A century of peptide therapeutics, from insulin to semaglutide

Key points

• Since insulin, more than 80 peptide drugs have reached the market, and a 2022 review counted 33 non-insulin peptides approved since 2000 [1][2].
• Two Nobel Prizes mark the origin of the class: insulin (1923) and the first synthesis of a polypeptide hormone, oxytocin (1955) [3][5].
• Worldwide peptide drug sales in 2019 were more than double the 2013 figure [2].
• Short half-life and poor oral absorption were largely solved by chemistry: albumin binding through acylation and gastric absorption with SNAC [9][10][11].
• The result is drugs with hard outcomes: semaglutide was associated with 20% fewer major cardiovascular events in SELECT [14].

US status (October 2026): Semaglutide is FDA-approved as Ozempic, Rybelsus and Wegovy, and since the shortage ended on February 21, 2025, a 503A pharmacy may compound it only for a named patient inside FDA’s copy limits. See semaglutide status.

Peptides are a century-old drug class

When a patient calls a peptide new, the pharmacology says otherwise. Since the introduction of insulin almost a century ago, more than 80 peptide drugs have reached the market for diabetes, cancer, osteoporosis, multiple sclerosis, HIV infection and chronic pain [1]. A 2022 review counted 33 non-insulin peptide drugs approved worldwide since 2000 [2]. This post walks through the milestones. For current industry figures, see Peptide industry by the numbers.

• More than 80: peptide drugs on the market since insulin [1]
• 33: non-insulin peptides approved since 2000 [2]

1922 to 1955: hormones become drugs

On January 11, 1922, Leonard Thompson, a 14-year-old Toronto boy with diabetes, received the first insulin injection given as a treatment [4]. A year later, Frederick Banting and John Macleod received the Nobel Prize in Physiology or Medicine “for the discovery of insulin” [3]. In 1923 insulin became the first commercial peptide drug, and for decades it was extracted from bovine and porcine pancreas [2].

The second milestone was chemical. Vincent du Vigneaud produced oxytocin synthetically, and in 1955 he received the Nobel Prize in Chemistry “for his work on biochemically important sulphur compounds, especially for the first synthesis of a polypeptide hormone” [5]. For the first time, an active peptide did not depend on animal tissue. It could be manufactured. Synthetic oxytocin and vasopressin, together with insulin, opened the era of synthetic peptides [2].

The next decades copied the hormone and improved it

The strategy was simple: take a human hormone and modify its sequence to make it more stable or more selective [2]. That produced drugs that are routine in any hospital today:

• Desmopressin, a vasopressin analogue, for diabetes insipidus and nocturia [2].
• Leuprolide, derived from GnRH, for hormone-responsive prostate cancer, endometriosis, uterine fibroids and precocious puberty [2].
• Octreotide, a somatostatin analogue, still commonly used in acromegaly and gastroenteropancreatic neuroendocrine tumors 40 years after its development [6].
• Calcitonin, among the first animal-derived peptides to enter clinical use after the success of insulin [2].
• Teriparatide (2002) and abaloparatide (2017), acting on the PTH1 receptor in osteoporosis [2].

Teriparatide shows the level of evidence in this class. In a trial of 1,637 postmenopausal women with prior vertebral fractures, new vertebral fractures fell from 14% with placebo to 5% and 4% with the two doses studied, with minor side effects such as occasional nausea and headache [7].

Venom and snails supplied molecules too

In 1992, a New York group isolated exendin-4 from the venom of the Gila monster (Heloderma suspectum) [8]. Optimized as exenatide, in 2005 it became the first GLP-1 receptor agonist approved by the FDA [2]. The same period brought enfuvirtide (2003), the first approved antiviral peptide, which blocks HIV fusion with the cell, and ziconotide (2004), derived from the cone snail Conus magus, for severe chronic pain [2].

Chemistry solved the two historical limits

Peptides had two real problems. The first was half-life: natural peptides are chemically and physically unstable and are eliminated quickly [2]. Endogenous GLP-1 is degraded by DPP-4 and rapidly inactivated. GLP-2 has a half-life of about 7 minutes, and a single amino acid substitution in the analogue teduglutide extends it to 2 to 3 hours [2]. The second was the oral route: in the gut, peptides are poorly absorbed and degraded by proteolytic enzymes [10].

