Metformin
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Metformin
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| Systematic (IUPAC) name | |
| 1-(diaminomethylidene)-3,3-dimethyl-guanidine | |
| Identifiers | |
| CAS number | |
| ATC code | A10 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C4H11N5 |
| Mol. mass | 129.164 g/mol 165.63 g/mol (hydrochloride) |
| Pharmacokinetic data | |
| Bioavailability | 50 to 60% under fasting conditions |
| Metabolism | None |
| Half life | 6.2 hours |
| Excretion | Active renal tubular excretion by OCT2 |
| Therapeutic considerations | |
| Licence data |
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| Pregnancy cat. | |
| Legal status | |
| Routes | Oral |
Metformin (INN; trade names Glucophage, Diabex, Diaformin, Fortamet, Riomet, Glumetza and others) is an anti-diabetic drug from the biguanide class of oral antihyperglycemic agents. Other biguanides include the withdrawn agents phenformin and buformin. Metformin is the most popular anti-diabetic drug in the United States and one of the most prescribed drugs overall, with nearly 30 million prescriptions filled in 2005.[1]
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[edit] History
The biguanide class of anti-diabetic drugs originates from the French lilac (Galega officinalis), a plant known for several centuries to reduce the symptoms of diabetes mellitus.[2]
Metformin was first described in the scientific literature in 1957.[3] It was first marketed in France in 1979, but did not receive approval by the U.S. Food and Drug Administration (FDA) for Type 2 diabetes until 1994.[4] Bristol-Myers Squibb's Glucophage was the first presentation of metformin to be marketed in the United States, on March 3, 1995.[5] Generic formulations are now available.
[edit] Indications
The main use for metformin is in the treatment of diabetes mellitus type 2, especially when this accompanies obesity and insulin resistance.
It is also being used increasingly in polycystic ovarian syndrome (PCOS),[6] non-alcoholic fatty liver disease (NAFLD)[7] and premature puberty,[8] three other diseases that feature insulin resistance; these indications are still considered experimental. Although metformin is not licenced for use in PCOS, the United Kingdom's National Institute for Health and Clinical Excellence recommends that women with PCOS and a body mass index above 25 be given metformin when other therapy has failed to produce results.[9] The benefit of metformin in NAFLD has not been extensively studied and may be only temporary.[10]
Metformin is the only anti-diabetic drug that has been proven to reduce the cardiovascular complications of diabetes, as shown in a large study of overweight patients with diabetes.[11] Unlike the other most-commonly prescribed oral diabetes drugs, the sulfonylureas, metformin monotherapy will not induce hypoglycemia.[12]
[edit] Mechanism of action
The exact mechanism of action of metformin is uncertain despite its known therapeutic benefits. Its mode of action appears to be reduction of hepatic gluconeogenesis, decreased absorption of glucose from the gastrointestinal tract, and increased insulin sensitivity. The 'average' person with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one third.[13] It has also been shown to decrease intestinal absorption of glucose, and may also improve insulin sensitivity by increasing peripheral glucose uptake and utilization, although such an effect will occur nonspecifically following the lowering of glucose levels, regardless of how this lowering was achieved. A 2001 study showed that metformin stimulates the hepatic enzyme AMP-activated protein kinase (AMPK), which plays an important role in the metabolism of fats and glucose.[14]
[edit] Adverse effects
[edit] Lactic acidosis
The most serious side effect of metformin is lactic acidosis; this complication is rare if the contra-indications are followed, as it seems limited to those with impaired liver or kidney function.
Phenformin, another biguanide, was withdrawn because of an increased risk of lactic acidosis (up to 60 cases per million patient-years). However, metformin is safer and the risk of developing lactic acidosis is not changed by the medication, so long as it is not prescribed to the known high-risk groups.[15]
[edit] Gastrointestinal
The most common side effect of metformin is gastrointestinal upset, including diarrhea, cramps, nausea and vomiting. In a clinical trial of 286 subjects, 53.2% of the 141 who were given Metformin IR (as opposed to placebo) reported diarrhea, versus 11.7% for placebo, and 25.5% reported nausea/vomiting, versus 8.3% for those on placebo.[16]
Gastrointestinal upset can cause severe discomfort for patients; it is most common when metformin is first administered, or when the dose is increased. The discomfort can often be avoided by beginning at a low dose (1 to 1.7 grams per day) and increasing the dose gradually. Gastrointestinal upset after prolonged, steady use is less common.
Long-term use of metformin has been associated with increased homocysteine levels[17] and malabsorption of vitamin B12.[18][19] Higher doses and prolonged use are associated with increased incidence of B12 deficiency, and some researchers recommend screening or prevention strategies.[20]
[edit] Contraindications
Metformin is contraindicated in any condition that may increase the risk of lactic acidosis, including heart failure, kidney disorders (creatinine levels over 150 μmol/l,[21] although this is an arbitrary limit), lung disease and liver disease. It is recommended that metformin be temporarily discontinued before any radiographic procedure involving iodinated contrast (such as a CT scan or angiogram) as contrast may temporarily impair kidney function and indirectly lead to lactic acidosis.
[edit] Formulations
Metformin IR (immediate release) is available in 500 mg, 850 mg, and 1000 mg tablets.
Metformin SR (slow release) or XR (extended release) was introduced in 2004, in 500 mg and 750 mg strengths, mainly to counteract the most common side effects, as well as increase patient compliance (e.g. taking one tablet once a day instead of one tablet multiple times per day). No difference in glycemic control exists between the two preparations.
