists; dual and triple agonists addressing GLP-1, glucagon, amylin, and GIP receptors; a combination of an amylin analogue and a GLP-1 receptor agonist (semaglutide); and a unimolecular GLP-1 receptor agonist–GIP receptor antagonistic antibody in advanced stages of drug development (which is currently unapproved for treatment of type 2 diabetes, overweight or obesity, and MASLD. GIP= glucose-dependent insulinotropic polypeptide. HbA=glycated haemoglobin. MASH=metabolic dsyfunction-associated steatohepatits. MASLD=metabolic dysfunction- 1c associated steatotic liver disease. NA=not available. Table: Current status of clinical trials exploring advanced GLP-1-based medications for the treatment of type 2 diabetes and obesity, and their complications Review high (nausea in up to 12 % [vs up to 28% in phase 2], programme; NCT06066515 and NCT06077864), and a vomiting in up to 14% [vs up to 36%], and drug phase 2 study in adults with metabolic dysfunction- discontinuation due to adverse events in up to 8% [vs up associated steato hepatitis and liver fibrosis with and to 19%] of the exposed participants).122,143 Orforglipron without diabetes has been published.140 will further be studied as a novel treatment for type 2 Mazdutide is another once-weekly dual glucagon– diabetes in the ACHIEVE programme. The development GLP-1 receptor agonist126,134 that has been mainly studied of other small-molecular oral GLP-1 receptor agonists in Chinese people. In a phase 2 trial in people with type 2 (eg, lotiglipron and danuglipron) was halted due to liver diabetes, after 20 weeks of treatment, mazdutide (up to toxicity. 6 mg weekly) reduced HbA numerically more (by up to 1c 1·7% [19 mmol/mol]) compared with the selective GLP-1 Biased GLP-1 receptor agonism: a preferential receptor agonist dulaglutide (HbA reduction of 1·4% 1c stimulation of cAMP generation over β-arrestin [15 mmol/mol]).126 Bodyweight was reduced more by all recruitment doses of mazdutide (ie, 3–6 mg/week) than by Theoretically, biased agonism should prevent receptor dulaglutide.126 Similar to a previous phase 2 trial in internalisation in response to ligand binding, therefore Chinese adults with overweight or obesity,133 a recent preserving a greater number of GLP-1 receptors on the cell phase 3 trial (GLORY) described bodyweight reductions surface that are available for further stimulation. Overall, after 48 weeks of treatment with 6 mg/week mazdutide this approach aims to initiate greater and prolonged of 14·0% (vs an increase of 0·3% with placebo).134 With responses, resulting in larger eect sizes compared with mazdutide treatment, 51% of participants experienced non-biased agonists. Clinical results have been reported nausea and 43% experienced vomiting, but drug for ecnoglutide, which has been developed as a biased discontinuation rate due to adverse events was low (2%; GLP-1 receptor agonists. These results indicate a slightly table).126,134 A phase 3 programme (DREAMS) is currently greater reduction in HbA (0·25% more than dulaglutide, assessing mazdutide (4 mg and 6 mg weekly) as treatment 1c the selective GLP-1 receptor agonist) and bodyweight for type 2 diabetes in Chinese populations. Glucagon– (3% greater than dulaglutide)123 in people with type 2 GLP-1 receptor co-agonists therefore promise greater diabetes, and increased weight loss (13·3% greater than weight reduction than with selective GLP-1 receptor placebo treatment) in people with obesity.131 However, agonists, and do not compromise glucose-lowering given the established variability in eect sizes between eects in patients with type 2 diabetes. approved GLP-1 receptor agonists,144 whether ecnoglutide leads to substantially greater eectiveness compared with Amylin–GLP-1 receptor fixed combinations or other so-called unbiased compounds, is unclear. unimolecular dual agonists Amylin is co-secreted with insulin from pancreatic Dual glucagon–GLP-1 receptor agonists β-cells in response to food intake, delays gastric In human proof-of-concept studies, co-administration of emptying, inhibits glucagon secretion, improves GLP-1 and glucagon revealed benefits over GLP-1 glycaemia, increases satiety, and reduces food intake receptor agonists alone, including further reduction in without decreasing energy expenditure (appendix food intake, increased energy expenditure, increased p 6),146–148 with a mode of action that diers from GLP-1.149 hepatic fatty acid oxidation, reduced hepatic lipid Cagrilintide (once-weekly subcutaneous administration) accumulation, and improved mitochondrial function, is an amylin receptor agonist.150 without compromising glycaemic control.145 Cagrilintide has been studied in a fixed-dose combination Survodutide is a dual glucagon–GLP-1 receptor agonist. with the selective GLP-1 receptor agonist semaglutide (ie, In a phase 2 trial in people with T2D, after 16 weeks of CagriSema) for the treatment of overweight or obesity and treatment, doses of survodutide up to 2·7 mg once weekly in people with type 2 diabetes. In a phase 3 trial in people reduced HbA by up to 1·6% (95% CI 1·3–1·8) or with type 2 diabetes, cagrilintide–semaglutide 1c 17 mmol/mol (14–20) compared with semaglutide (1 mg (2·4 mg/week of cagrilintide and semaglutide each) once weekly; reduction of 1·5% [16 mmol/mol]; table).125 reduced HbA by 1·4% (95% CI 1·2–1·6) or 15 mmol/mol 1c Weight loss with survodutide (up to 7·7%) was greater (13–17), and bodyweight by 10·4% (9·5–11·2; placebo- than with semaglutide (5·3%) or placebo (0·9%). The risk corrected).127 In adults with overweight or obesity, of experiencing nausea (up to 46%), vomiting (up to 26%), cagrilintide–semaglutide reduced bodyweight by 17·3% or drug discontinuation (up to 30%) was greater than with (16·6–18·1; placebo-subtracted),135 along with reductions in semaglutide (nausea 9%, vomiting 2%, and drug waist circumference, blood pressure, and improved discontinuation due to adverse events 5%) or