Metformin: effective type 2 diabetes treatment and more

If metformin did nothing more than treat diabetes, which it does remarkably well, it would still be one of the major medical advances of the last century. But the most significant part of the metformin story may be written in the next few years. The FDA has approved a trial called TAME (Targeting Aging with Metformin). This trial is an attempt to determine if metformin can do more than anyone ever imagined—become the first medication proven to prolong life.    

It is possible that a decades-old drug found in millions of medicine cabinets around the globe could be the answer to a longer and healthier life—and not only for people with diabetes.      

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Metformin has been used in Europe since the 1950s to treat high blood sugar due to type 2 diabetes. It was first introduced in the US in 1995 and was originally marketed under brand names, like Glucophage and Glumetza. It is currently the first-line drug to lower blood sugar in type 2 diabetes (Marshall, 2017). However, over the past 50 years, healthcare providers and patients have found it useful in the treatment of a variety of conditions.

Metformin is part of a family of drugs derived from the French lilac (Witters, 2001). The active ingredient in the French lilac that lowers glucose levels is called guanidine. Guanidine was later synthesized into drugs that collectively formed the family called biguanides. Metformin is currently the only member of this class of drugs available as only it has proven to be both effective and safe. 

Probably one of the more fascinating things about metformin is its potential as an anti-aging drug. This should not be surprising considering how it positively affects so many cellular processes that affect our health. 

In terms of diabetes, metformin works to lower blood sugar levels primarily by blocking the production of glucose by the liver, a process called gluconeogenesis (Rena, 2017). Metformin may also work by increasing the ability of skeletal muscle to remove glucose from the bloodstream and use it for energy (Musi, 2002). 

But although metformin has been used for over 70 years, how it works isn't exactly clear. That said, a wide range of cellular effects have been discovered more recently, and metformin's story is beginning to be understood. That story begins with a bacterium, Streptomyces hygroscopicus, found in the soil of Rapa Nui, also known as Easter Island. 

A compound was isolated from the bacteria and was named rapamycin (after Rapa Nui) (Li, 2014). First used as an antifungal agent, it was noted to have a potent effect on the immune system and was used to prevent rejection in organ transplants. Today, drugs like everolimus and sirolimus are used to prevent rejection of organ transplants and treat some tumors are based on rapamycin and called "rapalogs." This turned out to be only the beginning of rapamycin's story.

Rapamycin has a wide range of effects because it can block a gene that makes proteins that are involved in cell growth and the metabolism of cells. The gene derives its name from rapamycin itself and is called mammalian Target Of Rapamycin (mTOR). It's implicated in a number of human diseases, including cancer, diabetes, neurological conditions, genetic disorders, and obesity.

The gene, mTOR, responds to multiple signals to make its proteins; everything from growth factors, nutrients, energy and oxygen levels that determine cell growth and proliferation, to the making of proteins and the building blocks of DNA. 

Moreover, evidence is beginning to accumulate, which indicates that mTOR plays a role in the aging process and the development of age-related diseases (Johnson, 2013). 

Metformin has been found to affect that very same gene as rapamycin, mTOR. Metformin increases an enzyme called Adenosine MonoPhosphate-activated Protein Kinase (AMPK). 

AMPK is an enzyme that becomes more active when the cell senses a low energy state. It activates cellular pathways that increase the cell's defenses to stress and may improve cell survival. One of the ways AMPK does this is by blocking the mTOR gene, which, in theory, can affect the aging process along with many other cellular activities.

Metformin's positive effects may also be due to mildly inhibiting Complex I of the mitochondria, commonly called "the powerhouse of the cell" (Vial, 2019). This is part of the cell's energy production machine, and slightly decreasing energy production may also lead to beneficial cellular changes.

Many studies in animal models have revealed a positive effect on longevity when metformin was added to their diets. In one study, for example, metformin increased the lifespan of different mouse breeds by 4%–6% (Martin-Montalvo, 2013). 

While not all studies have shown a longevity benefit with metformin, one large study has. In this study, observational data from the UK Clinical Practice Research Datalink (UKPDS) was used to compare patients with diabetes who had been treated with metformin to similar patients without diabetes. They reported, "Surprisingly, metformin-treated diabetic patients had survival rates similar to (and, among those aged > 70, even better than) their matched non-diabetic control group, despite the fact that the diabetic patients were more obese and had greater co-morbidities at baseline. Mortality benefits have also been described in other observational studies and long-term follow-up of the UKPDS cohort, which showed a 36% reduction in all-cause mortality in the metformin treatment group" (Bannister, 2014).

The authors concluded, "Intriguingly, these findings suggest that there may be a prognostic benefit of metformin prophylaxis in people without diabetes (Bannister, 2014).

For those with diabetes and those without, knowing about metformin while awaiting the results of the many research studies underway would seem prudent.

Metformin was originally indicated for lowering glucose in people with type 2 diabetes and is currently FDA-approved for the treatment of type 2 diabetes in adults and children ages 10 and up. Nevertheless, metformin is also commonly used "off-label" for a variety of seemingly unrelated conditions. The wide range of conditions affected was an initial indication that metformin had an impact on more than blood glucose levels. These conditions included:

• Polycystic Ovary Syndrome (PCOS) This is the most common female endocrine (hormonal) disorder affecting as many as 10% of women (Bozdag, 2016). Some of the common abnormalities include high androgen levels, menstrual irregularity, and insulin resistance. Women with PCOS are often treated with metformin, although the evidence it is effective is not conclusive (Lashen, 2010). 

