Although it cannot be strictly verified, many experts speculate that the earliest human medicine was probably alcohol. Archaeological evidence of winemaking dates back to around 6000 BCE, found in present-day Iran. Archaeologists discovered pots containing tartaric acid residues in the Zagros Mountains of Iran. Tartaric acid is a compound found in grapes, indicating that winemaking began in this region at least 8,000 years ago.
Besides Iran, archaeological sites in the Caucasus, Anatolia (modern Turkey), and the ancient Near East also show evidence of ancient winemaking. These early winemaking cultures were important parts of many ancient civilizations, playing vital roles in rituals, agriculture, trade, and also medicine and health.
For various wounds, using alcohol as an external disinfectant can obviously prevent infection and promote healing; drinking alcohol can help resist cold and relieve pain to some extent, which was very important under early human living conditions. Many symptoms could also be alleviated to some degree, so it is reasonable to believe humans began using alcohol both externally and internally very early.
In contrast, injections appeared much later. Although ancient China and India have legends of hollow bamboo needles for injecting medicine, without understanding “bacteria” and “viruses” and lacking sterilization, such practices often caused infections. Thus, injection medicine development underwent a long, gradual process.
The earliest modern syringe was designed in the 17th century by Sir Christopher Wren (1632–1723), made of glass and metal. In 1853, Scottish doctor Alexander Wood (1817–1884) significantly improved the syringe by inventing a hollow needle suitable for subcutaneous injection, enabling precise dosing with less pain. This was a major milestone in injection medicine, raising drug treatment standards.
In the 20th century, injection drugs made huge advances. The development of modern drugs led to various injectable medications, including vaccines, antibiotics, hormones, and painkillers. Insulin, discovered in 1921, quickly became indispensable for diabetic patients, revolutionizing diabetes treatment through injection.
Modern medical theory holds that most drugs must enter the bloodstream first to reach their target organs and exert effects. Except for intravenous drugs which enter blood directly, other routes (oral, inhalation, subcutaneous, intramuscular) require absorption through membranes before entering circulation. Drugs also undergo metabolism and clearance, so the amount reaching blood is less than the dose administered.
Pharmaceuticals use intravenous injection as the benchmark, expressing other routes’ efficiency as a percentage called “bioavailability.” Oral bioavailability is the fraction of drug reaching blood after oral dosing compared to intravenous injection. For example, if oral administration delivers half the drug amount of intravenous injection, oral bioavailability is 50%, and to achieve the same effect orally, the dose must be doubled.
You may ask: if so, why not just use intravenous injections to save drug costs? Largely, it’s a pharmacoeconomics issue. Injectable drugs, especially intravenous ones, have much higher production costs and require expensive storage and transportation. Patients usually need hospital visits for administration by medical staff, consuming medical resources. Patient adherence suffers, especially in chronic conditions requiring long-term medication. These factors reduce the social benefits and manufacturers’ profits.
In contrast, oral drugs are generally affordable, convenient for home use, and greatly improve adherence. This is why modern drug development mostly targets oral medications, ideally once-daily pills.
However, there is one major drug class still dominated by injections—peptide drugs.
Polypeptides, including oligopeptides, are molecules formed by amino acids linked by peptide bonds, mostly linear but sometimes cyclic. There is no strict distinction; generally, polypeptides have more amino acids than oligopeptides. Both are protein components, and their use as drugs dates back to the early 20th century.
Scientists began isolating and characterizing various peptides then. Insulin, mentioned above, is a peptide hormone and the first major breakthrough in peptide drug development. Currently, insulin is only available as injectable; oral insulin is not yet on the market. Synthetic growth hormone development is another important progress; used for treating growth disorders, it was among the earliest recombinant DNA products and remains injectable.
Early injectable peptide drug development was limited by lengthy, costly synthesis and purification, making commercial viability difficult. In the 1960s, Robert B. Merrifield of Rockefeller University invented solid-phase peptide synthesis (SPPS), revolutionizing peptide synthesis and earning the 1984 Nobel Prize in Chemistry. SPPS is more efficient, controllable, and automatable, greatly impacting biomedical research and pharma industry.
In the 1970s, discovery of brain peptides regulating central nervous function (endorphins) paved the way for more synthetic peptide drugs. Meanwhile, demand and investment in oral peptide drug development increased.
As noted, most drugs must enter the bloodstream to act. For oral drugs, a sufficient portion must be absorbed in the gastrointestinal tract and remain in circulation long enough (half-life) without rapid degradation or excretion, to reach target organs.
Quick readers may say: peptides are protein components, and we consume proteins daily—absorption shouldn’t be a problem, right? Actually, protein digestion and absorption are complex. Proteins are broken down in the stomach by acid and pepsin into smaller peptides; further digestion by pancreatic enzymes in the small intestine breaks peptides into smaller fragments; finally, intestinal peptidases break peptides into amino acid monomers, which can be absorbed into intestinal villi and transported into blood and lymph.
This shows that proteins and peptides are completely “disassembled” in the digestive tract, losing integrity and bioactivity. This is why eating fresh fish won’t make fish grow inside your stomach.