placebo physical functioning scores.135 The eects of the drug (nausea 12%, vomiting 4%, and drug discontinuation due combination were greater than the eects of either to adverse events 4%).125 A new weight loss plateau was not medication alone, but less than the sum of eects for both reached during the study period.125 Survodutide (3·6 mg medications.135 Gastrointestinal adverse events were and 6 mg once weekly) is currently undergoing phase 3 slightly more frequent with CagriSema than with trials as treatment for obesity (SYNCHRONIZE semaglutide alone.135 The REDEFINE-3 trial will assess the 902 Review eect of cagrilintide–semaglutide on cardiovascular events agonist with a GIP receptor antagonist will also provide in people with overweight or obesity, with and without more weight reduction than with a selective GLP-1 type 2 diabetes and pre-existing cardiovascular disease. receptor agonist alone.152 Maridebart cafraglutide is an Amycretin is a novel, unimolecular dual amylin– antagonistic GIP receptor antibody coupled with a GLP-1 GLP-1 receptor agonist that can be administered receptor agonist.153 In a phase 2 trial of people with subcutaneously136 or orally,137 and has been studied in obesity (with or without type 2 diabetes) who received people with overweight or obesity. In a phase 1b/2a trial maridebart cafraglutide every 4 weeks for 52 weeks, over 36 weeks, amycretin (once-weekly subcutaneous bodyweight was reduced by up to 16·2% (95% CI administration) dose-dependently reduced bodyweight by 13·5–18·9) compared with a 1·7% reduction with up to 23·2% (95% CI 15·6–30·8; 60 mg/week) placebo. Furthermore, HbA was reduced in the cohort 1c versus baseline (placebo-subtracted).136 Oral amycretin with type 2 diabetes by up to 1·5% (1·0–1·9) versus an (two tablets of 50 mg daily) reduced bodyweight by up to increase of 0·1% with placebo.129 The proportion of 11·8% (9·0–14·6; placebo-subtracted) after 12 weeks in a participants given the study drug who reported nausea phase 1 trial.137 The proportion of people reporting nausea (up to 87%) or vomiting (up to 92%) was high but or vomiting was high, as was the drug discontinuation somewhat improved by a slower dose escalation, and up rate with subcutaneous amycretin,136 but not with oral to 29% of participants discontinued drug treatment amycretin.137 because of adverse events. Similar eects of GIP receptor agonism and antagonism on bodyweight can be Triple GIP–GLP-1–glucagon receptor agonists explained by their dierent target pathways: GIP receptor Preclinical studies with the triple agonist retatrutide agonists act on GABAergic neurons, which leads to showed greater weight loss and reductions in plasma reduced food (energy) intake,11 whereas GIP receptor glucose concentration compared with tirzepatide.151 knock-out in GABAergic neurons sensitises people to Retatrutide is in clinical development for once-weekly weight loss induced by GLP-1 receptor agonists.154 administration (table) in people with obesity,138 type 2 Taken together, dual and triple agonists addressing diabetes,128 and MASLD.140 receptors for gastroenteropancreatic peptide hormones In the retatrutide phase 2 trial for people with with therapeutic potential promise greater eects overweight or obesity (BMI ≥30 kg/m²), or with a BMI of regarding glycaemic control and bodyweight reduction. at least 27 kg/m² with one or more weight-related However, at this stage, these medications carry a higher condition, the mean bodyweight reduction at week 48 in burden of (mainly gastrointestinal) adverse events the retatrutide (12 mg once-weekly) groups was up to compared with selective GLP-1 receptor agonists, 24·2% (95% CI 21·8–28·6) compared with 2·1% indicating a need to optimise dose-escalation regimens (0·7–3·5) with placebo.138 In a retatrutide phase 2 trial for and induce tolerance to such side-eects, or, in the choice people with type 2 diabetes, 36 weeks of treatment with of appropriate doses, avoid unnecessary nausea and retatrutide (of doses up to 12 mg/week) resulted in a vomiting. HbA reduction of up to 2·2% (SEM 0·1) or 24 mmol/mol 1c (SEM 1), compared with a 1·4% (SEM 0·1) or 15 mmol/mol Conclusions (SEM 1) reduction with dulaglutide 1·5 mg and a Incretin-based medications have gained an established 0·3% (SEM 0·2) or 3 mmol/mol (SEM 3) reduction with role in the treatment of type 2 diabetes and obesity. placebo.128 A dose-dependent reduction in bodyweight of Robust evidence exists for their cardiovascular benefits in up to 16·9% (SEM 1·3%) was also observed (3% [SEM 1] people with type 2 diabetes or obesity, and for preservation with placebo and 2% [SEM 1] with dulaglutide 1·5 mg/ of kidney function and prevention of kidney failure or week).128 Mild-to-moderate gastrointestinal side-eects cardiovascular death in people with type 2 diabetes and were reported in a similar proportion to the selective CKD. Within the spectrum of clinical obesity, closely GLP-1 receptor dulaglutide.128 However, adverse events associated conditions—including progression to type 2 leading to treatment discontinuation were experienced by diabetes, MASLD, heart failure with preserved ejection up to 17% of participants given retatrutide, compared fraction, obstructive sleep apnoea, and knee with 2% given dulaglutide and 4% given placebo. osteoarthritis—benefit in terms of symptomatic relief Currently, the ecacy and safety of retatrutide are being and improved prognoses. In addition, novel indications assessed for treatment of obesity in a programme of could arise, exemplified by several neurodegenerative phase 3 trials (TRIUMPH) in people with overweight or diseases and substance use disorders currently being obesity and type 2 diabetes. studied. Next-generation medications building on existing incretin-based medications could provide even GLP-1 receptor agonist–GIP receptor antagonist greater metabolic ecacy but require large-scale phase 3 combination trials to establish