Oral GLP-1 receptor agonists: competition for efficacy and tolerability.

# Oral GLP-1 receptor agonists: competition for efficacy and tolerability *The Lancet 2026* Comment Oral GLP-1 receptor agonists: competition for efficacy and tolerability Therapy for type 2 diabetes with GLP-1 receptor semaglutide (426 on 7 mg and 425 on 14 mg) for agonists initially necessitated subcutaneous injection 52 weeks. of a peptide analogue of the incretin hormone GLP-1.1 For HbA, there were mean reductions of –1·71% c Oral administration of a GLP-1 receptor agonist was (SE 0·07) with 12 mg orforglipron, –1·91% (0·08) with first achieved when the peptide semaglutide was co- 36 mg orforglipron, –1·23% (0·05) with 7 mg administered with an absorption enhancer, sodium semaglutide, and –1·47% (0·06) with 14 mg semaglutide, N-(8-[2-hydroxybenzoyl]amino) caprylate.2 With some meeting the primary outcome of non-inferiority inconvenience (oral administration with some water, (margin 0·3%) and secondary outcome of superiority. after overnight fasting and abstinence from food, fluid, Bodyweight decreased by means of 6·1% (0·4) with and intake of other medications for a further 30 min), 12 mg orforglipron and 8·2% (0·4) with 36 mg it became possible to use semaglutide orally.3 However, orforglipron versus 3·9% (0·3) with 7 mg semaglutide only about 1% of orally administered semaglutide is and 5·3% (0·3) with 14 mg semaglutide. Published Online February 26, 2026 absorbed and, reflecting this very low bioavailability, Adverse events were assessed by participant self- https://doi.org/10.1016/ daily administration is required despite the long report and the proportions of people reporting nausea S0140-6736(26)00360-0 See Articles page 1147 elimination half-life (~1 week) of semaglutide. Over the were higher with orforglipron (111 [26%] of 424 on past few years, it has proved possible to develop small 12 mg and 114 [27%] of 243 on 36 mg) than with molecule GLP-1 receptor agonists readily absorbed from semaglutide (54 [13%] of 426 on 7 mg and 90 [21%] the gastrointestinal tract.4 Accordingly, the question has of 425 on 14 mg). Similarly, the prevalences of vomiting arisen as to how the only approved oral GLP-1 receptor were higher with orforglipron (72 [17%] on 12 mg agonist semaglutide2 and orforglipron, a small-molecule and 70 [17%] on 36 mg) than semaglutide (32 [8%] on GLP-1 receptor agonist under development for the 7 mg and 44 [10%] on 14 mg). Similar relationships management of type 2 diabetes and obesity,4 compare in were evident for diarrhoea and constipation. Overall, terms of efficacy, safety, and tolerability. the burden of gastrointestinal adverse events was This important comparison has now been addressed higher with orforglipron and apparently independent of by Julio Rosenstock and colleagues5 in ACHIEVE-3, a dose (249 [59%] on 12 mg and 245 [58%] on 36 mg), multinational, multicentre, open-label, randomised, whereas those associated with semaglutide were dose- phase 3 trial that assessed non-inferiority and dependent (157 [37%] on 7 mg and 193 [45%] on superiority of orforglipron compared with semaglutide 14 mg), as is typical for peptide GLP-1 receptor agonists.6 for mean change in HbA₁ at week 52 from baseline. 37 (9%) participants on 12 mg orforglipron and 41 (10%) c The trial involved 1698 people with type 2 diabetes on 36 mg orforglipron stopped study treatment because inadequately controlled with metformin from of adverse events compared with 19 (4%) on 7 mg 131 medical research centres and hospitals in semaglutide and 21 (5%) on 14 mg semaglutide. Argentina, China, Japan, Mexico, and the USA, It has been suggested that a more accurate and with broad representation, including 1234 (76·7%) structured evaluation of gastrointestinal adverse Hispanic or Latino, 334 (20·0%) American Indian and events, incorporating clear definitions of symptoms Alaska Native, 202 (12·1%) Asian, and 65 (3·9%) Black and their severity, should be used routinely in clinical or African American participants, with a mean HbA trials of GLP-1 receptor agonists.7 An