Metformin

from Wikipedia, the free encyclopedia
Structural formula
Metformin structural formula
General
Non-proprietary name Metformin
other names

1,1-dimethyl biguanide

Molecular formula C 4 H 11 N 5
External identifiers / databases
CAS number
PubChem 4091
DrugBank DB00331
Wikidata Q19484
Drug information
ATC code

A10 BA02

Drug class

Antidiabetic drug

properties
Molar mass 129.16 g · mol -1
Physical state

firmly

Melting point

218–220 ° C (hydrochloride)

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
07 - Warning

Caution

H and P phrases H: 302-315-319
P: 305 + 351 + 338
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Metformin is a drug from the biguanide group , which is usually used for non -insulin-dependent diabetes (type 2 diabetes mellitus) and especially for slightly overweight (pre-obesity) and pathological overweight ( obesity ). It is one of the longest and most widely used oral anti-diabetic drugs . Studies have shown that it reduces the incidence of cardiovascular events in type 2 diabetes.

Working principle

Chemically, metformin belongs to the biguanides . Its mode of action is still not fully understood. The effect of metformin is probably based on three mechanisms: On the one hand, it inhibits the formation of new glucose ( gluconeogenesis ) in the liver. Experimental studies have shown that metformin inhibits mitochondrial glycerol-3-phosphate dehydrogenase . As a result, fewer metabolites are available in the cytosol for the formation of new glucose (see also glycerol-3-phosphate shuttle ), and more lactate is produced . This can explain the rare side effect of lactic acidosis when overdosed. In addition to the uptake of sugar ( glucose ) with food, this metabolic pathway, with which glucose is obtained from the conversion of amino acids and other metabolic products, is an important factor influencing the blood sugar level. In addition, metformin is said to inhibit the absorption of glucose in the intestine and also to inhibit insulin resistance decrease, which improves uptake by muscle cells . However, both effects have not yet been proven with certainty.

application

diabetes

Metformin is indicated in patients in whom diet and exercise cannot adequately control blood sugar levels. According to the guidelines of the German Diabetes Society, metformin should be used as a first-line therapy with nutritional advice as a single substance. If this does not lower the blood sugar sufficiently, it can be combined with other oral anti-diabetic drugs such as sulfonylureas , insulin sensitizers or dipeptidyl peptidase-4 inhibitors (DPP4 inhibitors) as well as with insulin itself.

Metformin is available in strengths of 500 mg, 850 mg and 1000 mg for oral administration in order to be able to adjust the blood sugar level individually . The tablets are given with or after meals. After an initial phase of around 14 days, in which one starts with low or medium doses, a dose adjustment based on the blood glucose level is usually necessary. If the kidney function is impaired, the dose must be reduced. Metformin has positive and protective properties in liver diseases. However, since the hepatic lactate elimination can be restricted, it should no longer be used in advanced liver cirrhosis or alcohol intoxication.

To increase patient compliance and reduce the number of tablets to be taken, metformin can be combined with an insulin sensitizer such as pioglitazone , a DPP4 inhibitor such as vildagliptin or an SGLT-2 inhibitor such as dapagliflozin ; Corresponding fixed combinations are available in stores.

Polycystic Ovary Syndrome (Off-Label)

Metformin has been used for years outside of its approved indications (i.e. in off-label use ) in the treatment of polycystic ovarian syndrome , where it appears to block the pathologically increased production of the male sex hormone testosterone . It is intended to give women suffering from polycystic ovarian syndrome an opportunity to nevertheless become pregnant.

In this case, the costs will not be covered by the statutory health insurance .

Other uses

Abuse in weight training

Bodybuilders are supposed to abuse metformin for fat loss.

Obesity

Because of its beneficial effect on body weight in adults, attempts have been made to use metformin in overweight children as well - but without the desired effect.