clinical benefits, safety, and tolerability. Although agents such as tirzepatide have been designed More widespread use, together with the future availability to provide stimulation to both GIP and GLP-1 receptors, of generic drugs, should reduce treatment costs, which recent research has shown that combining a GLP-1 currently restrict availability for many people who could Review benefit from the rapidly emerging portfolio of incretin- 3 Mojsov S, Weir GC, Habener JF. Insulinotropin: glucagon-like based therapies. peptide I (7–37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. Contributors J Clin Invest 1987; 79: 616–19. MAN, KRT, MHT, and MB: conceptualisation, literature search, data 4 Kreymann B, Williams G, Ghatei MA, Bloom SR. Glucagon-like interpretation, writing, and reviewing and editing. MAN: drafting figures peptide-1 [7–36]: a physiological incretin in man. Lancet 1987; and table. KRT, MHT, and MB: reviewing and editing figures and table. 2: 1300–04. All authors approved the final version before submitting for publication. 5 Nauck MA, Abd El Aziz M, Quast DR. Meta-analysis of head-to- head clinical trials comparing incretin-based glucose-lowering Declaration of interests medications and basal insulin: an update including recently MAN has been a member of advisory boards or has consulted for developed glucagon-like peptide-1 (GLP-1) receptor agonists and the Boehringer Ingelheim, Eli Lilly & Co, Medtronic, Merck, Sharp & glucose-dependent insulinotropic polypeptide/GLP-1 receptor Dohme, NovoNordisk, Pfizer, Regor, Sun Pharma, and Structure co-agonist tirzepatide. Diabetes Obes Metab 2023; 25: 1361–71. Therapeutics (Gasherbrum); has served on the speakers bureau of 6 Müller TD, Finan B, Clemmensen C, DiMarchi RD, Tschöp MH. AstraZeneca, Eli Lilly & Co, Medscape, Medical Learning Institute, The new biology and pharmacology of glucagon. Physiol Rev 2017; NovoNordisk, Sanofi, and Sun Pharma; has received support for 97: 721–66. attending meetings or travel from Eli Lilly & Co and NovoNordisk; and is 7 Scheen AJ, Lefèbvre PJ. Glucagon, from past to present: a century on a Data Monitoring and Safety Board for Inventiva. KRT has received of intensive research and controversies. Lancet Diabetes Endocrinol investigator-initiated grant support from Travere, Bayer, Benaroya 2023; 11: 129–38. Research Institute, the Doris Duke Charitable Foundation, and 8 Sánchez-Garrido MA, Brandt SJ, Clemmensen C, Müller TD, Breakthrough-T1D; reports consultancy fees from Boehringer DiMarchi RD, Tschöp MH. GLP-1/glucagon receptor co-agonism Ingelheim, Eli Lilly, Novo Nordisk, AstraZeneca, Alnylam, Bayer, and for treatment of obesity. Diabetologia 2017; 60: 1851–61. ProKidney; and reports speaker fees from Novo Nordisk, Bayer, and 9 Finan B, Ma T, Ottaway N, et al. Unimolecular dual incretins Boehringer Ingelheim. She reports US National Institutes of Health maximize metabolic benefits in rodents, monkeys, and humans. research grants R01MD014712, U2CDK114886, UL1TR002319, Sci Transl Med 2013; 5: 209ra151. U54DK083912, U01DK100846, OT2HL161847, UM1AI109568, 10 Zhang Q, Delessa CT, Augustin R, et al. The glucose-dependent OT2OD032581, and US Centers for Disease Control and Prevention insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS–GIPR signaling. Cell Metab 2021; 33: 833–844. project numbers 75D301-21-P-12254 and 75D301-23-C-18264. She reports being chair of Data Safety Monitoring boards for the US National 11 Liskiewicz A, Khalil A, Liskiewicz D, et al. Glucose-dependent insulinotropic polypeptide regulates body weight and food intake Institutes of Health National Institute of Diabetes and Digestive and via GABAergic neurons in mice. Nat Metab 2023; 5: 2075–85. Kidney Disease, and the George Clinical Institute, and reports being a 12 Finan B, Yang B, Ottaway N, et al. A rationally designed monomeric member of the Data Safety Monitoring Board for AstraZeneca. peptide triagonist corrects obesity and diabetes in rodents. Nat Med She reports leadership roles as chair for the Diabetic Kidney Disease 2015; 21: 27–36. Collaborative for the American Society of Nephrology, chair for Kidney 13 Coskun T, Sloop KW, Loghin C, et al. LY3298176, a novel dual GIP Week 2025 Program Committee, member of the American Heart and GLP-1 receptor agonist for the treatment of type 2 diabetes Association publication committee, and a member of the American mellitus: from discovery to clinical proof of concept. Mol Metab Heart Association–American College of Cardiology Cardiovascular 2018; 18: 3–14. Kidney Metabolic Guideline Committee. MHT has delivered scientific 14 Frías JP, Davies MJ, Rosenstock J, et al, and the SURPASS-2 lectures for Boehringer Ingelheim (2024), KG (2024), AstraZeneca Investigators. Tirzepatide versus semaglutide once weekly in (2024), Lilly Deutschland (2024), and Novo Nordisk (2024). He is co- patients with type 2 diabetes. N Engl J Med 2021; 385: 503–15. founder of the biotech startup Bluewater Biotech (founded in 2024) and 15 Aronne LJ, Horn DB, le Roux CW, et al, and the SURMOUNT-5 has, in this role, received support for meetings and travels, and co- Trial Investigators. Tirzepatide as compared with semaglutide for founder of Penguin (formerly Ghrelco, founded in 2024). As CEO and the treatment of obesity. N Engl J Med 2025; 393: 26–36. CSO of Helmholtz Munich until September 2025, he was co-responsible 16 Lee MMY, Sattar N, Pop-Busui R, et al, and the SOUL Trial for countless collaborations of the employees with a multitude of Investigators. Cardiovascular and kidney outcomes and mortality companies and institutions, worldwide. In this capacity, he discussed with long-acting injectable and oral glucagon-like peptide 1 receptor potential projects with and has signed contracts for the centre’s agonists in individuals with type 2 diabetes: a systematic review and institute(s) related to research collaborations worldwide, including but meta-analysis of randomized trials. Diabetes Care 2025; 48: 846–59. not limited to pharmaceutical corporations such as Boehringer 17 Pfeer MA, Claggett B, Diaz R, et al, and the ELIXA Investigators. Ingelheim, Novo Nordisk, Roche Diagnostics, Arbormed, Eli Lilly, SCG Lixisenatide in patients with type 2 diabetes and acute coronary Cell Therapy, and others. As the CEO of Helmholtz Munich, he was syndrome. N Engl J Med 2015; 373: 2247–57. further overall responsible for commercial technology transfer activities. 