Continuing Education Activity

Metformin, an antidiabetic agent, was approved by the U.S. Food and Drug Administration (FDA) in 1994 for treating type 2 diabetes. This medication comes in both immediate- and extended-release formulations and is often combined with other antidiabetic agents. The off-label indications of metformin include managing gestational diabetes, addressing weight gain issues caused by antipsychotic medication, preventing type 2 diabetes, and treating and preventing polycystic ovary syndrome (PCOS). Metformin is currently the only antidiabetic medication for prediabetes recommended by the American Diabetes Association (ADA). Furthermore, regarding potential indications, researchers are studying metformin for its possible antiaging, anticancer, and neuroprotective effects. This activity offers a comprehensive review of metformin's indications, contraindications, and adverse effects. In addition, it emphasizes the crucial role played by the interprofessional team in effectively managing patients with diabetes.

Objectives:

• Identify the approved and off-label indications for metformin use, such as type 2 diabetes, prediabetes, gestational diabetes, antipsychotic-induced weight gain, and PCOS.
• Differentiate the various drug-drug interactions associated with metformin, identifying their clinical presentations.
• Screen patients for contraindications and risk factors associated with metformin, particularly related to severe renal dysfunction and hepatic impairment.
• Collaborate with other interprofessional healthcare team members to optimize diabetes management by incorporating metformin therapy into a comprehensive treatment plan for type 2 diabetes and improving the outcomes.

Indications

Metformin, an antidiabetic agent, was approved by the U.S. Food and Drug Administration (FDA) in 1994 for treating type 2 diabetes. This medication comes in both immediate- and extended-release formulations and is often combined with other antidiabetic agents.[1]

When individuals are diagnosed with type 2 diabetes, doctors typically suggest lifestyle modifications such as improving their diet and increasing their physical activity. Metformin is commonly prescribed as a monotherapy or in combination with other medications when lifestyle interventions, such as changes in diet and exercise, prove ineffective in lowering hyperglycemia. As per the American Diabetes Association (ADA), metformin stands as the preferred first-line agent for treating type 2 diabetes in both adult and pediatric patients 10 or older. According to the Standards of Medical Care in Diabetes 2018, if a patient's hemoglobin A1C (HbA1c) level is less than 9% at diagnosis, metformin monotherapy is the recommended approach. However, if the HbA1c level is greater than 9%, metformin is recommended as part of the combination therapy. Notably, metformin is not indicated for the treatment of type 1 diabetes.[2]

The off-label indications of metformin include managing gestational diabetes, addressing weight gain issues caused by antipsychotic medication, preventing type 2 diabetes, and treating and preventing polycystic ovary syndrome (PCOS). Metformin is currently the only ADA-recommended antidiabetic medication used for prediabetes.[2] Furthermore, researchers are studying metformin for its potential antiaging, anticancer, and neuroprotective effects.[3]

Mechanism of Action

Metformin, classified as a biguanide drug, effectively lowers blood glucose levels by decreasing glucose production in the liver, diminishing intestinal absorption, and enhancing insulin sensitivity. As a result, metformin effectively lowers both basal and postprandial blood glucose levels. Metformin plays a crucial role in PCOS by reducing insulin levels, which leads to decreased luteinizing hormone and androgen levels. This normalization of hormone levels helps regulate the menstrual cycle in women. Clinicians must advise premenopausal women about the increased potential for pregnancy while taking metformin.[3]

In cases of gestational diabetes, metformin is recommended as a viable alternative to insulin. As hyperglycemia during pregnancy can be linked to congenital malformations, metformin aids in reducing blood glucose levels during this period. According to Facts and Comparisons, metformin was previously categorized as class B for pregnancy under the old FDA system. Notably, the drug crosses through the placenta and can also be present in breast milk.

