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Mechanism of Action
US Drug Names
500 mg PO 3 times per day. After roughly 1 month, 33% of females with PCOS will ovulate compared to 4% with placebo. When metformin is added to clomiphene therapy for PCOS with infertility, roughly 86% of patients ovulate in comparison to roughly 8% on clomiphene alone. Worldwide data of metformin use in PCOS to regulate menstrual cycles and decrease ovarian steroidogenesis are relatively extensive. Metformin-failure may occur in severely obese patients, so weight loss and dietary control are also recommended.
Limited data indicate that 425 mg PO once daily with dinner may be effective. Thirty-eight females with precocious puberty (average age at study initiation 7.9 +/- 0.2 years, average age at diagnosis of precocious puberty 6.8 +/- 0.2 years), low birth weight (less than 2.9 kg for term birth or -1SD for gestational age at preterm birth), and prepuberty (Tanner breast stage 1) were randomized to 425 mg of metformin at bedtime (n = 19) or no therapy (n = 19) in an open-label fashion; patients did not have a history of diabetes mellitus, adrenal hyperplasia, or thyroid abnormalities. After 24 months, patients treated with metformin experienced statistically significant improvements in metabolic abnormalities (i.e., insulin resistance, androgen excess, atherogenic lipid profile, and adipose body composition) as well as a 0.4 year delay in the clinical onset of puberty (defined as Tanner breast stage 2); additionally, metformin treatment was associated with a 1-year delay in the puberty-associated insulin-like growth factor-I rise. Preliminary 3-year data indicate that metformin treatment is associated with a delay in menarche (5/19 patients in the no treatment group have undergone menarche compared to 0/19 patients in the metformin-treated group, p = 0.016). Furthermore, the patients treated with metformin maintained gains in height and lean mass.
Limited data indicate that 825 mg PO once daily with dinner may be effective. Twenty-two females with onset of puberty (defined as Tanner breast stage 2) between 8 and 9 years of age (average age at onset 8.6 +/- 0.1 years) and low birth weight (2.8 kg or less for term birth or -1.5 SD for gestational age) were randomized to 850 mg metformin once daily (n = 10) or no treatment (n = 12) in an open-label fashion for 36 months. At enrollment, these patients had a height greater than or equal to 1 SD above midparenteral height for chronological age and bone age of greater than 1 year above chronological age; in addition, all patients had central and progressive puberty. Treatment with metformin resulted in a delay of menarche by a median of 1 year (p < 0.01) and increases in near-adult height (height gain over 42 months of treatment was 16 cm for the untreated group vs. 19.5 cm for the metformin-treated group, p <= 0.05). In addition, patients are still being followed and height has ceased in almost all of the patients in the untreated group, while 4/10 patients in the metformin-treated group continue to grow at a rate of greater than 2 cm/year. In addition, those patients receiving metformin had a leaner body composition and demonstrated lower levels of insulin resistance with improved lipid profiles.
500 mg PO once nightly for 1 week, then titrate to 500 mg PO twice daily. Further titration of the daily dose by 500 mg every 1 to 2 weeks to attain glycemic targets is used. Max: If needed, up to 2.5 to 3 grams/day PO, given in 2 or 3 divided doses, has been studied in gestational diabetes mellitus (GDM). Metformin is not recommended for routine use during pregnancy.Many studies and analyses of metformin in use in pregnancy have been published. The American College of Obstetricians and Gynecologists (ACOG) and the American Diabetes Association (ADA) continue to recommend human insulin as the standard of care in women with GDM requiring medical therapy. Per ACOG, metformin is a preferred second-line choice for women who decline insulin therapy or are unable to safely administer insulin. Per the ADA, metformin may be used to treat GDM as a treatment option; however, metformin does cross the placenta. While no teratogenic effects have been associated with metformin, no long-term safety data are available. Metformin may cause a lower risk of neonatal hypoglycemia and less maternal weight gain than insulin; however, some data suggest that metformin may slightly increase the risk of prematurity. The ADA notes that in some clinical studies, nearly 50% of GDM patients initially treated with metformin have needed the addition of insulin in order to achieve acceptable glucose control. 
850 mg PO once daily for 1 month, then increase to 850 mg PO twice daily, unless GI adverse effects necessitate a longer titration period.   According to the American Diabestes Association (ADA) Standards of Care, metformin should be considered in those with prediabetes, especially for those with a BMI of 35 kg/m2 and greater, those less than 60 years of age, and women with prior gestational diabetes mellitus.
