With 60 years of clinical use, Metformin is the most widely prescribed drug for the treatment of diabetes. Metformin was approved by the U.S. Food and Drug Administration in 1995 and has since become the most prescribed drug for diabetes in the United States. Although, the exact molecular mechanism of action of metformin remains partly unknown despite its use for over 60 years and more than 24,000 articles in PubMed, its main mechanism of action is widely recognized as inhibition of mitochondrial complex I → inhibits oxidative phosphorylation→ low ATP → high AMP/ADP (energetic stress) → activation of AMPK (an enzyme that senses low energy levels and activates numerous pathways to restore the intracellular ATP)→ increased glucose transport into cells and glucose metabolism (increased insulin sensitivity).

As perhaps the most important cellular energy sensor, AMP-activated protein kinase (AMPK) is activated in response to a variety of conditions that deplete cellular energy levels, such as nutrient starvation, hypoxia  and exposure to toxins that inhibit the mitochondrial respiratory chain complex. In response, AMPK alters the activity of many other genes and proteins, helping keep cells alive and functioning even when they’re running low on fuel. 

The net effect of AMPK activation is inhibition of gluconeogenesis in the liver, stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipogenesis, inhibition of adipocyte lipolysis,  and modulation of insulin secretion by pancreatic beta-cells. Activation of AMPK signifies low energy within the cell, so all of the energy consuming pathways like protein synthesis are inhibited, and pathways that generate energy are activated to restore appropriate energy levels in the cell.

Yes, Metformin activates AMPK, but it mimics energy deprived state by inhibiting the mitochondrial transport chain complex-I, which essentially poisons the mitochondria leading to ATP production mainly via glycolysis which produces only 2 ATP. On contrast, without metformin approximately 36 ATP are produced from the three stages in cellular respiration – glycolysis, the Krebs cycle (citric acid cycle), and the electron transport chain. So, cells treated with metformin become energetically inefficient, and display increased glycolysis and reduced glucose metabolism through the citric acid cycle. 

Most studies still concentrate on the liver as the main target of metformin, arguing that the blood glucose-lowering effect of metformin is mediated mainly through the suppression of hepatic glucose production. However, after oral administration, the highest concentration of metformin is not found in the liver but in the intestinal epithelium [link][link][link]

Metformin causes a futile intestinal-hepatic cycle which increases energy expenditure and slows down development of a type 2 diabetes-like state.

Up to 300 times higher concentrations of metformin accumulate in the intestine than in the circulation, where it alters nutrient metabolism in intestinal epithelial cells and microbiome, leading to increased lactate production. Hepatocytes use lactate to make glucose at the cost of energy expenditure, creating a futile intestine-liver cycle. 

So, it is not rocket science that, preasbsorptive metformin activates AMPK in gastrointestinal cells due to mitochondrial inhibition which leads to significantly increased glucose consumption in the intestine and consequently indirectly lowers blood glucose by reducing the amount of glucose that goes into the bloodstream. So, inhibition of transepithelial glucose transport in the intestine is responsible for lowering blood glucose levels during an early response to oral administration of metformin. By the way, Metformin was more effective in lowering blood glucose levels when it was administrated orally as compared to its intravenous administration.

Furthermore, there is convincing evidence that metformin changes intestinal microbiota in humans and the gut metabolome, but the significance of this finding for whole-body glucose metabolism remains unclear. On the other hand, the activation of the glucose-lactate-glucose futile cycle during long-term treatment with metformin, which includes both the intestine and the liver, results in increased energy consumption.  Increased conversion of glucose-1-13C to glucose-1,6-13C under metformin strongly supports a futile cycle of lactic acid production in the intestinal wall, and usage of the produced lactate for gluconeogenesis in liver.

Metformin activates AMPK in liver cells, which inhibits gluconeogenesis and the liver excretes less glucose. Complex I inhibition and AMPK activation are possibly the most widely studied outcomes of metformin treatment, and they are invoked as the mechanism of metformin-mediated inhibition of hepatic gluconeogenesis & lipogenesis, decrease in triglyceride accumulation, and increase in hepatic insulin sensitivity.

Pretty smart, yes?

Metformin also activates AMPK in skeletal muscle which  increases insulin-mediated glucose uptake into skeletal muscle cells (increased insulin sensitivity). But, on the other hand, we know that when AMPK is activated by ATP depletion, AMPK switches on catabolic pathways that generate ATP while switching off anabolic pathways and other ATP-consuming processes, which restores the energy balance. So it is not rocket science, that Metformin blunts the benefits of exercise by reducing mitochondrial ATP production in skeletal muscle by as much as 48%. In simple terms, Metformin abolishes the improvement in mitochondrial respiration after exercise training.

