A century of peptide therapeutics: from insulin to semaglutide

A century, not a fad

In public conversation, "peptide" sounds new. In pharmacology it is the opposite. 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 pain¹. A 2022 review counted 33 non-insulin peptide drugs approved worldwide since 2000². This article walks through the milestones of that history; for current industry figures, see More than 70 billion in two peptides.

1922–1955: 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 treatment⁴. 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 pancreas².

The second milestone was chemical. Vincent du Vigneaud studied oxytocin and succeeded in producing it synthetically; 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 peptides².

Copying the hormone and improving it

The following decades applied one strategy: take a human hormone and modify its sequence to make it more stable or more selective². That produced drugs that are routine in any hospital today:

• Desmopressin, a vasopressin analogue, for diabetes insipidus and nocturia².
• Leuprolide, derived from GnRH, for hormone-responsive prostate cancer, endometriosis, uterine fibroids and precocious puberty².
• Octreotide, a somatostatin analogue, still commonly used in acromegaly and gastroenteropancreatic neuroendocrine tumours 40 years after its development⁶.
• Calcitonin, among the first animal-derived peptides to enter clinical use after the success of insulin².
• Teriparatide (2002) and abaloparatide (2017), acting on the PTH1 receptor in osteoporosis².

Teriparatide illustrates 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 headache⁷.

From venom to the clinic

Nature also supplied molecules. 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 FDA². 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 pain².

The historical limits and how chemistry solved them

Peptides had two real problems. The first was half-life: natural peptides are chemically and physically unstable and are eliminated quickly². 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 2–3 hours². The second was the oral route: in the gut, peptides are poorly absorbed and degraded by proteolytic enzymes¹⁰.

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 binding⁹. Today semaglutide is more than 99% bound to albumin and has a half-life of about one week¹¹. Tirzepatide, a 39-amino-acid modified peptide, uses a C20 fatty diacid for the same purpose, with a half-life of about 5 days¹².

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 junctions¹⁰.

The incretin era

After exenatide came liraglutide (2009), lixisenatide (2013), dulaglutide (2014) and semaglutide (2017)². Oral semaglutide has carried an FDA label since 2019¹¹, and in 2022 the FDA approved tirzepatide, a GIP and GLP-1 receptor agonist¹². 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 placebo¹³. 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.

What it means for the physician

When a patient asks about peptides, the answer does not start from zero. This is the same class that brought insulin, oxytocin, desmopressin, leuprolide, octreotide and teriparatide, with a century of pharmacology, Nobel Prizes and trials with hard outcomes¹²³⁵. That history does not by itself validate every new molecule: each peptide needs its own evidence. But it places the subject where it belongs, in established medicine. The physician who knows that trajectory can guide the patient with data; see also The peptide universe.