750 mg to 2 g PO daily in 2 to 3 divided doses has been studied in clinical trials. Doses up to 2.55 g/day have also been used. To minimize GI adverse effects, most trials initiated therapy with 250 mg or 500 mg PO twice daily or 850 mg PO once daily, and increased the dose gradually based on tolerability.       The AACE/ACE guidelines for patients with obesity provide a strong recommendation with strong evidence for the use of metformin in promoting modest weight loss and metabolic improvement in patients who are taking antipsychotic medications.
1 g to 2 g PO once daily was the maintenance dose range in clinical trials. To minimize GI adverse effects, trials initiated therapy with 500 mg PO once daily and titrated dosage upwards in 500 mg increments every 2 to 6 weeks based on tolerability.  The AACE/ACE guidelines for patients with obesity provide a strong recommendation with strong evidence for the use of metformin in promoting modest weight loss and metabolic improvement in patients who are taking antipsychotic medications.
Blood glucose goals for adults with type 1 or type 2 diabetes :
A1C goals for adults with type 1 or type 2 diabetes :
A1C goals for children and adolescents with type 2 diabetes :
2,550 mg/day PO for regular-release tablets and oral solution; 2,000 to 2,500 mg/day PO for extended-release tablets depending on product used; 2,000 mg/day PO for extended-release suspension.
Use more than 1,000 mg/day PO with caution in older adult. Adult Max: 2,550 mg/day PO for regular-release tablets and oral solution; 2,000 to 2,500 mg/day PO for extended-release tablets depending on product used; 2,000 mg/day PO for extended-release suspension.
2,000 mg/day PO for regular-release tablets, oral solution, and extended-release suspension; safe and effective use has not been established for extended-release tablets.
10 years and older: 2,000 mg/day PO for regular-release tablets, oral solution, and extended-release suspension; safe and effective use has not been established for extended-release tablets.
Less than 10 years: Safety and efficacy have not been established.
Safety and efficacy have not been established.
Generally avoid metformin use in hepatic impairment; hepatic disease increases the risk of metformin-associated lactic acidosis.
eGFR more than 45 mL/minute/1.73 m2: No dosage adjustment needed. Obtain an eGFR at least annually in all patients taking metformin.
eGFR 30 to 45 mL/minute/1.73 m2: Initiation of metformin is not recommended. Obtain an eGFR at least annually in all patients taking metformin. In patients whose eGFR is initially greater than 45 mL/minute/1.73 m2, and then later falls below 45 mL/minute/1.73 m2, assess the benefits and risks of continuing treatment. Discontinue metformin if the patient's eGFR later falls below 30 mL/minute/1.73 m2. The ADA and others suggest it is reasonable to decrease the dose by 50% (or use one-half the maximum recommended dose) and monitor renal function every 3 months in those with an eGFR less than 45 mL/minute/1.73 m2. Do not initiate the drug in patients at this stage. Additional caution is required in patients with anticipated significant fluctuations in renal status or those at risk for abrupt deterioration in kidney function, based on previous history, other comorbidities, albuminuria, and medication regimen (e.g., potent diuretics or nephrotoxic agents).
eGFR less than 30 mL/minute/1.73 m2: Use is contraindicated.
Metformin use is contraindicated. Metformin is dialyzable; hemodialysis will efficiently remove accumulated metformin in the case of drug-induced lactic acidosis, provided metformin is halted.