Not only that, there are preliminary findings that metformin may inhibit skeletal muscle mass gains in response to resistance training in the elderly.  Recently in september 2019,  The MASTERS ( Metformin to Augment Strength Training Effective Response in Seniors) trial found that Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults.

Since cardiorespiratory fitness is one of the strongest factors for survival into old age, and since it decreases with age, the effect of metformin on this factor is concerning, because Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Ironically, reporting and findings of randomised trials of metformin have resulted in continuing uncertainty regarding whether it reduces risk of diabetes-related complications, particularly cardiovascular disease. Furthermore, there is a lack of cardiovascular endpoint data directly relevant to a significant proportion of the patients with type 2 diabetes worldwide for whom metformin is the recommended first-line medication.

A study of over 7,000 patients with Alzheimer’s disease showed that, metformin increased the risk of developing Alzheimer’s. In a cohort study that followed about 9300 patients with T2DM in Taiwan for up to 12 years, the risk for Parkinson’s disease (PD) or Alzheimer’s dementia was more than double during a 12-year period for those who took metformin vs those who did not — even after adjusting for multiple confounders. The use of metformin may be associated with an increased risk for dementia in older African Americans with diabetes. This research was presented at the 2018 Alzheimer’s Association International Conference, held July 22-26, 2018 in Chicago, Illinois. So, supplementation with B12 is suggested with metformin use

In simple terms, Metformin Could Be Dangerous To Your Brain.

There have even been a handful of reports of metformin-induced hepatotoxicity (toxicity in the liver). In a case of nonalcoholic liver disease, metformin was pegged as the cause of jaundice, nausea, fatigue, and unintentional weight loss, two weeks after initiating treatment, due to abnormalities in liver enzymes caused by the drug.

Imagine reductions in ATP production were observed in the brain or the heart or the GI tract which leads to neurocognitive decline, psychiatric instability, neuropathy, heart rate, rhythm and blood pressure abnormalities, along with gastrointestinal distress to name but a few. Underlying all of these symptoms, and indeed, all mitochondrial dysfunction, is an overwhelming sense of fatigue and malaise.

Moreover, when insulin producing beta cells are exposed to metformin without metabolic challenges, beta cell proliferation is known to be suppressed and apoptosis is promoted [link,link,link]. Prolonged exposure results in apoptosis either via c-JNK activation and caspase-3cascade [link] or via increasing AMPK-dependent autophagy [link]. Metformin exposure also impairs insulin secretion in primary human islets, mouse islets and, mouse and rat pancreatic beta cell lines in a normoglycaemic environment [link,link]. Therefore, metformin overdosing or exposure without metabolic challenges might result in potential beta cell toxicity. 

Metformin is excreted almost entirely unchanged in urine so reduced kidney function may lead to accumulation of both metformin and lactate and therefore, a metformin-associated lactic acidosis (MALA). So it’s not a secret that, Metformin may have an adverse effect on renal function in patients with T2D and moderate CKD. Mild to moderate renal impairment is common among metformin initiators. Even, FDA recommends against starting metformin therapy in patients with estimated glomerular filtration rate (eGFR) below 45 mL/min/1.73m2

Metformin alters immune reactivity first by damaging the mitochondrial ATP factory and reducing energy production capacity and then by inhibiting the signaling cascades that would normally respond to the danger signals.

So, what gives? Is metformin healthy and anti-aging, or not?

In a retrospective 2014 analysis of 78,241 adult type 2 diabetics in their 60s, those who took metformin lived longer, on average, than healthy controls of 90,463 without diabetes of the same age. This has led a growing body of doctors beginning to prescribe the drug off-label, so that their patients may benefit from its purported anti-aging effects. Such widespread speculation demands deeper scientific investigation.

One may ask, what about the epidemiological evidence which has linked metformin to decrease the risk of cancer and cancer-related mortality?

Studies published in 2018 and 2015 suggest that people taking metformin may have a lower risk for cancer, with some studies suggesting a reduced risk of 30% to 50%. Data from two large-scale, population-based, case-control studies of breast and colorectal cancers etiology, conducted in Northern Israel since 1998 found that, Metformin use prior to diagnosis of cancer was associated with a decrease in risk of both breast cancer (OR = 0.821, 0.726–0.928, p = 0.002) and colorectal cancer (OR = 0.754, 0.623–0.912, p = 0.004).

But, it’s also hard to tell if metformin itself lowered cancer risk in the supporting studies because other treatments and interventions may have been involved. 

But, how Metformin may work to reduce cancer?