The answer to the first problem was acylation. Liraglutide carries a fatty acid that lets it bind reversibly to albumin, prolonging its presence in plasma. Semaglutide optimized the fatty acid and linker to maximize that binding [9]. Today semaglutide is more than 99% bound to albumin and has a half-life of about one week [11]. Tirzepatide, a 39-amino-acid modified peptide, uses a C20 fatty diacid for the same purpose, with a half-life of about 5 days [12].

The answer to the second problem was SNAC. Co-formulated with this absorption enhancer, tablet semaglutide is absorbed in the stomach, close to the tablet surface. SNAC protects it from enzymatic degradation through a local buffering effect and only transiently enhances absorption, with no evidence of an effect on tight junctions [10].

The limits that remain. The absolute bioavailability of oral semaglutide is approximately 0.4 to 1%, and the tablet must be taken fasting, at least 30 minutes before the first food, with no more than 4 ounces (about 120 mL) of water [11]. Most peptide drugs are still given by injection [2]. Efficacy also has a tolerability cost: in SELECT, adverse events leading to treatment discontinuation occurred in 16.6% with semaglutide versus 8.2% with placebo [14].

The incretin era produced hard outcomes

After exenatide came liraglutide (2009), lixisenatide (2013), dulaglutide (2014) and semaglutide (2017) [2]. Oral semaglutide has carried an FDA label since 2019 [11], and in 2022 the FDA approved tirzepatide, a GIP and GLP-1 receptor agonist [12].

In SURMOUNT-1, with 2,539 adults without diabetes who had obesity, or overweight with at least one weight-related complication, tirzepatide was associated with a mean weight reduction of up to 20.9% at 72 weeks, versus 3.1% with placebo [13]. In SELECT, with 17,604 adults with established cardiovascular disease, overweight or obesity and no diabetes, semaglutide was associated with 20% fewer cardiovascular deaths, non-fatal myocardial infarctions or non-fatal strokes (HR 0.80) [14]. What comes next is covered in After semaglutide. Where compounding of these two drugs stands now is covered in compounded GLP-1s after the shortage.

What this history means for your practice

When a patient asks about peptides, you are not starting from zero. This is the class that brought insulin, oxytocin, desmopressin, leuprolide, octreotide and teriparatide, with a century of pharmacology, Nobel Prizes and trials with hard outcomes [1][2][3][5].

That history does not validate every new molecule. Each peptide needs its own evidence, and each has its own regulatory status, which the peptide status tracker lists compound by compound. The history does place the subject where it belongs, in established medicine. See also The peptide universe, and for how MDside runs approved GLP-1 care, weight management.

References

1. Muttenthaler M, et al. Trends in peptide drug discovery. Nat Rev Drug Discov. 2021;20(4):309-325. PMID 33536635. Link
2. Wang L, et al. Therapeutic peptides: current applications and future directions. Signal Transduct Target Ther. 2022;7(1):48. PMID 35165272. Link
3. NobelPrize.org. The Nobel Prize in Physiology or Medicine 1923: Frederick Grant Banting and John James Rickard Macleod, “for the discovery of insulin”. Link
4. NobelPrize.org. The “miracle” discovery that reversed the diabetes death sentence. Link
5. NobelPrize.org. Vincent du Vigneaud: Facts. The Nobel Prize in Chemistry 1955. Link
6. Lamberts SWJ, Hofland LJ. Anniversary review: octreotide, 40 years later. Eur J Endocrinol. 2019;181(5):R173-R183. PMID 31398712. Link
7. Neer RM, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344(19):1434-41. PMID 11346808. Link
8. Eng J, et al. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. J Biol Chem. 1992;267(11):7402-5. PMID 1313797. Link
9. Knudsen LB, Lau J. The discovery and development of liraglutide and semaglutide. Front Endocrinol (Lausanne). 2019;10:155. PMID 31031702. Link
10. Buckley ST, et al. Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist. Sci Transl Med. 2018;10(467):eaar7047. PMID 30429357. Link
11. U.S. Food and Drug Administration. Rybelsus (semaglutide) tablets, prescribing information. NDA 213051, revised 09/2019. Link
12. U.S. Food and Drug Administration. Mounjaro (tirzepatide) injection, prescribing information. NDA 215866, 2022. Link
13. Jastreboff AM, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-216. PMID 35658024. Link
14. Lincoff AM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221-32. PMID 37952131. Link

This is general information, not medical or legal advice. Rules vary by state and change. Confirm your own facts with counsel.