18 Marso SP, Daniels GH, Brown-Frandsen K, et al, and the LEADER As President of the Ludwig-Maximilians-Universität München since Steering Committee, and the LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. October 2025, he has been co-responsible for countless collaborations of N Engl J Med 2016; 375: 311–22. the employees with a multitude of companies and institutions, 19 Marso SP, Holst AG, Vilsbøll T. Semaglutide and cardiovascular worldwide. He confirms that, to the best of his knowledge, none of the outcomes in patients with type 2 diabetes. N Engl J Med 2017; above funding sources or collaborations were involved in or had an 376: 891–92. influence on the preparation of this manuscript. MB received honoraria 20 Holman RR, Bethel MA, Mentz RJ, et al, and the EXSCEL Study as a consultant and speaker from Amgen, AstraZeneca, Bayer, Group. Eects of once-weekly exenatide on cardiovascular outcomes Boehringer Ingelheim, Lilly, Novo Nordisk, Novartis, and Sanofi; and as in type 2 diabetes. N Engl J Med 2017; 377: 1228–39. a consultant from Abbott; and reports chairing a Clinical Trial Data 21 Hernandez AF, Green JB, Janmohamed S, et al, and the Harmony Safety Monitoring Board for Boehringer Ingelheim. Outcomes Committees and Investigators. Albiglutide and Acknowledgments cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, We thank Professor Timo Dirk Müller for helpful discussions. randomised placebo-controlled trial. Lancet 2018; 392: 1519–29. References 22 Gerstein HC, Colhoun HM, Dagenais GR, et al, and the REWIND 1 Bell GI, Sanchez-Pescador R, Laybourn PJ, Najarian RC. Investigators. Dulaglutide and cardiovascular outcomes in type 2 Exon duplication and divergence in the human preproglucagon diabetes (REWIND): a double-blind, randomised placebo-controlled gene. Nature 1983; 304: 368–71. trial. Lancet 2019; 394: 121–30. 2 Holst JJ, Ørskov C, Nielsen OV, Schwartz TW. Truncated glucagon- 23 Husain M, Birkenfeld AL, Donsmark M, et al, and the PIONEER like peptide I, an insulin-releasing hormone from the distal gut. 6 Investigators. Oral semaglutide and cardiovascular outcomes in FEBS Lett 1987; 211: 169–74. patients with type 2 diabetes. N Engl J Med 2019; 381: 841–51. 904 Review 24 Gerstein HC, Sattar N, Rosenstock J, et al, and the AMPLITUDE-O 44 Gerstein HC, Colhoun HM, Dagenais GR, et al, and the REWIND Trial Investigators. Cardiovascular and renal outcomes with Investigators. Dulaglutide and renal outcomes in type 2 diabetes: efpeglenatide in type 2 diabetes. N Engl J Med 2021; 385: 896–907. an exploratory analysis of the REWIND randomised, placebo- 25 Ru CT, Baron M, Im K, O’Donoghue ML, Fiedorek FT, controlled trial. Lancet 2019; 394: 131–38. Sabatine MS. Subcutaneous infusion of exenatide and 45 Shaman AM, Bain SC, Bakris GL, et al. Eect of the glucagon-like cardiovascular outcomes in type 2 diabetes: a non-inferiority peptide-1 receptor agonists semaglutide and liraglutide on kidney randomized controlled trial. Nat Med 2022; 28: 89–95. outcomes in patients with type 2 diabetes: pooled analysis of 26 Perkovic V, Tuttle KR, Rossing P, et al, and the FLOW Trial SUSTAIN 6 and LEADER. Circulation 2022; 145: 575–85. Committees and Investigators. Eects of semaglutide on chronic 46 Tuttle KR, Bosch-Traberg H, Cherney DZI, et al. Post hoc analysis kidney disease in patients with type 2 diabetes. N Engl J Med 2024; of SUSTAIN 6 and PIONEER 6 trials suggests that people with 391: 109–21. type 2 diabetes at high cardiovascular risk treated with semaglutide 27 McGuire DK, Marx N, Mulvagh SL, et al. Oral semaglutide and experience more stable kidney function compared with placebo. cardiovascular outcomes in high-risk type 2 diabetes. N Engl J Med Kidney Int 2023; 103: 772–81. 2025; 392: 2001–12. 47 Tuttle KR, Bain SC, Bosch-Traberg H, et al. Eects of once-weekly 28 Linco AM, Brown-Frandsen K, Colhoun HM, et al, and the SELECT semaglutide on kidney disease outcomes by KDIGO risk category in Trial Investigators. Semaglutide and cardiovascular outcomes in the SUSTAIN 6 trial. Kidney Int Rep 2024; 9: 2006–15. obesity without diabetes. N Engl J Med 2023; 389: 2221–32. 48 Heerspink HJL, Sattar N, Pavo I, et al. Eects of tirzepatide versus 29 Becker RH, Stechl J, Msihid J, Kapitza C. Lixisenatide resensitizes insulin glargine on kidney outcomes in type 2 diabetes in the the insulin-secretory response to intravenous glucose challenge in SURPASS-4 trial: post-hoc analysis of an open-label, people with type 2 diabetes—a study in both people with type 2 randomised, phase 3 trial. Lancet Diabetes Endocrinol 2022; diabetes and healthy subjects. Diabetes Obes Metab 2014; 10: 774–85. 16: 793–800. 49 Apperloo EM, Tuttle KR, Pavo I, et al. Tirzepatide associated with 30 Sattar N, Lee MMY, Kristensen SL, et al. Cardiovascular, mortality, reduced albuminuria in participants with type 2 diabetes: pooled and kidney outcomes with GLP-1 receptor agonists in patients with post hoc analysis from the randomized active- and placebo- type 2 diabetes: a systematic review and meta-analysis of controlled SURPASS-1–5 clinical trials. Diabetes Care 2025; randomised trials. Lancet Diabetes Endocrinol 2021; 9: 653–62. 48: 430–36. 31 Badve SV, Bilal A, Lee MMY, et al. Eects of GLP-1 receptor agonists 50 Colhoun HM, Lingvay I, Brown PM, et al. Long-term kidney on kidney and cardiovascular disease outcomes: a meta-analysis of outcomes of semaglutide in obesity and cardiovascular disease in randomised controlled trials. Lancet Diabetes Endocrinol 2025; the SELECT trial. Nat Med 2024; 30: 2058–66. 