Metformin
Drugs

Author: Davide Massano
Date: 14/01/2008

Description

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).

  • AMPK inhibits mTOR

??? 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.

Comments
2013-12-17T23:33:25 - Gianpiero Pescarmona

Association of B12 deficiency and clinical neuropathy with metformin use in type 2 diabetes patients, 2013

L’EMA estende l’uso della metformina per il trattamento del diabete di tipo 2

Use of metformin to treat diabetes now expanded to patients with moderately reduced kidney function

Mitochondrial dysfunction in breast cancer cells prevents tumor growth: understanding chemoprevention with metformin. 2013

  • Metformin is a well-established diabetes drug that prevents the onset of most types of human cancers in diabetic patients, especially by targeting cancer stem cells. Metformin exerts its protective effects by functioning as a weak "mitochondrial poison," as it acts as a complex I inhibitor and prevents oxidative mitochondrial metabolism (OXPHOS). Thus, mitochondrial metabolism must play an essential role in promoting tumor growth. To determine the functional role of "mitochondrial health" in breast cancer pathogenesis, here we used mitochondrial uncoupling proteins (UCPs) to genetically induce mitochondrial dysfunction in either human breast cancer cells (MDA-MB-231) or cancer-associated fibroblasts (hTERT-BJ1 cells). Our results directly show that all three UCP family members (UCP-1/2/3) induce autophagy and mitochondrial dysfunction in human breast cancer cells, which results in significant reductions in tumor growth. Conversely, induction of mitochondrial dysfunction in cancer-associated fibroblasts has just the opposite effect. More specifically, overexpression of UCP-1 in stromal fibroblasts increases β-oxidation, ketone body production and the release of ATP-rich vesicles, which "fuels" tumor growth by providing high-energy nutrients in a paracrine fashion to epithelial cancer cells. Hence, the effects of mitochondrial dysfunction are truly compartment-specific. Thus, we conclude that the beneficial anticancer effects of mitochondrial inhibitors (such as metformin) may be attributed to the induction of mitochondrial dysfunction in the epithelial cancer cell compartment. Our studies identify cancer cell mitochondria as a clear target for drug discovery and for novel therapeutic interventions.
2009-10-17T20:57:22 - ymera pignochino

Metformin as Anti-Tumor Agent

PRO

Metformin Shows Promise as Potential Anti-Tumor Agent.
Sunday August 2, 2009
A study from the University of Texas M.D. Anderson Cancer Center shows a possible link between the diabetes drug, metformin, and better outcomes for women with breast cancer.
(gonzaleg-Angulo JCO july 2009 see attachment below)
The study consisted of 2,529 women with breast cancer who had chemotherapy before surgery. 155 of the women were diabetic and 87 of those women were taking metformin at time of the study.
The group with the highest "cancer-free" rate after chemotherapy and before surgery, were the diabetic women who were taking metformin. 24% of that group were free from cancer compared to 8% of the diabetic women who were not taking metformin and 16% of the women who did not have diabetes.
"http://diabetes.about.com/b/2009/08/02/metformin-shows-promise-as-potential-anti-tumor-agent.htm"

Low doses of the commonly used diabetes drug metformin may be an effective treatment for breast cancer, primarily because the drug appears to target breast cancer stem cells, Harvard Medical School researchers reported online September 14 in Cancer Research. Cancer stem cells, also called tumor-initiating cells, are thought to be relatively rare cells that can give rise to new tumors and are resistant to standard cancer treatments.
In the study, the combination of metformin and the chemotherapy agent doxorubicin was more effective than either drug alone at eliminating cancer cells and cancer stem cells in cultured cell lines of four genetically distinct breast cancer types, including HER2-positive and triple-negative breast cancers. In a breast cancer mouse model, the drug combination eliminated tumors and prevented regrowth, whereas doxorubicin alone only reduced tumor size and did not prevent regrowth, and metformin alone had little effect.
With both drugs, regression was quicker and, more importantly, there was no relapse.
When the researchers analyzed cell populations taken from the tumors of mice after three cycles of treatment, they found almost no cancer stem cells in the animals that received the drug combination but found the stem cells easily in tumors from mice given only doxorubicin. The highly beneficial effect of the combination treatment and the limited effect of either drug alone support the cancer stem cell hypothesis.
"http://www.cancer.gov/ncicancerbulletin/092209/page3"