Metformin is an oral biguanide used to improve glycemic control in adult and pediatric patients 10 years and older with type 2 diabetes mellitus (DM). The actions of metformin differ from, yet complement, those of other antidiabetic therapies. Metformin is first-line in the treatment of type 2 DM. The combination of metformin with lifestyle interventions should be initiated in most patients at the time of diagnosis of type 2 DM. Metformin was chosen as the initial drug therapy based on its efficacy, safety, and cost. While metformin carries a low risk for lactic acidosis as outlined in the prescribing information and boxed warning of all metformin-containing products, care in prescribing and monitoring can reduce this risk. In patients with established cardiovascular (CV) disease, heart failure (HF), or chronic kidney disease (CKD), a sodium-glucose co-transporter 2 (SGLT2) inhibitor or glucagon-like peptide-1 receptor agonist (GLP-1 RA) with proven CV benefit and reduction of CKD progression is recommended for add-on therapy, independent of baseline A1C or individualized A1C target. In a follow-up study to the UKPDS, researchers found that after 10-years of resuming typical care, patients originally randomized to metformin therapy had a 33% relative reduction in the risk of myocardial infarction and a 27% relative reduction in the risk of death from any cause as compared to patients receiving conventional therapy; the reductions in cardiovascular risk persisted even though A1C concentrations were similar in the 2 groups after 1 year of follow-up. In patients with prediabetes, metformin reduces the risk of future diabetes by 25% to 30% and may confer cardiovascular benefit. Metformin has been found useful in the off-label treatment of polycystic ovary syndrome (PCOS); it lowers serum androgens and restores normal menstrual cycles and ovulation, and may improve pregnancy rates. Additionally, limited data indicate that it may delay puberty onset in females with precocious puberty and delay menarche onset in females with early-normal onset of puberty.
NOTE: Globally, as well as in the U.S., some metformin ER products have been recalled from the market because they may contain unacceptable levels of N-nitrosodimethylamine (NDMA), a probable human carcinogen. FDA testing has not shown NDMA in IR metformin products. NDMA has been linked with cancers of the digestive tract, bladder, kidney, and others. The FDA has required testing of manufactured products. If testing shows NDMA above the acceptable daily intake limit, the manufacturer must inform the FDA and should not release the lot for consumer use. Patients taking prescription metformin ER who wish to stop taking these products should talk to their health care professional about other treatment/product options first and should not stop taking their metformin product on their own.
For storage information, see the specific product information within the How Supplied section.
Oral Solution (e.g., Riomet oral solution)
Oral extended-release Suspension (e.g., Riomet ER suspension)
Reconstitution method for oral extended-release suspension (prior to dispensing):
Gastrointestinal (GI) adverse effects are the most common side effects experienced by patients taking metformin. In clinical trials, diarrhea was experienced by 53.2% of patients receiving immediate-release metformin monotherapy, and was a reason for drug discontinuation in 6%. Extended-release formulations cause diarrhea in roughly 9.6% of patients. Nausea and vomiting are reported in 6.5% to 25.5% of all patients taking metformin; with the lower incidences seen in patients receiving extended-release products. Other common GI effects include flatulence (1% to 12.1%), indigestion or dyspepsia (1% to 7.1%), and abdominal pain or discomfort (1% to 6.4%). GI effects occurring in 1% to 5% of patients included anorexia, dysgeusia (metallic taste or other taste disturbance), and a change in stool appearance. Frequent side effects tend to decline with continued use and can be minimized by initiating therapy with low doses of metformin, and extended-release formulas lower GI side effect incidences. In pediatric patients with diabetes mellitus type 2 treated with metformin, the adverse event profiles and incidences are similar to those seen in adults.   
The risk of hypoglycemia is not common with metformin monotherapy; hypoglycemia was reported in 1% to 5% of patients during clinical trials.     Other studies have reported varying incidences of hypoglycemia. In a nested case-control analysis (n = more than 50,000 subjects with type 2 diabetes mellitus), the rate of hypoglycemia due to metformin yielded a crude incidence rate of 3.3 cases among 100,000 person-years compared vs. 4.8 cases among sulfonylurea users per 100,000 person-years. In a separate systematic review, the rates for hypoglycemia with metformin monotherapy varied in the studies reviewed between 0% to 21%, with the risk of major hypoglycemic episodes due to metformin reported to be rare. Hypoglycemia is more common when metformin is coadministered with other oral hypoglycemic agents (especially sulfonylureas), when ethanol has been ingested, or when there is deficient caloric intake or strenuous exercise not compensated by caloric supplementation. Since metformin reverses insulin resistance and subsequently causes a decrease in insulin concentrations, metformin-induced hypoglycemia is usually mild and does not necessitate the discontinuation of therapy. In overdose, hypoglycemia is noted in roughly 10% of patients, but a causal association with metformin is not established. Patients should be aware of the common, early symptoms and signs of low blood sugar, such as feeling anxious, dizzy, or irritable, impaired concentration, increased hunger, unusually weak or tired, sweating, shakiness, headache, blurry vision, or a fast heartbeat. Headache has also been reported as a side effect with metformin therapy, in the absence of hypoglycemia. During clinical trials, the incidence of headache with metformin immediate-release therapy was 5.7%.   
