Oral small-molecule GLP-1 receptor agonist for type 2 diabetes and obesity.

# Oral small-molecule GLP-1 receptor agonist for type 2 diabetes and obesity *The Lancet 2025* Comment Oral small-molecule GLP-1 receptor agonist for type 2 diabetes and obesity See Articles page 2927 With the rising use of nutrient-stimulating hormone- change in bodyweight. The study population consisted based therapy for the treatment of obesity, developing of 1613 participants with type 2 diabetes, of whom oral alternatives could help address the limitations of 757 (46·9%) were female and 1143 (70·9%) were White. injectable therapies, including needle phobia, injection Participants had a mean age of 56·8 years (SD 10·7), mean site reaction, and storage concerns, and could ultimately baseline BMI of 35·6 kg/m2 (6·6), and mean baseline improve patient acceptability. Peptide-based oral GLP-1 HbA of 8·05% (0·75). All participants received lifestyle 1c receptor agonists, such as oral semaglutide, are limited modification emphasising a healthy, balanced diet by the need for diet restriction, timing of administration, rather than caloric restriction. In ATTAIN-2, orforglipron and low oral bioavailability.1 Peptide-based GLP-1 demonstrated superior bodyweight reduction at all doses receptor agonists are also more costly to manufacture compared with placebo. The mean percentage change in and require refrigeration. Orforglipron is a new small- bodyweight from baseline was dose-dependent, ranging molecule, non-peptide GLP-1 receptor agonist designed from –5·1% (95% CI –6·0 to –4·2) with orforglipron for once-daily oral administration with an improved 6 mg to –9·6% (–10·5 to –8·7) with orforglipron 36 mg. bioavailability of 79%. The efficacy and safety of Participants receiving orforglipron also had greater dose- orforglipron have previously been examined in people dependent reduction in HbA , ranging from 1·22% with 1c with obesity2 and in people with type 2 diabetes on 6 mg to 1·66% with 36 mg, compared with 0·47% with diet control,3 achieving a mean bodyweight reduction placebo. These clinical benefits were further supported by of 4·5–11% and significant glycated haemoglobin patient-reported outcome assessments, which suggested (HbA ) lowering, with an acceptable side-effect profile. improved patient acceptability for oral orforglipron, 1c In The Lancet, Deborah B Horn and colleagues4 report highlighting its role as an alternative to subcutaneous the results of ATTAIN-2, a phase 3, double-blind, placebo- GLP-1 receptor agonists. controlled trial investigating efficacy and safety of The changes in bodyweight reported in ATTAIN-2 orforglipron in people with type 2 diabetes and obesity appear similar to those reported for people with with a BMI of 27 kg/m2 or higher and HbA of 7–10%. obesity and type 2 diabetes with peptide-based GLP-1 1c Participants were randomly assigned 1:1:1:2 to oral monoagonists,5,6 although weight loss was less than orforglipron (6 mg, 12 mg, or 36 mg) or placebo for reported with dual GLP-1 and glucose-dependent 72 weeks. The primary endpoint was the percentage insulinotropic polypeptide receptor agonists.7 However, differences in baseline characteristics and design might limit direct comparisons in the absence of head-to- head trials. Notably, the glycaemic improvement associated with orforglipron appears greater than some existing oral and subcutaneous peptide-based GLP-1 receptor agonists.6,8 A mean HbA decline of 1·66% was 1c observed with the top dose of orforglipron 36 mg daily and approximately one in four participants receiving orforglipron 36 mg daily reached normoglycaemia (HbA 1c less than 5·7%). In pharmacological studies, orforglipron displays partial agonism at the GLP-1 receptor, stimulating cAMP accumulation over β-arrestin recruitment9 and augmenting insulin secretion.10 The potential for orforglipron as a potent oral antihyperglycaemic agent makes it useful for people with type 2 diabetes in need of better glycaemic control and in diabetes prevention. 2866 segamI ytteG aiv eemmreT tatiN Ascletis Ex. 2047 Page 1 of 3 Comment Development of several small-molecule GLP-1 significant reduction of cardiorenal endpoints has been receptor agonists was discontinued due to concerns of reported with peptide-based GLP-1 receptor agonists;14,15 hepatotoxicity.11,12 Although the exact mechanism for the however, whether a similar magnitude of protection observed liver injury is unknown, one hypothesis relates can be achieved with orforglipron would need to be to impaired liver metabolism and drug transport in a confirmed in dedicated cardiovascular outcome trials. subset of participants.11 In contrast, there were no clinically In summary, orforglipron represents another advance significant hepatotoxic signals reported in ATTAIN-2. in the