Eur J Endocrinol. 2005 Feb;152(2):269-75.
Effects of metformin and ethinyl estradiol-cyproterone acetate on lipid levels in obese and non-obese women with polycystic ovary syndrome.
Rautio K, Tapanainen JS, Ruokonen A, Morin-Papunen LC.
Departments of Obstetrics and Gynecology, University Hospital of Oulu, PO Box 5000, FIN-90 014, Finland.

OBJECTIVE: Women with polycystic ovary syndrome (PCOS) exhibit risk factors for cardiovascular diseases such as abdominal obesity, insulin resistance and dyslipidemia. Insulin sensitizers, especially metformin, have been shown to improve these metabolic disturbances, but there are only a few studies on their effects on serum lipids in polycystic ovary syndrome. METHODS: Thirty-five women with PCOS (18 obese and 17 non-obese) were randomized to 6-month treatments with metformin or ethinyl estradiol-cyproterone acetate oral contraceptive pills. RESULTS: In the whole-study population (non-obese and obese women) serum levels of high-density lipoprotein cholesterol increased from 1.4+/-0.2 to 1.6+/-0.1 mmol/l (means +/-s.e. throughout) at 3 and 6 months (P < 0.001), the total cholesterol:high-density lipoprotein cholesterol ratio decreased significantly from 3.8+/-0.3 to 3.3+/-0.2 at 6 months (P < 0.001) and a similar trend was observed in serum triglyceride levels during metformin treatment. In the oral contraceptive group, serum levels of total cholesterol increased from 4.9+/-0.3 to 5.4+/-0.3 mmol/l (P < 0.05), high-density lipoprotein cholesterol increased from 1.2+/-0.1 to 1.5+/-0.1 mmol/l (P < 0.001), the total cholesterol:high-density lipoprotein cholesterol ratio decreased from 4.6+/-0.4 to 3.7+/-0.2 (P < 0.001) and triglycerides increased from 1.3+/-0.1 to 1.9+/-0.2 mmol/l at 6 months of treatment (P < 0.001). Serum low-density lipoprotein cholesterol levels remained unchanged during both treatments. Milder but similar changes in the subgroups of obese and non-obese women were observed during both treatments. Moreover, in the whole-study population both systolic (P = 0.02) and diastolic (P = 0.05) blood pressures decreased over the 6 months of metformin treatment. CONCLUSION: In women with PCOS, metformin treatment had beneficial effects on lipid profile and blood pressure, and therefore it could be useful in the prevention of cardiovascular complications in these women.

BMJ. 2003 Oct 25;327(7421):951-3.
Metformin in polycystic ovary syndrome: systematic review and meta-analysis.
Lord JM, Flight IH, Norman RJ.
Department of Endocrinology and Metabolism, Peninsula Medical School, South West Centre for Reproductive Medicine, Derriford Hospital, Plymouth, Devon, PL6 8DH.

OBJECTIVE: To assess the effectiveness of metformin in improving clinical and biochemical features of polycystic ovary syndrome. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Randomised controlled trials that investigated the effect of metformin compared with either placebo or no treatment, or compared with an ovulation induction agent. SELECTION OF STUDIES: 13 trials were included for analysis, including 543 women with polycystic ovary syndrome that was defined by using biochemical or ultrasound evidence. MAIN OUTCOME MEASURE: Pregnancy and ovulation rates. Secondary outcomes of clinical and biochemical features of polycystic ovary syndrome. RESULTS: Meta-analysis showed that metformin is effective in achieving ovulation in women with polycystic ovary syndrome, with odds ratios of 3.88 (95% confidence interval 2.25 to 6.69) for metformin compared with placebo and 4.41 (2.37 to 8.22) for metformin and clomifene compared with clomifene alone. An analysis of pregnancy rates shows a significant treatment effect for metformin and clomifene (odds ratio 4.40, 1.96 to 9.85). Metformin has an effect in reducing fasting insulin concentrations, blood pressure, and low density lipoprotein cholesterol. We found no evidence of any effect on body mass index or waist:hip ratio. Metformin was associated with a higher incidence of nausea, vomiting, and other gastrointestinal disturbance. CONCLUSIONS: Metformin is an effective treatment for anovulation in women with polycystic ovary syndrome. Its choice as a first line agent seems justified, and there is some evidence of benefit on variables of the metabolic syndrome. No data are available regarding the safety of metformin in long term use in young women and only limited data on its safety in early pregnancy. It should be used as an adjuvant to general lifestyle improvements and not as a replacement for increased exercise and improved diet.

