DESCRIPTION
Metformin is an oral anti-diabetic drug from the biguanide class and it is used as an oral antidiabetic drug
INDICATIONS
It is the first-line drug of choice for the treatment of type 2 diabetes, particularly in overweight and obese people and those with normal kidney function (to reduce risk of lactic acidosis).
MOLECULAR MECHANISM
Metformin mediates its action by stimulating adenosine monophosphate-activated protein kinase (AMPK).
??? in liver and muscle to improve glucose and lipid metabolism.
Protein Aminoacids Percentage (Width 700 px)
From the evolutionary point of view the sequence is from the oldest to the newest:
mTOR --> AAPK1 --> AAKB1 --> AAKG1
mTOR regulation of protein synthesis was probably strictly regulated by AA availability, mainly by methionine and leucine
Later on the control of the activity was dependent on AAPK1, on AAPK1+AAPKB1 and finally in recent times by AAPK1+AAPKB1+AAKG1
- AMPK also reduces enzymatic pathways involved in incraesing fatty acid production by the liver. (ACC = acteyl-CoA carboxylase; SREPB-1 = sterol-regulatory-element-binding-protein-1) In this manner it reduces storage of fat in the liver and in the blood carrier protein (VLDL or very low density lipoprotein) that shuttles triglycerides (trigs) and the body.
see Oral antihyperglycemic therapy for type 2 diabetes mellitus. CMAJ. 2005
Anti-folate activity
Metabolomic fingerprint reveals that metformin impairs one-carbon metabolism in a manner similar to the antifolate class of chemotherapy drugs, 2012
Because the biosynthetic pathways within the one-carbon network compete for a limiting pool of folate cofactors and folate-binding proteins can serve as “sinks” that sequester specific folates and thereby inhibit folate-dependent pathways, metformin-induced sequestration of 5-formimino-THF can simultaneously impairs the de novo nucleotide biosynthetic pathway while promoting GSH depletion.
Standard Anti-folate Therapy
SIDE EFFECTS
- Lactic acidosis Case Report, 2009 (limited to those with impaired liver or kidney function).
Metformin associated lactic acidosis 2009
- Gastrointestinal (diarrhea, cramps, nausea and vomiting).
Metformin Induces a Dietary Restriction–Like State and the Oxidative Stress Response to Extend C. elegans Healthspan via AMPK, LKB1, and SKN-1 2009
Cell cycle arrest in Metformin treated breast cancer cells involves activation of AMPK, downregulation of cyclin D1, and requires p27Kip1 or p21Cip1 2008
COMBINATION
Metformin is available in combination with sulfonylureas to improve the treatment.
* Carenza di B12 in terapia protratta con metformina*
I pazienti diabetici trattati per lungo tempo con metformina hanno un rischio aumentato di andare incontro a una carenza di vitamina B12 (con aumento della concentrazione ematica di omocisteina) i cui livelli andrebbero pertanto costantemente monitorati nel corso della terapia. La raccomandazione emerge dai risultati di un trial olandese multicentrico randomizzato placebo-controllato, nel quale 360 pazienti con malattia di tipo 2 in terapia insulinica sono stati trattati con 850 mg di metformina o placebo tre volte al giorno per 4,3 anni. L'outcome primario era rappresentato dalla modificazione percentuale delle concentrazioni di vitamina B12, acido folico e omocisteina dal basale ai mesi 4, 17, 30, 43 e 52. Rispetto al placebo, il trattamento con metformina è risultato associato a una riduzione media di concentrazione di vitamina B12 del 19% (P<0,001) e di acido folico del 5% (P=0,033), e a un aumento di omocisteinemia del 5% (P=0,091). Dopo correzione per indice di massa corporea e fumo, non si è trovato alcun effetto significativo della metformina sulla concentrazione dell'acido folico. Il rischio assoluto di carenza di vitamina B12 (<150 pmol/l) al termine dello studio è risultato di 7,2 punti percenutali maggiore nel gruppo metformina rispetto a quello placebo, con un numero necessario per nuocere (NNH) di 13,8 per 4,3 anni. Anche il rischio assoluto di un basso livello di vitamina B12 (150-220 pmol/l) alla fine del trial era di 11,2 punti percentuali superiore nei soggetti trattati con metformina rispetto al placebo, con un NNH di 8,9. I pazienti con carenza di vitamina B12 a fine studio avevano un livello medio di omocistenemia pari a 23,7 micromol/l, da raffrontare con i 18,1 micromol/l dei soggetti con bassi livelli di vitamina B12 (P=0,003) e i 14,9 micromol/l di quelli con normale concentrazione (>220 pmol/l) di vitamina B12 (P<0,001 in confronto a carenza B12; P=0,005 in confronto a basso livello B12).
BMJ, 2010; 340:c2181
Diabetes Obes Metab. 2010 Dec 3. doi: 10.1111/j.1463-1326.2010.01349.x. [Epub ahead of print]
Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomised clinical trials., 2010
Lamanna C, Monami M, Marchionni N, Mannucci E.
Background: Some studies suggested that metformin could reduce cardiovascular risk to a greater extent than that determined by glucose reduction. Aim of the present meta-analysis is the assessment of the effects of metformin on the incidence of cardiovascular events and mortality. Methods: An extensive search of Medline, EMBASE, and the Cochrane Library (any date up to October 31st, 2009) was performed for all trials containing the word ''metformin''. Randomized trials with a duration≥52 weeks were included. A meta-regression analysis was also performed to identify factors associated with cardiovascular morbidity and mortality in metformin-treated patients. Results: A total of 35 clinical trials were selected including 7,171 and 11,301 participants treated with metformin and comparator, respectively who had 451 and 775 CV events, respectively. Overall, metformin was not associated with significant harm or benefit on cardiovascular events (MH-OR 0.94[0.82-1.07], p=0.34). A significant benefit was observed in trials versus placebo/no therapy (MH-OR 0.79[0.64-0.98], p=0.031), but not in active-comparator trials (MH-OR 1.03[0.72-1.77], p=0.89). Metaregression showed a significant correlation of the effect of metformin on cardiovascular events with trial duration and with minimum and maximum age for inclusion, meaning that the drug appeared to be more beneficial in longer trials enrolling younger patients. It is likely that metformin monotherapy is associated with improved survival (MH-OR: 0.801[0.625;1.024], p=0.076). However, concomitant use with sulfonylureas was associated with reduced survival (MH-OR: 1.432[1.068;1.918], p=0.016). Conclusion: Available evidence seems to exclude any overall harmful effect of metformin on cardiovascular risk, suggesting a possible benefit versus placebo/no treatment. The observed detrimental effect of the combination with sulfonylureas deserves further investigation.
Hypothyroidism
Miscellaneous
Administration with metformin (150 mg / kg, p.o.), a widely used oral hypoglycemic agent, to diabetic animals further reduced circulating thyroid hormones and caused drug-induced hypothyroidism.