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Metformin

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Last Update: May 2, 2022.

Continuing Education Activity

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. Metformin also has several non-FDA-approved indications, including gestational diabetes, management of antipsychotic-induced weight gain, type 2 diabetes prevention, and 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. This activity reviews the indications, contraindications, and adverse effects of metformin and highlights the role of the interprofessional team in managing patients with diabetes mellitus.

Objectives:

  • Describe the mechanism of action of metformin.
  • Identify the approved and off-label indications for using metformin.
  • Review the potential adverse effects of metformin.
  • Explain interprofessional team strategies for enhancing care coordination and communication to advance the use of metformin for type 2 diabetes and improve outcomes.
Access free multiple choice questions on this topic.

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 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 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 glucose production in the liver, decreasing intestinal absorption, and increasing insulin sensitivity. Metformin decreases both basal and postprandial blood glucose levels. 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]

Pharmacokinetics

  • Bioavailability: 50 to 60% for metformin hydrochloride 500 mg tablet based on fasted conditions 
  • Food effect: Decrease extent of absorption and delays absorption (Cmax 40% lower, AUC 25% lower, Tmax extend by 35 minutes for fed vs. fasted)
  • The volume of distribution: 654 ± 358 L for 850 mg strength
  • Plasma protein binding: Negligible
  • Steady-state plasma concentration: within 24 to 48 hours 
  • Elimination: Excreted unchanged in the urine (no hepatic metabolism or biliary excretion)
  • Elimination half-life: approximately 6.2 hours

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. The 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.

Recommended Adult Dosing

Treatment of Diabetes Mellitus type 2 [5]

  • The initial dose of 500 mg once or twice a day or 850 mg once a day is recommended for immediate release oral formulation. The daily dose is often titrated weekly in increments of 500 mg or 850 mg to reduce GI adverse effects. The typical maintenance dose is 850mg or 1000 mg twice a day.
  • On the other hand, the initial dose of 500 mg once or 1000 mg once a day is recommended for extended-release oral formulation. This daily dose can be titrated weekly in increments of 500 mg for up to 6 weeks. After that, a maximum dose of 2000 mg once or twice a day is recommended for extended-release formulation.

Off-labeled Uses

Prevention of Diabetes Mellitus Type 2 [6]

  • The initial dose of 850 mg once a day for a month is recommended for immediate release oral formulation. To achieve the desired outcome, this dose may increase up to 850 mg twice a day.

Treatment of Antipsychotic-induced Weight Gain [7] [8] [9]

  • The initial dose of 750 mg up to 2000 mg is recommended in two to three divided doses for immediate release oral formulation. A maximum dose of 2550 mg daily is also used in some studies.  
  • For extended-release formulation, the initial dose of 500 mg once is recommended and may be increased by 500 mg every two to six weeks based on the dose tolerability of patients.  A maximum dose of 1000 mg to 2000 mg daily is recommended for extended-release formulation. 

Treatment of Gestational Diabetes Mellitus [10] [11]

  • The initial dose of 500 mg once or twice a day is recommended for immediate release oral formulation. Then, it may increase up to 2000 mg - 2500 mg in two to three divided doses to achieve the glycemic targets. To achieve glycemic targets, the insulin may be coadministered with metformin therapy. 

Treatment of Oligomenorrhea due to PCOS [12] [13]

  • The initial dose of 500 mg once or twice a day is recommended for immediate release oral formulation. The daily dose is often titrated weekly in increments of 500 mg to minimize  GI adverse effects.

Specific Patients Population

Patient with Renal Impairment: Dosage adjustment is based on a periodic assessment of renal function. Generally, malnourished, debilitated, and elderly patients should not be titrated to the maximum dose.[14]

  • No dosage adjustment is necessary when the estimated glomerular filtration rate (eGFR) is above 60 mL per minute per body surface area. Clinicians should monitor renal function annually.
  • If eGFR >45 to <60 mL per minute per body surface area, no dosage adjustment is necessary, and clinicians should monitor renal function every three to six months.
  • For patients who have eGFR between 30 to 45 mL per minute per body surface area, initiation of therapy is not recommended in the manufacturer label. However, 500 mg daily dose with evening meal is recommended by some researchers.
  • Metformin therapy is contraindicated when eGFR is below 30 mL per minute per body surface area.