13: 15–28. 51 Borlaug BA, Zile MR, Kramer CM, et al. Eects of tirzepatide on 32 Sattar N, McGuire DK, Pavo I, et al. Tirzepatide cardiovascular circulatory overload and end-organ damage in heart failure with event risk assessment: a pre-specified meta-analysis. Nat Med 2022; preserved ejection fraction and obesity: a secondary analysis of the 28: 591–98. SUMMIT trial. Nat Med 2024; 31: 544–51. 33 Nicholls SJ, Pavo I, Bhatt DL, et al. Cardiovascular outcomes with 52 Mann JFE, Buse JB, Idorn T, et al. Potential kidney protection with tirzepatide versus dulaglutide in type 2 diabetes. N Engl J Med 2025; liraglutide and semaglutide: exploratory mediation analysis. 393: 2409–20. Diabetes Obes Metab 2021; 23: 2058–66. 34 Bonaca MP, Catarig AM, Houlind K, et al, and the STRIDE Trial 53 Tuttle KR, Lakshmanan MC, Rayner B, Zimmermann AG, Investigators. Semaglutide and walking capacity in people with Woodward B, Botros FT. Body weight and eGFR during symptomatic peripheral artery disease and type 2 diabetes dulaglutide treatment in type 2 diabetes and moderate-to-severe (STRIDE): a phase 3b, double-blind, randomised, placebo-controlled chronic kidney disease (AWARD-7). Diabetes Obes Metab 2019; trial. Lancet 2025; 405: 1580–93. 21: 1493–97. 35 Drucker DJ. The cardiovascular biology of glucagon-like peptide-1. 54 Heerspink HJL, Sattar N, Pavo I, et al. Eects of tirzepatide versus Cell Metab 2016; 24: 15–30. insulin glargine on cystatin C-based kidney function: a SURPASS-4 36 Nauck MA, Meier JJ, Cavender MA, Abd El Aziz M, Drucker DJ. post hoc analysis. Diabetes Care 2023; 46: 1501–06. Cardiovascular actions and clinical outcomes with glucagon-like 55 Apperloo EM, Gorriz JL, Soler MJ, et al. Semaglutide in patients peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. with overweight or obesity and chronic kidney disease without Circulation 2017; 136: 849–70. diabetes: a randomized double-blind placebo-controlled clinical 37 Ussher JR, Drucker DJ. Glucagon-like peptide 1 receptor agonists: trial. Nat Med 2025; 31: 278–85. cardiovascular benefits and mechanisms of action. Nat Rev Cardiol 56 Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. 2023; 20: 463–74. Gastroenterology 2007; 132: 2131–57. 38 Buse JB, Bain SC, Mann JFE, et al, and the LEADER Trial 57 Hviid AVR, Sorensen CM. Glucagon-like peptide-1 receptors in the Investigators. Cardiovascular risk reduction with liraglutide: kidney: impact on renal autoregulation. Am J Physiol Renal Physiol an exploratory mediation analysis of the LEADER trial. 2020; 318: F443–F54. Diabetes Care 2020; 43: 1546–52. 58 Alicic RZ, Cox EJ, Neumiller JJ, Tuttle KR. Incretin drugs in 39 Konig M, Riddle MC, Colhoun HM, et al. Exploring potential diabetic kidney disease: biological mechanisms and clinical mediators of the cardiovascular benefit of dulaglutide in type 2 evidence. Nat Rev Nephrol 2021; 17: 227–44. diabetes patients in REWIND. Cardiovasc Diabetol 2021; 20: 194. 59 Michos ED, Bakris GL, Rodbard HW, Tuttle KR. Glucagon-like 40 Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists peptide-1 receptor agonists in diabetic kidney disease: a review of in the treatment of type 2 diabetes—state-of-the-art. Mol Metab their kidney and heart protection. Am J Prev Cardiol 2023; 14: 100502. 2021; 46: 101102. 60 Fujita H, Morii T, Fujishima H, et al. The protective roles of GLP-1R 41 Mann JFE, Ørsted DD, Brown-Frandsen K, et al, and the signaling in diabetic nephropathy: possible mechanism and LEADER Steering Committee and Investigators. Liraglutide therapeutic potential. Kidney Int 2014; 85: 579–89. and renal outcomes in type 2 diabetes. N Engl J Med 2017; 61 Sourris KC, Ding Y, Maxwell SS, et al. Glucagon-like peptide-1 377: 839–48. receptor signaling modifies the extent of diabetic kidney disease 42 Tuttle KR, Lakshmanan MC, Rayner B, et al. Dulaglutide through dampening the receptor for advanced glycation end versus insulin glargine in patients with type 2 diabetes and products-induced inflammation. Kidney Int 2024; 105: 132–49. moderate-to-severe chronic kidney disease (AWARD-7): 62 Wong CK, McLean BA, Baggio LL, et al. Central glucagon-like a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol peptide 1 receptor activation inhibits Toll-like receptor agonist- 2018; 6: 605–17. induced inflammation. Cell Metab 2024; 36: 130–143. 43 Tuttle KR, Rayner B, Lakshmanan MC, et al. Clinical outcomes by 63 Tuttle KR, Wilson JM, Lin Y, et al. Indicators of kidney fibrosis in albuminuria status with dulaglutide versus insulin glargine in patients with type 2 diabetes and chronic kidney disease treated participants with diabetes and CKD: AWARD-7 exploratory analysis. with dulaglutide. Am J Nephrol 2023; 54: 74–82. Kidney360 2020; 2: 254–62. Review 64 Rubino D, Abrahamsson N, Davies M, et al, and the STEP 4 84 Sanyal AJ, Newsome PN, Kliers I, et al, and the ESSENCE Study Investigators. Eect of continued weekly subcutaneous semaglutide Group. Phase 3 trial of semaglutide in metabolic dysfunction- vs placebo on weight loss maintenance in adults with overweight or associated steatohepatitis. N Engl J Med 2025; 392: 2089–99. obesity: the STEP 4 randomized clinical trial. JAMA 2021; 85 Bowie K. Semaglutide: FDA approves weight loss jab to treat severe 325: 1414–25. liver disease. BMJ 2025; 390: r1788. 65 McGowan BM, Bruun JM, Capehorn M, et al, and the STEP 86 Lilly. Lilly’s tirzepatide was superior to placebo for MASH 10 Study Group. Ecacy and safety of once-weekly semaglutide resolution, and more than half of patients achieved improvement in 2·4 mg versus placebo in people with obesity and prediabetes (STEP fibrosis at 52 weeks. June 8, 2024. https://investor.lilly.com/news- 10): a randomised, double-blind, placebo-controlled, multicentre releases/news-release-details/lillys-tirzepatide-was-superior-placebo- phase 3 trial. Lancet Diabetes Endocrinol 2024; 12: 631–42. mash-resolution-and-more (accessed Sep 20, 2025). 