Metformin (Glucophage®) has been prescribed for type-2 diabetes, or T2D since its approval by the FDA in 19941-2. In 2002, Metformin became the most commonly prescribed oral anti-hyperglycemic medication. Currently, it is being taken daily by over 200 million people. Like the majority of prescription drugs, it is based on a similar compound found in nature that was effective for many, but had some severe adverse side effects. That is, the perennial plant Galega officinalis (also known as Goat’s Rue and French Lilac) was used to treat frequent urination and increased thirst, which now are symptoms of hyperglycemia. This herb contains a bioactive compound that contains a chemical structure called biguanidine. Metformin also has this group, but the rest of the structure is different, making it much safer, with far fewer adverse side effects.
Metformin is also quite useful in preventing T2D in people who are pre-diabetic. It reduces the amount of glucose that is released from the liver and increases the transport of glucose into muscles, increasing insulin sensitivity and decreasing glucose absorption from the gastrointestinal tract. Metformin accumulates in the gut, where it inhibits the absorption of glucose, activates key enzymes and helps build a healthy microbiome. This can be especially important to T2D patients who often have an unhealthy microbiome and a leaky gut. Metformin may also be useful in treating other diseases, and possibly even slowing down aging. It reduces the incidence of cancer and mortality, while helping people retain proper cognitive function. It may also affect aging by activating AMP-activated protein kinase (AMPK) and reducing DNA damage. So, metformin favorably influences metabolic and cellular processes that are closely linked to the development of age-related problems, such as inflammation and cellular senescence. Since it is so inexpensive and easy to obtain, metformin could be especially useful in countries where many people don’t have much money.
Perhaps the most exciting potential use of metformin is in extending the lifespan of not just people who have diabetes, but also in slowing down the aging process. It does this by affecting several biochemical pathways that are important in how prediabetics age.
Metformin (850 mg twice daily) was administered to subjects in a Diabetes Prevention Program (DPP). It reduced the incidence of T2D by 31% compared to placebo after three years and prevented diabetes. Moreover, metformin improved risk factors for cardiovascular diseases and subclinical atherosclerosis (coronary artery calcium) in male participants. Partly due to these important health benefits of metformin, some scientists are rejecting the idea that we die of old age. Instead, we die of cumulative failures that occur within our cells and tissues. These failures are not inevitable breakdowns. They are reversible conditions of aging.
One of the most important of these failures is a less active AMPK. Its concentration is relatively high when we are young, but decreases with age. Recent studies have suggested that increasing the activity of AMPK can prevent and possibly reverse the life-shortening effects of aging. Some scientists are beginning to refer to AMPK as a suppressor of aging itself. As AMPK decreases when we age, we become less energetic and more obese, while becoming increasingly vulnerable to cancer and diseases associated with impaired DNA and protein function. As a person accumulates abdominal fat, this leads to reduced insulin sensitivity, system-wide smoldering inflammation and metabolic syndrome. This, in turn, can lead to many forms of cancer, as well as cardiovascular, neurodegenerative and autoimmune diseases (including T2D).
The modern Western lifestyle with its overabundance of nutrients and low level of physical activity exacerbates this. When a person’s caloric intake is too high and/or physical activity too low, AMPK activation decreases. As a result, cells decrease their energy-releasing ATP-generating activities and shift to energy-storing processes that generate new fat deposits and make excess new glucose. Moreover, energy inefficiency eventually leads to the dysfunctions that are often described as inevitable diseases (or symptoms) of aging. So, restoring the activity of AMPK in the elderly may not only increase longevity, but also help to fight the symptoms of aging. This hypothesis was supported by a clinical study in which subjects with T2D either received metformin (which activates AMPK) or placebo. They were compared to subjects who did not have T2D. It was found that the subjects who were diabetic and received metformin lived a median of 15% longer than did matched controls without diabetes.
Also, metformin may help save the lives of diabetics who are exposed to the SARS-CoV-2 virus that causes Covid-193-4. Metformin inhibits the growth of this virus in cell culture. So, it may help prevent infection before the disease can emerge. However, millions have been infected. One of the strongest determinants of how severe the disease becomes is the patient’s control of hyperglycemia. Since metformin is so effective in this, it saves the lives of many diabetics. In addition, people who take metformin are often protected from the severe problems caused by long Covid5.
