Metformin helps reduce excessively high blood glucose (sugar) levels in type 2 diabetes patients by decreasing glucose production in the liver, decreasing glucose absorption from the intestine, and improving insulin sensitivity by increasing peripheral glucose uptake and utilization. It does not cause low blood sugars except in special, rare circumstances. 

In diabetics, on average in lowers the fasting blood glucose by 59 mg/dL and hemoglobin A1c by 1.8%.  It tends to lower bad LDL-cholesterol and raise good HDL-cholesterol.  

The most common side-effect of metformin is diarrhea which occurred 41% more often 41% of patients on metformin vs. placebo in one study.  This caused 6% of patients to drop out of that study. Nausea/vomiting (17%), gas (6%), and indigestion (3%) were other side-effects with the percentages the frequent more often than with the placebo.

The one severe side-effect of metformin, which occurs only very rarely, is lactic acidosis.  This occurs once every 33,000 patient-years of treatment, but has a 50% fatality rate if it occurs.  Lactic acidosis is caused by metformin accumulation in patients with kidney problems which interfere with eliminating metformin.  Serum creatinine levels help determine the degree of risk.  First signs might be malaise, acute abdominal pain, and drowsiness.  It especially occurs in the elderly with kidney failure.

There is a large volume of research supporting the use of metformin treatment in diabetes mellitus, androgenization, anovulation, infertility, and recurrent miscarriage. Although metformin is known to cross the placenta, there is, as yet, no evidence of teratogenicity (Obstet Gynecol Surv. 2004 Feb;59(2):118-27).  It is also helpful in polycystic ovary syndrome (PCOS), a common condition characterized by menstrual abnormalities and clinical or biochemical features of hyperandrogenism. Features of PCOS may manifest at any age, ranging from childhood (premature puberty), teenage years (hirsutism, menstrual abnormalities), early adulthood and middle life (infertility, glucose intolerance) to later life (diabetes mellitus and cardiovascular disease).

Patients on metformin should take folic acid and B-12 supplements since metformin slightly decreases these (J Intern Med. 2003 Nov;254(5):455-63). The United Kingdom Prospective Diabetes Study (UKPDS) reported that metformin was associated with a 32% reduction in any diabetes related endpoint (p<0.002), a 39% reduction in myocardial infarction (p<0.01) and a non-significant 29% fall in microvascular complications.  The benefits observed included diabetes-related mortality (reduced by 42%, compared with diet treatment, p=0.017), all-cause mortality (reduced by 36%, p=0.011), myocardial infarction (reduced by 39%, p=0.01), and any diabetes-related endpoint (reduced by 32%, p=0.002). Other clinical and experimental studies have shown metformin to be associated with improved outcomes and support the conclusions from the UKPDS. In addition, a well-designed retrospective analysis has shown significantly lower mortality rates in patients receiving metformin compared with patients treated with sulphonylurea monotherapy. The use of metformin as a treatment should be avoided in patients over 80 years of age because of declining kidney function.

Metformin Helps Lose 18#: 22 morbidly obese were treated for 24 weeks and lost 6% (18 pounds) with a 10% decrease in LDL and >10% decrease in fasting insulin. Weight loss appeared due to ameliorating insulin resistance. Metformin may also help prevent DM. Metformin also increases fertility in polycystic ovary disease. In 118 women with polycystic disease and treated with metformin, 91% ovulated, and had normal pregnancy rates. 60 were on metformin throughout the pregnancy and over 90% had healthy babies. Normally, polycystic disease makes it difficult to ovulate and conceive and even then, women often lose the pregnancy in the first trimester. 70% of polycystic women eventually get diabetes type II. Glueck, Jewish Hosp, Cincinnati, Metabolism 12/99 (Darby 2004 1000 mg tab $25/100); The usual dosage for diabetes is 1500-2000/day. This is $15/month. However, prices on the internet range from $50-$100. Metformin should be taken with meal. Because of 42% more women getting diarrhea, 17% nausea, and 7% flatulence on higher dose studies, metformin should probably best be started at 500 mg/day and then increased to 500 mg twice a day.

Metformin Doesn't Replace Exercising: In the Diabetes Prevention Programme, lifestyle intervention in individuals with impaired fasting glucose or impaired glucose tolerance reduced the risk of developing type 2 diabetes by 58%, whereas treatment with metformin reduced the risk of type 2 diabetes by only 31%. Malays J Pathol. 2002 Dec;24(2):71-6

Metformin Helps Lose 18# and Keep It Off: In another randomized study of 30 non-diabetic women, those on metformin 500 three times a day and a carbohydrate-modified diet actually did better than those of 500 four times a day. All women in the first group lost over 10% and 67% of the second group did. The average weight loss was 18 pounds when combined with a dieting program. After one year, those stopping metformin regained 50% of their weight within 6 months, while 89% of those continuing on metformin maintained their weight loss without counseling. Metformin and carbohydrate-modified diet: a novel obesity treatment protocol: preliminary findings from a case series of nondiabetic women with midlife weight gain and hyperinsulinemia. Mogul HR, Peterson SJ, Weinstein BI, Zhang S, Southren AL. Heart Dis. 2001 Sep-Oct;3(5):285-92. Another study showed the first year's weight loss was maintained for 2-4 years in patients continuing on metformin.