66 Aronne LJ, Sattar N, Horn DB, et al, and the SURMOUNT-4 87 Harrison SA, Bedossa P, Guy CD, et al, and the MAESTRO-NASH Investigators. Continued treatment with tirzepatide for Investigators. A phase 3, randomized, controlled trial of resmetirom maintenance of weight reduction in adults with obesity: in NASH with liver fibrosis. N Engl J Med 2024; 390: 497–509. the SURMOUNT-4 randomized clinical trial. JAMA 2024; 88 Blackman A, Foster GD, Zammit G, et al. Eect of liraglutide 331: 38–48. 3·0 mg in individuals with obesity and moderate or severe 67 Garvey WT, Batterham RL, Bhatta M, et al, and the STEP 5 Study obstructive sleep apnea: the SCALE Sleep Apnea randomized Group. Two-year eects of semaglutide in adults with overweight or clinical trial. Int J Obes (Lond) 2016; 40: 1310–19. obesity: the STEP 5 trial. Nat Med 2022; 28: 2083–91. 89 Bliddal H, Bays H, Czernichow S, et al, and the STEP 9 Study 68 Zhao L, Cheng Z, Lu Y, et al. Tirzepatide for weight reduction in Group. Once-weekly semaglutide in persons with obesity and knee Chinese adults with obesity: the SURMOUNT-CN randomized osteoarthritis. N Engl J Med 2024; 391: 1573–83. clinical trial. JAMA 2024; 332: 551–60. 90 Wang L, Volkow ND, Kaelber DC, Xu R. Semaglutide or tirzepatide 69 Jastrebo AM, Aronne LJ, Ahmad NN, et al, and the SURMOUNT-1 and optic nerve and visual pathway disorders in type 2 diabetes. Investigators. Tirzepatide once weekly for the treatment of obesity. JAMA Netw Open 2025; 8: e2526327. N Engl J Med 2022; 387: 205–16. 91 Lakhani M, Kwan ATH, Mihalache A, et al. Association of glucagon- 70 Rubino DM, Greenway FL, Khalid U, et al, and the STEP like peptide-1 receptor agonists with optic nerve and retinal adverse 8 Investigators. Eect of weekly subcutaneous semaglutide vs daily events: a population-based observational study across 180 countries. liraglutide on body weight in adults with overweight or obesity Am J Ophthalmol 2025; 277: 148–68. without diabetes: the STEP 8 Randomized Clinical Trial. JAMA 92 Chou CC, Pan SY, Sheen YJ, et al. Association between semaglutide 2022; 327: 138–50. and nonarteritic anterior ischemic optic neuropathy: a multinational 71 Yki-Järvinen H. Combination therapies with insulin in type 2 population-based study. Ophthalmology 2025; 132: 381–88. diabetes. Diabetes Care 2001; 24: 758–67. 93 Abbass NJ, Nahlawi R, Shaia JK, et al. The eect of semaglutide and 72 Rubino F, Cummings DE, Eckel RH, et al. Definition and GLP-1 RAs on risk of nonarteritic anterior ischemic optic diagnostic criteria of clinical obesity. Lancet Diabetes Endocrinol neuropathy. Am J Ophthalmol 2025; 274: 24–31. 2025; 13: 221–62. 94 Scheen AJ. GLP-1 receptor agonists, body composition, skeletal 73 Lingvay I, Cohen RV, Roux CWL, Sumithran P. Obesity in adults. muscle and risk of sarcopaenia: from promising findings in animal Lancet 2024; 404: 972–87. models to debated concern in human studies. Diabetes Metab 2025; 74 Haase CL, Lopes S, Olsen AH, Satylganova A, Schnecke V, 51: 101681. McEwan P. Weight loss and risk reduction of obesity-related 95 Chen AS, Batsis JA. Treating sarcopenic obesity in the era of outcomes in 0·5 million people: evidence from a UK primary care incretin therapies: perspectives and challenges. Diabetes 2025; database. Int J Obes (Lond) 2021; 45: 1249–58. published online July 11. https://doi.org/10.2337/dbi25-0004. 75 le Roux CW, Astrup A, Fujioka K, et al, and the SCALE Obesity 96 Sattar N, Neeland IJ, Dahlqvist Leinhard O, et al. Tirzepatide and Prediabetes NN8022-1839 Study Group. 3 years of liraglutide versus muscle composition changes in people with type 2 diabetes placebo for type 2 diabetes risk reduction and weight management (SURPASS-3 MRI): a post-hoc analysis of a randomised, open-label, in individuals with prediabetes: a randomised, double-blind trial. parallel-group, phase 3 trial. Lancet Diabetes Endocrinol 2025; Lancet 2017; 389: 1399–409. 13: 482–93. 76 Jastrebo AM, le Roux CW, Stefanski A, et al. Tirzepatide for 97 Nunn E, Jaiswal N, Gavin M, et al. Antibody blockade of activin obesity treatment and diabetes prevention. N Engl J Med 2024; type II receptors preserves skeletal muscle mass and enhances fat 392: 958–71. loss during GLP-1 receptor agonism. Mol Metab 2024; 80: 101880. 77 Kosiborod MN, Petrie MC, Borlaug BA, et al, and the STEP-HFpEF 98 During MJ, Cao L, Zuzga DS, et al. Glucagon-like peptide-1 receptor DM Trial Committees and Investigators. Semaglutide in patients is involved in learning and neuroprotection. Nat Med 2003; 9: 1173–79. with obesity-related heart failure and type 2 diabetes. N Engl J Med 99 Li Q, Jia M, Yan Z, et al. Activation of glucagon-like peptide-1 2024; 390: 1394–407. receptor ameliorates cognitive decline in type 2 diabetes mellitus 78 Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al, and the STEP- through a metabolism-independent pathway. J Am Heart Assoc 2021; HFpEF Trial Committees and Investigators. Semaglutide and heart 10: e020734. failure with preserved ejection fraction and obesity. N Engl J Med 100 Seminer A, Mulihano A, O’Brien C, et al. Cardioprotective glucose- 2023; 389: 1069–84. lowering agents and dementia risk: a systematic review and meta- 79 Packer M, Zile MR, Kramer CM, et al. Tirzepatide for heart failure analysis. JAMA Neurol 2025; 82: 450–60. with preserved ejection fraction and obesity. N Engl J Med 2024; 101 Novo Nordisk. Evoke phase 3 trials did not demonstrate a 392: 427–37. statistically significant reduction in Alzheimer’s disease 80 Butler J, Shah SJ, Petrie MC, et al, and the STEP-HFpEF Trial progression. https://www.novonordisk.com/content/nncorp/ Committees and Investigators. Semaglutide versus placebo in global/en/news-and-media/news-and-ir-materials/news-details. people with obesity-related heart failure with preserved ejection html?id=916462 (accessed Nov 24, 2025). fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF 102 Athauda D, Maclagan K, Skene SS, et al. Exenatide once weekly DM randomised trials. Lancet 2024; 403: 1635–48. versus placebo in Parkinson’s disease: a randomised, double-blind, 81 Armstrong MJ, Gaunt P, Aithal GP, et al, and the LEAN trial team. placebo-controlled trial. Lancet 2017; 390: 1664–75. Liraglutide safety and ecacy in patients with non-alcoholic 103 Aviles-Olmos I, Dickson J, Kefalopoulou Z, et al. Exenatide and the steatohepatitis (LEAN): a multicentre, double-blind, randomised, treatment of patients with Parkinson’s disease. J Clin Invest 2013; placebo-controlled phase 2 study. Lancet 2016; 387: 679–90. 