Metformin decreases the absorption of vitamin B12; asymptomatic vitamin B12 deficiency was reported with metformin monotherapy in 7% of patients during clinical trials. The decrease is possibly due to interference with B12 absorption from the B12-intrinsic factor complex; however, it is only very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin treatment or vitamin B12 (cyanocobalamin) supplementation. Metformin may also decrease folate concentrations leading to folate deficiency. During clinical trials, serum folic acid concentrations did not decrease significantly. Measurement of hematologic parameters on an annual basis is advised. Certain individuals (those with inadequate vitamin B12, folic acid, or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2- to 3-year intervals may be useful. Rare cases of megaloblastic anemia have been reported with metformin (none in the U.S.); incidence rates are expected to be less than 1% for symptomatic deficiency.    
Mild weight loss may occur during therapy with metformin, perhaps as a result of its ability to cause anorexia. Such weight loss can be expected in almost any patient with type 2 diabetes receiving metformin monotherapy; however, weight loss may attenuate when metformin is combined with other treatments. A mean weight loss of 1 to 8.4 lbs was reported in clinical trials of adults receiving metformin immediate-release products as monotherapy; a mean weight loss of 2 to 3 lbs was reported in pediatric studies. When extended-release tablets were used, the weight loss was not clinically significant in adults and mean reductions ranged from 0.7 to 2.2 lbs.   
Lactic acidosis is a rare but serious form of metabolic acidosis that can occur if metformin accumulates during treatment; when it occurs, it is fatal in approximately 50% of cases. The onset of lactic acidosis often is subtle, and accompanied only by early nonspecific symptoms such as malaise and myalgia (1 to 5% of patients), and quickly followed by respiratory distress (dyspnea 1 to 5%), increasing somnolence, and nonspecific abdominal distress. Lactic acidosis is a medical emergency that must be treated in a hospital setting; metformin should be discontinued immediately, and general supportive measures promptly instituted. Prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery.    Lactic acidosis is characterized by elevated blood lactate levels (more than 5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels greater than 5 mcg/mL are generally present. More marked lactic acidosis/metabolic acidosis may be associated with hypothermia, hypotension, and resistant bradyarrhythmias. The reported incidence of lactic acidosis in patients receiving metformin is very low (approximately 0.03 cases/1,000 patient-years); of nearly 20,000 patients in clinical trials, there were no reports of lactic acidosis. A nested case-control study of 50,048 patients with type 2 diabetes mellitus demonstrated that during concurrent use of oral diabetes drugs, there were 6 identified cases of lactic acidosis; all of the subjects had relevant comorbidities known to be risk factors for lactic acidosis. The incidence of lactic acidosis in metformin recipients without comorbid conditions appears to be no different than in recipients of other antidiabetic agents. Risk factors include significant renal insufficiency, the presence of multiple concomitant medical/surgical problems (e.g., liver disease, alcoholism, cardiorespiratory insufficiency, or other conditions associated with tissue hypoperfusion or hypoxemia), and exposure to multiple concomitant medications known to increase risks. The risk of lactic acidosis increases with the degree of renal impairment and the patient's age. Lactic acidosis is less likely to occur with metformin than with other biguanide agents (e.g., phenformin), because metformin is not metabolized, does not bind to liver or plasma proteins, and is excreted by active tubular processes. Regular monitoring of renal function and by use of the minimum effective dose of metformin may reduce the risk of this adverse reaction. Patients should be informed to discontinue metformin should symptoms suggestive of lactic acidosis appear and promptly report the symptoms to their physician.    
The following miscellaneous adverse reactions were reported in 1% to 5% of patients treated with metformin and occurred more commonly than in patients treated with placebo: lightheaded (dizziness), nail disorder, rash (unspecified), hyperhidrosis (sweating increased), chest pain (unspecified) or chest discomfort, chills, flu syndrome or upper respiratory infection, flushing, and palpitations.   
Liver function test abnormalities (elevated hepatic enzymes) or hepatitis have been reported very rarely in patients taking metformin and have resolved upon metformin discontinuation. During postmarketing experience with metformin, cholestasis and hepatocellular or mixed hepatocellular liver injury have been reported.   
