In 2015, when Tu Youyou won the Nobel Prize in Medicine for her discovery of artemisinin, people not only congratulated the first Chinese female scientist to win the Nobel Prize but also became interested in artemisinin derived from the plant Artemisia annua (sweet wormwood). Some remarked: “I never expected such a significant discovery to come from something so commonplace in daily life.”
In fact, throughout the history of modern medicine, there are many examples of using plant materials to process, extract, and synthesize drugs. For instance, the chemotherapy drug paclitaxel, used to treat ovarian, breast, and lung cancers, is synthesized from the bark of the Pacific yew tree; one of the key components of antiviral drugs for avian influenza, oseltamivir, is derived from the commonly found star anise.
In the field of diabetes, there is also a drug with significant ties to natural plants: metformin, which has been used clinically to treat diabetes since the 1950s. As a biguanide hypoglycemic agent, it is derived from a plant known as Galega officinalis (goat’s rue), also called French lilac or Spanish clover. It was discovered around the same time as insulin but initially received less attention due to insulin’s rapid effects and significant therapeutic benefits. However, as the medical community’s understanding of diabetes matured, the treatment approach for diabetes evolved. Metformin, with over sixty years of clinical application, has become a first-line treatment in major type 2 diabetes guidelines both domestically and internationally, as it not only lowers blood sugar but also has a certain weight loss effect. Behind this lies a wealth of hidden historical impressions.
In 1922, metformin was first synthesized by two Irish scientists, Werner and Bell. After a series of studies, the first commercially viable metformin tablet appeared in 1959. By 1995, the original metformin drug officially entered China. Today, metformin has been around for 100 years, providing continuous help to countless diabetes patients. Looking back from the present, we can see that the development history of metformin resonates with the treatment trends of diabetes. To some extent, the development of metformin symbolizes a microcosm of the past century’s advancements in diabetes treatment and reflects the shift in people’s concepts of chronic disease health management.
Metformin:
From Obscurity to First-Line Medication
Galega officinalis:
As early as the Middle Ages in Europe, it was observed that goats fed on Galega officinalis (goat’s rue) produced more milk but also experienced severe hypoglycemia, sometimes leading to death. At that time, people made tea from goat’s rue to alleviate polyuria, a typical symptom of diabetes.
In the 1920s, goat’s rue was introduced to the United States and was classified as a harmful plant due to its association with livestock deaths. However, this caught the attention of Irish scientists, who extracted guanidine from goat’s rue and conducted research on a series of biguanide derivatives, leading to the birth of metformin.
Meanwhile, insulin was discovered by Canadian physiologist Frederick Banting. With its rapid blood sugar-lowering advantages, insulin quickly gained favor among doctors and patients, with some believing that diabetes had been “conquered.”
However, the negative effects of solely using insulin for diabetes treatment began to emerge. Due to the immature synthesis methods of insulin at the time, patients could experience hypoglycemia, excessive weight gain, and fat atrophy. Combined with the medical community’s research on diabetes treatment mechanisms, it was widely believed that other more precise, effective, and stable-acting medications were needed during the early and stable stages of diabetes.
In 1957, Dr. Jean Sterne from France and his colleagues first used metformin in clinical diabetes treatment.
The development of ideas sparked a new wave of research and led to metformin receiving overdue attention for its stability and gentleness. During this process, two significant diabetes research studies emerged, further elevating metformin to a larger stage.
The first was the UKPDS (United Kingdom Prospective Diabetes Study), which began in 1977. Through research and long-term follow-up of thousands of newly diagnosed type 2 diabetes patients, it was found that patients using metformin had a significantly reduced risk of myocardial infarction. In the second decade, metformin still reduced the risk of myocardial infarction by 33%, showing a clear advantage over sulfonylureas and insulin.
The second noteworthy study was the Chinese Diabetes Prevention Study, which began in Daqing in 1986. Professor Li Guangwei, who experienced the entire process, stated: “China was one of the earliest countries to conduct diabetes prevention research. The active lifestyle interventions from 1986 to 1992 proved that diabetes can be prevented. Following that, a 30-year follow-up further demonstrated that diabetes prevention can reduce cardiovascular diseases and mortality risk. Both were the first reports in the world.”
If the past focus of diabetes treatment was primarily on blood sugar levels, then these two studies and many subsequent large clinical trials broadened the perspective of diabetes treatment, incorporating early prevention and reducing the risk of late complications into the theory and practice of disease treatment. Professor Li Guangwei remarked: “In the past, our goal in treating diabetes was to control the patient’s blood sugar to prevent future heart disease. Now, we look at whether diabetes patients can achieve normal blood sugar levels through early rational medication and maintain it for three months before stopping medication. We then observe whether they can remain normal for two or three years. For those who have been ill for a long time, we aim to achieve blood sugar targets and reduce weight in obese patients to delay the onset of future complications.”
Shifting the focus from blood sugar to outcomes is currently the core strategy in diabetes treatment. Metformin plays a crucial role in this. “Metformin can be used in combination with all hypoglycemic agents, and it can also change insulin sensitivity and restore the insulin secretion function of β-cells. Treatment guidelines have consistently emphasized the foundational role of metformin,” Professor Li Guangwei stated. “In addition to controlling blood sugar, another key aspect is weight loss. Even if blood sugar is well controlled, if the patient is excessively obese, the risk of cardiovascular disease increases. Focusing on outcomes means that lowering blood sugar is not enough; long-term clinical outcomes such as the risk of myocardial infarction, stroke, and mortality must also be reduced.”