approach has c of 8·3% (SD 1·1) and a BMI of 35·1 kg/m² (7·1). These been advocated that would allow derivation of a participants (mean age 53·9 years [SD 11·1], of whom burden of gastrointestinal adverse events score, 825 [48·6%] were female and 873 [51·4%] were taking into account the number of relevant events, male) were randomly assigned to treatment with their severity, and their effect on overall wellbeing, 12 mg or 36 mg per day of orforglipron (424 on 12 mg including decisions to discontinue drug treatment.8 and 423 on 36 mg), or 7 mg or 14 mg per day of oral This strategy would allow a more robust comparison 1120 segamI ytteG aiv aciscaB Comment of treatment approaches, including dose-escalation or oral semaglutide: patients in need of a substantial regimens. In ACHIEVE-3,5 the time course of the improvement in glycaemia or bodyweight might prevalence of nausea suggests a more prominent prefer orforglipron and those with a higher priority reduction (perhaps reflecting the development of for tolerability might favour oral semaglutide, with tolerance) with the higher dose of semaglutide, whereas the difference regarding convenience (in favour of the prevalence of vomiting was stable, even when orforglipron treatment) in mind. The study also attests of moderate severity, with orforglipron, as observed to the increasing competition for superior efficacy and previously.9 These apparent differences might reflect tolerability within the subcutaneous, and now oral, the pharmacokinetic properties of orforglipron and GLP-1 receptor agonist class. Future research should semaglutide,3,10 particularly more prominent daily peak aim at improving tolerability, most likely by designing concentrations with orforglipron, because of the much and testing potentially more effective dose-escalation longer elimination half-life for semaglutide.3,10 regimens to enhance the generation of tolerance against In view of the absence of a placebo control, baseline nausea and vomiting. assess ment of gastrointestinal symptoms would have MAN has been member on advisory boards or has consulted with Boehringer been appropriate, particularly given the expected Ingelheim, Eli Lilly, Medtronic, Merck, Sharp & Dohme, Novo Nordisk, Pfizer, Regor, Sun Pharma, and Structure Therapeutics (Gasherbrum); has served on the high prevalence in a population with advanced type 2 speakers bureau of AstraZeneca, Eli Lilly, Medscape, Medical Learning Institute, and Novo Nordisk, Sanofi, and Sun Pharma; has received support for attending diabetes.11 The protocol of ACHIEVE-3 allowed temporary meetings and/or travel from Eli Lilly and Novo Nordisk; and is on a Data dose reduction in the event of intolerable adverse Monitoring and Safety Board for Inventiva. MH was a member of the Scientific and Clinical Advisory Board of Glyscend Therapeutics, a company that owns gastrointestinal effects, along with dietary measures orally administered, gut-targeted, polymer therapies—the company closed in and anti-emetic medications, but also requested that, January, 2025, and these stock options were then null and void; is an unpaid member of the Clinical Advisory Boards for both Alstemi Medical (which is if possible, investigators resume dose escalation and developing an intra-orally anchored feeding tube) and Altrix Bio (which is keep participants in the study on a dose close to the developing a non-absorbable oral therapy to form a temporary barrier in the stomach and small intestine for management of type 2 diabetes and obesity); assigned one. Although this approach is justified, it is and reports travel support from the European Association for the Study of intuitively probable that medication adherence and Diabetes. persistence will be substantially lower in a real-world *Michael A Nauck, Michael Horowitz situation. michael.nauck@rub.de It should also be appreciated that oral semaglutide Diabetes, Endocrinology, Metabolism Section, Medical Department I, Josef-Hospital, Ruhr University Bochum, 44791 Bochum, Germany (MAN); has been studied at higher doses than those used in the Institute