Metformin


Article Author:
Calette Corcoran


Article Editor:
Tibb Jacobs


Editors In Chief:
Vijay Lapsia


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Trevor Nezwek
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
10/27/2018 12:31:43 PM

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 used 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 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[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, metformin is being studied for its possible antiaging, anticancer, and neuroprotective effects[3].

Mechanism of Action

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[3].

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[2]. 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[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. 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.

Adverse Effects

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[1]. 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[1]. 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.

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.

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 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 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[6]. Metformin should be stopped on the day of 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, 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[2].

Toxicity

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[5].


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Metformin - Questions

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Which of the following oral hypoglycemic agents is considered to be "weight neutral" with the potential for modest weight loss?



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In patients taking metformin, what is the incidence rate for developing lactic acidosis?



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Which diabetic medication should be withheld from a patient with impaired renal function who is about to undergo iodinated intravenous contrast administration?



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Which of the following is true regarding patients with diabetes mellitus who are taking metformin and require iodinated?



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What is a potential adverse effect of metformin?



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Which of the following medications is used to improve insulin resistance?



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Which of the following does not increase the release of insulin?



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What is the feared complication of metformin?



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What is the mechanism of action of metformin?



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Which of the following diabetic medications may cause lactic acidosis?



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Which one of the following diabetic medications has no effect on release of insulin from the pancreas?



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Which of the following medications works by decreasing gluconeogenesis?



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A 78-year-old female with hypertension and diabetes mellitus is new to your practice. She is on lisinopril 40 mg a day and metformin extended-release 1 gram a day. Her blood pressure is well controlled, and the exam is unremarkable. Laboratories show a glucose of 190 mg/dL, hemoglobin A1c 6.5%, potassium 4.6 mEq/L, creatinine 1.8 mg/dL, and 1+ protein in the urine. A review of her records shows an increase in her creatinine compared to a year ago. What is the appropriate management?



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Biguanides control hyperglycemia in type 2 diabetes mellitus primarily by acting in which organ?



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What is the best initial pharmacologic treatment for diabetes mellitus type 2?



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A patient with type 2 diabetes that is being treated with glipizide has been diagnosed with diabetes. Which of the following drugs is least likely to cause hypoglycemia?



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Which of the following is the route of administration for metformin?



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In rare cases, metformin can cause which of the following?



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A patient with type 2 diabetes mellitus presents complaining of nausea, vomiting, abdominal bloating, tachypnea, and feeling weak. Palpation reveals a tender and enlarged liver and elevated liver enzymes. His serum bicarbonate is low, and his lactate level reads high at 4.5 mmol/L. Which anti-glycemic drug is the most likely culprit?



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A patient recently switched to metformin extended release and is concerned because she has noticed the tablet in her stools. What counsel should she be given?



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Metformin is in which of the following drug classes?



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Which patient would least likely benefit from the use of metformin for the prevention of diabetes mellitus type 2?



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Which mineral or vitamin deficiency is associated with metformin use?



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Which benefit does not occur with metformin use?



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A patient presents with type 2 diabetes. They have not been previously treated. Their hemoglobin A1c is 10%, and their current blood glucose is 190 mg/dl. What is the recommended first-line pharmacologic therapy?



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In women of childbearing age that are taking metformin, what is an important counseling point?



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A 75-year-old patient presents with malaise and respiratory distress. Their lactate levels are elevated. They are taking metformin, lisinopril, and ranolazine. They have a glomerular filtration rate (GFR) of 18 ml/min/1.73m2 and just received iodinated radiologic contrast. Which of the following is not a risk factor for the development of metformin-related lactic acidosis?



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Metformin - References

References

Blonde L,Dipp S,Cadena D, Combination Glucose-Lowering Therapy Plans in T2DM: Case-Based Considerations. Advances in therapy. 2018 Jul     [PubMed]
8. Pharmacologic Approaches to Glycemic Treatment: {i}Standards of Medical Care in Diabetes-2018{/i}. Diabetes care. 2018 Jan     [PubMed]
Wang YW,He SJ,Feng X,Cheng J,Luo YT,Tian L,Huang Q, Metformin: a review of its potential indications. Drug design, development and therapy. 2017     [PubMed]
Foretz M,Guigas B,Bertrand L,Pollak M,Viollet B, Metformin: from mechanisms of action to therapies. Cell metabolism. 2014 Dec 2     [PubMed]
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     [PubMed]
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. Annals of internal medicine. 2018 May 1     [PubMed]

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