Semaglutide, oral — clinical evidence
Assessed outcomes with certainty ratings, contributing trials and the reasoning for each rating.
§3Clinical evidence
§3.1Type 2 diabetes mellitus
Anchor outcome. Change in HbA1c (%, mmol/mol).
Effect as recorded. −1.2 to −1.4 % HbA1c at 26 weeks with 14 mg versus placebo; PIONEER 1 estimated difference −1.1 % (95 % CI −1.3 to −0.9) for 14 mg.[1,2]
Certainty. High certainty Ten-trial phase 3 programme with consistent dose-response.
Contributing trials. PIONEER-1 · PIONEER-6. Full structured abstracts are published for each.
Full evidence extract for type 2 diabetes mellitus · Indication assessment
§3.2Atherosclerotic cardiovascular disease and cardiovascular risk reduction
Anchor outcome. Three-point major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke).
Effect as recorded. MACE hazard ratio 0.79 (non-inferiority design) in PIONEER 6; 0.86 in the event-driven SOUL trial; PIONEER 6 HR 0.79 (95 % CI 0.57 to 1.11); SOUL HR 0.86 (95 % CI 0.77 to 0.96).[2,3]
Certainty. Moderate certainty PIONEER 6 was powered for non-inferiority only. SOUL provides the superiority result; the Institute grades moderate rather than high pending independent replication of the oral formulation result.
Contributing trials. PIONEER-6 · SOUL. Full structured abstracts are published for each.
Full evidence extract for atherosclerotic cardiovascular disease and cardiovascular risk reduction · Indication assessment
§3.3Obesity and overweight in adults
Anchor outcome. Percentage change in body weight from baseline.
Effect as recorded. −15.1 % body weight with oral 50 mg at 68 weeks versus −2.4 % with placebo; estimated difference −12.7 percentage points (95 % CI −14.2 to −11.3).[3,4]
Certainty. Moderate certainty The 50 mg obesity dose is a different formulation strength from the diabetes product; certainty is downgraded one level for single-trial evidence at that dose.
Contributing trials. OASIS-1. Full structured abstracts are published for each.
Full evidence extract for obesity and overweight in adults · Indication assessment
References cited on this page
References are numbered in order of first citation in this document. Each superscript in the text links to its entry below.
- Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, Jeppesen OK, Lingvay I, Mosenzon O, Pedersen SD, Tack CJ, Thomsen M, Vilsbøll T, Warren ML, Bain SC. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. New England Journal of Medicine 2019;381(9):841–851. doi:10.1056/NEJMoa1901118 · PMID 31185157
- Aroda VR, Rosenstock J, Terauchi Y, Altuntas Y, Lalic NM, Morales Villegas EC, Jeppesen OK, Christiansen E, Hertz CL, Haluzík M. PIONEER 1: randomized clinical trial of the efficacy and safety of oral semaglutide monotherapy in comparison with placebo in patients with type 2 diabetes. Diabetes Care 2019;42(9):1724–1732. doi:10.2337/dc19-0749 · PMID 31186300
- Knop FK, Aroda VR, do Vale RD, Holst-Hansen T, Laursen PN, Rosenstock J, Rubino DM, Garvey WT. Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet 2023;402(10403):705–719. doi:10.1016/S0140-6736(23)01185-6 · PMID 37364590
- McGuire DK, Marso SP, Deanfield JE, Hovingh GK, Sattar N, Kahn SE, Hardt-Lindberg S, Rasmussen S, Ripa MS, Wolski K, Nissen SE, Lincoff AM. Oral semaglutide and cardiovascular outcomes in high-risk type 2 diabetes (SOUL): a randomised, double-blind, placebo-controlled trial. New England Journal of Medicine 2025;392(22):2001–2012. doi:10.1056/NEJMoa2501006
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