The direct solution is injecting active peptide drugs into veins or under the skin or muscles, though injection lowers patient convenience and increases costs.
The pharmaceutical industry solved the blood entry problem physically via injections, then sought ways to extend circulation time. Cutting-edge scientists now explore “nanorobots” to escort drugs in blood, a promising but distant technology.
Since physical methods lag, chemical methods are used, with semaglutide as a prime example. Semaglutide, a GLP-1 analogue, has been extensively studied and chemically modified to prolong half-life dramatically—from 2 minutes to 160 hours—achieving once-weekly injections. This was done by replacing metabolically vulnerable amino acids with unnatural ones and adding lipid-like protective “shields” to bind blood albumin, delaying degradation.
Though these chemical modifications are challenging, the team succeeded, making semaglutide a blockbuster drug for type 2 diabetes.
But is oral semaglutide possible? Should chemical or physical methods solve the oral absorption challenge?
After the previous discussion, you might think that since oral drugs enter the GI tract, physical methods like “nanorobots” are impractical for now.
Let’s look at chemical methods first.
Semaglutide’s chemical modifications extend circulation time but do little to protect the drug from the harsh GI environment, where active proteins and peptides can’t survive. Even semaglutide’s 160-hour half-life doesn’t prevent degradation in the stomach, so oral bioavailability is zero. Achieving oral bioavailability breakthroughs chemically alone is very difficult.
The team turned back to physical methods, especially formulation development—packaging drugs to improve stability and absorption.
Formulations vary greatly (tablets, coated tablets, enteric-coated tablets, etc.) with goals to ensure stable efficacy, improve patient experience, and consider transport and shelf-life costs.
The goal of oral semaglutide formulation R&D is clear: achieve a breakthrough from zero oral bioavailability.
Since insulin’s discovery and injection therapy, efforts to develop oral insulin have spanned nearly a century without success, but they accumulated valuable experience. Enteric coatings protect drugs from stomach acid and release them in the alkaline intestine. Nanoparticles and liposomes have played key roles, e.g., in COVID-19 mRNA vaccines.
Which technology suits semaglutide? After some trials, the team focused on absorption-enhancing excipients.
Excipient research is a very active field. Data show an excipient called “SNAC” is an effective absorption enhancer, with good oral bioavailability itself (40% in rats), and it improves GI absorption of various drugs. Semaglutide’s metabolic stability is excellent; although some is lost in acidic stomach, enough remains to reach the GI tract. With SNAC’s help, a small amount of intact semaglutide might be absorbed into blood.
Theoretically feasible but practically challenging. In lab animal studies, the team mixed semaglutide with increasing SNAC ratios and repeatedly tested blood levels:
This was a historic breakthrough—oral semaglutide formulation moved from “zero” bioavailability to “one.”
Subsequent human trials found oral bioavailability only 1%, but the drug’s potency and safety matched injections. Dosing was slightly increased, with similar effect and duration.
Oral semaglutide was successfully launched. Whether it completely replaces injections or not, it brings new hope for oral peptide drugs and expands future drug development paths.
The formulation team studied this new formulation and found it very different from small-molecule drugs.
Small-molecule drugs are usually absorbed in the intestines, but clinical research and preclinical animal model studies show that the absorption of the semaglutide and SNAC combination formulation occurs in the stomach and is limited to the area near the tablet surface. SNAC effectively prevents enzymatic degradation through local buffering action and can temporarily enhance absorption. This absorption mechanism is compound-specific, transcellular, and there is no evidence that it affects tight junctions between cells.
Although semaglutide finally enters the bloodstream intact with the help of a large amount of excipient SNAC, the amount absorbed is very limited and still has great room for improvement. You might say that if the percentage entering the bloodstream is low, just increase the dose. As long as the effective dose is reached, the same effect should occur. Theoretically correct, but the pharmaceutical industry is not based on theory; strict and standardized clinical trials are necessary to address the issue. More importantly, oral semaglutide can no longer just be compared to placebo but must be benchmarked against other successful type 2 diabetes drugs, including injectable semaglutide. Only similar or superior data can gain acceptance from doctors and patients and allow the company to achieve commercial success.
The phase III clinical trials for oral semaglutide tablets are code-named “PIONEER,” meaning “Peptide InnOvatioN for Early diabEtes tReatment,” a selective acronym. It includes 12 phase III clinical trials aiming to prove that the oral tablet is as safe and effective as the approved injectable form and is more effective than competitor products in lowering blood sugar.
