Metformin

Metformin hydrochloride, hereafter metformin, is a medication that doctors prescribe to treat type 2 diabetes, a condition where the body fails to respond effectively to the hormone insulin, leading to high blood sugar levels. In 1922, Emil Werner and James Bell, chemists working at Trinity College in Dublin, Ireland, were among the first to synthesize a compound with metformin’s modern chemical formula, namely dimethylbiguanide. At first, physicians didn’t recognize the compound’s ability to lower high blood sugar levels. However, the drug found other uses: physicians prescribed it to treat malaria and flu in the 1940s. Metformin as a treatment for diabetes became popular in the 1990s. In addition to type 2 diabetes, physicians also prescribe metformin to those with polycystic ovary syndrome, or PCOS, as some of its symptoms are similar to those of diabetes. Treating PCOS helps to reduce infertility caused by irregular or no ovulation. Metformin’s wide range of uses has helped hundreds of millions of people across the globe in managing diabetes, but also in treating PCOS and malaria.

1. Hormones and Blood Sugar: Some Background
2. History of the Medication
3. First Uses
4. Metformin for Diabetes
5. Other Uses and Impact

Hormones and Blood Sugar: Some Background

As a treatment for type 2 diabetes, metformin works by helping lower blood glucose levels. Glucose, a sugar, serves as the body’s primary source of energy. One obtains glucose by consuming carbohydrates, long chains of sugars that exist in foods. The digestive system breaks down those carbohydrates into glucose, which is then absorbed into the bloodstream. Insulin is a hormone produced by the pancreas that tells cells to take up glucose from the bloodstream and use it for energy. If the body cannot produce enough insulin or effectively respond to it, glucose levels remain high in the blood. A persistently high concentration of blood sugars can lead to issues such as heart or kidney disease. Certain types of diabetes are reversible, such as prediabetes, but type 2 diabetes is chronic. Prediabetes is a condition in which one has high blood sugar levels, but not high enough that physicians consider them to have diabetes. Insulin resistance is a precursor to prediabetes, and is when the body has trouble using insulin but is not entirely unresponsive to it.

History of the Medication

Long before scientists had synthesized metformin in the lab, people were using an herbal form of the drug to address certain ailments. The herb they used was Galega officinalis, or goat’s rue. People in medieval Europe used tinctures of the plant to treat frequent and intense urination, a symptom that scientists later recognized as a symptom of diabetes. In the late 1800s, scientists found that the herb is rich in guanidine, a chemical building block that is also a component of metformin. In 1879, Bernhard Rathke, a chemist working in Germany, synthesized biguanidine, which is composed of two molecules of guanidine bonded together. Rathke synthesized the compound by combining guanidine with a byproduct of a reaction between phosphorus chloride and sulfonylurea, without any insight into the compound’s ability as a drug. Then, in 1918, C.K. Watanabe, a chemist in the US, published a study showing that guanidine can reduce blood sugar levels in small animals.

Werner and Bell, two chemists working at Trinity College in Dublin, Ireland, were the first to synthesize a chemical with the modern chemical structure of metformin, in 1922. That chemical was dimethylbiguanide, which consists of a biguanide component, along with two methyl, or 1-carbon and 3-hydrogen, groups attached to one nitrogen atom in the structure.. Seven years later, in 1929, scientists Erich Hesse and Gert Taubman, working in Germany, found that dimethylbiguanide was able to reduce blood sugar levels in animals. As of 2026, chemists classify metformin and similar compounds as biguanides. That is because they are all derivatives of the chemical biguanidine and, as drugs, have similar antihyperglycemic effects, meaning the ability to reduce high blood sugar levels.

Despite evidence suggesting that metformin had antihyperglycemic properties, doctors in the 1930s and 1940s did not use it to treat diabetes. According to Clifford J. Bailey, a diabetes researcher in the US, the medication went underappreciated at the time because the correlation between metformin and antihyperglycaemic properties was not strong, since Hesse and Taubman’s results were produced in nondiabetic small animals. For approximately a decade after the 1940s, there was no further investigation into the chemical for its use as a medication for those with diabetes.