J Clin Endocrinol Metab 2003 Mar;88(3):1323-32
Metformin rapidly increases insulin receptor activation in human liver and signals preferentially through insulin-receptor substrate-2
Gunton JE, Delhanty PJ, Takahashi S, Baxter RC
Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St. Leonards, Sydney, New South Wales 2065 Australia

Metformin decreases endogenous glucose production by the liver. Few studies have examined the effect of metformin on the insulin-signaling pathway in liver models, and none have presented data on the effect in normal human liver. Huh7 human hepatoma cells and primary human hepatocytes were used. Insulin receptor (IR) and IR substrates (IRS)-1 and -2 were assessed by immunoprecipitation and immunoblot. Normal human liver was used to assay IR kinase activity (IR-KA). Tyrphostin AG1024 was used to inhibit IR-KA and examine effects on deoxyglucose uptake. Metformin (1 micro g/ml) increased IR tyrosine phosphorylation by 78% (P = 0.0007) in 30 min in human hepatocytes and Huh7 cells and increased IRS-2 but not IRS-1 activation, and the downstream increase in deoxyglucose uptake was mediated via increased translocation of GLUT-1 to the plasma membrane. Metformin did not augment maximal or submaximal insulin-stimulated IR activation. Metformin increased basal IR-KA by 150% (P = 0.0001). AG1024 inhibited metformin-induced IR-beta phosphorylation in a concentration-dependent manner and abolished metformin-induced 2-deoxyglucose uptake. This study demonstrates that the mechanism of action of metformin in liver involves IR activation, followed by selective IRS-2 activation, and increased glucose uptake via increased GLUT-1 translocation. The effect of metformin was completely blocked by an IR inhibitor.

Diabetes Metab 1996 Feb;22(1):43-50
Is metformin safe enough for ageing type 2 diabetic patients?
Gregorio F, Ambrosi F, Filipponi P, Manfrini S, Testa I.
Anti-Diabetic Unit, E. Profili General Hospital, Fabriano (AN), Italy.

We assessed the effect of adding low doses of metformin to sulfonylurea therapy in 76 elderly Type 2 diabetic patients by monitoring glycaemic control and blood lactate for one year. Metformin markedly improved glycaemic control. Fasting lactate concentrations were not affected and post-meal lactate peaks were minimally increased. Additional benefits included an improvement in some lipid parameters, a reduction in serum uric acid and a significant weight loss in overweight patients. Metformin was clinically well-tolerated. Instead of advanced age alone, renal function and/or any other age-related factor likely to contribute to lactate overproduction should be the basis for deciding on metformin therapy. No evidence indicated that metformin should be denied "a priori" to ageing Type 2 diabetic patients.

J Clin Endocrinol Metab 1991 Dec;73(6):1294-301
Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects
DeFronzo RA, Barzilai N, Simonson DC
Department of Medicine, University of Texas Health Science Center, San Antonio 78284-7877

The effect of metformin on glucose metabolism was examined in eight obese (percent ideal body weight, 151 +/- 9%) and six lean (percent ideal body weight, 104 +/- 4%) noninsulin-dependent diabetic (NIDD) subjects before and after 3 months of metformin treatment (2.5 g/day). Fasting plasma glucose (11.5-8.8 mmol/L), hemoglobin-A1c (9.8-7.7%), oral glucose tolerance test response (20.0-17.0 mmol/L; peak glucose), total cholesterol (5.67-4.71 mmol/L), and triglycerides (2.77-1.52 mmol/L) uniformly decreased (P less than 0.05-0.001) after metformin treatment; fasting plasma lactate increased slightly from baseline (1.4 to 1.7 mmol/L; P = NS). Body weight decreased by 5 kg in obese NIDD subjects, but remained constant in lean NIDD. Basal hepatic glucose production declined in all diabetics from 83 to 61 mg/m2.min (P less than 0.01), and the decrease correlated (r = 0.80; P less than 0.01) closely with the fall in fasting glucose concentration. Fasting insulin (115 to 79 pmol/L) declined (P less than 0.05) after metformin. During a 6.9 mmol/L hyperglycemic clamp, glucose uptake increased in every NIDD subject (113 +/- 15 to 141 +/- 12 mg/m2.min; P less than 0.001) without a change in the plasma insulin response. During a euglycemic insulin clamp, total glucose uptake rose in obese NIDD subjects (121 +/- 10 to 146 +/- 9 mmol/m2.min; P less than 0.05), but decreased slightly in lean NIDD (121 +/- 10 to 146 +/- 0.5; P = NS). Hepatic glucose production was suppressed by more than 80-90% in all insulin clamp studies before and after metformin treatment. In conclusion, metformin lowers the fasting plasma glucose and insulin concentrations, improves oral glucose tolerance, and decreases plasma lipid levels independent of changes in body weight. The improvement in fasting glucose results from a reduction in basal hepatic glucose production. Metformin per se does not enhance tissue sensitivity to insulin in NIDD subjects. The improvement in glucose metabolism under hyperglycemic, but not euglycemic, conditions suggests that metformin augments glucose-mediated glucose uptake. Metformin has no stimulatory effect on insulin secretion.