Prevention of various diseases

Several studies suggest that metformin can reduce the risk of cancer in people with type 2 diabetes. In a study published in the journal Diabetes Care in 2009 , there was a clear difference between the groups among the study participants in terms of newly occurring cancers : 7.3 percent of the patients taking metformin developed cancer. Cancer was found in 11.6 percent of diabetics without metformin treatment. The mean time to onset of cancer was 3.5 years in the metformin group and 2.6 years in the comparison group. There was therefore a lower cancer-related death rate among study participants taking metformin. Taking into account possible influencing factors such as gender, age, BMI , HbA1c , poverty (measured with the so-called Carstairs score), smoking and the use of other drugs, metformin therapy showed a 37 percent reduction in cancer risk. Other studies e.g. B. in connection with colon, prostate or breast cancer show similar results.

In a meta-analysis published in 2011 of 5 studies with a total of 108,161 type 2 diabetics, treatment with metformin led to a significantly reduced risk of developing malignant tumors of the rectum. Molecular biological or genetic explanations were not found, which is why further investigations are necessary.

The US Food and Drug Administration approved a study with 3,000 subjects in fall 2015. The study, which will begin in 2019, will take part in people between the ages of 70 and 80 who suffer from cancer, cardiovascular diseases or cognitive disorders (e.g. dementia) or have an increased risk of them. It is to be investigated whether the life expectancy of the test persons can be extended by metformin and whether the course of already existing diseases is positively influenced. The FDA's decision attracted particular attention as it is the first time it approves a study aimed not directly at preventing, treating, or curing a disease, but rather to slow the aging process.

According to an animal study published in 2019, metformin can partially repair brain damage after a stroke in mice, but only in female mice: estrogen promoted this effect, but testosterone inhibited it.

Contraindications and restrictions on use

Metformin is contraindicated in diabetic ketoacidosis or diabetic coma.

In addition, metformin must not be used in severe renal insufficiency , hepatic insufficiency , alcoholism or those accompanying circumstances that can promote acidification due to lactic acid . These include unstable heart failure or a fasting cure . Heart attack, shock or severe infections prohibit its use. The suspicion that patients with emphysema or COPD III are at increased risk for metformin-induced lactic acidosis was dispelled by a Cochrane report.

So far (as of 2015) no evidence of a teratogenic effect could be found in any of the studies. Animal experiments also did not reveal any harmful effects on prenatal development. In patients who are pregnant or who want to become pregnant, it is nevertheless recommended, as a precaution, not to treat diabetes with metformin, but to bring about normalization of the blood sugar level with insulin. Metformin crosses the placenta and is excreted in breast milk. It should only be used during pregnancy and breastfeeding mothers in justified cases in the form of a so-called therapeutic attempt, e.g. B. when the necessary insulin dosages are very high.

Before operations , anesthesia , examinations with intravascular administration (via the blood) of contrast media or intensive medical care, metformin should be discontinued 24 to 48 hours before the event due to the risk of overacidification ( acidosis ) of the blood ( lactic acidosis ).

Cortisone or glucocorticoids, asthma medication and diuretics can cause interactions. This reduces the blood sugar lowering effect. When taking cardiovascular drugs that belong to the ACE inhibitor group, it can lead to an undesirable, increased decrease in blood sugar level.

Metformin should not be used during breastfeeding. During pregnancy, a doctor should be consulted before use.

The risk of lactic acidosis is increased if metformin and large amounts of alcohol are taken at the same time. Metformin is therefore contraindicated in alcohol-dependent patients. With metformin, however, the risk of lactic acidosis is much lower than with phenformin, which is no longer on the market in Germany due to this risk. Therefore, an occasional moderate alcohol consumption combined with a meal containing carbohydrates is considered safe for patients taking metformin. This means that women can consume a glass of wine, sparkling wine (around 100 ml) or beer (around 250 ml) and men accordingly twice as much (women up to 10 g alcohol / day, men up to 20 g alcohol / day) with a meal. Alcoholic beverages rich in carbohydrates should be avoided.