First Uses

In the 1940s, when World War II led to a shortage of medications to treat malaria in Allied soldiers, scientists created a metformin-like medication. In World War II, there were two sides: the Axis powers and the Allied powers. The Allied powers included England, the United States, the Soviet Union, and China, while the Axis powers included Japan, Germany, and Italy. The war mostly took place on two fronts: the Pacific theater and the European theater. Malaria posed a threat to soldiers’ health, since, in the Pacific theater, the tropical climate came with malaria-carrying mosquitoes. The Axis powers prevented the main treatment for malaria, quinine, from reaching England by blockading quinine production sites in the Dutch East Indies, a Dutch colonial territory that is independent and called Indonesia in 2026. A different treatment for malaria came in the form of proguanil, which a team of scientists in Britain synthesized in 1945. Proguanil contains a biguanide component in its structure that not only treats malaria, but also has antihyperglycemic properties, although the scientists did not know that at the time.

In the late 1940s, in the Philippines, when a local outbreak of influenza occurred, someone modified proguanil to another biguanide-containing chemical called flumamine in order to treat influenza. Although it went by the name of flumamine at the time, it was chemically identical to metformin in its modern drug form. The drug contained dimethylbiguanide, but in salt form, hence the hydrochloride in the full form of metformin’s name. The addition of a salt makes the chemical soluble and more stable, which makes it fit for drug usage. Although it is not certain who synthesized it, or why they did, Eusebio Garcia, a scientist working in the Philippines at the time, recorded its effects on the patients with flu who used the medication. In the study that Garcia published in 1950, “Flumamine, a New Synthetic Analgesic and Anti-flu Drug,” he noted that an unspecified scientist, studying the effect of different biguanide-derivatives on malaria, out of curiosity, gave it to someone with symptoms of flu, and noticed that the medication quelled those symptoms. Garcia conducted a study on thirty people with influenza with that background knowledge. His results supported the previous scientist’s results. Due to similarities he saw in other drugs, Garcia inferred that due to the biguanide component in the chemical’s structure, the medication was likely to work by reducing blood sugars, which starves the parasite, and keeps it from multiplying. The formula of metformin went largely unchanged for the rest of its existence, although there are companies that add ingredients to the medication to make it slower-acting.

Metformin for Diabetes

In 1956, Jean Sterne, a physician who researched clinical pharmacology at Aron Laboratories in Paris, France, studied multiple biguanides, including metformin, for their antidiabetic properties. Eusebio Garcia’s publication on flumamine led him to explore the antihyperglycaemic properties of the medication. Further studies from other scientists showed that metformin is more effective at lowering blood sugar in people with diabetes compared with laboratory animals. In 1957, Aron Laboratories released the drug in France under the name Glucophage, which means glucose-eater. In the following years, Ungar Freedman and Seymour Shapiro, chemists working in the US, published studies on other biguanides such as phenformin and buformin. The names metformin, phenformin, and buformin all date from the 1950s and reflect the particular chemical group attached to the biguanide structure, namely methyl, phenethyl, or butyl, respectively. Freedman and Shapiro found that phenformin was more effective in reducing blood sugars as compared to metformin, and as a result phenformin became a more popular option for doctors to prescribe to those with high blood sugar in the US. By 1959, the US Vitamin Corporation released phenformin as a drug on the US market, where Bailey notes the medication was especially popular. Although metformin wasn’t approved for usage in the US, and was unpopular in other countries, some clinics in Europe were consistently prescribing it to treat diabetes.

Soon after, though, many patients on phenformin experienced lactic acidosis, a side effect of the medication that causes lactic acid to build up in the blood stream, which can push the body’s internal conditions out of a healthy pH range, possibly being fata. The US Food and Drug Administration, or FDA, removed phenformin from the market in 1978. Bailey notes that metformin had a smaller percentage of users report that side effect, and yet its reputation was damaged by proxy, almost causing its discontinuation. In addition, treating diabetes with insulin became more popular as well, which shifted attention away from biguanides like metformin. Insulin first became available as a drug that doctors could prescribe for diabetes in 1922.