CONTRO

2009-10-08T08:33:24 - Gianpiero Pescarmona

Am J Cardiovasc Drugs. 2007;7(3):219-24.
Effects of simvastatin and metformin on inflammation and insulin resistance in individuals with mild metabolic syndrome. 2007

Bulcão C, Ribeiro-Filho FF, Sañudo A, Roberta Ferreira SG.

Division of Endocrinology, Department of Internal Medicine, Federal University of São Paulo, São Paulo, Brazil. cbulcao@uol.com.br
Abstract

BACKGROUND: In addition to lipid-lowering and insulin-sensitizing actions, statins (HMG-CoA reductase inhibitors) and metformin may have pleiotropic effects. OBJECTIVE: To study the effect of simvastatin and metformin on insulin sensitivity and inflammatory markers. METHODS: Forty-one subjects with body mass index (BMI) 25-39.9 kg/m(2) and impaired glucose tolerance were randomized to receive simvastatin or metformin for 16 weeks. Blood samples were obtained for measurement of metabolic and inflammatory parameters before and after each treatment. RESULTS: As expected, when compared with simvastatin, metformin therapy resulted in significant reductions in mean BMI, fasting plasma glucose, and homeostasis model assessment-insulin resistance (HOMA-IR), whereas simvastatin treatment resulted in significantly reduced total cholesterol, low-density lipoprotein-cholesterol (LDL-C), and apolipoprotein B levels. Independently of the medication used, significant decreases in C-reactive protein (CRP) and interleukin (IL)-6 were detected from baseline to treatment end. CRP showed a mean reduction of 0.12 +/- 0.04 mg/dL (p = 0.002) over the 16-week intervention period and IL-6 a mean reduction was 0.35 +/- 0.17 pg/mL (p = 0.046). No change was observed in the tumor necrosis factor-alpha levels. Baseline values of CRP and IL-6 and their percentage declines were correlated (r = 0.71 and r = 0.67, respectively; p < 0.001). In simvastatin recipients, no correlation was detected between reductions in CRP or IL-6 and lipids, whereas in metformin recipients, reductions in inflammatory markers were not correlated to BMI and HOMA-IR. CONCLUSION: Our findings suggest that both metformin and simvastatin have similar beneficial effects on low-grade inflammation, in addition to their classical effects on glucose and lipid metabolism. Moreover, they confirm the importance of treating at-risk individuals even before the precipitation of overt diabetes mellitus or full-blown metabolic syndrome.

Metformina riduce Tsh in diabetici ipotiroidei
In pazienti diabetici con ipotiroidismo, l'impiego di metformina riduce in maniera significativa i livelli serici dell'ormone Tsh (thyroid stimulating hormone), senza incidere su quelli della tetra-iodotironina (T4). A stabilirlo è uno studio condotto da un gruppo italiano presso l'Università di Brescia. In particolare, il gruppo di ricerca coordinato da Carlo Cappelli ha valutato le variazioni a breve e lungo termine dei livelli di ormoni tiroidei sia in pazienti diabetici con ipotiroidismo, sottoposti o meno a terapie con levotiroxina (L-T4), sia in individui con diabete di tipo 2 e normali funzioni tiroidee. Dopo un anno di trattamento con metformina, è stato registrato un decremento di Tsh soltanto nei diabetici ipotiroidei trattati (da 2,37 a 1,41) o non trattati (da 4,5 a 2,93) con L-T4. Nessun cambiamento significativo è stato, invece, rilevato nei livelli circolanti di T4. "Il nostro suggerimento è quello di andare a rivalutare in maniera scrupolosa la funzionalità tiroidea in questi pazienti dopo 6-12 mesi di trattamento con metformina" ha commentato Cappelli (L.A.).

Diabetes Care 2009, 32, 1589-1590

Attachments
AddThis Social Bookmark Button