As stated above, the main mechanism of action of Metformin is widely recognized as inhibition of mitochondrial complex I → inhibits oxidative phosphorylation → low ATP → high AMP/ADP (energetic stress) → activation of AMPK which inhibits mTOR phosphorylation in the AMPK/mTOR signaling pathway, which may lead to the arrest of tumor cell cycle and the inhibition of cell growth and proliferation, which finally results in cell apoptosis.

Also, according to articles ‘metformin and cancer’ as the search terms published within the last 15 years to 15 February 2019 in the available databases including; Medline via PubMed and EMBASE via Elsevier, the potential anticancer activity of metformin was due to activation of AMPK .

On the other hand, cancer cells are known to be generally highly glycolytic (Warburg effect) and are thus not supposed to be very sensitive to mitochondrial poison. But, even if the proportion of mitochondrial ATP production is reduced in cancer cells, some mitochondrial ATP production exists and its reduction could be toxic. So, cancer cells exposed to metformin display a greater compensatory increase in aerobic glycolysis, highlighting their metabolic vulnerability. So, theoretically Metformin may act as an anti cancer agent.

By the way, Rotenone (a broad-spectrum insecticidepiscicide, and pesticide) is a well-known strong mitochondrial complex I inhibitor, yet associated with toxic effects, has also shown anti-cancer activity. 

But, Recent study on 55 629 T2DM patients found no evidence of a protective effect of metformin on individual cancer outcomes. In a recent 2020 cohort, metformin use was associated with increased risk of being diagnosed with prostate cancer.  After adjusting for baseline characteristics, metformin use was significantly associated with 76% and 77% increased odds of high-grade PCa and overall PCa, respectively, the investigators reported in Prostate Cancer and Prostatic Diseases.

So, when we contrast the reduction in glucose mediated by Metformin with the damage this medication does to the mitochondria and immune signaling, along with its ability to leach vitamin B12 and reduce aerobic capacity, one cannot help but wonder if we are causing more harm than good.  Metformin use is associated with an increase in methylmalonic acid (MMA) and worsening neuropathy score in patients with type 2 diabetes. Diagnosis of vitamin B12 deficiency can, however, be difficult, because functional vitamin B12 deficiency can occur regardless elevated serum B12 levels (normal reference range 140 to 450 pmol/L).

Researchers and advocates have been trying from 2015 to launch the TAME (Targeting Aging with Metformin) trial in USA nationwide that will engage over 3,000 individuals between the ages of 65-79. These trials will test whether those taking metformin will experience delayed development or progression of age-related chronic diseases—such as heart disease, cancer, and dementia—compared with those who take a placebo. Groundbreaking TAME trial, which directly targets aging as an endpoint, finally begins in November 2019, reveals lead clinician Dr Nir Barzilai. 

Whether metformin itself is a success or a failure, the trial will very likely revolutionise the way that aging research is done. Lets hope for the best.

Has the effectiveness of metformin actually been proven?

Ever since the results of the UKPDS 34 study were published in 1998, metformin has been considered as the first-line pharmacological treatment for type 2 diabetes.  Its efficacy was supposedly conclusively demonstrated in the UKPDS 34 study published in 1998 (reduction in mortality: RR=0.64; CI 95% (0.45 to 0.91) and in myocardial infarction: RR=0.61; CI 95% (0.41 to 0.89). However, these rather impressive results regarding total 10 year mortality (ARR=0.07; NNT=14) in a small subgroup of obese type 2 diabetes patients (342 in the metformin group vs. 411 patients in the conventional group) have never been reproduced .

For instance, the home study in 2009  evaluated the efficacy of metformin versus placebo (in addition to insulin). After four years of follow-up, no statistically significant difference was found for total mortality: RR=1.48; CI 95% (0.54 to 4.09) or for IDM: RR=0.99; CI 95% (0.25 to 3.90). Taking into account all the other randomized clinical trials (RCTs) having evaluated the specific effectiveness of metformin in DT2 patients, it becomes evident that although metformin is considered the gold standard, its benefit/risk ratio remains uncertain. We cannot exclude a 25% reduction or a 31% increase in all-cause mortality. We cannot exclude a 33% reduction or a 64% increase in cardiovascular mortality.

Even in 2019, Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommend that “Metformin remains the preferred option for initiating glucose-lowering medication in type 2 diabetes and should be added to lifestyle measures in newly diagnosed patients” referring to a single result from the UKPDS 34 study in 342 patients! 

Today 20 years after UKPDS 34 study, why no other studies cannot duplicate the positive effects of Metformin as in UKPDS 34 study?