123: 2730–36. 82 Newsome PN, Buchholtz K, Cusi K, et al, and the NN9931-4296 104 Meissner WG, Remy P, Giordana C, et al, and the LIXIPARK Study Investigators. A placebo-controlled trial of subcutaneous semaglutide Group. Trial of lixisenatide in early Parkinson’s disease. in nonalcoholic steatohepatitis. N Engl J Med 2021; 384: 1113–24. N Engl J Med 2024; 390: 1176–85. 83 Loomba R, Hartman ML, Lawitz EJ, et al, and the SYNERGY-NASH Investigators. Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis. N Engl J Med 2024; 391: 299–310. 906 Review 105 Vijiaratnam N, Girges C, Auld G, et al. Exenatide once a week 125 Blüher M, Rosenstock J, Hoefler J, Manuel R, Hennige AM. versus placebo as a potential disease-modifying treatment for Dose-response eects on HbA and bodyweight reduction of 1c people with Parkinson’s disease in the UK: a phase 3, multicentre, survodutide, a dual glucagon/GLP-1 receptor agonist, compared double-blind, parallel-group, randomised, placebo-controlled trial. with placebo and open-label semaglutide in people with type 2 Lancet 2025; 405: 627–36. diabetes: a randomised clinical trial. Diabetologia 2024; 67: 470–82. 106 McGarry A, Rosanbalm S, Leinonen M, et al. Safety, tolerability, and 126 Zhang B, Cheng Z, Chen J, et al. Ecacy and safety of mazdutide ecacy of NLY01 in early untreated Parkinson’s disease: in Chinese patients with type 2 diabetes: a randomized, double- a randomised, double-blind, placebo-controlled trial. Lancet Neurol blind, placebo-controlled phase 2 trial. Diabetes Care 2024; 2024; 23: 37–45. 47: 160–68. 107 Shawki SM, Saad MA, Rahmo RM, Wadie W, El-Abhar HS. 127 Davies MJ, Bajaj HS, Broholm C, et al. Cagrilintide–semaglutide in Liraglutide improves cognitive and neuronal function in 3-NP rat adults with overweight or obesity and type 2 diabetes. N Engl J Med model of Huntington’s disease. Front Pharmacol 2021; 12: 731483. 2025; 393: 648–59. 108 Jerlhag E. The therapeutic potential of glucagon-like peptide-1 for 128 Rosenstock J, Frias J, Jastrebo AM, et al. Retatrutide, a GIP, GLP-1 persons with addictions based on findings from preclinical and and glucagon receptor agonist, for people with type 2 diabetes: clinical studies. Front Pharmacol 2023; 14: 1063033. a randomised, double-blind, placebo and active-controlled, parallel- 109 Yammine L, Verrico CD, Versace F, et al. Exenatide as an adjunct to group, phase 2 trial conducted in the USA. Lancet 2023; nicotine patch for smoking cessation and prevention of 402: 529–44. postcessation weight gain among treatment-seeking smokers with 129 Jastrebo AM, Ryan DH, Bays HE, et al. Once-monthly maridebart pre-diabetes and/or overweight: study protocol for a randomised, cafraglutide for the treatment of obesity—a phase 2 trial. placebo-controlled clinical trial. BMJ Open 2023; 13: e072707. N Engl J Med 2025; 393: 843–57. 110 Klausen MK, Jensen ME, Møller M, et al. Exenatide once weekly for 130 Wharton S, Aronne LJ, Stefanski A, et al. Orforglipron, an oral alcohol use disorder investigated in a randomized, placebo- small-molecule GLP-1 receptor agonist for obesity treatment. controlled clinical trial. JCI Insight 2022; 7: e159863. N Engl J Med 2025; published online Sept 16. https://doi. 111 Probst L, Monnerat S, Vogt DR, et al. Eects of dulaglutide on alcohol org/10.1056/nejmoa2511774. consumption during smoking cessation. JCI Insight 2023; 8: e170419. 131 Ji L, Gao L, Xue H, et al. Ecacy and safety of a biased GLP-1 112 Qeadan F, McCunn A, Tingey B. The association between glucose- receptor agonist ecnoglutide in adults with overweight or obesity: dependent insulinotropic polypeptide and/or glucagon-like a multicentre, randomised, double-blind, placebo-controlled, peptide-1 receptor agonist prescriptions and substance-related phase 3 trial. Lancet Diabetes Endocrinol 2025; 13: 777–89. outcomes in patients with opioid and alcohol use disorders: a real- 132 le Roux CW, Steen O, Lucas KJ, Startseva E, Unseld A, world data analysis. Addiction 2025; 120: 236–50. Hennige AM. Glucagon and GLP-1 receptor dual agonist 113 Hendershot CS, Bremmer MP, Paladino MB, et al. Once-weekly survodutide for obesity: a randomised, double-blind, placebo- semaglutide in adults with alcohol use disorder: a randomized controlled, dose-finding phase 2 trial. Lancet Diabetes Endocrinol clinical trial. JAMA Psychiatry 2025; 82: 395–405. 2024; 12: 162–73. 114 Zhang Y, Kahng MW, Elkind JA, et al. Activation of GLP-1 receptors 133 Ji L, Jiang H, Cheng Z, et al. A phase 2 randomised controlled trial attenuates oxycodone taking and seeking without compromising of mazdutide in Chinese overweight adults or adults with obesity. the antinociceptive eects of oxycodone in rats. Nat Commun 2023; 14: 8289. Neuropsychopharmacology 2020; 45: 451–61. 134 Ji L, Jiang H, Bi Y, et al. Once-weekly mazdutide in Chinese adults 115 Bornebusch AB, Fink-Jensen A, Wortwein G, Seeley RJ, with obesity or overweight. N Engl J Med 2025; 392: 2215–25. Thomsen M. Glucagon-like peptide-1 receptor agonist treatment 135 Garvey WT, Blüher M, Osorto Contreras CK, et al. Coadministered does not reduce abuse-related eects of opioid drugs. eNeuro 2019; cagrilintide and semaglutide in adults with overweight or obesity. 6: ENEURO.0443-18.2019. N Engl J Med 2025; 393: 635–47. 