More abstracts here:
http://www.niddk.nih.gov/health/diabetes/summary/metform/metform.htm

Drug information

GENERIC NAME: metformin
BRAND NAME: Glucophage , Glucophage XR

DRUG CLASS AND MECHANISM: Metformin is an oral medication that lowers blood glucose (sugar) and is used for treating type 2 diabetes. Insulin is a hormone produced by the pancreas that lowers glucose levels in blood by reducing the amount of glucose made by the liver and by increasing the removal of glucose from the blood by muscle and fat tissues. Diabetes results because of reduced production of insulin and reduced uptake (and effects) of insulin on the body's tissues. Metformin acts by increasing the sensitivity of liver, muscle, fat, and other tissues to the uptake and effects of insulin. These actions lower the level of sugar in the blood. Unlike glucose-lowering drugs of the sulfonylurea class, e.g. glyburide (Micronase; Diabeta) or glipizide (Glucotrol), metformin does not increase the concentration of insulin in the blood and, therefore, does not cause excessively low blood glucose levels (hypoglycemia) when used alone. In scientific studies, metformin reduced the complications of diabetes such as heart disease, blindness and kidney disease. Metformin was approved by the FDA in December of 1994.

PREPARATIONS: Metformin tablets: 500, 850, and 1000 mg. Glucophage XR (extended release) tablets: 500 and 750 mg

STORAGE: Store at room temperature between 20-25°C (68-77°F).

PRESCRIBED FOR: Metformin is used for treating type II diabetes in adults and children. It may be used alone or in combination with other diabetic medications. Metformin also has been used to prevent the development of diabetes in people at risk for diabetes and to treat polycystic ovaries.

DOSING: For adults, metformin usually is begun at a dose of 500 mg twice a day or 850 mg once daily. The dose is gradually increased by 500 mg weekly or 850 mg every two weeks as tolerated and based on the response of the levels of glucose in the blood. The maximum daily dose is 2550 mg given in three divided doses. If Glucophage XR tablets are used, the starting dose is 500 mg daily with the evening meal. The dose can be increased by 500 mg weekly up to a maximum dose of 2000 mg once daily or in two divided doses. Metformin should be taken with meals.

For pediatric patients 10-16 years of age, the starting dose is 500 mg twice a day. Dosage can be increased by 500 mg weekly up to a maximum dose of 2000 mg. Glucophage XR has not been studied in children.

DRUG INTERACTIONS: Cimetidine (Tagamet), by decreasing the elimination of metformin from the body, can increase the amount of metformin in the blood by 40%. This may increase the frequency of side effects from metformin.

PREGNANCY: There are no adequate studies in pregnant women. Most experts agree that insulin is the best treatment for pregnant women with diabetes.

NURSING MOTHERS: Metformin is excreted into breast milk and can therefore be transferred to the nursing infant. Nursing mothers should not use metformin.

SIDE EFFECTS: The most common side effects with metformin are nausea, vomiting, gas, bloating, diarrhea and loss of appetite. These symptoms occur in one out of every three patients. These side effects may be severe enough to cause therapy to be discontinued in one out of every 20 patients. These side effects are related to the dose of the medication and may decrease if the dose is reduced.

A serious--though rare--side effect of metformin is lactic acidosis. Lactic acidosis occurs in one out of every 30,000 patients and is fatal in 50% of cases. The symptoms of lactic acidosis are weakness, trouble breathing, abnormal heartbeats, unusual muscle pain, stomach discomfort, light-headedness and feeling cold. Patients at risk for lactic acidosis include those with reduced function of the kidneys or liver, congestive heart failure, severe acute illnesses, and dehydration.

For more information how to use this medicine click here:
http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a696005.html

Caution! Before starting to take this medicine, it is vital that you should consult your doctor! Do not use it on your own initiative, without medical advice.

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METFORMIN (glucophage)
Brand name: Adimet
Manufacturer: Merckle GmbH

Health information and news

Dosage	Packing	Price	Pay now
850 mg	120 tab	USD 34.00
850 mg	240 tab	USD 34.00

Antihyperglycemic agent
Metformin is used to treat a type of diabetes mellitus (sugar diabetes) called type 2 diabetes. With this type of diabetes, insulin produced by the pancreas is not able to get sugar into the cells of the body where it can work properly. Using metformin will help to lower blood sugar when it is too high and help restore the way you use food to make energy.
Metformin does not help patients who have insulin-dependent or type 1 diabetes because they cannot produce insulin from their pancreas gland. Their blood glucose is best controlled by insulin injections.