• Gestational diabetes: This is diabetes that occurs during pregnancy, usually in the second or third trimester. Traditionally, insulin was the mainstay of drug therapy when lifestyle modifications were not sufficient. However, many healthcare providers treat people with gestational diabetes with metformin instead of insulin (Tripathi, 2017).

• PrediabetesThis occurs when glucose regulation begins to fail but has yet to become full-blown diabetes. Metformin is often used to treat prediabetes and has been shown to decrease the risk of progression to diabetes by 31% (DPPRG, 2002).

• Preventing weight gain induced by antipsychotic treatment: Metformin has also been found effective in decreasing weight gain and metabolic abnormalities in those taking antipsychotic medications (de Silva, 2016). 

One study showed that metformin reduced cardiovascular events and death due to cardiovascular disease in people with type 2 diabetes, including those with baseline cardiovascular disease (Han, 2019). Another study showed that metformin protected against heart attacks better than sulfonylureas even when hemoglobin A1C, a measure of blood sugar control, was the same in both groups (Holman, 2008). 

There is conflicting research, but one large study showed that metformin use is associated with a decreased risk of cancer and death from cancer (Gandini, 2014). Unfortunately, this has not been shown in studies designed to test metformin's effect on cancer.

There are also conflicting data about metformin's ability to protect against cognitive decline and dementia, but most of the research suggests that metformin may be protective (Cheng, 2014).

Metformin is available in regular release tablets and extended-release tablets. The regular release tablets are available in 500 mg, 850 mg, and 1,000 mg doses, and the extended-release tablets are available in 500 mg, 750 mg, and 1,000 mg doses. In the US, the maximum dose of either formulation is 2,000 mg daily. The only difference between the 500 mg and 1,000 mg tablets are in the flexibility of dosing they allow. The 500 mg dose allows people to increase their dose slowly, which can improve the tolerability of metformin.

Most healthcare providers recommend taking metformin with food to decrease the gastrointestinal side effects that are more common when people first start taking metformin. It is also often recommended that people work their way up to their full dose. For example: if your healthcare provider wants you to take 1,000 mg twice a day for a total of 2,000 mg daily, s/he may recommend you start by taking one 500 mg tablet once a day with a meal. After two weeks, you would increase to 500 mg twice daily with meals for another two weeks. After another two weeks, you would take 1,000 mg with breakfast and 500 mg with dinner, and two weeks after that, you would start taking 1,000 mg twice daily with meals. In this way, it may take up to 2 months to reach the full dose of metformin prescribed. This may seem tedious, but it often helps people tolerate a medicine that will help them live a longer and healthier life rather than just starting at the full dose and stopping due to side effects.

The most common side effects of metformin are gastrointestinal, including diarrhea, nausea, vomiting, and abdominal pain. These side effects can be minimized by taking metformin with food and increasing the dose slowly over time. 

Vitamin B12 deficiency can occur after prolonged use in some people. The American Diabetes Association (ADA) recommends that people using metformin long-term have their vitamin B12 levels checked as well as people taking metformin who have anemia or neuropathy (ADA, 2019). If vitamin B12 levels are not checked, neuropathy (nerve pain) caused by B12 deficiency can be mistaken for neuropathy caused by diabetes itself, which can delay treatment of the deficiency. 

Serious side effects, like lactic acidosis, are extremely rare. Metformin should not be used in people with advanced kidney disease, but it is safe to use in those with mild-moderate kidney disease. If you have kidney problems or poor kidney function, your healthcare provider will work with you to determine if metformin is appropriate for you. 

Although metformin has an excellent safety profile, overdoses can be dangerous. Most cases of metformin overdose that have been described in the medical literature have been due to intentional suicide attempts. Never take more metformin than what is prescribed. The maximum dose of metformin is 2,000 mg per day. If overdosed, metformin can cause lactic acidosis, which is a life-threatening condition. The symptoms of lactic acidosis include:

• Nausea, vomiting, diarrhea

• Rapid, shallow breathing

• Fast heart rate

• Muscle aches

• Abdominal pain

• Weakness

• Fatigue, lethargy, and unusual sleepiness

• Decreased appetite 

• Headaches

If you, or someone you know, experience these symptoms after taking more than the recommended amount of metformin, you should seek emergency medical treatment. Lactic acidosis is a medical emergency, which can be lethal. Treatment should be administered in an intensive care unit (ICU) and may include dialysis to remove the drug from the bloodstream.

There are many drugs that can interact with metformin. Tell your healthcare provider about all of your medications before starting metformin. Some important drugs that interact with metformin include:

• Other drugs used to lower blood sugar in diabetes

• Drugs that affect the kidneys

• Certain HIV drugs

• Certain drugs used in autoimmune diseases, such as lupus

This is not a complete list. For a full list of drugs that interact with metformin, check the Prescriber's Digital Reference (PDR).

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Current version

August 08, 2019

Written by

Tzvi Doron, DO

Fact checked by

Michael Reitano, MD

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About the medical reviewer

Dr. Michael Reitano, MD