In an ISMP safety report, metformin was noted as 1 of the 25 drugs having the strongest signals for rhabdomyolysis with 20 cases reported over 1 year to the FDA Adverse Event Reporting System (FAERS).
Do not use metformin in patients who have a known metformin hypersensitivity.
Metformin should not be used for Type 1 diabetes mellitus. Metformin is not an effective treatment of and use is contraindicated in diabetic ketoacidosis (DKA). DKA, with or without coma; DKA should be treated with insulin.
Metformin is contraindicated in patients with metabolic acidosis. Metformin is associated with a risk for lactic acidosis and therefore should not be used in patients with lactic acidosis, a form of metabolic acidosis. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a rare but serious complication that can occur due to metformin accumulation; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia or significant renal dysfunction.    Certain medications used concomitantly with metformin may also increase the risk of lactic acidosis. Lactic acidosis is characterized by elevated blood lactate levels, acidemia, electrolyte disturbances, an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels more than 5 mcg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin is very low; in more than 20,000 patient-years exposure to metformin in clinical trials, there have been no reports of lactic acidosis and approximately 0.03 cases/1,000 patient-years have been estimated with post-marketing surveillance. A nested case-control study of 50,048 patients with type 2 diabetes mellitus demonstrated that during concurrent use of oral diabetes drugs, there were 6 identified cases of lactic acidosis. The crude incidence rate was 3.3 cases per 100,000 person-years in patients treated with metformin; it should be noted that all of the subjects had relevant comorbidities known to be risk factors for lactic acidosis. The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradycardia with more marked acidemia. The patient and the prescriber must be aware of such symptoms and the patient should be instructed to notify the physician immediately if they occur. Metformin should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful.
Gastrointestinal (GI) side effects are common during metformin initiation. However, once a patient is stabilized on any dose of metformin, GI symptoms are unlikely to be drug related. Later occurrence of GI symptoms may be due to a change in clinical status and may increase the risk of lactic acidosis or other serious disease. Patients stable on metformin therapy who complain of an increase in GI symptoms should undergo laboratory investigation to determine the etiology of the GI symptoms. These include, but are not limited to, diarrhea and nausea/vomiting. Furthermore, withholding metformin therapy until the cause of the GI symptoms is known may be necessary. Finally, diarrhea and nausea/vomiting may alter gastric emptying and caloric intake, which could all affect blood glucose control, especially increasing the risk of low blood glucose. Patients should be advised to contact their prescriber if an increase in gastrointestinal symptoms occurs while taking metformin; patients should also be advised to monitor their blood glucose concentrations more frequently.
Metformin is substantially eliminated by the kidney and the risk of lactic acidosis increases with the degree of intrinsic renal disease or impairment. Certain medications that are eliminated via the kidney when used concomitantly with metformin may also increase the risk of lactic acidosis. Prior to initiating treatment in any patient, obtain an estimated glomerular filtration rate (eGFR) to assess renal function. Metformin is contraindicated for use in patients with renal failure or severe renal impairment (defined as eGFR below 30 mL/minute/1.73 m2). Initiating metformin in patients with an eGFR between 30 to 45 mL/minute/1.73 m2 is not recommended. Obtain an eGFR at least annually in all patients taking metformin. In those patients at increased risk for the development of renal impairment such as the elderly, renal function should be assessed more frequently. In patients taking metformin whose eGFR later falls below 45 mL/minute/1.73 m2, assess the benefits and risks of continuing treatment. Discontinue metformin if the patient’s eGFR later falls below 30 mL/minute/1.73 m2. Based on the results of a comprehensive FDA safety review, the FDA concluded that metformin can be used safely in patients with mild renal impairment, and in some patients with moderate renal impairment. The measure of kidney function used to determine whether a patient can receive metformin has been changed from serum creatinine to the eGFR; this is because in addition to serum creatinine concentration, the eGFR takes into account additional parameters that are important, such as the patient’s age, gender, race and/or weight.  