Metformin continued to be largely unused as a diabetes treatment until the 1980s, when scientists released studies supporting its efficacy in treating type 2 diabetes, known at the time as non-insulin-dependent diabetes. Physicians at the time started to recognize that type of diabetes as being caused by insulin resistance, rather than not being able to produce insulin, which is characteristic of type 1 diabetes. Type 1 diabetes is an autoimmune type of diabetes that affects the pancreas’s ability to produce insulin by attacking the insulin-producing cells of the pancreas, called beta cells. They began to consider metformin for its ability to address insulin resistance. In 1994, the FDA approved the medication in the US, after a couple scientists from Lipha Pharmaceuticals, a company based in New York City, New York, that had, at the time, recently acquired Glucophage from Aron Laboratories, presented a case for it.

Bailey mentions that while those developments were important for metformin’s rise in popularity, the study that pushed metformin to widespread dominance was the United Kingdom Prospective Diabetes study, or UKPDS. The UKDPS was a longitudinal study that scientists conducted from 1977 to 1999 on the effects of managing type 2 diabetes with different medications, which included metformin. The study group included around 7,600 newly-diagnosed type 2 diabetics, and although only ten percent of the group took metformin in the study, it helped those individuals manage their diabetes. The study’s results also showed that symptoms of diabetes that physicians previously thought were unavoidable, such as microvascular complications that affect the kidneys and the heart, are not unavoidable with the help of antihyperglycemic medications like metformin. The results of the UKPDS encouraged physicians on a wider scale to start integrating a medication approach to type 2 diabetes treatment. Not long after, physicians started to consider it a first-line medication, or the initial and preferred treatment, for the management of that condition.

Other Uses and Impact

Metformin is not only an effective treatment for diabetes; it can also treat other conditions with symptoms of insulin resistance, such as polycystic ovarian syndrome, or PCOS. PCOS is a disorder of hormone imbalances that affects women. The primary imbalance is higher than average levels of androgens, or male-typical sex hormones. In the 1990s, physicians and researchers of PCOS suggested metformin as a treatment for certain symptoms of PCOS. A decade prior, a few researchers published studies on how PCOS can affect metabolism, since they observed a trend in women with the disorder being obese or overweight. A 2021 study by Thomas Barber and Stephen Franks found that around thirty-eight to eighty-eight percent of women with PCOS were overweight or obese by body mass index standards, which is a method of measuring body fat according to weight and height. The research from the 1980s highlighted an association between PCOS and insulin resistance. After the approval of metformin by the FDA in 1994, John E. Nestler, a researcher in endocrinology in the US, published a number of articles in the 1990s pushing for the adoption of metformin as a treatment for PCOS. National health organizations such as the European Society for Human Reproduction and Embryology and the American Society for Reproductive Medicine recognize Nestler’s work as a landmark trial in PCOS research. As of 2026, for those with PCOS, physicians prescribe metformin, off-label, as a first-line medication for insulin resistance, and as a second-line medication for infertility.

In 2026, metformin is a first-line oral medication available in the form of a tablet or a liquid syrup. The tablets come in doses ranging from 500 milligrams to 1000 milligrams. Physicians often start a patient on metformin with 500 milligrams once a day, but gradually increase the dosage until a person’s blood sugar is under control. They also suggest the patient maintain a healthy lifestyle by eating a healthy diet and consistently exercising, as the medication will be less effective without lifestyle factors like those. Metformin has a few contraindications, or conditions that can make taking the medication inadvisable, namely if a patient has kidney disease or heart disease. Those with kidney or heart disease are more susceptible to lactic acidosis, which is the reason why many of the patients taking metformin before physicians noted it were experiencing lactic acidosis.

Since 2011, metformin has been on the World Health Organization’s list of essential medications. That list of essential medications functions as a standard for countries to create their own list of medications that would be vital to a functional healthcare system. Upwards of 150 million people across the world use the medication daily, which is around two percent of the world population. Although it has had a number of hurdles as a result of the popularity of other treatments since its first-recorded synthesis, physicians ultimately consider metformin to be a first-line medication that helps manage type 2 diabetes, a disease that affects almost five-hundred million individuals across the world.

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