Semaglutide Research History: Discovery, Key Trials and Regulatory Timeline

Semaglutide is a prescription medicine belonging to the glucagon-like peptide-1 (GLP-1) receptor agonist class. This page sets out, in chronological order, what the published literature records about where the molecule came from, which trials defined its evidence base, and how its regulatory status has been described in peer-reviewed sources. This page is for educational purposes only and is not medical advice; consult a licensed physician or the prescribing clinician for any question about whether a medicine is appropriate for an individual.

Origins: from native GLP-1 to a long-acting analogue

The scientific lineage of semaglutide was traced in a 2019 review in Frontiers in Endocrinology written by Novo Nordisk scientists, which described how the company moved from native GLP-1 — a hormone cleared from circulation within minutes — through the once-daily analogue liraglutide and then to semaglutide, using fatty-acid acylation to promote reversible albumin binding and extend time in circulation (PMID 31031702). That review reported that the same acylation platform underpinned both molecules, with semaglutide engineered for a substantially longer duration of action than liraglutide (PMID 31031702).

The practical problem the chemists faced, as the review described it, was that enzymatic degradation by dipeptidyl peptidase-4 and rapid renal clearance limited native GLP-1 to a pharmacological curiosity rather than a usable medicine, so structural protection and albumin affinity had to be engineered simultaneously (PMID 31031702).

Who discovered semaglutide, and when

The primary discovery paper was published in 2015 in the Journal of Medicinal Chemistry by Jesper Lau and colleagues at Novo Nordisk, under the title "Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide" (PMID 26308095). The study described three structural changes relative to human GLP-1: substitution with α-aminoisobutyric acid at position 8 to reduce degradation, an arginine substitution at position 34, and acylation at lysine 26 with a C18 fatty diacid attached through a γ-glutamic acid and oligoethylene-glycol linker (PMID 26308095). Researchers reported a plasma half-life of 46.1 hours in minipigs for the resulting compound, which the authors presented as consistent with once-weekly administration in humans (PMID 26308095).

In short, the answer to "who discovered semaglutide" is a medicinal-chemistry team at Novo Nordisk, and the publicly dated milestone is the 2015 discovery paper (PMID 26308095), with the broader development programme summarised retrospectively in 2019 (PMID 31031702).

Chronology of key publications

The first large phase 3 trial in type 2 diabetes

SUSTAIN 1, published in The Lancet Diabetes & Endocrinology in 2017, was a double-blind, randomised, placebo-controlled, multinational phase 3a trial of once-weekly semaglutide monotherapy in drug-naive adults with type 2 diabetes over 30 weeks (PMID 28110911). The study randomised 388 participants and reported mean HbA1c reductions of 1.45 percentage points with 0.5 mg weekly and 1.55 percentage points with 1.0 mg weekly, compared with 0.02 percentage points on placebo (PMID 28110911). Researchers also reported mean body-weight reductions of 3.73 kg and 4.53 kg in the two semaglutide groups versus 0.98 kg with placebo (PMID 28110911).

Regulatory timeline as described in the literature

The 2018 Drugs article "Semaglutide: First Global Approval" recorded the first regulatory authorisation of once-weekly injectable semaglutide, granted in the United States in December 2017 for adults with type 2 diabetes, and summarised the development programme leading to that decision (PMID 29363040). Subsequent regulatory expansion into weight management was described in a 2023 review in Trends in Cardiovascular Medicine, which reported that a 2.4 mg once-weekly formulation was authorised for chronic weight management and that phase 3 obesity trials reported mean weight reductions in the region of 15% (PMID 34942372).

A parallel formulation thread concerns oral delivery. A 2020 review in Nature Reviews Drug Discovery described co-formulation of semaglutide with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC) as a landmark in oral peptide therapeutics, enabling systemic absorption of a peptide that would otherwise be degraded in the gastrointestinal tract (PMID 31848464). That review placed the tablet formulation in the wider context of attempts to make peptide medicines orally available (PMID 31848464).

Head-to-head comparison research

In 2021, the SURPASS-2 trial published in the New England Journal of Medicine compared once-weekly tirzepatide at 5 mg, 10 mg and 15 mg with once-weekly semaglutide 1 mg in 1,879 adults with type 2 diabetes over 40 weeks (PMID 34170647). The study reported mean HbA1c reductions of 2.01, 2.24 and 2.30 percentage points across the tirzepatide groups and 1.86 percentage points with semaglutide, and mean weight reductions of 7.6 kg, 9.3 kg and 11.2 kg versus 5.7 kg respectively (PMID 34170647). This trial is frequently cited as the first large randomised comparison of the two agents (PMID 34170647).