Patient with Hepatic Impairment: The manufacturer recommends avoiding metformin therapy in a patient with hepatic impairment due to the potential risk factor of lactic acidosis. 

Pregnant Women: It is considered a US FDA pregnancy category B drug. It is not recommended to use during pregnancy.

Breastfeeding Women: Metformin is present in breast milk. Breastfeeding is generally acceptable till the relative infant dose is below 10 mg per kg per day.[15]

Pediatric Patients: Metformin is not recommended for patients below ten years.

Geriatric Patients: The conservative initial and maintenance dose should be considered for patients with advanced age. This patient population may have decreased renal function, and the dose should be adjusted based on a careful assessment of renal function.

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 in 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, including malaise, respiratory distress, elevated lactate levels, and anion gap acidosis. Risk factors include hepatically or renally impaired patients, the elderly, surgery, hypoxia, and alcoholism.[16] 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.

Drug Interactions

  • 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, defined as a glomerular filtration rate (GFR) less than 30 ml/min/1.732. This limitation also equates to serum creatinine (SCr) 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.[16][2]

Metformin dosing should also stop on the day of any surgery. Other contraindications include hypersensitivity to metformin and metabolic acidosis.

Metformin's package insert advises the discontinuation of metformin before giving iodinated contrast agents in patients with 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.[17]

Monitoring

Monitoring for any oral antidiabetic agent includes fasting blood glucose, postprandial blood glucose, and hemoglobin A1C (HbA1c) every 3 to 6 months.

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. Monitoring renal function is needed to aid in the prevention of lactic acidosis, especially in the elderly.[18][19][18]

Vitamin B12 deficiency can sometimes occur with long-term metformin use. Therefore, 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.[20]

Enhancing Healthcare Team Outcomes

All interprofessional healthcare team members, including clinicians, mid-level practitioners, nurses, and pharmacists, 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. While it is a safe and well-tolerated drug, the nurses still need to monitor its use, be aware of contraindications and interactions, and document any potential issues. Pharmacists should verify dosing, perform medication reconciliation, and counsel patients. If there are any concerns, clinicians should be informed, so all team members have the same information and are operating from the same page, optimizing therapeutic outcomes. [Level 5]

Review Questions

References

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Zheng W, Li XB, Tang YL, Xiang YQ, Wang CY, de Leon J. Metformin for Weight Gain and Metabolic Abnormalities Associated With Antipsychotic Treatment: Meta-Analysis of Randomized Placebo-Controlled Trials. J Clin Psychopharmacol. 2015 Oct;35(5):499-509. [PubMed: 26280837]
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Nachum Z, Zafran N, Salim R, Hissin N, Hasanein J, Gam Ze Letova Y, Suleiman A, Yefet E. Glyburide Versus Metformin and Their Combination for the Treatment of Gestational Diabetes Mellitus: A Randomized Controlled Study. Diabetes Care. 2017 Mar;40(3):332-337. [PubMed: 28077460]
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Costello M, Shrestha B, Eden J, Sjoblom P, Johnson N. Insulin-sensitising drugs versus the combined oral contraceptive pill for hirsutism, acne and risk of diabetes, cardiovascular disease, and endometrial cancer in polycystic ovary syndrome. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD005552. [PubMed: 17253562]
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Morin-Papunen L, Vauhkonen I, Koivunen R, Ruokonen A, Martikainen H, Tapanainen JS. Metformin versus ethinyl estradiol-cyproterone acetate in the treatment of nonobese women with polycystic ovary syndrome: a randomized study. J Clin Endocrinol Metab. 2003 Jan;88(1):148-56. [PubMed: 12519844]
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Lalau JD, Kajbaf F, Bennis Y, Hurtel-Lemaire AS, Belpaire F, De Broe ME. Metformin Treatment in Patients With Type 2 Diabetes and Chronic Kidney Disease Stages 3A, 3B, or 4. Diabetes Care. 2018 Mar;41(3):547-553. [PubMed: 29305402]
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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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