Metformin is recognized as weight-neutral, with the potential to induce modest weight loss. Moreover, the drug is unlikely to cause hypoglycemia and may have potential cardioprotective effects, further adding to its value in diabetes treatment.[3] Metformin typically takes approximately 3 hours to take effect after administration, and its half-life is about 20 hours. Metformin is not significantly metabolized in the liver nor exhibits substantial protein binding. Instead, it is primarily eliminated through the kidneys, mostly unchanged. Hence, monitoring renal function is crucial when using metformin to ensure safe and effective treatment.[4]

Pharmacokinetics

• Bioavailability: Under fasting conditions, the bioavailability of the metformin hydrochloride 500 mg tablet is 50% to 60%.
• Food effect: Food intake decreases the extent of absorption and delays the absorption of metformin. Specifically, when metformin is taken with food, the maximum concentration (Cmax) is 40% lower, the area under the curve (AUC) is 25% lower, and the time to reach maximum concentration (Tmax) is extended by 35 minutes compared to when the drug is taken in a fasted state.
• The distribution volume: The distribution volume for the 850 mg strength of metformin is approximately 654 ± 358 L.
• Plasma protein binding: Metformin exhibits negligible plasma protein binding.
• Steady-state plasma concentration: Steady-state plasma concentration is reached within 24 to 48 hours.
• Elimination: Metformin is excreted unchanged in the urine, with no significant hepatic metabolism or biliary excretion.
• Elimination half-life: The elimination half-life of metformin is approximately 6.2 hours.

Administration

Metformin is an oral medication typically prescribed at daily doses ranging from 500 to 2550 mg. To reduce the risk of experiencing gastrointestinal (GI) upset, it is recommended to administer metformin with a meal. Metformin is available in 2 formulations: immediate-release form, which requires twice-daily dosing, and extended-release form, which requires once-daily dosing. Daily doses of metformin are often titrated weekly in 500 or 850 mg increments to mitigate the risk of adverse effects in patients who are administered the drug. Physicians recommend taking metformin consistently at the same time every day.

Extended-release tablets of metformin are usually taken once daily, ideally with an evening meal, and it is recommended to swallow the tablet with a full glass of water. Metformin is an effective, safe, and affordable medication, which may also lower the risk of cardiovascular events and mortality (ADA, 2023).[5]

Recommended Adult Dosages

Treatment of Type 2 Diabetes 

• Immediate-release oral formulation: For the immediate-release oral form of metformin, it is recommended to begin with an initial dosage of either 500 mg, once or twice daily, or 850 mg, once daily. The daily dose of metformin is often titrated every week in increments of 500 or 850 mg to minimize any adverse GI effects. The typical maintenance dose of the medication is 850 or 1000 mg twice daily.[6]
• Extended-release oral formulation: For the extended-release oral form of metformin, it is recommended to begin with an initial dosage of either 500 mg or 1000 mg once daily. The daily dose of metformin is often titrated every week in increments of 500 mg for up to 6 weeks. After this initial titration phase, the recommended maximum dose for this formulation is 2000 mg, taken once or twice daily.[6]

Off-Labeled Uses

Prevention of Type 2 Diabetes 

• For the immediate-release oral formulation of metformin, it is recommended to begin with an initial dosage of 850 mg, once daily, for a month. The dosage may be increased to 850 mg twice daily to achieve the desired outcome if needed.[7]

Treatment of Antipsychotic-Induced Weight Gain

• Immediate-release oral formulation: For the immediate-release oral form of metformin, it is recommended to begin with an initial dosage of 750 mg up to 2000 mg, divided into 2 to 3 doses. A maximum daily dose of 2550 mg is also utilized in certain studies.[8][9][10]
• Extended-release oral formulation: For the extended-release formulation, it is recommended to begin with an initial dosage of 500 mg once, which may be increased by 500 mg every 2 to 6 weeks based on the patient's ability to tolerate the dose. A maximum dosage of 1000 to 2000 mg daily is recommended for this formulation.[8][9][10]

