metformin

see also:

• oral hypoglycaemic agents
• radiologic contrast media precautions and adverse reactions

• a biguanide oral hypoglycaemic agent which is very useful in the treatment of patients with insulin resistance
• it was developed from the herb Galega officianalis and 1st synthesized in 1922 but overshadowed by the 1st use of insulin in the same year
• it was eventually studied in trials for diabetics in 1957 as Glucophage in the same year that a related biguanide, phenformin was studied then energetically marketed globally while metformin was mainly marketed in Europe, particularly, France where it was manufactured.
• phenformin was removed from market in 1977 after it was confirmed that it was associated with life threatening lactic acidosis which was initially suggested in 1959. Phenformin was particularly problematic in this regard as it was metabolised by the liver and it accumulates in people with a genetic deficiency of the enzyme cytochrome P450 2D6.
• in contrast, metformin is mainly excreted by the kidneys and lactic acidosis is mainly confined to overdoses and those with advanced renal failure.
• nevertheless, as a result of these concerns, metformin fell out of favour until its benefits were rediscovered in 1995 leading to it becoming the 1st choice for obese patients with type 2 diabetes mellitus, then in 2012, experts in USA and Europe declared that it should be 1st choice for all patients with type 2 diabetes.
• metformin is now also used to Rx polycystic ovary syndrome (PCOS) (which is associated with insulin resistance), gestational diabetes, and is showing promise in the prevention of cancers such as pancreatic cancer (it appears to lower risk by ~62%) and it may appear to decrease overall cancer risk by 25-37%.
• a major issue for ED doctors in patients who take metformin is the significantly increased risk of radiologic contrast media precautions and adverse reactions in iv contrast media use in radiology such as CT scans which needs active management to prevent nephrotoxicity and subsequent lactic acidosis.
• sold under various trade names, including Glucophage XR, Carbophage SR, Riomet, Fortamet, Glumetza, Obimet, Gluformin, Dianben, Diabex, and Diaformin
• the slow release versions are mainly to reduce GIT side effects and to improve compliance
• tablets are usually 500mg or 1000mg although there is a 850mg immediate release form and a 750mg slow and extended release forms

• usual dose is 500-1000mg bd or tds

• those at risk of lactic acidosis
  • significant renal impairment
  • severe lung disease
  • severe liver disease
  • severe acute exacerbations of congestive cardiac failure HOWEVER, a 2007 systematic review of controlled trials, suggested metformin is the only antidiabetic drug not associated with any measurable harm in people with heart failure, and that it may reduce mortality in comparison with other antidiabetic agents
  • iv contrast media
    • see radiologic contrast media precautions and adverse reactions

• diarrhea, cramps, nausea, vomiting and increased flatulence are common
• life threatening lactic acidosis is fortunately rare
• vitamin B12 malabsorption

• metformin requires the presence of growth differentiation factor 15 (GDF15) to activate its main pharmacological target (AMPK) and have antidiabetic effects
  • Growth differentiation factor-15 (GDF-15) is a cytokine secreted by a variety of cells like macrophages, adipocytes, normally expressed in high amounts by placenta. It is also highly expressed in multiple carcinomas like Colon, Breast, Pancreas, Liver, and Ovarian.
• it improves hyperglyceamia primarily by suppressing glucose production by the liver via:
  • activation of AMP-activated protein kinase (AMPK), an enzyme that plays an important role in insulin signaling
  • increases the levels of miRNA let-7, a signalling molecule in several physiological functions but the expression of which is reduced in diabetic states
    • MicroRNAs (micro RNAs (miRNAs)) are fundamental post-transcriptional modulators of several critical cellular processes
    • miRNAs have a central role in regulating a number of genes, particularly those genes involved in signaling pathways, and several physiological processes in human cells, including (but not limited to) cellular proliferation, lifespan, metabolism, and cell cycle control
    • Extracellular vesicles (EVs) can package, release, and transfer miRNAs between cells in a somewhat selective manner where they can be taken up by target cells and then release their contents into the target cells
    • miRNA let-7 functions as an essential regulator of the function and differentiation of both innate and adaptive immune cells
    • in mammals, let-7 is among the miRNAs with the highest expression level in numerous cell types in different species.
    • Let-7 family members are involved in critical physiological processes, such as organ development, growth, tissue regeneration, metabolism, and various types of cancer and are associated with viral infection, dysfunction of liver cells, and immune response ¹⁾
  • activating the conversion of glucose to lactate and acetate in the intestine - these two metabolites reach the liver via the portal vein and trigger processes that reduce hepatic glucose production.
• it increases insulin sensitivity, enhances peripheral glucose uptake, increases fatty acid oxidation and decreases absorption of glucose from the gastrointestinal tract
• it may antagonise the action of glucagon, thus reducing fasting glucose levels

• slowly absorbed
• peak plasma concentrations reached 1-3hrs after oral dose
• steady state achieved within 1-2 days of Rx
• less than 0.01% is un-ionised in blood, hence it is not lipophilic and does not enter cells readily, although it has a large appparent Vd of 300-1000L after a single dose, presumably as it is mainly distributed to RBC's
• it is not metabolised
• elimination is renal excretion with average plasma half-life of 6.2hrs, while RBC half life is much longer at ~18 hours

• most common symptoms following overdose appear to include vomiting, diarrhoea, abdominal pain, tachycardia, drowsiness, and, rarely, hypoglycaemia or hyperglycaemia.
• the major potentially life-threatening complication of metformin overdose is lactic acidosis, particularly if doses over 5,000mg in adults
• in healthy children, unintentional doses of less than 1,700 mg are unlikely to cause any significant toxic effects