Semaglutide: Discovery and Regulatory History

Introduction

The development of semaglutide is traceable to a chain of basic scientific discoveries spanning four decades, beginning with the characterization of the glucagon gene in the early 1980s and progressing through incremental advances in peptide chemistry, receptor pharmacology, and drug delivery. This article provides a chronological reference account of those discoveries and the regulatory milestones that followed, illustrating how foundational academic research translated into one of the most fully characterized compound regulatory histories in the GLP-1RA class.

The Discovery Period: GLP-1 and the Incretin Concept (1980s)

The scientific foundation for GLP-1 receptor agonists was established by researchers working independently on the glucagon gene and its products. In the early 1980s, Joel Habener and colleagues at the Massachusetts General Hospital decoded the anglerfish and hamster proglucagon complementary DNA sequences, revealing that the glucagon gene encoded not only glucagon but two additional glucagon-like peptide sequences — initially designated GLP-1 and GLP-2 [1]. These sequences were co-encoded downstream of the glucagon coding region and had been previously uncharacterized.

Jens Holst and colleagues in Denmark, working in parallel, developed radioimmunoassays that demonstrated proglucagon is processed differently in intestinal L-cells than in pancreatic alpha-cells, liberating two glucagon-like peptides rather than glucagon itself [2]. This differential tissue-specific processing was a critical insight: it indicated that gut-derived GLP-1, not pancreatic glucagon, was the biologically active product in the enteroinsular axis.

The physiological significance of these peptides was established in 1987. Mojsov and colleagues at Massachusetts General Hospital reported in the Journal of Clinical Investigation that GLP-1(7-37) — a truncated form of the full proglucagon sequence — was a potent stimulator of insulin secretion from the perfused rat pancreas at picomolar concentrations [3]. That same year, Holst and colleagues published complementary evidence characterizing GLP-1(7-36) amide as the principal circulating form and a physiological incretin in humans [4]. The incretin effect — the augmentation of insulin secretion following oral versus intravenous glucose delivery — was shown to be substantially mediated by GLP-1. Svetlana Mojsov's work identifying the active N-terminus of GLP-1 was a pivotal contribution to establishing the molecular identity of the physiologically relevant form.

A central challenge for therapeutic development was identified early: endogenous GLP-1 is degraded within two minutes in the circulation by the enzyme dipeptidyl peptidase-4 (DPP-4) at the N-terminal Ala8 residue and by renal filtration, rendering the native peptide unsuitable as a pharmaceutical agent in unmodified form [5]. This challenge became the organizing design problem for the field of GLP-1 analogue development.

Early Research and Structural Engineering (1990s–2000s)

Research programs aimed at developing DPP-4-resistant GLP-1 analogues began in the 1990s. Daniel Drucker's laboratory at the University of Toronto continued to characterize the molecular biology of proglucagon and the physiological roles of GLP-1 and GLP-2 throughout this period, providing mechanistic underpinning for therapeutic development [2].

At Novo Nordisk, Lotte Bjerre Knudsen and colleagues pursued the strategy of engineering GLP-1 analogues with extended plasma half-lives through fatty-acid acylation — linking a fatty acid chain to the peptide backbone to promote reversible binding to serum albumin, thereby reducing renal clearance and protecting against proteolysis. This approach produced liraglutide, a GLP-1 analogue bearing a C16 fatty acid moiety connected via a glutamic acid spacer to lysine at position 26 of a modified GLP-1(7-37) backbone [6]. Liraglutide achieved a half-life of approximately 13 hours in humans, enabling once-daily administration [6]. The discovery and early development of liraglutide at Novo Nordisk was described by Knudsen and Lau in a 2019 review published in Frontiers in Endocrinology [6].

Liraglutide demonstrated clinical proof-of-concept for the once-daily long-acting GLP-1RA approach and received FDA approval for type 2 diabetes in 2010. The liraglutide program established both the structural engineering principles and the regulatory pathway that the subsequent semaglutide program would build upon — a deliberate progression from a 13-hour half-life compound toward the once-weekly target. The discovery histories of other GLP-1/incretin-class compounds developed during this same era are covered in the mazdutide history and cagrilintide history articles in this library.

