Metformin

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset is often subtle, accompanied by nonspecific symptoms (eg, malaise, myalgias, respiratory distress, somnolence, abdominal pain); elevated blood lactate levels (>5 mmol/L); anion gap acidosis (without evidence of ketonuria or ketonemia); increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Risk factors for lactic acidosis include patients with renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), ≥65 years, having a radiologic study with contrast, surgery and other procedures, hypoxic states (eg, acute heart failure), excessive alcohol intake, and hepatic impairment. Discontinue immediately if lactic acidosis is suspected; prompt hemodialysis is recommended. Lactic acidosis should be suspected in any patient with diabetes receiving metformin with evidence of acidosis but without evidence of ketoacidosis. Discontinue use in patients with conditions associated with dehydration, hypoperfusion, sepsis, or hypoxemia. Temporarily discontinue therapy in patients with restricted food and fluid intake. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function.

Long-term metformin use is associated with vitamin B12 deficiency; monitor vitamin B12 serum concentrations periodically with long-term therapy. Monitoring of B12 serum concentrations should be considered in all patients receiving metformin and in particular those with peripheral neuropathy or anemia (ADA 2018d). Disease-related concerns:

Metformin may be used in patients with stable heart failure (HF); avoid use in unstable or hospitalized patients with heart failure (ADA 2018h). Risk of lactic acidosis may be increased secondary to hypoperfusion. In a scientific statement from the American Heart Association, metformin has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: major) (AHA [Page 2016]). Use of metformin in patients with HF may be associated with reduced mortality and reduction in hospital readmission for HF (Crowley 2017; Eurich 2013).

The manufacturer recommends to generally avoid use in patients with hepatic impairment due to potential for lactic acidosis. However, continued use of metformin in patients with diabetes with liver dysfunction, including cirrhosis, may be associated with a survival benefit in carefully selected patients (Brackett 2010; Crowley 2017; Zhang 2014).

Metformin is substantially excreted by the kidney; assess renal function prior to initiation of therapy and periodically thereafter using estimated glomerular filtration rate (eGFR); the risk of metformin accumulation and lactic acidosis increases with degree of renal impairment. Use is contraindicated in patients with eGFR 2. Assess benefits/risks of metformin use in patients with eGFR 30 to 45 mL/minute/1.73 m2; if used, dosage reduction is recommended (ADA [Lipska 2011]; Inzucchi 2014; McCulloch 2017). Some experts recommend avoiding initiation of metformin in these patients (AACE [Garber 2017]; ADA [Lipska 2011]; Inzucchi 2014), while others suggest initiation may be reasonable in the absence of active kidney disease and/or conditions that predispose to hypoperfusion and hypoxemia (McCulloch 2017). Use of concomitant medications that may affect renal function (ie, affect tubular secretion) may also affect metformin disposition. Metformin should be withheld in patients with dehydration and/or prerenal azotemia.

It may be necessary to discontinue metformin and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery). Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Use with caution; risk of metformin associated lactic acidosis increases with age. Dosage form specific issues:

Insoluble tablet shell (Glumetza 1,000 mg tablet) may remain intact and be visible in the stool. Other extended-released tablets (Fortamet, Glucophage XR, Glumetza 500 mg) may appear in the stool as a soft mass resembling the tablet. Other warnings/precautions:

Not indicated for use in patients with type 1 diabetes mellitus or with diabetic ketoacidosis (DKA).

Instruct patients to avoid excessive acute or chronic ethanol use; ethanol may potentiate metformin's effect on lactate metabolism.

Temporarily discontinue metformin at the time of or before iodinated contrast imaging procedures in patients with an eGFR 30 to 60 mL/minute/1.73 m2; or with a history of hepatic disease, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. Reevaluate eGFR 48 hours after imaging procedure; restart if renal function is stable. Alternatively, the American College of Radiology (ACR) guidelines recommend that metformin may be used prior to or following administration of iodinated contrast media in patients with no evidence of acute kidney injury (AKI) and with an eGFR ≥30 mL/minute/1.73 m2; ACR guidelines recommend temporary discontinuation of metformin in patients with known AKI or severe chronic kidney disease ([stage IV or V [ie, eGFR 2]) or who are undergoing arterial catheter studies (ACR 2017).

Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.

Metformin should be withheld the day of surgery (all other oral hypoglycemic agents should be withheld the morning of surgery or procedure) (ADA 2018e). Restart only after normal oral intake resumed and normal renal function is verified.