Today, weight loss has become an unavoidable topic in diabetes treatment. Professor Li Guangwei shared a case of a newly diagnosed diabetes patient in their thirties who, through early treatment, weight loss, and lifestyle control, has maintained normal blood sugar for five years without injections or medication. This patient continues to persevere. Research abroad has also reported that maintaining a daily intake of 800 kilocalories, equivalent to three chive-filled pancakes, resulted in a weight loss of over 15 kilograms, with 60% of newly diagnosed diabetes patients achieving normal blood sugar levels. Over time, the risks of paralysis, blindness, and amputations will inevitably decrease. Professor Li Guangwei stated: “Unlike before, diabetes patients today can see hope, which motivates them. In the past, many people developed various complications ten or twenty years after diagnosis; this situation will certainly change in the future.”
Meanwhile, this new treatment approach is also being disseminated to doctors in more municipal and county hospitals. Professor Li Guangwei mentioned that he has visited many municipal hospitals across the country and observed that many grassroots doctors work extremely hard, but many still make the same mistakes that older doctors made two or three decades ago. He believes that after experienced doctors personally guide them in ward rounds, the current advanced theories will be reflected and implemented in their clinical practice.
Metformin:
From “Cornerstone” to the Future
Since 2000, the role of metformin in diabetes treatment has become increasingly important.
In September 2022, the European Diabetes Congress concluded. Professor Li Guangwei represented his research team from the China Diabetes Prevention Study (CDPP) and shared new research findings. A group of 1,700 prediabetic individuals (including those with elevated fasting blood sugar but normal postprandial blood sugar, and those with elevated fasting and postprandial blood sugar) was divided into two groups: one received lifestyle interventions of simply eating less and being more active, while the other received metformin combined with lifestyle interventions. After at least two years of follow-up, it was found that the group receiving metformin combined with lifestyle interventions had a 17% lower risk of developing diabetes compared to the other group. Professor Li Guangwei stated: “Currently, there are 120 million diabetes patients in China, and 250 million people are at risk of diabetes. We have already seen that the combination of medication and lifestyle interventions is effective; next, we need to determine the timing of medication intervention and identify the appropriate population for medication intervention.”
Today, there are many chronic diseases like diabetes that accompany patients long-term. Doctors are gradually realizing that eradicating chronic diseases is an impossible task; therefore, delaying the onset of chronic diseases in at-risk populations and minimizing their impact on lifespan has become a crucial aspect of future chronic disease management. The commonly mentioned “early screening, early diagnosis, early prevention, and early treatment” also stems from this.
As the “cornerstone” of diabetes treatment and prevention, metformin, which has been around for 100 years, has also been discovered to have new potential applications in other clinical areas. Ms. Mao Jingmei, head of the Merck Medical Department, who has a deep understanding of metformin, shared with us various new exploratory application fields of metformin: “As the original research company of metformin, Merck has been continuously exploring its potential. In addition to cardiovascular protection, metformin has also shown some research on anti-tumor effects (Expert Consensus on Clinical Application of Metformin, 2018) and reducing the severity of COVID-19 (Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19 2022). For patients with polycystic ovary syndrome who are unable to conceive, doctors also use metformin in combination with other treatments (Expert Consensus on Clinical Application of Metformin, 2018).”
Perhaps the most exciting news is the potential of metformin in anti-aging, particularly in age-related diseases like Alzheimer’s disease. Ms. Mao Jingmei stated: “Although the causes of Alzheimer’s disease remain unclear, recent years have seen research in the United States exploring the relationship between metformin use in primates closely related to humans and anti-aging. In today’s aging trend, we can reconsider: if metformin can find its relationship with aging through protein mechanisms or technical research, its significance will change.”
Looking back over the past 100 years, the development of metformin and its functions align closely with people’s views and understanding of chronic diseases. Our relationship with chronic diseases may not be one of confrontation but rather one that emphasizes balance and efficiency. As Ms. Mao Jingmei stated: “Diabetes is not frightening; with standardized treatment and a healthy lifestyle, we can be healthy individuals who can still work normally and enjoy life.”
When we talk about diabetes again,
What can we expect?
With metformin being listed as a first-line treatment in major type 2 diabetes guidelines, the treatment of diabetes has undergone a long evolution, shifting from simple blood sugar control to a strategy that focuses on the entire life cycle of the patient. Regarding the future, Professor Li Guangwei stated: “Our current treatment strategies can allow patients to live better, but more people need to know: diabetes indeed has many harms, but it also has a bright future. As long as we start with prevention, targeting young people, diabetes patients can also have a bright and happy future.”
“Ancient physicians treated diseases before they occurred,” Ms. Mao Jingmei also believes that preventing diabetes is an important and necessary task. “Diabetes can be prevented and controlled. We hope to work together with all sectors of society to promote healthy lifestyles and standardized treatments, strengthen early diagnosis and treatment of diabetes, and enhance public awareness of scientific diabetes management. At the same time, we also hope to innovate in medications and improve drug accessibility so that every diabetes patient can enjoy a healthy, beautiful, and dignified life.”
From the data, the number of diabetes patients is so high that the distance between the public and the disease is becoming closer. However, compared to the past fear of diabetes, people today have a better understanding of the disease. After a century, metformin remains relevant and continues to play an important role in the prevention and treatment of diabetes, helping more people return to a normal life.
Note: Professor Li Guangwei is the head of the Endocrinology Department at Fuwai Hospital, Chinese Academy of Medical Sciences, and the chief expert in endocrinology at the China-Japan Friendship Hospital.
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