Analytics

For a reliable qualitative and quantitative determination of metformin, the coupling of HPLC with mass spectrometry is used after appropriate sample preparation . This applies to the analysis of serum or plasma samples. This method is also suitable for the reliable determination of metformin in wastewater samples. In forensic issues in the case of lactic acidosis , this analytical approach has also been used successfully.

Side effects

If the contraindications are observed, gastrointestinal complaints such as diarrhea, nausea and vomiting often occur as side effects , usually only at the beginning of treatment , which can often be avoided by slowly increasing the dose over 2-3 weeks.

The Drugs Commission of the German Medical Association (AKdÄ) reported in March 2013 on the "Increase in spontaneous reports of metformin-associated lactic acidosis " ("From the UAW database").

In the case of infections with massive vomiting and persistent, severe diarrhea, metformin should be discontinued due to the risk of over-acidification of the organism. Life-threatening lactic acidosis can occur in patients with kidney failure and in connection with anesthesia . Metformin should therefore be discontinued 48 hours before and after surgery.

Low blood sugar ( hypoglycaemia ) does not occur under therapy with metformin alone, but can occur after excess alcohol, as alcohol itself lowers the blood sugar level.

According to a clinical study, there is an increased risk of vitamin B12 deficiency with long-term use of metformin .

Environmental aspects

Metformin and its main transformation product guanylurea have been regularly detected in sewage treatment plant runoffs and surface waters. Guanylurea was measured in concentrations of over 200 micrograms per liter in the Erpe river near Berlin. These values ​​are in the range of the highest detection concentrations of drug transformation products in the aquatic environment. The Rhine near Basel carries over a whole year ago, about 13 tons of the antidiabetic drug for the North Sea.

literature

Trade names

Monopreparations

Biocos (D), Diabesin (D), Diabetase (D), Diabetex (A), Espa formin (D), Glucobon Biomo (D), Glucophage (D, A, CH), Juformin (D), Mediabet (D) , Meglucon (A), Mescorit (D), Met (D), Metfin (CH), Metfogamma (D), Metformin-CT (D), Siofor (D), numerous generics (D, A, CH)

Combination preparations

Avandamet (D, A, CH), Competact (D, A, CH), Diabiformin (CH), Efficib (A), Eucreas (D, A), Janumet (D, A, CH), Komboglyze (D), Pioglitazone / Metformin hydrochloride (A), Synjardy (EU), Velmetia (D, A), Vildagliptin / Metformin hydrochloride (A), Xigduo (D), Zomarist (A)