Even though most people who get Covid-19 recover completely within a few weeks, some continue to experience symptoms after their initial recovery. This has been called post-Covid-19 syndrome or "long Covid-19." The problem has several names, including persistent post-Covid syndrome (PPCS). The National Institutes of Health refer to long-term Covid-19 symptoms as PASC, which stands for post-acute sequelae of SARS-CoV-2. More common terms are post-Covid syndrome, long Covid or long-term Covid. These health problems are sometimes called post-Covid-19 conditions. They are generally considered to be effects of Covid-19 that persist for more than four weeks after initially testing positive for the SARS-CoV-2 virus. By this time, the patients test negative for the virus. It has been effectively removed from their bodies by their immune systems. Still, they suffer the long term effects. Even those who had mild versions of the disease are vulnerable. Common signs and symptoms that linger over time include: fatigue, shortness of breath or difficulty breathing, cough, joint pain, chest pain, problems with memory, concentration or sleep, muscle pain or headache, fast or pounding heartbeat, loss of smell or taste, depression or anxiety, fever, dizziness when you stand, worsened symptoms after physical or mental activities.
The SARS-CoV-2 virus can attack the body many ways, causing damage to the lungs, heart, nervous system, kidneys, liver and other organs Also, mental health problems can arise from grief and loss, unresolved pain or fatigue, or from PTSD after treatment in the intensive care unit (ICU). A bad case of Covid-19 can produce scarring and other permanent damage in the lungs. They can recover after, but it can take months for lung function to return to pre-Covid-19 levels. Breathing exercises and respiratory therapy can help. SARS-CoV-2 infection can leave some people with heart problems, including inflammation of the heart muscle. One study found that many people who recovered from Covid-19 had signs of ongoing heart inflammation, which could lead to the common symptoms of shortness of breath, palpitations and rapid heartbeat. The SARS-CoV-2 virus has also caused kidney disease. Some people suffer from a loss of smell and taste. For about a quarter of people with Covid-19 who have these symptoms, the problem resolves in a couple of weeks. In others, these symptoms persist. Though not life-threatening, prolonged distortion of these senses can be devastating and can lead to lack of appetite, anxiety and depression.
Some people also suffer from brain fog, fatigue, headaches and dizziness. After surviving Covid-19, some people are left with lingering anxiety, depression and other mental health issues. Physical changes such as pain and weakness can be complicated by long periods of isolation, stress from job loss and financial difficulties, and grief from the deaths of loved ones and the loss of good health. Patients who were hospitalized have a particularly challenging recovery. People who have spent time in the ICU have a higher risk of problems with mental health, cognition and physical recovery. Prolonged time in the ICU can cause delirium. The strange surroundings, multiple mind-altering medications, isolation and loss of control can leave patients with lasting and recurrent sensations of terror or dread, including PTSD. Long-term Covid-19 symptoms also occur in other diseases. So, it is important to seek medical attention to see if there are other problems, such as cardiovascular or lung disease. A loss of smell, depression, anxiety or insomnia should not be dismissed as unimportant or simply psychosomatic, or all in your head. Any symptom that interferes with one’s daily life should be reported to your doctor, who can help you address these problems and improve the quality of your life. If you experience new chest pain, difficulty breathing, bluish lips or any other sign of a life-threatening problem, call emergency services right away.
Some children have experienced long-term Covid-19. It has even affected some who were quite healthy before being infected by the SARS-CoV-2 virus. Heart inflammation after Covid-19 is a concern, especially among young athletes returning to their sports after a mild or even asymptomatic case. They should be screened for any signs of heart damage to ensure it is safe for them to resume activity. Multisystem inflammatory syndrome in children (MIS-C) can develop 1–2 months after the acute infection with the virus and cause high fever, organ dysfunction and inflammation.
So, metformin not only saves lives, but prevents human suffering. However, it does cause severe adverse side effects in some people. So, as with all prescription medicines, it should only be taken under the supervision of a physician and a pharmacist. It is not a dietary supplement.
Finally, a healthy diet and lifestyle can help prevent hyperglycemia in most people. This can be done through a Mediterranean diet consisting of many fruits and vegetables, whole grains, olive oil, seafood and legumes. Physical activity, positive thinking, mindfulness, prayer and meaningful, loving relationships also help.
1 Baker, C. et al. Should metformin remain the first-line therapy for treatment of type 2 diabetes? Therapeutic Advances in Endocrinology and Metabolism, Volume 12, p. 1-13, 2021.
2 Foretz, M. Metformin: update on mechanisms of action and repurposing potential. Nature Reviews Endocrinology, May, 2023.
3 Pedrosa, A.R. et al. Metformin in SARS-CoV-2 infection: A hidden path – from altered inflammation to reduced mortality. A review from the literature. Journal of Diabetes and Its Complications Volume 37, article 108391, 2023.
4 Ma, Z. & Krishnmurthy, M. Is metformin use associated with low mortality in patients with type 2 diabetes mellitus hospitalized for COVID-19? A multivariable and propensity score-adjusted meta-analysis. PLoS ONE Volume 18, article e0282210, 2023.
5 McCarthy, M.W. Metformin as a potential treatment for Covid-19. Expert Opinion in Pharmacology, 2023.