Cardiovascular and kidney outcome trials

The SELECT trial, published in 2023, enrolled 17,604 adults aged 45 years or older with overweight or obesity and established cardiovascular disease but without diabetes, and compared once-weekly semaglutide 2.4 mg with placebo over a mean follow-up of 39.8 months (PMID 37952131). Researchers reported a primary composite cardiovascular endpoint in 6.5% of the semaglutide group versus 8.0% of the placebo group, a hazard ratio of 0.80 (PMID 37952131).

A prespecified analysis of SELECT published in The Lancet in 2024 examined participants with obesity and prevalent heart failure at baseline, reporting cardiovascular outcomes within that subgroup (PMID 39181597). In the same year, an analysis of the FLOW trial in the Journal of the American College of Cardiology reported heart failure outcomes among participants who had both type 2 diabetes and chronic kidney disease (PMID 39217553). Together, these publications extended the evidence base from glycaemic and weight endpoints toward hard clinical outcomes in defined populations (PMID 37952131, PMID 39217553).

Recent research directions

A 2025 systematic review in Pharmacological Reviews catalogued emerging pharmacotherapies for obesity and situated semaglutide among incretin-based agents under active investigation (PMID 39952695). Body composition has become a specific research question: the SEMALEAN study, published in Diabetes, Obesity and Metabolism, examined the impact of semaglutide on fat mass, lean mass and muscle function in patients with obesity (PMID 41068996). Readers comparing publications should note that single studies differ in population, duration and endpoints, which limits direct comparison across the chronology above (PMID 39952695).

Adverse Events in the Trials: What Studies Report

Across the published programme, gastrointestinal events dominated the reported tolerability profile. SUSTAIN 1 reported nausea as the most frequent adverse event in the semaglutide groups over 30 weeks (PMID 28110911). SURPASS-2 reported that the most common adverse events with both tirzepatide and semaglutide 1 mg were gastrointestinal and mostly mild to moderate, including nausea, diarrhoea and vomiting (PMID 34170647). In SELECT, researchers reported that more participants discontinued treatment because of adverse events in the semaglutide group than in the placebo group, with gastrointestinal disorders the leading reason (PMID 37952131). Trial-reported adverse events describe what occurred under study conditions and are not a substitute for the approved product labelling or clinical judgement.

How to read this history

• Discovery is dated to a specific paper: the 2015 structural description from Novo Nordisk chemists (PMID 26308095).
• Approval milestones are documented separately from efficacy data: the first global approval review appeared in 2018 (PMID 29363040).
• Indications broadened over time: from glycaemic endpoints in type 2 diabetes (PMID 28110911) to weight management (PMID 34942372) and cardiovascular outcomes (PMID 37952131).
• Formulation science ran in parallel: oral delivery via absorption-enhancer co-formulation was reviewed in 2020 (PMID 31848464).

Regulatory status and clinical context

Semaglutide is a prescription medicine, first authorised for type 2 diabetes as documented in 2018 (PMID 29363040) and later authorised in a 2.4 mg once-weekly formulation for chronic weight management as described in a 2023 review (PMID 34942372). Approved indications, labelling and contraindications are set by national regulators and can differ between countries. Any question about suitability, interactions, monitoring or administration belongs with a prescribing clinician and the approved product information, not with a summary of the literature.

References

• Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide (Journal of Medicinal Chemistry, 2015)
• Efficacy and safety of once-weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1) (The Lancet Diabetes & Endocrinology, 2017)
• Semaglutide: First Global Approval (Drugs, 2018)
• The Discovery and Development of Liraglutide and Semaglutide (Frontiers in Endocrinology, 2019)
• Advances in oral peptide therapeutics (Nature Reviews Drug Discovery, 2020)
• Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes (The New England Journal of Medicine, 2021)
• Semaglutide for the treatment of obesity (Trends in Cardiovascular Medicine, 2023)
• Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (The New England Journal of Medicine, 2023)
• Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial (Lancet, 2024)
• Effects of Semaglutide on Heart Failure Outcomes in Diabetes and Chronic Kidney Disease in the FLOW Trial (Journal of the American College of Cardiology, 2024)
• Emerging pharmacotherapies for obesity: A systematic review (Pharmacological Reviews, 2025)
• Impact of Semaglutide on fat mass, lean mass and muscle function in patients with obesity: The SEMALEAN study (Diabetes, Obesity & Metabolism, 2026)