Discovery of Semaglutide (2010–2015)

The Novo Nordisk research team's goal for the next-generation compound was to engineer a GLP-1 analogue with a sufficiently extended half-life for once-weekly administration. Lau, Bloch, Schäffer, Ursula Knudsen, and colleagues from Novo Nordisk, led by Lotte Bjerre Knudsen, designed a series of molecules exploring different acyl-chain lengths, linker chemistries, and amino-acid substitution patterns to optimize albumin binding affinity, DPP-4 resistance, and GLP-1R potency simultaneously [7].

The resulting compound incorporated three structural modifications relative to native GLP-1(7-37): substitution of Ala8 with alpha-aminoisobutyric acid (Aib) to prevent DPP-4 cleavage; substitution of Lys34 with Arg34 to eliminate an undesired acylation site; and acylation of Lys26 through a linker comprising two gamma-glutamic acid spacers and a mini-PEG chain to a C18 fatty diacid moiety [7]. The resulting albumin affinity was substantially higher than that of liraglutide, corresponding to a terminal plasma half-life of approximately 165 hours in humans — consistent with the once-weekly target [7].

The synthesis and structure-activity characterization of semaglutide were published in the Journal of Medicinal Chemistry in 2015 by Lau and colleagues [7]. The reported GLP-1R binding affinity was 0.38 ± 0.06 nM; the dramatically enhanced albumin affinity and protraction profile relative to liraglutide were the defining pharmacokinetic achievements of the program [7]. The paper established semaglutide as the lead candidate for clinical development as a once-weekly GLP-1RA.

Regulatory Milestones (2016–2025)

Clinical development proceeded through the SUSTAIN program (subcutaneous formulation in type 2 diabetes) and the PIONEER program (oral formulation using the SNAC absorption-enhancer system). The companion published research article in this library covers the trial data underpinning each regulatory decision.

December 2017: FDA approved a subcutaneous formulation of semaglutide for glycemic management in adults with type 2 diabetes mellitus, as an adjunct to diet and exercise. This approval was supported by data from the SUSTAIN clinical trial program, including the SUSTAIN-6 cardiovascular outcomes trial reported by Marso and colleagues in 2016, which demonstrated statistically significant superiority over placebo on the primary MACE composite endpoint [8].

September 2019: FDA approved an oral tablet formulation of semaglutide for the same glycemic management indication in type 2 diabetes. This marked the first oral GLP-1 receptor agonist to receive FDA approval — a notable delivery-science milestone — supported by data from the PIONEER clinical trial program, including the PIONEER 6 cardiovascular safety trial reported by Husain and colleagues in 2019 [9].

June 2021: FDA approved a higher-concentration subcutaneous formulation for chronic weight management in adults with obesity (BMI ≥30 kg/m²) or overweight (BMI ≥27 kg/m²) with at least one weight-related comorbidity, in combination with a reduced-calorie diet and physical activity. This was supported primarily by data from the STEP clinical program, including the STEP 1 trial reported by Wilding and colleagues in 2021 [10].

August–November 2023: Following reporting of the SELECT trial superiority data by Lincoff and colleagues — demonstrating a statistically significant 20% relative risk reduction in the primary MACE composite in a non-diabetic cardiovascular disease population — the FDA approved an additional cardiovascular risk-reduction indication for the higher-concentration subcutaneous formulation [11]. This marked a meaningful expansion of the compound's evidenced regulatory profile beyond glycemic management.

February 2025: The FDA determined that the semaglutide injection product shortage — declared in 2022 amid rapid demand growth — was resolved. This determination governed the timeline for compounding under the Federal Food, Drug, and Cosmetic Act: the enforcement discretion period for 503A pharmacy compounding of semaglutide injection products concluded April 28, 2025, and for 503B outsourcing facilities concluded May 22, 2025, consistent with the statutory framework for shortage-based compounding [12].

