From Plant to Pill: A Look at Metformin’s 100-Year History

Like any new invention, each medication on the market today has a unique story of how it came to be. From its initial inception and development to modern-day uses, the journey isn’t always a straight line. This was the case with metformin, a popular Type 2 diabetes medication.

Over the course of the last century, metformin was discovered then forgotten, only to be rediscovered years later. Then, similar medications were removed from the market for safety reasons. This cast a shadow over metformin’s reputation until experts started to realize its potential. Fast forward to today, and metformin is one of the most commonly prescribed medications in the U.S.

What is the origin of metformin?

Metformin comes from a plant called Galega officinalis, known as french lilac or goat’s rue. Goat’s rue was first used in medieval Europe to treat a variety of conditions, including worms, seizures, and fever. It was also used to treat symptoms that we associate today with diabetes, including frequent thirst and urination.

Although the plant had been used for centuries to treat diabetes-related symptoms, it wasn’t until 1918 when guanidine, a compound found in goat’s rue, was discovered to have blood glucose (sugar)-lowering effects in animals. After this finding, researchers started exploring ways to use it for diabetes treatment.

When was metformin discovered?

During the 1920s, guanidine was used to make several different compounds. Some of these compounds, galegine and synthalin, were being used for diabetes. But, they were discontinued due to their toxic effects.

Biguanides, which were made by fusing two guanidine compounds together, seemed to be promising alternatives that were less toxic. Metformin, first discovered in 1922, was originally one of several biguanides being tested.

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What was metformin originally developed for?

Due to their blood glucose-lowering effects, metformin and other biguanides were originally being explored for people with diabetes. But given that insulin had become much more accessible during this time, interest in these compounds dwindled until years later.

Metformin was rediscovered in the 1940s — but for an entirely different purpose. During the search for antimalarial drugs, it was repurposed under the name flumamine. After successfully treating someone with both malaria and influenza (the flu), it was used to treat a local flu outbreak.

Flumamine is no longer available. But a similar biguanide called proguanil is still used in combination with other medications for malaria today. And metformin continues to be studied for viral infections, including COVID-19.

When was metformin first used clinically?

Metformin was first used to treat diabetes in Europe in the late 1950s, followed by Canada in the early 1970s. But metformin wasn’t as potent as other biguanides, so it wasn’t used as often. About 20 years later in 1995, it was finally approved in the U.S.

Despite metformin’s approval, there were lingering safety concerns surrounding its use. This created an uphill battle before metformin was used more widely.

History of safety concerns

Metformin is the only biguanide that’s still used today. But decades before metformin became a first-choice diabetes treatment, two other biguanide medications were on the scene: phenformin and buformin.

Phenformin, the most potent of the three, started gaining popularity in the U.S. and other countries. It was around this time that oral diabetes medications called sulfonylureas also became available. Phenformin didn’t have the same risk of weight gain and low blood glucose (hypoglycemia) as sulfonylureas. So this made it a common sulfonylurea alternative.

But in the late 1970s, phenformin was taken off the market due to a high risk of a potentially life-threatening condition called lactic acidosis. Lactic acidosis occurs when lactic acid builds up in the blood. Buformin, although never approved in the U.S., was also withdrawn. The lactic acidosis risk with metformin, however, was significantly lower, so it remained on the market.

After careful examination, metformin was ultimately approved in the U.S. Though, the removal of phenformin and buformin from the market continued to cast a shadow on metformin’s reputation. The FDA also gave it a boxed warning, its strictest warning, for lactic acidosis.

And since the kidneys remove metformin from the body, poor kidney function could increase lactic acidosis risk. Heart failure was also a risk factor. So, the FDA also limited metformin’s use in people with kidney problems. Metformin was also contraindicated in people with heart failure, meaning that it shouldn’t ever be used.

New evidence is reviewed

In 1998, findings from the UK Prospective Diabetes Study showed long-term cardiovascular benefits from metformin. This helped position it as a first-choice treatment for diabetes. And years later in 2006 and 2016, the FDA reviewed additional studies on metformin’s safety.

Based on these findings, the FDA removed the heart failure contraindication, and then revised the restrictions for certain people with kidney problems. Today, more people with kidney problems are able to take metformin. As long as your kidneys work well enough, you can take metformin at the same or reduced dose.

How is metformin used today?

Diabetes treatment is highly individualized and may look different for everyone. But for many adults and children, metformin is often a first-choice treatment option. For best results, metformin should be taken in combination with a diabetes-friendly diet and regular exercise.

Metformin is often used in combination with other medications to achieve blood glucose goals. Metformin doesn’t have any direct alternatives in the same drug class, but there are many alternative medications that can help manage diabetes if you can’t take metformin.

In addition to being approved for Type 2 diabetes, metformin also has many off-label uses. Examples of these include:

• Weight loss

• Prediabetes

• Gestational diabetes

• Fertility

• Polycystic ovary syndrome (PCOS)

Researchers continue to explore other uses for metformin, including cancer prevention and potential anti-aging benefits.

Why trust our experts?

Written by:

Amber Walsh, PharmD Candidate

Amber works as an intern pharmacist for a major community pharmacy chain. She has 2 years of experience so far in this practice environment.

Edited by:

Alyssa Billingsley, PharmD

Alyssa Billingsley, PharmD, is the director of pharmacy content for GoodRx. She has over a decade of experience as a pharmacist and has worked in clinical, academic, and administrative roles.

Reviewed by:

Christina Aungst, PharmD

Christina Aungst, PharmD, is a pharmacy editor for GoodRx. She began writing for GoodRx Health in 2019, transitioning from freelance writer to editor in 2021.

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