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Metformin

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Last Update: February 7, 2020.

Indications

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 available in several combination products with other antidiabetic agents.[1]

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 patients with type-2 diabetes mellitus 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.[2]

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.[2] As for potential indications, researchers are studying metformin for its possible antiaging, anticancer, and neuroprotective effects.[3]

Mechanism of Action

Metformin is a biguanide drug that 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.[3]

In gestational diabetes, metformin is recommended as an alternative to insulin. Hyperglycemia is associated with congenital malformations. Therefore, metformin works to decrease blood glucose during pregnancy. Per Facts and Comparisons, metformin was in the class B pregnancy category, under the old FDA system. It crosses the placenta and is present in breast milk.

Metformin is considered weight neutral with the potential for modest weight loss. It is also unlikely to cause hypoglycemia and may be potentially cardioprotective.[3] 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. Metformin is renally eliminated, mostly unchanged, and monitoring of renal function is important.[4]

Administration

Metformin is an oral medication typically dosed from 500 to 2550 mg per day and administered with a meal to decrease GI upset. The daily dose is often titrated weekly in increments of 500 mg or 850 mg to reduce this risk. Recommendations are 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.

Adverse Effects

Metformin is generally regarded as 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[3]. 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.[2]

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.[3] 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.[5] 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.

Specific 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 an increased hypoglycemic effect. Some of these drugs include androgens, alpha-lipoic acid, salicylates, selective serotonin reuptake inhibitors, quinolones, prothionamide, pegvisomant, and other antidiabetic agents. The recommendation is for clinicians to monitor patients who are concomitantly taking these medications with metformin.

Contraindications

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 limitation 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.[5][2]

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 stopping metformin in cases of nausea, vomiting, and dehydration. Recommendations also include avoiding metformin in hepatically impaired or unstable heart failure patients.[6] Metformin dosing should also stop on the day of any surgery. Other contraindications include hypersensitivity to metformin and metabolic acidosis.

Monitoring

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, clinicians should monitor renal function via GFR 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 should have monitoring every three 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.[2]

Toxicity

Metformin overdose correlates with hypoglycemia and lactic acidosis. If the clinician suspects lactic acidosis due to toxic metformin levels, they should immediately discontinue the medication, and start hemodialysis. 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.[7]

Enhancing Healthcare Team Outcomes

Healthcare workers, including nurse practitioners who look after patients with diabetes mellitus, should be familiar with metformin. It is the drug of choice for patients with type-2 diabetes mellitus. The drug is very safe, is cardioprotective, and enables weight loss. More importantly, the drug is relatively cheap. At the same time, the clinicians should encourage patients with diabetes mellitus to discontinue smoking, eat healthily, and participate in regular exercise.

Questions

To access free multiple choice questions on this topic, click here.

References

1.
Blonde L, Dipp S, Cadena D. Combination Glucose-Lowering Therapy Plans in T2DM: Case-Based Considerations. Adv Ther. 2018 Jul;35(7):939-965. [PubMed: 29777519]
2.
American Diabetes Association. 8. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018 Jan;41(Suppl 1):S73-S85. [PubMed: 29222379]
3.
Wang YW, He SJ, Feng X, Cheng J, Luo YT, Tian L, Huang Q. Metformin: a review of its potential indications. Drug Des Devel Ther. 2017;11:2421-2429. [PMC free article: PMC5574599] [PubMed: 28860713]
4.
Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: from mechanisms of action to therapies. Cell Metab. 2014 Dec 02;20(6):953-66. [PubMed: 25456737]
5.
Hsu WH, Hsiao PJ, Lin PC, Chen SC, Lee MY, Shin SJ. Effect of metformin on kidney function in patients with type 2 diabetes mellitus and moderate chronic kidney disease. Oncotarget. 2018 Jan 12;9(4):5416-5423. [PMC free article: PMC5797060] [PubMed: 29435189]
6.
Chamberlain JJ, Johnson EL, Leal S, Rhinehart AS, Shubrook JH, Peterson L. Cardiovascular Disease and Risk Management: Review of the American Diabetes Association Standards of Medical Care in Diabetes 2018. Ann. Intern. Med. 2018 May 01;168(9):640-650. [PubMed: 29610837]
7.
Leonaviciute D, Madsen B, Schmedes A, Buus NH, Rasmussen BS. Severe Metformin Poisoning Successfully Treated with Simultaneous Venovenous Hemofiltration and Prolonged Intermittent Hemodialysis. Case Rep Crit Care. 2018;2018:3868051. [PMC free article: PMC5964555] [PubMed: 29854476]
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Bookshelf ID: NBK518983PMID: 30085525

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