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.[28550] [60711] [60715] [64593]

The risk of hypoglycemia is not common with metformin monotherapy; hypoglycemia was reported in 1% to 5% of patients during clinical trials.[24568] [28550] [60711] [60715] [64593] 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.[34580] 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.[43853] 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%.[28550] [60711] [60715] [64593]

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.[28550] [60711] [60715] [64593] [63388]

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.[28550] [60711] [60715] [64593]

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.[28550] [60711] [60715] [64593] 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.[34580] 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.[43853] [28550] [60711] [60715] [64593]

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.[28550] [60711] [60715] [64593]

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.[28550] [60711] [60715] [64593]

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).[63529]

Metformin should not be used for Type 1 diabetes mellitus, which requires insulin therapy. Metformin use is also contraindicated in diabetic ketoacidosis (DKA), with or without coma.[28550] [60711] [64593]

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.[28550] [60711] [60714] [60715] 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.[34580] 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.[28550]

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.[28550] Metformin is contraindicated for individuals 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 and 45 mL/minute/1.73 m² is not recommended per FDA-approved labeling; however, guidelines recommend metformin use in patients with type 2 diabetes, chronic kidney disease, and an eGFR of 30 mL/minute/1.73 m² or greater. Initiate metformin at 50% of recommended dose and titrate upwards to a maximum of 1,000 mg/day in these patients.[66645] [68091] 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 adult, renal function should be assessed more frequently. For individuals 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.[28550]

Metformin should be used with caution in patients with congestive heart failure requiring pharmacologic treatment. Acute hypoxia and acute serious cardiac conditions (e.g., acute heart failure, cardiogenic shock, or acute myocardial infarction) or other conditions characterized by acute hypoxia have been associated with the development of lactic acidosis and may cause prerenal azotemia in patients taking metformin. If such events occur, discontinue metformin.[28550] [60711] [64593] A systematic review evaluating antidiabetic agents and outcomes in patients with heart failure and diabetes concluded that metformin was not associated with any measurable harms; in this analysis, metformin use was associated with reduced mortality.[34437]

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.[28550]

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.[60699] [28550]

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.[28550] [60711] [60715] [64593]

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.[28550]

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).[32890] Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment.[28550]

Reported clinical experience has not identified differences in responses between metformin-treated geriatric and younger adults, but caution is recommended. Metformin is substantially excreted by the kidney and the risk of adverse reactions (including lactic acidosis) is greater in those 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 those at increased risk for the development of renal impairment such as geriatric patients, renal function should be assessed more frequently.[60699] 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. In other older adults, do not exceed maximum metformin dosage recommendations based on age and/or renal function. Elderly, debilitated, or malnourished patients are also particularly susceptible to hypoglycemic effects of antidiabetic agents; monitor blood glucose frequently.[28550]

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.[28550] [60711] [64593] In some cases, metformin has been 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 crosses the placenta with fetal concentrations similar or higher than maternal levels.[31404] [69005] Published data from postmarketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.[28550] [60711] [64593] 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.[64926] [62358] 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.[64926] [62358] [69005] Many studies and analyses of metformin use in pregnancy have been published.[46201] [46203] In a meta-analysis of 21 randomized controlled trials (n = 4,545) comparing the efficacy and safety of metformin alone or as add-on therapy to insulin versus insulin alone in pregnant persons with GDM or type 2 diabetes, metformin users had significantly reduced maternal weight gain, gestational hypertension, maternal hypoglycemia, neonatal hypoglycemia, NICU admissions, birth weight of 4,000 grams or more, and large for gestational age (LGA) compared with insulin therapy alone. However, metformin-exposed pregnancies have been associated with higher rates of spontaneous preterm birth and small for gestational age infants compared to insulin therapy.[69005]

Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1 during breast-feeding. These studies indicate that maternal use during breast-feeding is not expected to result in side effects to a healthy nursing infant. Some experts recommend using metformin with caution if the patient is breastfeeding a newborn or a premature neonate with reduced renal function.[31407] [31408] [31409] [32459] [70364] The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for metformin and any potential adverse effects on the breastfed child, as available studies were not specifically designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.[28550] [60711] [60714] [64593] If metformin is discontinued and blood glucose is not controlled on diet and exercise alone, insulin therapy should be considered and remains the treatment of choice during lactation for most patients.[64926] 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 be an alternative if postprandial glucose control is needed.[46303] 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.[31568] 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.[46104]