realm of GLP-1 receptor agonist therapies for Three people receiving orforglipron experienced clinically people living with type 2 diabetes and obesity, achieving significant elevations in liver enzymes secondary to clinically meaningful weight and glucose reductions gallbladder disease but, overall, the mean alanine without the inconvenience of injections. Better aminotransferase and aspartate aminotransferase con- bioavailability and lower transport and manufacturing centrations decreased across all orforglipron groups. costs have the potential to substantially improve Although the reasons for these differences are unclear, access to GLP-1 receptor agonist treatments globally, it would be prudent to monitor long-term liver safety of including in low-income and middle-income countries. small-molecule GLP-1 receptor agonists in the real world. However, advancements in medical treatments for In real-world settings, over half of people receiving obesity should not undermine the role of prevention GLP-1 receptor agonists discontinue treatment and environmental factors that foster an obesogenic within the first year, with gastrointestinal side- cycle, especially in underserved communities. The next effects being a common reason.13 In ATTAIN-2, step calls for global implementation strategies that treatment discontinuation due to adverse events personalise incretin-based therapies based on clinical (predominantly gastrointestinal) was observed with phenotype as well as patient preference and tolerability orforglipron (6·1–9·9% vs 4·1% with placebo), which and combine affordable medical therapies with lifestyle was similar to previous trials of orforglipron (ranging changes to achieve meaningful and sustainable from 4·4% to 10·3%).2,3 Although it is reassuring that improvem ents in health. gastrointestinal side-effects of orforglipron (diarrhoea, EW-KC reports travel sponsorship by Boehringer Ingelheim and Novo Nordisk. vomiting, nausea, constipation) were similar to other EC reports speaker honoraria from Novo Nordisk, Medtronic, Roche, Sanofi, and Sinocare, and institutional research grant support from Medtronic Diabetes. All peptide-based GLP-1 receptor agonists, these were more proceeds have been donated to the Chinese University of Hong Kong for common during the dose escalation period. Appropriate research purposes. dose escalation strategies would be important in Edith Wing-Kar Chow, *Elaine Chow ensuring persistence and adherence. e.chow@cuhk.edu.hk While the efficacy and safety of orforglipron in Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China ATTAIN-2 are promising, several important questions (EW-KC, EC); Phase 1 Clinical Trial Centre, Prince of Wales Hospital, The Chinese remain. The study did not report detailed body University of Hong Kong, Hong Kong Special Administrative Region, China (EW-KC, EC); Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The composition assessments, and the impact of small- Chinese University of Hong Kong, Hong Kong Special Administrative Region, molecule GLP-1 receptor agonists on excess adiposity, China (EW-KC, EC); Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China (EC) including visceral adiposity and muscle mass, is of 1 Buckley ST, Bækdal TA, Vegge A, et al. Transcellular stomach absorption of a relevance. The 36 mg orforglipron dose did result in an derivatized glucagon-like peptide-1 receptor agonist. Sci Transl Med 2018; 10: eaar7047. 8·3 cm mean decrease in waist circumference as well 2 Wharton S, Aronne LJ, Stefanski A, et al, and the ATTAIN-1 Trial as improvements in lipid and inflammatory indices. Investigators. Orforglipron, an oral small-molecule GLP-1 receptor agonist for obesity treatment. N Engl J Med 2025; 393: 1796–806. There are scant clinical data on CNS penetration of 3 Rosenstock J, Hsia S, Nevarez Ruiz L, et al, and the ACHIEVE-1 Trial small-molecule GLP-1 receptor agonists clinically and Investigators. Orforglipron, an oral small-molecule GLP-1 receptor agonist, in early type 2 diabetes. N Engl J Med 2025; 393: 1065–76. consequent effects on food intake and satiety. Moreover, 4 Horn DB, Ryan DH, Kis SG, et al. Orforglipron, an oral small-molecule GLP-1 receptor agonist, for the treatment of obesity in people with type 2 although overall weight loss was greater with orforglipron diabetes (ATTAIN-2): a phase 3, double-blind, randomised, multicentre, compared with placebo, over 30% of participants lost less placebo-controlled trial. Lancet 2025; 406: 2927–44. 5 Davies M, Færch L, Jeppesen OK, et al, and the STEP 2 Study Group. than 5% of their weight despite receiving the highest Semaglutide 2·4 mg once a week in adults with overweight or obesity, and dose. The mechanisms behind the varying responses type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet 2021; 397: 971–84. to GLP-1 receptor agonists are not fully understood. A Ascletis Ex. 2047 Page 2 of 3 Comment 6 Davies MJ, Bergenstal R, Bode B, et al, and the NN8022-1922 Study Group. 