According to the manufacturer, metformin should be used with caution in patients with congestive heart failure requiring pharmacologic treatment. However, a systematic review evaluating antidiabetic agents and outcomes in patients with heart failure and diabetes concluded that metformin is not associated with any measurable harm in patients with heart failure; in this analysis, metformin was associated with reduced mortality. It should be noted that in acute congestive heart failure characterized by acute hypoxia, lactic acidosis has occurred in patients taking metformin. To reduce the risk of lactic acidosis, metformin should be promptly withheld in the presence of any condition associated with hypoxemia. Acute hypoxia and acute cardiac disease (e.g., acute heart failure, cardiogenic shock, or acute myocardial infarction) and other conditions characterized by acute hypoxia have been associated with the development of lactic acidosis and may cause prerenal azotemia. If such events occur, discontinue metformin.
Metformin administration increases the risk for lactic acidosis. Since the liver is important for clearing accumulated lactic acid, metformin is not recommended in patients with clinical or laboratory evidence of hepatic disease as the risk of lactic acidosis may be increased. Hepatic disease also causes altered gluconeogenesis, which may affect glycemic control. Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients should be warned against excessive ethanol ingestion (ethanol intoxication) while taking metformin due to the increased risk for lactic acidosis. Those with ethanol intoxication are also particularly susceptible to hypoglycemic effects of oral antidiabetic agents. Metformin use should be avoided by those patients with alcoholism.
Discontinue metformin at the time of or before radiographic contrast administration in patients with an estimated glomerular filtration rate (eGFR) between 30 and 60 mL/minute/1.73 m2; in patients with a history of hepatic disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR the 48 hours after the imaging procedure; restart metformin if renal function is stable. 
To reduce the risk of lactic acidosis, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Metformin therapy should be temporarily suspended for any surgery, except for minor procedures where intake of fluids and food is not restricted. Do not restart this drug until oral intake is resumed and renal function has been evaluated as normal. Temporary use of insulin in place of oral antidiabetic agents may be necessary during periods of physiologic stress (e.g., burns, systemic infection, trauma, surgery, or fever). Any change in clinical status, including diarrhea or vomiting, may also increase the risk of lactic acidosis and may require laboratory evaluation in patients on metformin and may require the drug be withheld.
Delayed stomach emptying may alter blood glucose control; monitor patients with diarrhea, gastroparesis, GI obstruction, ileus, or vomiting carefully. Conditions that predispose patients to developing hypoglycemia or hyperglycemia may alter antidiabetic agent efficacy. Hyperglycemia related conditions include drug interactions, female hormonal changes, high fever, severe psychological stress, and uncontrolled hypercortisolism or hyperthyroidism. Metformin causes hypoglycemia infrequently in the absence of risk factors as monotherapy. Conditions associated with an increased risk for hypoglycemia include debilitated physical condition, drug interactions, malnutrition, uncontrolled adrenal insufficiency, pituitary insufficiency or hypothyroidism. More frequent blood glucose monitoring may be necessary in patients with these conditions while receiving metformin. There is also an increased risk of hypoglycemia when metformin is combined with insulin or an insulin secretagogue (e.g., sulfonylureas). Therefore, a lower dose of insulin or an insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with metformin. Monitor blood glucose.
Metformin may result in suboptimal vitamin B12 absorption, possibly due to interference with the B12-intrinsic factor complex. The interaction very rarely results in a pernicious anemia that appears reversible with discontinuation of metformin or with cyanocobalamin supplementation. Certain individuals may be predisposed to this type of anemia; a nested case-control study of 465 patients taking metformin (155 with vitamin B12 deficiency and 310 without) demonstrated that dose and duration of metformin use may be associated with an increased odds of vitamin B12 deficiency. Each 1 gram/day increment in dose significantly increased the odds of vitamin B12 deficiency (OR 2.88, 95% CI 2.15 to3.87) as did taking metformin for 3 years or more (OR 2.39, 95% CI 1.46 to 3.91). Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment.
