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    Metformin May Extend Life for a Nickel a Pop

    Billionaires are doing it, should you?

    Metformin may extend life. Cheap, seemingly safe, and the billionaires of Silicon Valley have been rumored to take it. But should you? To find out why someone would take a diabetes medication for longevity, I asked our go-to PhD scientist, Mike James for the facts.

    What does metformin do?

    In diabetics, metformin produces a decrease in blood glucose. It also decreases cholesterol in the blood, produces weight loss and improves cardiovascular health. It decreases glucose in the blood by decreasing the production of glucose in the liver, decreasing absorption of glucose from the intestine, and increasing the movement of glucose out of the blood and into cells where it can be used for fuel. It does not cause blood glucose to go too low (hypoglycemia). 

    How long has metformin been around?

    Like some of us, metformin did not find its true calling until it was over 50 years old.  Metformin was originally synthesized in 1922 based on structures of two natural compounds, guanidine and galegine. These compounds are found in the plant Galega officinalis (Goat’s Rue), a traditional medicine. Goat’s Rue had been found to lower high blood sugar. Some synthetic guanidine derivatives were tested for their effects on blood sugar, but were found to have significant side effects and were soon overshadowed by insulin in the treatment of diabetes.

    Metformin was shelved until it was tested as a treatment for malaria in the 1940s and was observed to lower blood glucose. This led to the study of metformin for treating diabetes.  Metformin and similar compounds (biguanides) were used to treat diabetes in Europe in the late 1950s. Two similar compounds, phenformin and buformin, were abandoned in most countries due to the risk of lactic acidosis (a buildup of lactic acid in the blood). Despite usage in Europe to treat diabetes, metformin was not approved in the US until 1994. Since that time, metformin has been used to treat millions of diabetic patients and remains a mainstay of diabetic therapy

    Ok, but if I am not a diabetic, why would I take metformin?

    Metformin treatment has been associated with longer life in diabetics compared to those treated with another class of drugs, sulfonylureas, and even when compared to age and sex-matched non-diabetic controls. Metformin has been associated with a decreased incidence of cancer and improved brain function.

    The excitement about metformin is based in part on a large (180,926 patients) retrospective clinical trial out of Scotland that showed that diabetics treated with metformin had a greater survival rate (they were less likely to die during the study period) than diabetic patients treated with another class of diabetes drugs, sulfonylureas.  Even more interesting, the diabetics treated with metformin had a better survival rate than matched non-diabetic control patients. The survival rate was 38% lower in the sulfonylurea group compared with the metformin group and 15% lower in the non-diabetic group. In addition, several epidemiological studies (studies looking back at large populations of patients) have shown that metformin has been associated with a decrease in the number of cases of cancer and cancer deaths. Other studies have suggested that treatment with metformin is associated with better cognition (brain function).

    Sounds good, people seem to live longer, but what are the dangers of metformin?

    Most commonly, metformin messes with your gut — diarrhea, nausea, vomiting, gas. These effects are usually not severe enough to make folks stop taking it. A very rare but serious side effect of metformin is lactic acidosis (a buildup of lactic acid in the blood). Lactic acidosis is more common in patients with liver and kidney problems.

    Should I take metformin?

    Metformin has been around for a long time and has been given to millions of patients. It is used as the initial treatment for diabetes in most cases. Overall it has a very good safety record. Do not take it if you have any problems with liver or kidney function. As a preventative, it is not advisable for metformin to be given to people with kidney or liver problems due to the increased risk of lactic acidosis.

    It’s off label, so are there recommended dosages for metformin?

    Since the potential benefits of metformin were seen in diabetic patients at therapeutic doses, that seems like a reasonable starting point for potential “anti-aging” effects. Doses usually start at 500 mg twice a day with meals or 850 mg once a day with a meal.  Doses in diabetics are usually escalated up to 1500-2550 mg a day in divided doses every 8-12 hours with meals. In other words, maintenance doses could be 500 mg up to 850 mg three times a day with meals or 750 mg to 1275 mg twice a day with meals. Metformin is also available in a once-daily extended-release form. Doses start at 500-1000 mg once daily with dinner and can be escalated up to 2000-2500 mg once daily with dinner.  Metformin is given with meals to minimize gastrointestinal effects.