12 Buckeridge C, Cobain S, Bays HE, et al. Efficacy and safety of danuglipron Efficacy of liraglutide for weight loss among patients with type 2 diabetes: (PF-06882961) in adults with obesity: a randomized, placebo- the SCALE diabetes randomized clinical trial. JAMA 2015; 314: 687–99. controlled, dose-ranging phase 2b study. Diabetes Obes Metab 2025; 7 Chow E, Chan JCN. The emerging role of incretins and twincretins. 27: 4915–26. Nat Rev Endocrinol 2022; 18: 73–74. 13 Rodriguez PJ, Zhang V, Gratzl S, et al. Discontinuation and reinitiation of 8 Aroda VR, Rosenstock J, Terauchi Y, et al, and the PIONEER 1 Investigators. dual-labeled GLP-1 receptor agonists among US adults with overweight or PIONEER 1: randomized clinical trial of the efficacy and safety of oral obesity. JAMA Netw Open 2025; 8: e2457349-e. semaglutide monotherapy in comparison with placebo in patients with 14 Sattar N, Lee MMY, Kristensen SL, et al. Cardiovascular, mortality, and type 2 diabetes. Diabetes Care 2019; 42: 1724–32. kidney outcomes with GLP-1 receptor agonists in patients with type 2 9 Kawai T, Sun B, Yoshino H, et al. Structural basis for GLP-1 receptor activation diabetes: a systematic review and meta-analysis of randomised trials. by LY3502970, an orally active nonpeptide agonist. Proc Natl Acad Sci USA Lancet Diabetes Endocrinol 2021; 9: 653–62. 2020; 117: 29959–67. 15 Ling J, Chow E. Glucagon-like peptide receptor-1 receptor agonists: the 10 Jones B, Buenaventura T, Kanda N, et al. Targeting GLP-1 receptor emerging fourth pillar in type 2 diabetes and chronic kidney disease? trafficking to improve agonist efficacy. Nat Commun 2018; 9: 1602. Med (N Y) 2024; 5: 845–47. 11 Buckeridge C, Tsamandouras N, Carvajal-Gonzalez S, Brown LS, Hernandez-Illas M, Saxena AR. Once-daily oral small-molecule glucagon-like peptide-1 receptor agonist lotiglipron (PF-07081532) for type 2 diabetes and obesity: two randomized, placebo-controlled, multiple-ascending-dose phase 1 studies. Diabetes Obes Metab 2024; 26: 3155–66. Neoadjuvant quadruplet chemotherapy PAXG for pancreatic cancer Published Online Perioperative management of localised pancreatic ductal The quadruplet regimen PAXG (cisplatin, nab- November 20, 2025 adenocarcinoma (PDAC) is informed by resectability paclitaxel, capecitabine, and gemcitabine) was https://doi.org/10.1016/ S0140-6736(25)01864-1 criteria, which consider anatomy together with biological evaluated in a small randomised phase 2 trial (PACT-19) See Articles page 2945 and clinical factors.1 In patients with resectable PDAC, in advanced PDAC, showing a 6-month progression-free adjuvant mFOLFIRINOX (modified 5-fluorouracil, survival of 74% compared with 46% in patients receiving leucovorin, irinotecan, and oxaliplatin) is a standard of gemcitabine–nab-paclitaxel.6 Using multiagent regi- care;2,3 however, many are unable to receive this regimen mens can overcome tumour heterogeneity and due to inadequate performance status after surgery. Trials resistance, and switch approaches have further shown have evaluated various neoadjuvant chemotherapy regi- the efficacy of this approach.7 mens; notably, two randomised controlled trials did not In The Lancet, Michele Reni and colleagues report confirm superiority of mFOLFIRINOX or FOLFIRINOX the results of CASSANDRA8 to assess the superiority of over gemcitabine–nab-paclitaxel (SWOG 1505)4 and PAXG over mFOLFIRINOX in patients with resectable gemcitabine with radiation (PREOPANC-2).5 and borderline resectable PDAC. This study was initially an open-label, randomised, phase 2 trial that became a phase 3 trial and used a 2 × 2 multifactorial design to compare the PAXG regimen with mFOLFIRINOX for patients with resectable and borderline resectable PDAC. The trial was designed first to test the superiority of PAXG and second to document the optimal duration of neoadjuvant chemotherapy. Following 4 months of neoadjuvant chemotherapy, patients underwent a second randomisation to either continue neoadjuvant chemotherapy for a further 2 months (totalling 6 months) followed by surgery or to proceed to surgery followed by a further 2 months of adjuvant treatment. Of 260 patients enrolled, 134 (52%) were classified as borderline resectable PDAC, including patients with anatomically resectable PDAC and a carbohydrate antigen 19-9 (CA19-9) more than 500 IU/mL. 2868 segamI ytteG aiv regeurK Ascletis Ex. 2047 Page 3 of 3 --- [PDF原文](https://sci-net.xyz/storage/7482676/e8a9f3eccee3a3abbc8d4da1dd717a46fa6b385b1edd47fd6fed9082d9175696/Oral-small-molecule-GLP-1-receptor-agonist-for-type-2-diabetes-and-obesity.pdf) DOI: 10.1016/S0140-6736(25)02381-5