for Clinical Chemistry and Laboratory Medicine, University Medicine present trial. Reductions in HbA of 1·8% with doses Greifswald, Greifswald, Germany (MAN); Endocrine and Metabolic Unit, Royal c Adelaide Hospital, Adelaide, SA, Australia (MH); Adelaide Medical School, of 25 mg per day and 2·0% with 50 mg per day and Adelaide University, Adelaide, SA, Australia (MH) reductions bodyweight of 7·3% with 25 mg and 8·5% with 1 Nauck MA, Tuttle KR, Tschöp MH, Blüher M. Glucagon-like peptide-1 50 mg have been observed,12 with effect sizes similar to receptor agonists and next-generation incretin-based medications: metabolic, cardiovascular, and renal benefits. Lancet 2026; published online those reported for orforglipron in the present study; this Jan 14. https://doi.org/10.1016/S0140-6736(25)02105-1. also applies to the proportions of participants reporting 2 Davies M, Pieber TR, Hartoft-Nielsen ML, Hansen OKH, Jabbour S, Rosenstock J. Effect of oral semaglutide compared with placebo and nausea (145 [27%] of 534 on 25 mg and 146 [27%] of subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. JAMA 2017; 318: 1460–70. 535 on 50 mg) and vomiting (91 [17%] of 534 on 25 mg 3 Granhall C, Donsmark M, Blicher TM, et al. Safety and pharmacokinetics of and 97 [18%] of 535 on 50 mg).12 These comparisons single and multiple ascending doses of the novel oral human GLP-1 analogue, oral semaglutide, in healthy subjects and subjects with type 2 suggest that, in principle, orforglipron and oral diabetes. Clin Pharmacokinet 2019; 58: 781–91. semaglutide can be used at doses associated with similar 4 Kawai T, Sun B, Yoshino H, et al. Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist. effect sizes and adverse events. Proc Natl Acad Sci USA 2020; 117: 29959–67. Accordingly, the outcomes of the current study 5 Rosenstock J, Yabe D, Cox D, et al. Efficacy and safety of once-daily oral orforglipron compared with oral semaglutide in adults with type 2 diabetes should not be interpreted to indicate that orforglipron (ACHIEVE-3): a multinational, multicentre, non-inferiority, open-label, randomised, phase 3 trial. Lancet 2026: published online Feb 26. https://doi. is, generally speaking, more efficacious than oral org/10.1016/S0140-6736(26)00202-3. semaglutide. The important study by Rosenstock 6 Kang YM, Punov V, Lim S, Nauck MA. Comparative efficacy and tolerability of currently approved incretin mimetics: a systematic analysis of placebo- and colleagues,5 in conjunction with other reports, controlled clinical trials. Diabetes Obes Metab 2025; 27: 3736–46. provides information that will guide the clinician in the 7 Jalleh RJ, Jones KL, Nauck M, Horowitz M. Accurate measurements of gastric emptying and gastrointestinal symptoms in the evaluation of glucagon- treatment of type 2 diabetes with either orforglipron like peptide-1 receptor agonists. Ann Intern Med 2023; 176: 1542–43. Comment 8 Jalleh RJ, Talley NJ, Horowitz M, Nauck MA. The science of safety: adverse 11 Quan C, Talley NJ, Jones MP, Spies J, Horowitz M. Gain and loss of effects of GLP-1 receptor agonists as glucose-lowering and obesity gastrointestinal symptoms in diabetes mellitus: associations with medications. J Clin Invest 2026; 136: e194740. psychiatric disease, glycemic control, and autonomic neuropathy over 9 Rosenstock J, Hsia S, Nevarez Ruiz L, et al. Orforglipron, an oral small- 2 years of follow-up. Am J Gastroenterol 2008; 103: 2023–30. molecule GLP-1 receptor agonist, in early type 2 diabetes. N Engl J Med 2025; 12 Aroda VR, Aberle J, Bardtrum L, et al. Efficacy and safety of once-daily oral 393: 1065–76. semaglutide 25 mg and 50 mg compared with 14 mg in adults with type 2 10 Ma X, Liu R, Pratt EJ, Benson CT, Bhattachar SN, Sloop KW. Effect of food diabetes (PIONEER PLUS): a multicentre, randomised, phase 3b trial. Lancet consumption on the pharmacokinetics, safety, and tolerability of once-daily 2023; 402: 693–704. orally administered orforglipron (LY3502970), a non-peptide GLP-1 receptor agonist. Diabetes Ther 2024; 15: 819–32. Physiologically guided CABG in valve surgery