Controlled clinical studies of metformin did not include sufficient numbers of older patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between geriatric and younger adult patients. Use metformin with caution in geriatric patients. Metformin is substantially excreted by the kidney and the risk of adverse reactions (including lactic acidosis) is greater in patients with reduced renal function. Because aging is associated with renal function decline, care should be taken with dose selection and titration. Obtain an estimated glomerular filtration rate (eGFR) at least annually in all patients taking metformin. In patients at increased risk for the development of renal impairment such as geriatric patients, renal function should be assessed more frequently. Unless estimated renal function via the eGFR is determined to be normal, do not use metformin in geriatric patients 80 years of age and older. Generally, elderly or debilitated patients should not be titrated up to maximum metformin dosages. Elderly, debilitated, or malnourished patients are also particularly susceptible to hypoglycemic effects of antidiabetic agents; monitor blood glucose frequently. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA, the use of antidiabetic medications should include monitoring (e.g., periodic blood glucose) for effectiveness based on desired goals for that individual and to identify complications of treatment such as hypoglycemia or impaired renal function. Metformin has been associated with lactic acidosis, which is more likely to occur under the following conditions: serum creatinine of 1.5 mg/dL or higher in males or 1.4 mg/dL or higher in females, abnormal creatinine clearance from any cause, age of 80 years or older unless measurement of creatinine clearance verifies normal renal function, radiologic studies in which intravascular iodinated contrast materials are given, congestive heart failure requiring pharmacologic management, or acute/chronic metabolic acidosis with or without coma (including diabetic ketoacidosis).
Premenopausal anovulatory females with insulin resistance (i.e., those with polycystic ovary syndrome (PCOS)) may resume ovulation as a result of metformin therapy; patients may be at risk of conception if adequate contraception is not used in those not desiring to become pregnant. In some cases, metformin is used as an adjunct in PCOS patients to regulate menstrual cycles or to enhance fertility. Metformin is not recommended for routine use during pregnancy. Metformin does pass through the placenta and the fetus is likely exposed to therapeutic concentrations of metformin. The American College of Obstetricians and Gynecologists (ACOG) and the American Diabetes Association (ADA) continue to recommend human insulin as the standard of care in women with diabetes mellitus or gestational diabetes mellitus (GDM) requiring medical therapy.  Per ACOG, in women who decline insulin therapy or are unable to safely administer insulin, metformin is the preferred second-line choice. Per the ADA, metformin may be used to treat GDM as a treatment option; however, no long term safety data are available for any oral agent. Metformin may cause a lower risk of neonatal hypoglycemia and less maternal weight gain than insulin; however, some data suggest that metformin may slightly increase the risk of prematurity. The ADA notes that in some clinical studies, nearly 50% of GDM patients initially treated with metformin have needed the addition of insulin in order to achieve acceptable glucose control.  Many studies and analyses of metformin use in pregnancy have been published. The data suggest no increase in the rates of expected birth defects or other adverse outcomes in exposed infants and studies comparing metformin to insulin in the treatment of gestational diabetes have generally found no significant differences in glycemic control or pregnancy outcomes.  
Small studies indicate that metformin is excreted in human breast milk. Infant hypoglycemia or other side effects are a possibility; however, adverse effects on infant plasma glucose have not been reported in human studies. Animal data show that metformin is excreted into breast milk and reaches levels similar to those in plasma.   Furthermore, the use of metformin 2550 mg/day by mothers breast-feeding their infants for 6 months does not affect growth, motor, or social development; the effects beyond 6 months are not known. In all of these studies, the estimated weight-adjusted infant exposure to metformin ranged from 0.11% to 1.08% of the mother's dose. While the manufacturers of metformin recommend that a decision should be made to discontinue breast-feeding or discontinue the drug, the results of these studies indicate that maternal ingestion of metformin during breast-feeding is probably safe to the infant. However, a risk and benefit analysis should be made for each mother and her infant; if patients elect to continue metformin while breast-feeding, the mother should be aware of the potential risks to the infant. If metformin is discontinued and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered. Because acarbose has limited systemic absorption, which results in minimal maternal plasma concentrations, clinically significant exposure via breast milk is not expected ; therefore, this agent may represent a reasonable alternative for some patients. Tolbutamide is usually considered compatible with breast-feeding. Glyburide may be a suitable alternative since it was not detected in the breast milk of lactating women who received single and multiple doses of glyburide. If any oral hypoglycemics are used during breast feeding, the nursing infant should be monitored for signs of hypoglycemia, such as increased fussiness or somnolence.
Metformin has been shown to effectively lower glucose levels in children (ages 10 to 16 years) with type 2 diabetes. Metformin has not been adequately studied in children less than 10 years of age. 