Individual evidence

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  2. ↑ a b Datasheet Metformin hydrochloride from Sigma-Aldrich , accessed on November 5, 2016 ( PDF ).
  3. ↑ S-Naveed, A. Shafiq et al. a .: Degradation Study of Available Brands of Metformin in Karachi Using UV Spectrophotometer. In: J Diabetes Metab. Number 5, 2014, p. 328, doi : 10.4172 / 2155-6156.1000328 .
  4. ↑ Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group . In: The Lancet . 352, No. 9131, 1998, pp. 854-865. PMID 9742977 .
  5. ↑ a b H. Mehnert: Diabetology in clinic and practice . 5th edition. Georg Thieme Verlag, 2003, ISBN 3-13-512805-9 , p. 219 ff . ( limited preview in Google Book search).
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    Madiraju et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 2014; 510: 542-546. doi : 10.1038 / nature13270
  7. ↑ A. Natali, E. Ferrannini: Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review. In: Diabetologia. Volume 49, Number 3, March 2006, pp. 434-441, doi : 10.1007 / s00125-006-0141-7 . PMID 16477438 . (Review).
  8. ↑ Richard Daikeler, idols Use, Sylke Waibel: diabetes. Evidence-based diagnosis and therapy. 10th edition. Kitteltaschenbuch, Sinsheim 2015, ISBN 978-3-00-050903-2 , p. 157 f. (quoted).
  9. ↑ P. Schweikert-Wehner: Diabetes in hepatic insufficiency: Targeted selection and dosage of antidiabetic drugs . In: Doctors newspaper (ed.): Perspektiven der Diabetologie . No. 115/41 . Doctors Verlag, Berlin 2018.
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    JMM Evans u. a .: Abstract: Metformin and reduced risk of cancer in diabetic patients . British Medical Journal , April 22, 2005, accessed March 24, 2011.
    Metformin Suppresses Colorectal Aberrant Crypt Foci in a Short-term Clinical Trial . Abstract of the American Association for Cancer Research , September 2010, DOI: 10.1158 / 1940-6207.CAPR-10-0186 , accessed on May 2, 2017.
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    Maren Emmerich: Drugs against getting older? Book review of "The Secret of Human Aging" . Spectrum of Science , July 30, 2015, accessed on May 2, 2017.
    Ernst Mauritz: Study approved: anti-diabetes drugs could soon be the official anti-aging pill . Courier , December 2, 2015, accessed May 2, 2017.
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  19. ↑ a b Merck Serono GmbH: Specialist information Glucophage® 500/850/1000 mg film-coated tablets. As of April 2017.
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  21. ↑ metformin . ( Memento of the original from July 21, 2016 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. embryotox.de, updated on September 24, 2013, accessed on May 2, 2017. @1@ 2Template: Webachiv / IABot / www.embryotox.de
  22. ↑ Preoperative evaluation of adult patients before elective, non-cardiothoracic surgery. Joint recommendation of the DGAI, DGCH and DGIM. In: Anaesthesiology and Intensive Care Medicine. Volume 58, 2017, pp. 349-364. DOI: 10.19224 / ai2017.349
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  26. ↑ Strugaru AM, Kazakova J, Butnaru E, Caba IC, Bello-López MÁ, Fernández-Torres R: Simultaneous determination of metformin and glimepiride in human serum by ultra high performance liquid chromatography quadrupole time of flight mass spectrometry detection. , J Pharm Biomed Anal. 2019 Feb 20; 165: 276-283, PMID 30572192
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  28. ↑ Oertel R, Baldauf J, Rossmann J: Development and validation of a hydrophilic interaction liquid chromatography-tandem mass spectrometry method for the quantification of the antidiabetic drug metformin and six others pharmaceuticals in wastewater. , J Chromatogr A. 2018 Jun 29; 1556: 73-80, PMID 29748091
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  32. ↑ Martin Bischof, Bernhard Ludvik, Martin Kraupp, Christian Nanoff, Anton Luger: Diabetes mellitus . In: Bernhard Ludvik, Martin Bischof, Martin Kraupp, Anton Luger (eds.): Endocrinology and Metabolism (= MCW-Block, 10). Facultas.wuv, Vienna, 6th edition, 2012, ISBN 978-3-7089-0814-4 , p. 136.
  33. ↑ See vitamin B12 deficiency due to metformin . ( Memento of the original from March 4, 2016 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. Deutsches Ärzteblatt, May 21, 2010, accessed on May 2, 2017. J. de Jager, A. Kooy, P. Lehert, MG Wulffelé, J. van der Kolk, D. Bets, J. Verburg, AJ Donker, CD Stehouwer : Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomized placebo controlled trial. In: BMJ (Clinical research ed.). Volume 340, 2010, p. C2181, PMID 20488910 . PMC 2874129 (free full text). @1@ 2Template: Webachiv / IABot / www.aerzteblatt.de
  34. ↑ Posselt M, Jaeger A, Schaper JL, Radke M, Benskin JP: Determination of polar organic micropollutants in surface and pore water by high-resolution sampling-direct injection-ultra high performance liquid chromatography-tandem mass spectrometry . In: Environ. Sci .: Process. Impacts . December 20, 2018, pp. 1716–1727. doi : 10.1039 / C8EM00390D . PMID 30350841 .
  35. ↑ Andri Bryner: Keeping rivers clean is provision for drinking water . In: eawag.ch , September 9, 2014, accessed on March 15, 2020.