Physiological evaluation using fractional flow reserve (FFR) core laboratory. Based on coronary angiography and provides more accurate assessment of the haemodynamic angiography-derived FFR, an independent panel of significance of coronary artery stenosis than coronary surgeons created two CABG plans for each patient; an gio graphy alone. FFR-guided percutaneous coronary patients were then randomly assigned (1:1) to angio- inter vention (PCI) results in better short-term and long- graphy-derived FFR-guided surgery (n=396) or to term outcomes than PCI guided by coronary angiography coronary angiography-guided surgery (n=397), with or medical therapy alone.1,2 Angiography-derived FFR is a the operating surgeon masked to the allocated strategy. way to estimate FFR from standard coronary angio graphy Patients’ median age was 65 years (IQR 59–70), See Articles page 1161 images using computational fluid dynamics or related 221 (28%) were women, 571 (72%) were male, and most algorithms, without passing a pressure wire or admini- valve disease was degenerative (588 [74%]), followed stering hyperaemic agents, with overall good correlation by rheumatic (174 [22%]). Mitral regurgitation was with invasive, wire-based FFR.3 The role of FFR in patients present in 424 (54%) patients, aortic regurgitation in undergoing coronary artery bypass graft (CABG) surgery 289 (36%), aortic stenosis in 186 (23%), and mitral has been debatable and data are scarce. Previous studies stenosis in 116 (15%). Median left ventricular ejection have shown that FFR-guided CABG reduces the number fraction was 61%, median synergy between PCI with taxus of grafts used, thus simplifying the operation and and cardiac surgery score was low at 8 (indicating low- resulting in higher arterial graft patency; however, there complexity coronary artery disease), and the median STS is no definitive evidence that FFR use improves clinical PROM score was 2·8%. outc omes after CABG.4 Current guidelines recommend Concomitant CABG was done in 223 (56%) patients coronary angiography to assess severity of coronary in the angiography-derived FFR-guided group and in stenosis—a visually estimated diameter stenosis of 388 (98%) in the coronary angiography-guided group. at least 70% for non-left main disease and at least Patients assigned to guidance by angiography-derived 50% for left main disease has been used to define clinically FFR received fewer grafts, had shorter cardiopulmonary significant stenosis and to guide revascularisation bypass and aortic cross-clamp times, and required fewer strategy.5,6 Coronary artery disease is common in patients red blood cell transfusions than those in the coronary with valvular heart disease. There are scant data on the angiography-guided group. The primary 30-day outcome, utility of FFR in patients with valvular heart disease and which was a composite of death, myocardial infarction, co nc omitant coronary artery disease who are undergoing stroke, unplanned revascularisation, or new dialysis, surgery. occurred in 31 (7·8%) patients in the angiography-derived The FAVOR IV-QVAS trial by Yunpeng Zhu and colleagues FFR-guided group and 53 (13·4%) in the coronary is an investigator-initiated, multicentre, randomised, angiography-guided group (risk ratio 0·58 [95% CI triple-blinded study of 793 patients undergoing valve 0·38–0·89]; p=0·011). This difference was driven mainly surgery, with at least one clinically significant coronary by lower rates of myocardial infarction and acute renal stenosis (coronary stenosis ≥50% in a major coronary failure requiring new dialysis in the angiography-derived artery, diameter ≥1·5 mm), at 12 sites in China.7 FFR-guided group. The authors conclude that, in patients Angiography-derived FFR was done by an independent undergoing valve surgery with concomitant coronary 1122 segamI ytteG aiv nedragnwo --- [PDF原文](https://sci-net.xyz/storage/7932541/182ee2a83f2e0204dd9991ce61420ffd39dff1a37893f095f0ddce44444d6e1f/Oral-GLP-1-receptor-agonists-competition-for-efficacy-and-tolerability.pdf) DOI: 10.1016/S0140-6736(26)00360-0