Current Research Landscape

As of the date of this article, the semaglutide research literature encompasses over 300 clinical publications indexed on PubMed, reflecting one of the most extensive evidence bases in the GLP-1RA class. Active research areas include the ongoing ESSENCE trial evaluating semaglutide in metabolic dysfunction-associated steatohepatitis (MASH), with cirrhosis-free survival as the long-term primary endpoint [13]; exploratory studies in neurodegenerative conditions; and mechanistic research into the central nervous system pathways mediating the appetite-related findings observed in clinical trials, including a 2026 Nature Metabolism publication by Koehl and colleagues characterizing cAMP-dependent mechanisms in GLP-1R-expressing hindbrain neurons [14].

In 2024, the Albert Lasker Award for Basic Medical Research was awarded jointly to Joel Habener, Svetlana Mojsov, and Lotte Bjerre Knudsen in recognition of their foundational contributions to the discovery of GLP-1 and the development of GLP-1-based therapeutics — an acknowledgment from the biomedical community of the scientific significance of the research lineage that produced semaglutide [15]. Research-grade semaglutide from SpartaLabs with batch-level COA documentation is available for investigators working in this area.

References

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2. Holst JJ. Discovery, characterization, and clinical development of the glucagon-like peptides. J Clin Invest. 2007;117(11):3029–3031. doi:10.1172/JCI34307. PMC2040302.

3. Mojsov S, Weir GC, Habener JF. Insulinotropin: glucagon-like peptide I (7-37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J Clin Invest. 1987;79(2):616–619. doi:10.1172/JCI112855. PubMed PMID: 3543057.

4. Holst JJ, Orskov C, Nielsen OV, Schwartz TW. Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut. FEBS Lett. 1987;211(2):169–174. doi:10.1016/0014-5793(87)81430-8. PubMed PMID: 2890903.

5. Deacon CF, Johnsen AH, Holst JJ. Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Metab. 1995;80(3):952–957. doi:10.1210/jcem.80.3.7883856. PubMed PMID: 7883856.

6. Knudsen LB, Lau J. The Discovery and Development of Liraglutide and Semaglutide. Front Endocrinol (Lausanne). 2019;10:155. doi:10.3389/fendo.2019.00155. PubMed PMID: 30915025. PMC6474072.

7. Lau J, Bloch P, Schäffer L, et al. Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. J Med Chem. 2015;58(18):7370–7380. doi:10.1021/acs.jmedchem.5b00726. PubMed PMID: 26308095.

8. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375(19):1834–1844. doi:10.1056/NEJMoa1607141. PubMed PMID: 27633186.

9. Husain M, Birkenfeld AL, Donsmark M, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2019;381(9):841–851. doi:10.1056/NEJMoa1901118. PubMed PMID: 31185157.

10. Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989–1002. doi:10.1056/NEJMoa2032183. PubMed PMID: 33567185.

11. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389(24):2221–2232. doi:10.1056/NEJMoa2307563. PubMed PMID: 37952131.

12. U.S. Food and Drug Administration. Declaratory Order: Resolution of Shortages of Semaglutide. February 2025. Available at: https://www.fda.gov/media/185526/download

13. Loomba R, Hartman ML, Lawitz EJ, et al. Semaglutide 2.4 mg in Participants With Metabolic Dysfunction-Associated Steatohepatitis: Baseline Characteristics and Design of the Phase 3 ESSENCE Trial. Hepatology. 2024;81(4):1274–1286. doi:10.1097/HEP.0000000000001050. PubMed PMID: 39412509.

14. Koehl M, Larrieu J, Becker AE, et al. Semaglutide drives weight loss through cAMP-dependent mechanisms in GLP1R-expressing hindbrain neurons. Nat Metab. 2026. doi:10.1038/s42255-026-01534-8.

15. Lasker Foundation. 2024 Albert Lasker Award for Basic Medical Research. Commentary available: PMC11446598.