Metformin is an antihyperglycemic agent that improves glucose tolerance, lowering both basal and postprandial plasma glucose with mechanisms different from other classes of oral antidiabetic agents. Metformin decreases hepatic gluconeogenesis production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease. Metformin improve glucose utilization in skeletal muscle and adipose tissue by increasing cell membrane glucose transport. This effect may be due to improved binding of insulin to insulin receptors since metformin is not effective in diabetics without some residual functioning pancreatic islet cells. Unlike the sulfonylureas, metformin rarely causes hypoglycemia since it does not significantly change insulin concentrations. An important distinction is that sulfonylureas increase insulin secretion thus making them useful in non-obese patients with type 2 diabetes mellitus (DM) while metformin improves insulin resistance, a common pathophysiologic finding in obese patients with type 2 DM. Metformin causes a 10% to 20% decrease in fatty-acid oxidation and a slight increase in glucose oxidation. Unlike phenformin, metformin does not inhibit the mitochondrial oxidation of lactate unless plasma concentrations of metformin become excessive (i.e., in patients with renal failure) and/or hypoxia is present.
Clinically, metformin lowers fasting and postprandial hyperglycemia. The decrease in fasting plasma glucose is approximately 25% to 30%. Unlike oral sulfonylureas, metformin rarely causes hypoglycemia. Thus, metformin demonstrates more of an antihyperglycemic action than a hypoglycemic action. Metformin does not cause weight gain and in fact, may cause a modest weight loss due to drug-induced anorexia. Metformin also decreases plasma VLDL triglycerides resulting in modest decreases in plasma triglycerides and total cholesterol. Patients receiving metformin show a significant improvement in A1C, and a tendency toward improvement in the lipid profile, especially when baseline values are abnormally elevated.
Insulin resistance is a primary cause of polycystic ovarian syndrome (PCOS). In PCOS patients, metformin reduces insulin resistance and lowers insulin levels, which lowers serum androgen concentrations, restores normal menstrual cycles and ovulation, and may help to resolve PCOS-associated infertility. Metformin, when administered to lean, overweight, and moderately obese women with PCOS, has been found to significantly reduce serum leuteinizing hormone (LH) and increase follicle stimulating hormone (FSH) and sex hormone binding globulin (SHBG). Serum testosterone concentrations were also found to decrease by approximately 50%.
Metformin is administered orally. The drug is distributed rapidly into peripheral body tissues and fluids and appears to distribute slowly into erythrocytes and to a deep tissue compartment (most likely GI tissues). The highest concentrations are found in the GI tract (10 times the concentrations in the plasma) and lower concentrations in the kidney, liver, and salivary gland tissue. Metformin is negligibly bound to plasma proteins. Metformin is not metabolized by the liver and this fact may explain why the risk of lactic acidosis is much less for metformin than for phenformin (i.e., approximately 10% of patients have an inherited defect in the ability to metabolize phenformin). The drug is excreted by the kidneys, largely unchanged, through an active tubular process. Tubular secretion may be altered by many cationic drugs. Approximately 10% of an oral dose is excreted in the feces, presumably as unabsorbed metformin and about 90% of a dose is excreted by the kidneys within 24 hours. Although the average elimination half-life in the plasma is 6.2 hours in patients with normal renal function, metformin is distributed to and accumulates in red blood cells, which leads to a much longer elimination half-life in the blood (17.6 hours).
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: Organic cationic transporter-2 (OCT2), multidrug and toxin extrusion (MATE1 and MATE2k)
Drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) increase systemic exposure to metformin. Careful patient monitoring and dose adjustment of metformin and/or the potentially interfering drug is recommended with concurrent use.
Specific pharmacokinetic studies have not been performed in patients with hepatic dysfunction receiving metformin, but hepatic impairment may increase the risk of lactic acidosis.
Metformin will accumulate in patients with moderate to severe renal dysfunction. Increasing renal dysfunction is associated with an increased risk of lactic acidosis. In patients with decreased renal function (based on measured creatinine clearance, CrCl), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance. In patients with severe renal impairment (CrCl less than 30 mL/minute), the steady-state metformin exposure was approximately 40% higher than that of patients with normal renal function (AUC increase of 42% and Cmax increase of 35%). Metformin is removed by hemodialysis.
After administration of metformin 500 mg regular-release tablet PO as a single dose with food, the geometric mean metformin maximum concentration (Cmax) and exposure (AUC) differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal renal function.
The elderly, due to age-related decreased renal function, may accumulate metformin.
Gender does not appear to affect metformin pharmacokinetics.
Race does not appear to affect metformin pharmacokinetics.
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