[edit] Combinations
Metformin is often prescribed to type 2 diabetes patients in combination with rosiglitazone. This drug actively reduces insulin resistance, complementing the action of the metformin. In 2002, the two drugs were combined into a single product, Avandamet, marketed by GlaxoSmithKline.[22] In 2005, all current stock of Avandamet was seized by the FDA and removed from the market, after inspections showed the factory where it was produced was violating Good Manufacturing Practices.[23] The drug pair continued to be prescribed separately in the absence of Avandamet, which was available again by the end of that year.
In the United States, metformin is also available in combination with pioglitazone (trade name Actoplus Met) and the sulfonylureas glipizide (trade name Metaglip) and glibenclamide (trade name Glucovance).
[edit] References
- ^ The Top 300 Prescriptions for 2005 by Number of US Prescriptions Dispensed. RxList.com. Retrieved on January 9, 2007.
- ^ Witters L (2001). "The blooming of the French lilac". J Clin Invest 108 (8): 1105–7. PMID 11602616.
- ^ Ungar G, Freedman L, Shapiro S (1957). "Pharmacological studies of a new oral hypoglycemic drug". Proc Soc Exp Biol Med 95 (1): 190–2. PMID 13432032.
- ^ U.S. Food and Drug Administration (December 30, 1994). FDA Approves New Diabetes Drug. Press release. Retrieved on 2007-01-06.
- ^ GLUCOPHAGE Label and Approval History. U.S. Food and Drug Administration. Retrieved on 2007-01-08. Data available for download on FDA website.
- ^ Lord JM, Flight IHK, Norman RJ (2003). "Metformin in polycystic ovary syndrome: systematic review and meta-analysis". BMJ 327 (7421): 951–3. PMID 14576245. Free full text
- ^ Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N (2001). "Metformin in non-alcoholic steatohepatitis". Lancet 358 (9285): 893–4. PMID 11567710.
- ^ Reuters Health. Metformin Useful for Preventing Early Puberty in Girls With Precocious Pubarche. Retrieved on January 12, 2007.
- ^ UK National Collaborating Centre for Women’s and Children’s Health (February 2004). Fertility: assessment and treatment for people with fertility problems. Clinical Guideline 11. UK National Institute for Clinical Excellence. ISBN 1-84257-546-5. Free full textPDF (161 KiB)
- ^ Nair S, Diehl AM, Wiseman M, Farr GH Jr, Perrillo RP (2004). "Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial". Aliment Pharmacol Ther 20 (1): 23–28. PMID 15225167.
- ^ (1998) "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". Lancet 352 (9131): 854–65. PMID 9742977.
- ^ Kilo C, Mezitis N, Jain R, Mersey J, McGill J, Raskin P. "Starting patients with type 2 diabetes on insulin therapy using once-daily injections of biphasic insulin aspart 70/30, biphasic human insulin 70/30, or NPH insulin in combination with metformin". J Diabetes Complications 17 (6): 307-13. PMID 14583174.
- ^ Hundal R, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi S, Schumann W, Petersen K, Landau B, Shulman G (2000). "Mechanism by which metformin reduces glucose production in type 2 diabetes". Diabetes 49 (12): 2063–9. PMID 11118008. Free full textPDF (82 KiB)
- ^ Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman M, Goodyear L, Moller D (2001). "Role of AMP-activated protein kinase in mechanism of metformin action". J Clin Invest 108 (8): 1167–74. PMID 11602624. Free full text
- ^ Salpeter S, Greyber E, Pasternak G, Salpeter E (2003). "Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus: systematic review and meta-analysis". Arch Intern Med 163 (21): 2594–602. PMID 14638559.
- ^ (October 2004) Drug Facts and Comparisons 2005, 59th edition, Lippincott Williams & Wilkins. ISBN 1-57439-193-3.
- ^ Wulffele MG, Kooy A, Lehert P, Bets D, Ogterop JC, Borger van der Burg B, Donker AJ, Stehouwer CD. (Nov 2003). "Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial.". J Intern Med 254 (5): 455–63. PMID 14535967.
- ^ Andrès E, Noel E, Goichot B (2002). "Metformin-associated vitamin B12 deficiency". Arch Intern Med 162 (19): 2251–2. PMID 12390080.
- ^ Gilligan M (2002). "Metformin and vitamin B12 deficiency". Arch Intern Med 162 (4): 484–5. PMID 11863489.
- ^ Ting R, Szeto C, Chan M, Ma K, Chow K (2006). "Risk factors of vitamin B(12) deficiency in patients receiving metformin". Arch Intern Med 166 (18): 1975–9. PMID 17030830.
- ^ Jones G, Macklin J, Alexander W (2003). "Contraindications to the use of metformin". BMJ 326 (7379): 4–5. PMID 12511434. Free full text
- ^ GlaxoSmithKline (October 12, 2002). FDA Approves GlaxoSmithKline's Avandamet™ (rosiglitazone maleate and metformin HCl), The Latest Advancement in the Treatment of Type 2 Diabetes. Press release. Retrieved on 2006-12-27.
- ^ U.S. Food and Drug Administration (March 4, 2005). Questions and Answers about the Seizure of Paxil CR and Avandamet. Press release. Retrieved on 2006-12-27.