Treatment of Gestational Diabetes

• For the immediate-release oral form of metformin, it is recommended to begin with an initial dosage of 500 mg once or twice daily. The dosage may be gradually increased from 2000 to 2500 mg in 2 to 3 divided doses to achieve the desired glycemic levels. To achieve glycemic targets, insulin therapy may be coadministered with metformin.[11][12]

Treatment of Oligomenorrhea due to PCOS

• For the immediate-release oral form of metformin, it is recommended to begin with an initial dosage of 500 mg once or twice daily. The daily dose of metformin is often titrated every week in increments of 500 mg to minimize any adverse GI effects.[13][14]

Specific Patient Populations

Patient with renal impairment: Dosage adjustments for metformin are based on a periodic assessment of patients' renal function. Typically, malnourished, debilitated, and elderly patients should avoid being titrated to the maximum dose of metformin.[15]

• No dosage adjustment is necessary when the estimated glomerular filtration rate (eGFR) is above 60 mL/min per body surface area. Clinicians should monitor the renal function of their patients annually.
• No dosage adjustment is necessary for eGFR >45 and <60 mL/min per body surface area. Clinicians should monitor the renal function of their patients every 3 to 6 months.
• The initiation of therapy is not recommended for patients with an eGFR value between 30 and 45 mL/min per body surface area as per the manufacturer's label. However, some researchers suggest a 500 mg daily dose of metformin with an evening meal.
• Metformin therapy is contraindicated when the eGFR value is below 30 mL/min per body surface area.

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

Pregnant considerations: Metformin was previously categorized as a US FDA pregnancy category B drug. According to the American College of Obstetricians and Gynecologists (ACOG) guidelines, insulin remains the preferred choice for managing gestational diabetes. However, metformin could be considered an alternative for cases involving non-compliance or technical challenges with insulin administration.[16]

Breastfeeding considerations: Metformin can be detected in breast milk. Generally, breastfeeding is deemed acceptable as long as the relative infant dose remains below 10 mg/kg/d.[17]

Pediatric patients: Metformin is not recommended for individuals under the age of 10.

Older patients: For individuals of advanced age, it is recommended to begin with a lower initial and maintenance dose as a precaution. This patient population may exhibit decreased renal function, making it crucial for physicians to adjust the dose based on a thorough assessment of their renal health.

Adverse Effects

Metformin is generally considered safe and well-tolerated. However, adverse GI effects, such as diarrhea, nausea, and vomiting, are relatively common, affecting up to 30% of patients who take metformin.[3]

Less commonly, some patients may experience chest discomfort, headache, diaphoresis, hypoglycemia, weakness, and rhinitis while taking metformin. Prolonged use of metformin has been associated with decreased vitamin B12 levels; therefore, healthcare professionals should carefully monitor patients, especially those with anemia or peripheral neuropathy. In some cases, supplementation of vitamin B12 may be necessary.[2]

Metformin carries a black box warning for lactic acidosis, an infrequent yet severe adverse effect with an incidence rate of approximately 1 in 30,000 patients.[3] Lactic acidosis occurs due to lactate accumulation in the body, which cannot be eliminated quickly, leading to metabolic acidosis. This decrease in blood pH can result in nonspecific signs and symptoms such as malaise, respiratory distress, elevated lactate levels, and anion gap acidosis. Several risk factors contribute to developing lactic acidosis, including hepatic or renal impairment, advanced age, surgery, hypoxia, and alcoholism.[18] 

These risk factors either lower the blood's pH or hinder proper lactate elimination. Patients should be cautioned against excessive alcohol consumption while taking metformin. Although lactic acidosis is a rare adverse effect, it can lead to severe consequences such as hypotension, hypothermia, and even death.

