Metformin Restarting After Acute Illness: A Clinical Guide

What counts as a reason to stop metformin?

The boxed warning on lactic acidosis names the risk factors: renal impairment, certain drugs such as the carbonic anhydrase inhibitor topiramate, age 65 or older, a radiological study with contrast, surgery and other procedures, hypoxic states such as acute congestive heart failure, excessive alcohol intake, and hepatic impairment [2]. The immediate-release label also lists mitochondrial disease [1]. Metformin is not metabolized, and it decreases liver uptake of lactate [1]. It is cleared by the kidneys, and the label lists renal impairment among the risk factors for metformin-associated lactic acidosis [1][2].

The label also says that drugs which impair renal function, cause significant hemodynamic change or interfere with acid-base balance can raise the risk of lactic acidosis, and it suggests more frequent monitoring in that setting [1].

The eGFR numbers that decide a restart

The renal instructions in the label are short and specific [1]:

• eGFR below 30 mL/min/1.73 m²: contraindicated.
• eGFR between 30 and 45 mL/min/1.73 m²: starting metformin is not recommended, and a patient already taking it whose eGFR falls below 45 should have the benefit and risk of continuing assessed.
• eGFR falling below 30 at any point: discontinue.
• Everyone on metformin: an eGFR at least once a year, and more often in people at higher risk of renal impairment, such as older adults.

The label asks for an eGFR before metformin is started and periodic checks after that [1].

Restarting after iodinated contrast

The label says metformin may need to be discontinued at the time of, or before, an iodinated contrast imaging procedure [1]. It names three situations where the drug is stopped at the time of, or before, the procedure: an eGFR between 30 and 60 mL/min/1.73 m²; a history of hepatic impairment, alcoholism or heart failure; or intra-arterial iodinated contrast [1].

The label's explicit restart rule is for contrast: re-evaluate eGFR 48 hours after the imaging procedure, and restart metformin if renal function is stable [1]. For patients outside those three groups, the label's wording is that metformin may need to be discontinued, not that it must be [1].

The concern behind the rule is spelled out in the same section: intravascular iodinated contrast in metformin-treated patients has led to an acute decrease in renal function and to lactic acidosis [1].

Restarting after surgery or another procedure

The prescribing information says to temporarily discontinue metformin during surgery or another procedure while food and fluid intake is restricted [1]. The label says that withholding food and fluids during procedures may increase the risk of volume depletion, hypotension and renal impairment [1].

After sepsis, shock or acute heart failure

Several postmarketing cases of metformin-associated lactic acidosis occurred in acute congestive heart failure, particularly when accompanied by poor perfusion and low oxygen. Cardiovascular collapse (shock), acute myocardial infarction, sepsis and other conditions associated with low blood oxygen have been linked to lactic acidosis and can cause prerenal azotemia, and the label says to discontinue metformin when such an event occurs [1].

Two other label points matter when a patient has been acutely unwell. The prescribing information says to avoid metformin in patients with clinical or laboratory evidence of hepatic disease, because patients with hepatic impairment have developed lactic acidosis, which the label says may be due to impaired lactate clearance [1]. And alcohol potentiates metformin's effect on lactate metabolism, so the label warns against excessive alcohol intake while the drug is taken [1].

Medicines that change the decision

The label's interaction table includes these groups [1]:

• Carbonic anhydrase inhibitors (topiramate, zonisamide, acetazolamide, dichlorphenamide) lower serum bicarbonate and can cause a non-anion gap acidosis, which may increase the risk of lactic acidosis; the label suggests more frequent monitoring.
• Drugs that reduce metformin clearance through the kidney's OCT2 and MATE transport systems (ranolazine, vandetanib, dolutegravir, cimetidine) raise metformin exposure and may increase lactic acidosis risk; the label says to weigh the benefits and risks of using them together.
• Drugs that raise blood glucose (thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, isoniazid) can cause loss of glycemic control, and the label says to observe patients closely.

Warning signs the label describes

The onset of metformin-associated lactic acidosis is often subtle, with nonspecific symptoms: malaise, myalgias, respiratory distress, somnolence and abdominal pain [2]. Severe acidosis has produced hypothermia, hypotension and resistant bradyarrhythmias, and reported cases have included deaths [2]. The laboratory picture is a blood lactate above 5 mmol/L, an anion gap acidosis without ketones, a raised lactate-to-pyruvate ratio, and metformin plasma levels generally above 5 mcg/mL [2].

The label instructs that patients and their families be taught these symptoms and that, if they occur, metformin be discontinued and the symptoms reported [1]. If lactic acidosis is suspected, the label calls for general supportive measures in a hospital setting and prompt hemodialysis, and notes that metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions [2].

Dosing and follow-up

The label's dosing directions cover starting and titrating metformin: 500 mg twice daily or 850 mg once daily with meals, increased by 500 mg weekly or 850 mg every 2 weeks, to a maximum of 2,550 mg per day in divided doses [1]. The extended-release tablet starts at 500 mg once daily with the evening meal and goes up to a maximum of 2,000 mg once daily, swallowed whole [2].

For follow-up, the label asks for hematologic parameters on an annual basis and vitamin B12 every 2 to 3 years, noting that subnormal B12 levels were seen in about 7% of patients in 29-week trials [1].