What are the potential drug interactions with Metformin (Biguanide)?

From the Guidelines

Metformin has several important drug interactions that require monitoring, particularly with contrast dyes, alcohol, and certain medications that affect kidney function or glucose metabolism, as these can increase the risk of lactic acidosis or alter metformin's effectiveness. When taking metformin, it is essential to avoid combining it with contrast dyes used in imaging procedures, as this combination increases the risk of lactic acidosis, a rare but serious side effect 1. Temporarily stopping metformin 48 hours before and after receiving contrast media is recommended. Be cautious with alcohol consumption while on metformin, as excessive alcohol can increase the risk of lactic acidosis and hypoglycemia. Certain medications can raise metformin levels in the blood, including cimetidine, furosemide, nifedipine, and cationic drugs like trimethoprim. Conversely, metformin may interact with medications that affect blood glucose levels, such as corticosteroids, thiazide diuretics, and certain antipsychotics, potentially reducing metformin's effectiveness. ACE inhibitors and angiotensin receptor blockers may enhance metformin's blood glucose-lowering effects. These interactions occur because metformin is primarily eliminated unchanged through the kidneys, so drugs affecting kidney function can alter metformin levels. Additionally, medications that influence glucose metabolism can counteract metformin's action of reducing hepatic glucose production and improving insulin sensitivity. Always inform healthcare providers about all medications you're taking to avoid potentially harmful interactions.

Some key points to consider when taking metformin include:

• Monitoring kidney function regularly, especially in those with pre-existing kidney disease, as metformin may be contraindicated in those with advanced renal insufficiency 1
• Being aware of the risk of lactic acidosis, particularly in those with risk factors such as sepsis, hypoxia, or liver failure 1
• Gradually increasing the daily dose to minimize gastrointestinal side effects, and considering reduction or elimination of metformin for those experiencing persistent gastrointestinal side effects 1
• Monitoring for vitamin B12 deficiency, as metformin use is associated with an increased risk of deficiency 1

It is crucial to follow prescription guidelines carefully and inform healthcare providers about all medications being taken to avoid potentially harmful interactions and ensure safe and effective use of metformin. According to the most recent and highest quality study, metformin may be used safely in individuals with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m², but should be used with caution in those with hypoperfusion, hypoxemia, impaired hepatic function, or heart failure 1.

From the FDA Drug Label

Table 3: Clinically Significant Drug Interactions with Metformin Hydrochloride Tablets Carbonic Anhydrase Inhibitors Clinical Impact: Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis Concomitant use of these drugs with metformin hydrochloride tablets may increase the risk for lactic acidosis. Intervention: Consider more frequent monitoring of these patients. Examples: Topiramate, zonisamide, acetazolamide or dichlorphenamide Drugs that Reduce metformin hydrochloride tablet Clearance Clinical Impact: Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis Intervention: Consider the benefits and risks of concomitant use with metformin hydrochloride tablets. Examples: Ranolazine, vandetanib, dolutegravir, and cimetidine. Alcohol Clinical Impact: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Intervention: Warn patients against excessive alcohol intake while receiving metformin hydrochloride tablets Insulin Secretagogues or Insulin Clinical Impact: Coadministration of metformin hydrochloride tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia. Intervention: Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin. Drugs Affecting Glycemic Control Clinical Impact: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control Intervention: When such drugs are administered to a patient receiving metformin hydrochloride tablets, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin hydrochloride tablets, observe the patient closely for hypoglycemia Examples: Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.

The potential drug interactions with Metformin (Biguanide) include:

• Carbonic Anhydrase Inhibitors: may increase the risk for lactic acidosis
• Drugs that Reduce metformin hydrochloride tablet Clearance: may increase the risk for lactic acidosis
• Alcohol: potentiates the effect of metformin on lactate metabolism
• Insulin Secretagogues or Insulin: may increase the risk of hypoglycemia
• Drugs Affecting Glycemic Control: may lead to loss of glycemic control or hypoglycemia Examples of these drugs include:
• Topiramate, zonisamide, acetazolamide, dichlorphenamide
• Ranolazine, vandetanib, dolutegravir, cimetidine
• Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid 2

From the Research

Potential Drug Interactions with Metformin (Biguanide)

The potential drug interactions with Metformin (Biguanide) are primarily related to the increased risk of lactic acidosis. Some key points to consider are:

• Metformin increases plasma lactate levels in a plasma concentration-dependent manner by inhibiting mitochondrial respiration predominantly in the liver 3
• Elevated plasma metformin concentrations (as occur in individuals with renal impairment) and a secondary event or condition that further disrupts lactate production or clearance (e.g., cirrhosis, sepsis, or hypoperfusion), are typically necessary to cause metformin-associated lactic acidosis (MALA) 3
• The use of certain medications, such as antibiotics, can increase the risk of acute kidney injury (AKI) and subsequently MALA 4
• The concomitant use of medications that affect renal function, such as apixaban, may also increase the risk of MALA 5

Risk Factors for Metformin-Associated Lactic Acidosis

Some of the key risk factors for metformin-associated lactic acidosis include:

• Renal impairment, particularly moderate and severe renal impairment 3, 6
• Liver disease, particularly cirrhosis 3, 6
• Sepsis or hypoperfusion 3
• Use of certain medications, such as antibiotics 4
• Age-related changes in renal function, particularly in older adults 5
• Decreased clearance of drugs, particularly in older adults 5

Management and Prevention of Metformin-Associated Lactic Acidosis

Some key points to consider for the management and prevention of metformin-associated lactic acidosis are:

• Haemodialysis should systematically be performed in severe forms of lactic acidosis, since it provides both symptomatic and aetiological treatment (by eliminating lactate and metformin) 7
• Routine assessment of metformin plasma concentration is not easily available in all laboratories, but plasma metformin concentrations measured in the emergency room could ensure the correct diagnosis, eliminating metformin as the cause of lactic acidosis if low plasma levels occurred 6
• Guidelines for reducing or deprescribing metformin can be considered in older adults to prevent morbidity, mortality, and adverse outcomes in frail older adults with diabetes 5