Drug Interactions

• Specific drug interactions can raise the risk of lactic acidosis, which involve medications such as bupropion, carbonic anhydrase inhibitors, cephalexin, cimetidine, dolutegravir, ethanol, glycopyrrolate, iodinated contrast agents, lamotrigine, ranolazine, and topiramate.
• In addition, other drug interactions can enhance the hypoglycemic effect of metformin. These drugs include androgens, alpha-lipoic acid, salicylates, selective serotonin reuptake inhibitors, quinolones, prothionamide, pegvisomant, and other antidiabetic agents. Therefore, it is advisable for clinicians to carefully monitor patients who are concurrently taking these medications along with metformin.

Contraindications

Metformin is contraindicated in patients with severe renal dysfunction, which is defined as a GFR >30 mL/min/1.73². This limitation also applies to individuals with serum creatinine (SCr) levels greater than or equal to 1.5 in men and 1.4 in women or with abnormal creatinine clearance (CrCl). In addition, it is important to refrain from using medications that could harm the kidneys while taking metformin.[18][2] Metformin dosing should also be discontinued on the day of any surgery. In addition, other contraindications of metformin include hypersensitivity to metformin and metabolic acidosis.

According to metformin's package insert, patients with a GFR <60 mL/min/1.73², risk factors for lactic acidosis, or receiving contrast intra-articularly should discontinue metformin before being administered with iodinated contrast agents. Metformin may be resumed after the procedure once the patient's GFR has returned to normal. However, due to the risk of lactic acidosis, the package insert advises discontinuing metformin in cases of nausea, vomiting, and dehydration. In addition, metformin should be avoided in patients with hepatic impairment or those with unstable heart failure.[19]

Monitoring

Monitoring for oral antidiabetic agents involves regular assessments of fasting blood glucose, postprandial blood glucose, and HbA1c levels every 3 to 6 months. In addition, clinicians should monitor renal function by assessing GFR initially and periodically. For patients with a GFR of 60 to 45 mL/min/1.73², monitoring should be conducted every 3 to 6 months. Patients with a GFR <45 mL/min/1.73² should be monitored every 3 months to track their renal function closely. Regular monitoring is essential to help prevent the occurrence of lactic acidosis, particularly in older patients.[20][21]

Vitamin B12 deficiency can occasionally arise with long-term metformin use. Consequently, the ADA advises frequent monitoring of vitamin B12 levels, especially in patients with anemia or peripheral neuropathy. Moreover, patients on concomitant drugs, which can cause an increased risk of lactic acidosis, should undergo regular monitoring.[2]

Toxicity

Metformin overdose is associated with hypoglycemia and lactic acidosis. If the clinicians suspect lactic acidosis due to toxic metformin levels, they immediately recommend discontinuing the medication and initiating hemodialysis. Metformin is easily dialyzable owing to its small molecular weight and minimal protein binding. In cases of metformin toxicity, treatment primarily involves supportive care, as no specific antidote is available yet.[22]

Enhancing Healthcare Team Outcomes

All interprofessional healthcare team members, including physicians, mid-level practitioners, nurses, and pharmacists, who provide care for patients with diabetes should possess a thorough understanding of metformin. Metformin is the drug of choice for patients with type-2 diabetes.

Metformin is considered a safe and inexpensive medication that offers cardioprotective benefits and aids in weight loss, making it a valuable option for patients with diabetes. Nevertheless, clinicians should actively encourage other essential lifestyle modifications in patients with diabetes, including smoking cessation, adopting a healthy diet, and engaging in regular exercise or physical activity. Although metformin is a safe and well-tolerated drug, nurses, pharmacists, and other clinicians must remain vigilant in monitoring its use, being aware of contraindications and potential drug interactions, and diligently documenting any observed issues. Pharmacists play a crucial role in verifying dosing, conducting medication reconciliation, and counseling patients. Pharmacists should promptly notify the prescriber if any concerns arise and recommend modifications to the patient's drug regimen.

In case of any concerns, it is vital to inform all clinical team members to ensure everyone has access to the same information and operates from a unified data set. This coordinated interprofessional approach, with open communication and shared decision-making between healthcare providers, fosters optimized therapeutic outcomes.