    A preventative treatment would need to be well tolerated so lower doses would seem the most reasonable, e.g., 500 mg twice a day with meals or 1000 mg extended release once daily with dinner.

    Since metformin affects blood sugar, is there a change in how people feel about their energy level?

    In a person with normal blood sugar, metformin would not alter the blood sugar level and, therefore, would not affect energy levels through an effect on blood sugar. However, general weakness has been reported as a less common side effect with metformin — likely due to an effect separate from low blood sugar.  

    What time of day would one take metformin?

    Since it is recommended to take metformin with meals, 500mg twice a day (with breakfast and dinner) would seem to be the most convenient. The extended-release form could be taken as 1000 mg daily with dinner.

    Is anyone doing actual longevity tests on metformin?

    The TAME trial.  The Targeting Aging with MEtformin trial is “a novel clinical trial, that will test whether it can delay the onset of age-related diseases and conditions including cancer, cardiovascular disease and Alzheimer’s disease.”

    The trial is being sponsored by the American Federation for Aging Research (AFAR). It is different from most clinical trials in that they are appealing to the public to fund the trial.  Since metformin is available as a generic, funding from big pharma is highly unlikely. AFAR has raised $35 million from private donors. Their goal to completely fund the trial is $55 million. The investigators are currently determining which blood tests would be the best measures for age-related diseases. They have tentatively narrowed the list to nine blood tests.

    But would you personally take metformin?

    Would I take it? Yes. My only hesitation is that I have had ulcerative colitis for 35+ years and my gut is probably more sensitive than most. I plan to talk to my family doctor about a prescription at my next visit. I would give it a try and be on the lookout for gastrointestinal side effects.

    Why? The clinical evidence is compelling. Unless the positive effects on health and longevity attributed to metformin are found to be due to some currently unknown factor, it’s hard to argue against metformin. The risk:benefit ratio appears to be positive based on the current evidence.

    Review Articles:

    Justice JN, et al.  A framework for selection of blood-based biomarkers for geroscience-guided clinical trials: report from the TAME Biomarkers WorkgroupGeroscience  40:419-436 (2018). doi: 10.1007/s11357-018-0042-y

    Rotermund C et al.  The Therapeutic Potential of Metformin in Neurodegenerative Diseases.  Front Endocrinol (Lausanne).  19:400 (2018). doi: 10.3389/fendo.2018.00400

    Valencia, WM et al. Metformin and ageing: improving ageing outcomes beyond  glycaemic control.  Diabetologia. 60: 1630–1638 (2017). doi:10.1007/s00125-017-4349-5

    Barzilai, N, Crandall, JP, Kritchevsky, SB, Espeland, MA.  Metformin as a tool to target aging.  Cell Metab 23: 1060-1065 (2016).

    Personal correspondence:

    American Federation for Aging Research (AFAR).  Personal communication via email, February 2019.  AFAR is leading the efforts to establish and fund the Targeting Aging with MEtformin (TAME) trial.

    Public press references:

    Bakalar, Nicholas.  How Long Can People Live?  New York Times 19Nov2018.

    Barzilai, Nir.  Metformin and the TAME Trial: Magic Pill or Monumental Tool?  TEDMED Blog 29Aug2017.

    Zimlich, Rachael.  Could metformin be the fountain of youth?  Medical Economics 8Jan2016

    Brenoff, Ann.  This Popular Diabetes Drug Could Become Our Fountain Of Youth.  Huffington Post  30Nov2015

     

    Mike James, PhD
    Mike James, PhD
    Mike is a PhD pharmacologist who has done research in neuropharmacology, endocrinology, metabolic and cardiovascular diseases. He has also worked as an oncology pharmacist. Mike has published over twenty peer-reviewed articles and three invited reviews
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