Published Paper Details:

For more than 60 years, Metformin, a synthetic biguanide chemically derived from Galega officinalis, has been the first and most frequently chosen one of the first-line antihyperglycemic agents in the treatment of Type 2 Diabetes Mellitus (T2DM) patients. Its multifactorial mechanism of action in conjunction with a good safety profile and some cardio-protective effects make long-term use essentially the main reason for its continuous effectiveness. The major part of antidiabetic effect is due to the inhibition of Hepatic Glucose Production (HGP). Metformin after it is delivered to the liver cell via Organic Cation Transporter 1 (OCT1), only mildly inhibits mitochondrial respiratory chain Complex I. Due to the inhibition of oxidative phosphorylation, the cell experiences energetic stress; hence the AMP/ATP ratio increases and the irradiated AMP-Activated Protein Kinase (AMPK) is one. The activated AMPK then down-regulates the genes for gluconeogenesis (for example, PEPCK, G6Pase), glucose production being lowered accordingly. Metformin also alters the liver in a way that does not depend on AMPK. One of those ways involves glucagon ceasing stimulation of the cAMP pathway and at the same time inhibiting mitochondrial glycerol-3-phosphate dehydrogenase (mGPD). On the top of that, metformin doesn't depend entirely on the liver (extrahepatic/gut-mediated) mechanisms. Most of metformin's effect occurs in the intestine hence muscle glucose uptake is a result of increased gut glucose uptake by metformin. In addition, incretin hormone (GLP-1 and PYY) secretion which, among other things, is the main cause of the weight-neutral/weight-loss effect in metformin treated individuals, is also increased. Metformin is usually indicated to be the cause of an HbA1c reduction effect of 1.0% to 1.5%. The landmark UK Prospective Diabetes Study (UKPDS) provided the main proof of metformin's supremacy by demonstrating a substantial decrease of the first-time myocardial infarction and all-cause mortality in overweight individuals - a cardiovascular protection effect, which was prolonged and deepened for 20 years ("legacy effect"). In general, the medication is safe but some dose-related gastrointestinal symptoms have been reported as the most common side effects. The most important med, though seldom, risk is Metformin-Associated Lactic Acidosis (MALA) which mainly occurs in patients with renal impairment (eGFR <30 mL/min/1.73 m2). Also, the long-term exposure requires the monitoring of Vitamin B12 deficiency. In addition to that, Metformin has a few more potential effects on the positive side like anticancer capability via IMPK-mTOR pathway suppression, a good effect on PCOS and probably a gero protective agent (the focus of the TAME Trial). New drug classes (SGLT2i, GLP-1RA) with solid CVOT data are slowly but surely putting metformin in second place for patients with established cardiovascular disease as first-line treatment, however, it remains the most logical, evidence-based, cost-effective, and indispensable foundation for pharmacological intervention of T2DM worldwide.