May be, for that reason, is UKPDS study methodologically questionable? The effectiveness of metformin with regard to microvascular and macrovascular complications has never been proven in a randomized double-blind placebo-controlled clinical trial. And upon analysis of published randomized clinical trials taken as a whole, it becomes increasingly apparent that the effectiveness of metformin has not been proven, even when microvascular complications are involved. This observation leads to a more general interrogation on the fact that assessment of the clinical benefits of Metformin in general is presently lacking. 

Although metformin is not often acutely toxic, the underlying mechanisms manipulated by this drug suggest that it is likely to induce and not prevent, as is so frequently suggested, chronic illness.

To conclude, if the level of evidence concerning the efficacy of metformin is poor, and given the fact that it is proposed as firstline treatment, what are we to think of the other antidiabetic medicines? Even in 2019 American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) state “the absolute effectiveness of most oral medications rarely exceeds an 11 mmol/mol (1%) reduction in HbA1C“. 

So, it is high time to rigorously reassess antidiabetic medication on the basis not of the so-called surrogate HbA1c, but rather according to patient-relevant outcomes.

You might ask, what about the use of Metformin in PCOS?

Metformin is commonly prescribed to women with PCOS to improve the insulin sensitivity. But, Metformin has side effects such as occasional heartburn, indigestion, bloating and gas, diarrhea/constipation, weird taste in the mouth and pancreatitis, which are a common cause of treatment discontinuation.

A meta-analysis included 10 randomized controlled trials (RCTs) with a total of 845 infertile women with PCOS undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment, found that metformin has no clinical effect on the rate of pregnancy or live birth, but reduces the risk for ovarian hyperstimulation syndrome (OHSS). A later meta-analysis, including 12 RCTs and 1,516 patients, has shown the same results: metformin does not improve assisted reproductive technology outcomes among infertile patients with PCOS. The only benefit deriving from the use of metformin was the decrease in the risk for OHSS.

In conclusion, metformin represents the main insulin sensitizing agent in the management of infertile women with PCOS, with no clear benefit in improving live birth rates. Moreover, Metformin has other downfalls.

Metformin May Predispose Your Unborn Child to Neural Tube Defects

30% of people who take metformin for PCOS are vitamin B12 deficient. If you have PCOS and insulin resistance and low levels of B12, you don’t want to take a drug which could lower those levels even more.  However, B12 deficiency can also cause an increased risk of neural tube defects in unborn children. This is important for all women, but especially those who are trying to get pregnant. One study found that mothers with a vitamin B12 deficiency were up to nine times more likely to have a baby with neural tube defect, compared to those who did not have a deficiency.

Metformin During Pregnancy Leads to Heavier Mothers and Babies

It’s been shown that metformin can cross the placental barrier and therefore potentially impact the foetus. So metformin may cause metabolic changes in babies born to mothers who have taken the drug during pregnancy. These metabolic changes could predispose the child to complications later in life. A study found that in women who took metformin during pregnancy, both mother and baby were heavier one year postpartum compared to women who were given a placebo.

Metformin can Reduce Your Energy by up to  48%

As already stated above, Studies have shown that metformin depletes the mitochondria’s ability to produce energy, meaning that you are effectively operating on half the energy that you should have. This means that when you’re taking metformin for PCOS,  then the cells in all of your essential organs, including your brain and heart, your GI tract and muscle cells are only working at half capacity. It is no wonder women taking metformin for PCOS feel so fatigued all the time.

Metformin Kills Your Gut Bacteria

Gut bacteria is essential for immune function and proper weight regulation. Read any forum about metformin and you’ll find loads of stories from women who are having to base their everyday lives around where the nearest toilet just incase they have an ‘incident’. However, what most people don’t realise is that this side effect of metformin is much worse than suffering from loose stools. The reason that metformin has this effect is because it’s actually an antibiotic which seriously affects the microbiome (community of bacteria) living in the intestine. Several human and animal studies emphasized that metformin alters the gut microbiota composition by enhancing the growth of some bacteria, such as Akkermansia muciniphila, Escherichia spp. or Lactobacillus and by decreasing the levels of some other ones like Intestinibacter. 

PPIs, metformin, NSAIDs, opioids and antipsychotics were associated with increases in either members of class  Gammaproteobacteria  (including Enterobacter, Escherichia, Klebsiella, Citrobacter, Salmonella and Proteus) or members of family Enterococcaceae. All of them are frequently isolated pathogens from blood culture samples of patients with sepsis, especially critically ill and cancer patients.

On the other hand, some suggest that metformin alleviates diabetes symptoms by killing off B. fragilis, which decreases FXR activation and the resulting production of ceramides by boosting levels of FXR-inhibiting GUDCA. However, one newer study from September 2018 does suggest that metformin causes an “increase in abundance of opportunistic pathogens and further triggers the occurrence of side effects associated with the observed dysbiosis”.