116 Douton JE, Horvath N, Mills-Hunagle S, Nyland JE, Hajnal A, 136 Dahl K, Toubro S, Dey S, et al. Amycretin, a novel, unimolecular Grigson PS. Glucagon-like peptide-1 receptor agonist, liraglutide, GLP-1 and amylin receptor agonist administered subcutaneously: reduces heroin self-administration and drug-induced results from a phase 1b/2a randomised controlled study. Lancet reinstatement of heroin-seeking behaviour in rats. Addict Biol 2025; 406: 149–62. 2022; 27: e13117. 137 Gasiorek A, Heydorn A, Gabery S, et al. Safety, tolerability, 117 Wang W, Volkow ND, Wang Q, et al. Semaglutide and opioid pharmacokinetics, and pharmacodynamics of the first-in-class overdose risk in patients with type 2 diabetes and opioid use GLP-1 and amylin receptor agonist, amycretin: a first-in-human, disorder. JAMA Netw Open 2024; 7: e2435247. phase 1, double-blind, randomised, placebo-controlled trial. Lancet 118 Sørensen G, Reddy IA, Weikop P, et al. The glucagon-like peptide 1 2025; 406: 135–48. (GLP-1) receptor agonist exendin-4 reduces cocaine self- 138 Jastrebo AM, Kaplan LM, Frías JP, et al, and the Retatrutide administration in mice. Physiol Behav 2015; 149: 262–68. Phase 2 Obesity Trial Investigators. Triple-hormone-receptor 119 Angarita GA, Matuskey D, Pittman B, et al. Testing the eects of the agonist retatrutide for obesity—a phase 2 trial. N Engl J Med 2023; GLP-1 receptor agonist exenatide on cocaine self-administration and 389: 514–26. subjective responses in humans with cocaine use disorder. 139 Sanyal AJ, Bedossa P, Fraessdorf M, et al, and the 1404-0043 Trial Drug Alcohol Depend 2021; 221: 108614. Investigators. A phase 2 randomized trial of survodutide in MASH 120 Sloop KW, Cox AL, Wainscott DB, et al. The pharmacological basis and fibrosis. N Engl J Med 2024; 391: 311–19. for nonpeptide agonism of the GLP-1 receptor by orforglipron. 140 Sanyal AJ, Kaplan LM, Frias JP, et al. Triple hormone receptor Sci Transl Med 2024; 16: eadp5765. agonist retatrutide for metabolic dysfunction-associated steatotic 121 Nauck MA, Horowitz M. Non-peptide, once-per-day oral liver disease: a randomized phase 2a trial. Nat Med 2024; orforglipron to compete with established peptide-based, injectable 30: 2037–48. GLP-1 receptor agonists. Lancet 2023; 402: 429–31. 141 Wharton S, Blevins T, Connery L, et al, and the GZGI Investigators. 122 Rosenstock J, Hsia S, Nevarez Ruiz L, et al. Orforglipron, an oral Daily oral GLP-1 receptor agonist orforglipron for adults with small-molecule GLP-1 receptor agonist, in early type 2 diabetes. obesity. N Engl J Med 2023; 389: 877–88. N Engl J Med 2025; 393: 1065–76. 142 Horn DB, Ryan DH, Gilianovic Kis S, et al. Orforglipron, an oral 123 Zhu D, Wang W, Tong G, et al. Ecacy and safety of GLP-1 analog small-molecule GLP-1 receptor agonist, for the treatment of obesity ecnoglutide in adults with type 2 diabetes: a randomized, double- in people with type 2 diabetes (ATTAIN-2): a phase 3, double-blind, blind, placebo-controlled phase 2 trial. Nat Commun 2024; 15: 8408. randomised, multicentre, placebo-controlled trial. Lancet 2025; 124 He Y, Mi N, Cheng Z, et al. Ecacy and safety of cAMP-biased published online Nov 20. https://doi.org/10.1016/s0140- GLP-1 receptor agonist ecnoglutide versus dulaglutide in patients 6736(25)02165-8. with type 2 diabetes and elevated glucose concentrations on 143 Frias JP, Hsia S, Eyde S, et al. Ecacy and safety of oral orforglipron metformin monotherapy (EECOH-2): a 52-week, multicentre, open- in patients with type 2 diabetes: a multicentre, randomised, dose- label, non-inferiority, randomised, phase 3 trial. response, phase 2 study. Lancet 2023; 402: 472–83. Lancet Diabetes Endocrinol 2025; 13: 863–73. Review 144 Kang YM, Punov V, Lim S, Nauck MA. Comparative ecacy and 151 Coskun T, Urva S, Roell WC, et al. LY3437943, a novel triple tolerability of currently approved incretin mimetics: a systematic glucagon, GIP, and GLP-1 receptor agonist for glycemic control and analysis of placebo-controlled clinical trials. Diabetes Obes Metab weight loss: from discovery to clinical proof of concept. Cell Metab 2025; 27: 3736–46. 2022; 34: 1234–47. 145 Cegla J, Troke RC, Jones B, et al. Coinfusion of low-dose GLP-1 and 152 Killion EA, Lu SC, Fort M, Yamada Y, Véniant MM, Lloyd DJ. glucagon in man results in a reduction in food intake. Diabetes 2014; Glucose-dependent insulinotropic polypeptide receptor therapies 63: 3711–20. for the treatment of obesity, do agonists=antagonists? Endocr Rev 146 Lutz TA. Amylin, the prefrontal cortex, and impulsive eating. 2020; 41: bnz002. Biol Psychiatry 2024; 95: 914–15. 153 Véniant MM, Lu SC, Atangan L, et al. A GIPR antagonist 147 Lutz TA. Creating the amylin story. Appetite 2022; 172: 105965. conjugated to GLP-1 analogues promotes weight loss with improved 148 Dehestani B, Stratford NR, le Roux CW. Amylin as a future obesity metabolic parameters in preclinical and phase 1 settings. Nat Metab treatment. J Obes Metab Syndr 2021; 30: 320–25. 2024; 6: 290–303. 154 Wean J, Kowalsky AH, Laker R, et al. Specific loss of GIPR 149 Madsbad S, Holst JJ. The promise of glucagon-like peptide 1 receptor agonists (GLP-1RA) for the treatment of obesity: a look at phase 2 signaling in GABAergic neurons enhances GLP-1R agonist-induced and 3 pipelines. Expert Opin Investig Drugs 2025; 34: 197–215. body weight loss. Mol Metab 2025; 95: 102074. 150 Lau DCW, Erichsen L, Francisco AM, et al. Once-weekly cagrilintide Copyright © 2026 The Author(s). Published by Elsevier Ltd. This is an for weight management in people with overweight and obesity: Open Access article under the CC BY 4.0 license. a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial. Lancet 2021; 398: 2160–72. 908 --- [PDF原文](https://sci-net.xyz/storage/7932541/bb8e00c0e1a6650b7d7e9a7f1ed364dc4b2349c4ea730ed88361248d6e01292d/Glucagon-like-receptor-agonists-and-next-generation-incretin-based-medications-metabolic.pdf) DOI: 10.1016/S0140-6736(25)02105-1