Metformin

Metformin is sold under several trade names, including Glucophage XR, Carbophage SR, Riomet, Fortamet, Glumetza, Obimet, Gluformin, Dianben, Diabex, Diaformin, Siofor, Metfogamma and Glifor. The USDA cites it as a weed.

While endless pharmacovigilance has monitored the safety profile of metformin, its natural ancestor, G. officinalis (known as Professor Weed in the USA) is a Class A Federal Noxious Weed in 35 states of America, and appears on the database of poisonous plants. (Wiley)

History?

The discovery of metformin dates back to 17th century. Galega officinalis L., also known as the French lilac, was used as a herbal remedy to relieve the intense urination caused by the diabetes mellitus in medieval times [1]. The guanides are rich in French lilac and essential compounds in lowering blood glucose, which led to development of three biguanides, metformin, phenformn, and buformin. Among them metformin was found to be the most useful drug because of its low toxicity. It was first synthesized in 1922, but approved for treatment of diabetes in Europe until 1950s and by FDA in USA in 1994. It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.^[15]

Galega officinalis Linn was a herbal medicine in medieval Europe. G. officinalis (Leguminosae) is a perennial herb with white, blue or purple flowers that grows over three feet high and is found in most temperate regions, including Britain. Its common names include goat’s rue, French lilac, Spanish sanfoin and false indigo  Aerial parts of the plant were used medicinally in medieval Europe to treat plague, worms, snake bites, miasma, dysuria and St Vitus dance, and the plant was fed to livestock to increase milk yield.

Purpose?

• Metformin is the first-line medication prescribed to over 150 million patients worldwide for the treatment of type 2 diabetes,[5][6] particularly in people who are overweight.[7] It is also used in the treatment of polycystic ovary syndrome (PCOS).[5] Limited evidence suggests metformin may reduce chances of certain forms of cancer, arising from complications of diabetes.[8][9]
• The molecular mechanism of metformin is incompletely understood. Multiple potential mechanisms of action have been proposed, including; inhibition of the mitochondrial respiratory chain (complex I), activation of AMP-activated protein kinase (AMPK), inhibition of glucagon-induced elevation of cyclic adenosine monophosphate (cAMP) with reduced activation of protein kinase A (PKA), inhibition of mitochondrial glycerophosphate dehydrogenase, and an effect on gut microbiota.^[97][98][99]

Why Supplement?

• Metformin’s main effect is to decrease liver glucose production.^[79] It also has an insulin-sensitizing effect with multiple actions on tissues including the liver, skeletal muscle, endothelium, adipose tissue, and the ovary.^[38][95]
• Metformin decreases high blood sugar, primarily by suppressing liver glucose production (hepatic gluconeogenesis).^[79]
• A 2017 review and meta-analysis found that people with diabetes who were taking metformin had 7% lower all-cause mortality. They also had reduced cancer (breast, gastrointestinal, liver, pancreatic) than those on other therapies.
• Numerous epidemiologic studies have shown an association of metformin use with a decreased risk of cancer, as well as decreased cancer mortality. (There is also evidence from studies performed both in-vitro and in-vivo of metformin’s role in attenuating tumorigenesis. The mechanisms proposed relate to its effects on reducing insulin levels, improving insulin action, decreasing IGF-1 signaling (central to mammalian longevity), and reducing the senescent process (senolytics) as well as activation of AMP-kinase.
• A large population-based study evaluated the effect of metformin on five-year survival. Records of 78,000 diabetic patients treated with metformin were compared with records of 78,000 non-diabetic subjects and matched for relevant characteristics, such as age, smoking, cancer history, etc. Similar comparison was performed between 12,000 diabetic patients taking sulphonylurea (SU) drugs and 12,000 matched non-diabetic individuals. Not unexpectedly, SU-treated diabetic patients had ~40 percent greater mortality than their non-diabetic control group. However, mortality in metformin-treated diabetic patients was similar to the matched non-diabetic controls. In fact, among patients in their 70s, mortality was reduced by ~15 percent in metformin-treated diabetic patients compared with non-diabetic controls. These observations suggested that the protective action of metformin may extend beyond effects on specific age-related diseases. It was used to provide compelling evidence to support the design and conduct of studies to directly test whether human aging, and its diseases, could be effectively delayed.
• 40% of humans are non-responders to metformin, so only get the side-effects.

Leading Anti-Aging Scientists taking Metformin include:

• Ray Kurzweil
• David Sinclair
• Nobel laureate James Watson
• Ned David, cofounder of Silicon Valley startup Unity Biotechnology
• Robert Hariri, co-founder and president of Human Longevity Cellular Therapeutics

Dosage?

• Varies from 500mg to 2500mg by formulation. See Mayo Clinic recommendations
• In the United States, Metformin requires a doctor’s prescription
• Metformin has an oral bioavailability of 50–60% under fasting conditions, and is absorbed slowly.^[92][114]
• Metformin is not metabolized. It is cleared from the body by tubular secretion and excreted unchanged in the urine; metformin is undetectable in blood plasma within 24 hours of a single oral dose.^[92][118] The average elimination half-life in plasma is 6.2 hours.^[92] Metformin is distributed to (and appears to accumulate in) red blood cells, with a much longer elimination half-life: 17.6 hours^[92] (reported as ranging from 18.5 to 31.5 hours in a single-dose study of nondiabetics).^[118]

Clinical Trials?

• 1648 Completed Clinical Trials!
• 66 Active Trials, no longer recruiting
• Metformin and Aging Study in PreDiabetes Adults — 25 patient Phase 3 study with completion date of July 31, 2021.
• Metformin in Longevity (MILES) concluded in May 2018
  • Showed improved insulin sensitivity.
  • Of concern, it also found significantly reduced gene expression in muscles.
  • MILES, finished in 2017. Identified biomarkers to be used in TAME.
• TAME study: Targeting Aging With Metformin.
  • “Soon”, Barzilai and a team of gerontologists from 14 top aging research centers will begin a clinical trial to study the effects of metformin on aging. The trial will be an ambitious six-year, $77 million effort, involving 3,000 patients.
  • Despite getting the “green-light” in 2019 and multiple attempts to start it since 2015, TAME does not appear to have started.
• Berberine vs MetFormin

Side Effects and Adverse Events?

• Metformin is generally well tolerated.^[10]
• Common side effects include diarrhea, nausea and abdominal pain.^[5]
• It has a low risk of causing low blood sugar.^[5]
• High blood lactic acid level is a concern if the medication is prescribed inappropriately and in overly large doses.^[11]
• It should not be used in those with significant liver disease or kidney problems.^[5]
• Significantly reduced gene expression in muscles.
• While no clear harm comes from use during pregnancy, insulin is generally preferred for gestational diabetes.^[5][12]  (Wikipedia)

Data Sources:

• Wikipedia
• Healthspancampaign.org  Dr Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine in the Bronx
• Wired  (Really good article. Questions the stats of the trials a bit too.)
• Wiley
• Afar.org on TAME trial
• NIH.gov  (read this!)
• FrontiersIn.org
• Medium, Human Data for Metformin