Metformin Helped Lose 13#: In a 29-week 31-patient study of 2,550 mg/day, very obese patients lost from an average of 268# to 255#. Metformin reduces weight, centripetal obesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30. Glueck CJ, Fontaine RN, Wang P, Subbiah MT, Weber K, Illig E, Streicher P, Sieve-Smith L, Tracy TM, Lang JE, McCullough P. Metabolism. 2001 Jul;50(7):856-61

Metformin No Increase in Lactic Acidosis: A meta-analysis covering 56,000 patients found no evidence that metformin increased the risk of lactic acidosis. For type 2 diabetes mellitus, it has been shown to reduce total mortality rates compared with other antihyperglycemic treatments but was thought to increase the risk of lactic acidosis. Shelley R. Salpeter, Stanford University. Arch Intern Med. 2003 Nov 24;163(21):2594-602. Ed: This does not mean that metformin doesn't cause lactic acidosis, but that it is not the only cause, that other diabetes medicines may cause it as often, and that in any case it is a rare complication.

Metformin Can Prevent Diabetes: Four prospective randomized long-term studies have been recently completed and published (Diabetes Prevention Study, Diabetes Prevention Program, STOP-NIDDM trial, XENDOS Study). They clearly demonstrate the possibility to delay and/or prevent the onset of type 2 diabetes in at high-risk subjects with impaired glucose tolerance, through changes in lifestyle (dietary intervention, weight reduction, increased physical activity) or drug treatment (metformin, acarbose, orlistat). Ann Endocrinol (Paris). 2003 Jun;64(3 Suppl):S37-44. Ed: Of the medications, metformin is the least expensive (one month's supply roughly $25 vs. $80. vs. $140).  Also, it is the only one proven to lower mortality rates, although this is in individuals who have already developed diabetes.

Metformin Lowers Cancer Risk in Diabetics by 25%: In a DB PC study of 6,000 diabetic adults, the half assigned to take metformin developed 25% fewer cases of cancer during follow-up. The metformin simulates an enzyme AMPK which may keep cancer at bay. Metformin lowers insulin-like growth factor, which in higher levels has been linked to prostate, breast, and colon cancers. Metformin is currently being investigated as a general cancer preventive agent. Alessi et al. University of Dundee, BMJ  7/2005.

Metformin: One Case of Encephalopathy Reported: This case did not have lactic acidosis. Diabet Med. 2004 Feb;21(2):194-5

Metformin Lowers Folic Acid and B-12 Slightly: Give Calcium: In a 745-patient Dutch DB PC study of diabetics, 16 weeks of metformin, as compared with placebo, was associated with an increase in homocysteine of 4% (P=0.04) and with decreases in folate [-7%; P=0.02] and vitamin B12 [-14%; P<0.0001]. J Intern Med. 2003 Nov;254(5):455-63. Of patients who are prescribed metformin, 10-30% have evidence of reduced vitamin B12 absorption. B12-intrinsic factor complex uptake by ileal cell surface receptors is a process dependent on calcium. Metformin affects calcium-dependent membrane action. In a controlled study, patients receiving metformin had diminished B12 absorption and low serum total vitamin B12 and TCII-B12 levels because of a calcium-dependent ileal membrane antagonism, an effect reversed with supplemental calcium. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Bauman WA, et al. Mount Sinai School of Medicine, New York. . Diabetes Care 2000 Sep;23(9):1227-31.

Metformin Review: Metformin is the only currently available oral antidiabetic/hypoglycemic agent that acts predominantly by inhibiting hepatic glucose release. Because patients with type 2 diabetes often have excess hepatic glucose output, use of metformin is effective in lowering glycosylated hemoglobin (HbA1c) by 1 to 2 percentage points when used as monotherapy or in combination with other blood glucose-lowering agents or insulin. Other metabolic variables (eg, dyslipidemia, fibrinolysis) may be improved with the use of metformin. Body weight is often maintained or slightly reduced from baseline. Clin Ther. 2003 Dec;25(12):2991-3026

Metformin Lactic Acidosis Questioned: In a world literature search from 1959 to 1999, reports of 80 cases of lactic acidosis were found. The author calculated that there was no relationship between metformin blood levels and lactic acidosis blood levels or the occurrence of death. He concluded that the presence of metformin may have been coincidence rather than cause. J Intern Med. 2004 Feb;255(2):179-87

Urinary Tract Infections Increased by Diabetes Meds: In a case-control study of 901 cases of urinary tract infections and 913 controls, diabetes was reported in 13.1 and 6.8%. The age-adjusted odds ratio (OR) for UTI for diabetes was 2.2. Adjustment for frequency of sexual intercourse and history of UTI had little effect. Compared with nondiabetic women, higher UTI odds were seen in subjects who used oral hypoglycemic agents (OR 2.9) and insulin (2.6) but not in subjects with untreated diabetes or diabetes treated by lifestyle changes (1.3). Diabetes and the risk of acute urinary tract infection among postmenopausal women. Boyko EJ, Fihn SD, Scholes D, Chen CL, Normand EH, Yarbro P. Diabetes Care. 2002 Oct;25(10):1778-83

Combined Sulfonylureas and Biguanides Increase Mortality: While metformin as a single treatment for diabetes lowers mortality, when combined with sulfonylureas (glibenclamide or chlorpropamide), as Italian study of 928 followed for 55 months found an 88% increase in mortality.  All-cause mortality in diabetic patients treated with combinations of sulfonylureas and biguanides. Mannucci E, Monami M, Masotti G, Marchionni N. Diabetes Metab Res Rev. 2004 Jan-Feb;20(1):44-7; Glucovance is a combination of glyburide, a sulfonylurea, and metformin. Such combined treatment is very popular and has been a recommended treatment. Thiazolidinediones: Pioglitazone (Actos) ($179 for 30 mg) and Rosiglitazone (Avandia)($110 for 4 mg) have a small positive effect when added to metformin.

Metformin improves endothelial vascular reactivity in first-degree relatives of type 2 diabetic patients with metabolic syndrome and normal glucose tolerance: Double-blind study. de Aguiar LG, et al. State University of Rio de Janeiro, Brazil. . 

Thomas E. Radecki, M.D., J.D.

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