Metformin, FDA-approved in 1994, is an antidiabetic agent used in type 2 diabetes mellitus. Metformin comes in both immediate-release and extended-release and is used in several combination products with other antidiabetic agents.
Typically at diagnosis of type 2 diabetes, lifestyle management such as diet and exercise are recommended. Metformin is often used as monotherapy or in combination when diet and exercise are not effective at lowering hyperglycemia. According to the American Diabetes Association (ADA), metformin is the preferred first-line agent in type 2 diabetics in adults and children ten years and older. Per Standards of Medical Care in Diabetes 2018, if a patient’s A1c is less than 9% at diagnosis, then metformin monotherapy is recommended. If the A1c is greater than 9%, then metformin is recommended for use in combination therapy. Metformin is not indicated in type 1 diabetes mellitus.
Metformin also has several non-FDA approved indications including gestational diabetes, management of antipsychotic-induced weight gain, type 2 diabetes prevention, and both the treatment and prevention of polycystic ovary syndrome (PCOS). Currently, metformin is the only ADA-recommended antidiabetic for pre-diabetes. As for potential indications, metformin is being studied for its possible antiaging, anticancer, and neuroprotective effects.
Classified as a biguanide, metformin reduces blood glucose levels by decreasing the production of glucose in the liver, decreasing intestinal absorption and increasing insulin sensitivity. Metformin decreases both the basal and postprandial blood glucose. In PCOS, Metformin decreases insulin levels, which then decreases luteinizing hormone and androgen levels. Thus acting to normalize the menstruation cycle. It is important to advise premenopausal women of the increased potential for pregnancy when taking metformin.
In gestational diabetes, metformin is recommended as an alternative to insulin. Hyperglycemia is associated with congenital malformations. Therefore, metformin is used to decrease blood glucose during pregnancy. Per Facts and Comparisons, metformin is categorized as class B in pregnancy. It crosses the placenta and is present in breast milk.
Metformin is considered to be weight neutral with a potential for modest weight loss. It is also unlikely to cause hypoglycemia and may be potentially cardioprotective. The onset of metformin is about 3 hours after taking the medication with a half-life of 20 hours. Metformin is not metabolized in the liver nor does it have substantial protein binding. Therefore, metformin is renally eliminated mostly unchanged, and monitoring of renal function is important.
Metformin is an oral medication typically dosed from 500 to 2550 mg per day and administered with a meal to decrease GI upset. To decrease this risk, the daily dose is often titrated weekly in increments of 500 mg or 850 mg. It is recommended to take metformin at the same time every day. Extended-release tablets are typically taken once daily with an evening meal and should be swallowed with a full glass of water.
Metformin is regarded as being generally safe and well tolerated. Gastrointestinal side effects including diarrhea, nausea, and vomiting are very common and typically occur in up to 30% of patients taking metformin. Occurring less frequently, some patients experience chest discomfort, headache, diaphoresis, hypoglycemia, weakness, and rhinitis. Decreased vitamin B12 levels are associated with long-term metformin and should be monitored, particularly in anemic or peripheral neuropathy patients. Supplementation of vitamin B12 may be necessary.
Metformin has a black box warning for lactic acidosis. This side effect is rare but serious and has an incident rate of 1/30,000 patients. Lactate builds up in the body and cannot be eliminated easily, which leads to metabolic acidosis. This lowering of pH in the blood can cause nonspecific signs and symptoms, which include malaise, respiratory distress, elevated lactate levels, and anion gap acidosis. Risk factors include hepatically or renally impaired patients, elderly, surgery, hypoxia, and alcoholism. These risk factors act to decrease the pH in the blood or decrease proper elimination. Patients should be advised not to consume alcohol excessively while taking metformin. While this side effect is rare, lactic acidosis can cause hypotension, hypothermia, and death.
Certain drug interactions may increase the risk of developing lactic acidosis. These include but are not limited to bupropion, carbonic anhydrase inhibitors, cephalexin, cimetidine, dolutegravir, ethanol, glycopyrrolate, iodinated contrast agents, lamotrigine, ranolazine, and topiramate. Other drug interactions can contribute to the increased hypoglycemic effect. Some of these drugs include androgens, alpha-lipoic acid, salicylates, selective serotonin reuptake inhibitors, quinolones, prothionamide, pegvisomant and other antidiabetic agents. It is recommended to monitor patients who are concomitantly taking these medications with metformin.
Metformin is contraindicated in patients with severe renal dysfunction, which is defined as a glomerular filtration rate (GFR) less than 30 ml/min/1.732. This also equates to serum creatinine (SCr) of greater than or equal to 1.5 in men and 1.4 in women or abnormal creatinine clearance (CrCl). Any potentially renally toxic medication should not be used concomitantly.
Metformin's package insert advises the discontinuation of metformin before giving iodinated contrast agents in patients who have a GFR less than 60 ml/min/1.732, lactic acidosis risk factors or administration of contrast intra-articularly. Metformin may be restarted after the procedure once the patient’s GFR has normalized. Due to the risk of lactic acidosis, the package insert recommends metformin be stopped in cases of nausea, vomiting, and dehydration. It is also recommended to avoid use in hepatically impaired or unstable heart failure patients. Metformin should be stopped on the day of surgery. Other contraindications include hypersensitivity to metformin and metabolic acidosis.
Monitoring for any oral antidiabetic agent includes fasting blood glucose, postprandial blood glucose, and hemoglobin A1C (HbA1c) every 3 to 6 months. Per Facts and Comparisons, renal function via GFR is monitored initially and periodically. Patients with a GFR of 60 to 45 ml/min/1.732 are monitored every 3 to 6 months. Patients with a GFR of less than 45 ml/min/1.732 are monitored every 3 months. Vitamin B12 deficiency can sometimes occur with long-term metformin use. The ADA recommends frequently checking this level particularly in patients with anemia or peripheral neuropathy. Patients on concomitant drugs, which can cause an increased risk of lactic acidosis, should be monitored frequently.
Metformin overdose has been associated with hypoglycemia and lactic acidosis. If lactic acidosis is suspected due to toxic metformin levels, the medication should be immediately discontinued, and hemodialysis should be started. Metformin is an easily dialyzable medication due to its small molecular weight and lack of protein binding. Supportive care is used in the treatment of metformin toxicity as there is no antidote used.