The clinical trials evaluated the efficacy and safety of oral semaglutide tablets in over 11,000 patients at various stages of diabetes (average history 3.5 to 15 years), across a range of background treatments including monotherapy, add-on to one or two oral antidiabetic drugs, or add-on to insulin. The studies compared oral semaglutide tablets (3 mg, 7 mg, or 14 mg) with placebo and other common antidiabetic drugs (25 mg empagliflozin, 100 mg sitagliptin, or 1.8 mg liraglutide). In all groups, at 26 weeks, the oral semaglutide tablet groups showed greater reductions in glycated hemoglobin (HbA1c) than placebo, empagliflozin, or sitagliptin groups, and were roughly comparable to the liraglutide group. The percentage of patients achieving the American Diabetes Association recommended HbA1c target of 7.0% (53 mmol/mol) was higher in the oral semaglutide groups (7 mg: 42%–69%; 14 mg: 55%–77%) than placebo (7%–31%) and other comparator drugs (25%–62%). Oral semaglutide was also effective in type 2 diabetes patients with moderate renal impairment.
A Network Meta-Analysis (NMA) showed that once-daily 14 mg oral semaglutide significantly lowered HbA1c compared with most comparators, with no statistical difference compared to once-weekly injectable semaglutide (0.5 mg and 1 mg doses). Similar trends were observed in proportions of participants achieving HbA1c reductions to 7.0% and 6.5% and composite endpoints.
The PIONEER 11 and PIONEER 12 studies, primarily involving Chinese populations, demonstrated the outstanding efficacy of semaglutide tablets for early glucose control in type 2 diabetes patients. Results showed that whether used as monotherapy or combined with metformin, semaglutide tablets significantly lowered HbA1c, with reductions up to 1.6%, and also had blood pressure and lipid-lowering effects with good safety. In PIONEER 11, the proportion of newly diagnosed Chinese type 2 diabetes patients achieving HbA1c targets (<7.0%) with monotherapy reached as high as 92.3%. Furthermore, the proportion achieving a composite endpoint of quality target (HbA1c <7%, no severe or confirmed hypoglycemia, and no weight gain) was as high as 72.4%.
These results indicate that although the bioavailability is not ideal, the efficacy and safety of oral semaglutide tablets are comparable to injections, providing a new valuable option for type 2 diabetes patients. Further studies will continue to increase the number of patients receiving treatment.
In September 2019, the US FDA was the first to approve oral semaglutide tablets (brand name Rybelsus?) for marketing, followed by approvals from the European EMA and Japan’s PMDA, marking an important milestone in therapeutic peptide drug delivery, the result of over 30 years of research by Novo Nordisk scientists. On January 26, 2024, China’s National Medical Products Administration also approved semaglutide tablets (brand name 諾和忻?) for marketing in China.
From the perspective of development history, semaglutide started from the goal of blood sugar regulation, and through iterations and upgrades, expanded clinical trials have shown not only powerful glucose-lowering effects but also improvements and protection in multiple metabolic indicators including weight, blood pressure, lipids, and heart and kidney function. It has evolved from simple glucose management to directly relating to overall metabolic regulation mechanisms, gaining recognition in the pharmaceutical community and benefiting many patients worldwide. Additionally, semaglutide may benefit patients in more disease areas, such as metabolic dysfunction-associated steatohepatitis (MASH), chronic kidney disease, and brain diseases.
As the injectable Ozempic?, semaglutide already possesses many advantages such as higher homology, longer half-life, and smaller molecular weight. Its once-weekly injection interval is a major improvement over previous drugs requiring one to three daily injections, especially improving patient adherence.
Oral Rybelsus?, as a newer generation product, not only breaks through stomach acid, enzymatic, and membrane barriers in formulation technology, achieving a “zero to one” innovation for oral peptide drugs, but also complements injectable Ozempic? well. It allows more type 2 diabetes patients, including many with metabolic syndrome, to benefit from a simpler and safer treatment regimen, making it easier to control blood sugar and metabolic disorders and keep the disease at a “simple” stage, thereby improving quality of life. According to currently approved indications, Rybelsus? tablets can be used for newly diagnosed type 2 diabetes patients and those failing metformin or sulfonylurea therapy, while Ozempic? injections are mainly used for patients with inadequate oral drug efficacy.
Many readers may not know that breakthrough research on GLP-1 and its receptor’s blood sugar regulation mechanism occurred in the early 1980s. By the 1990s, preliminary clinical trial results showed that GLP-1 receptor agonists could be used for diabetes treatment, and the first injectable drug was launched in 2005, demonstrating quite good glucose-lowering effects.
Although most people have never heard of the first GLP-1 injectable drug, as a “first-in-class” it drew significant attention from pharmaceutical professionals, as many saw the potential for improvement and the ideal path to develop “me-better” drugs. Since then, GLP-1 receptor agonists became a hot field in type 2 diabetes drug development.
In 2009 (EU; US approval was 2010), once-daily liraglutide emerged as the first blockbuster drug in this field. In 2017, the iterative product semaglutide (Ozempic?) was launched, achieving once-weekly injections and quickly becoming a global phenomenon, almost a household name.
Oral semaglutide (Rybelsus?), although not a new drug by active ingredient but a new formulation, is no less innovative than developing a completely new drug in the field of peptide oral formulation development, as it truly represents a “zero” breakthrough.
We have every reason to believe that with further advancement in oral formulation technology, more oral peptide drugs will emerge to relieve suffering for patients with various diseases, allowing them to enjoy a high-quality life.
