LONG COVID – The presentation and severity of long COVID varies widely; symptoms can include fatigue with pain or mood swings, cognitive impairment, and ongoing respiratory problems. In a meta-analysis of 54 studies and 2 databases, the prevalence of long COVID 3 months after SARS-CoV-2 infection was estimated to be 6.2% (95% CI 2.4%-13.3%). Long COVID was more common in COVID-19 patients who required care in an ICU or a general hospital ward than in those who did not (43.1% and 27.5% vs 5.7%). It was most prevalent in adult females.1

MECHANISM OF ACTION – The mechanism by which metformin could decrease the risk of long COVID is unclear. Metformin has antiviral effects in vitro and can decrease levels of inflammatory biomarkers such as interleukins 1β and 6.2,3

CLINICAL STUDY – In a randomized, double-blind trial (COVID-OUT), 1431 adults 30-85 years old with an elevated body mass index who had tested positive for SARS-CoV-2 infection ≤3 days previously and experienced symptom onset ≤7 days previously received either metformin or placebo for 14 days; some patients also received the antiparasitic drug ivermectin or the antidepressant fluvoxamine. None of these drugs decreased the incidence of severe COVID-19 within 14 days, the primary endpoint, compared to placebo.4 In a prespecified secondary analysis (available only as a preprint), among 1125 patients who completed monthly follow-up surveys from day 60 to day 300, those who took metformin were significantly less likely than those who took placebo to report a diagnosis of long COVID (6.3% vs 10.6%; absolute risk reduction 4.3% [95% CI 1.1%-7.6%]; NNT 23.3). The effect was greatest in patients who started taking metformin within 4 days after symptom onset.5

ADVERSE EFFECTS – Metformin can cause GI adverse effects, including a metallic taste, nausea, diarrhea, and abdominal pain. Lactic acidosis occurs rarely; because of this risk, metformin is contraindicated for use in patients with an eGFR <30 mL/min/1.73 m², and starting the drug in patients with an eGFR of 30-45 mL/min/1.73 m² is not recommended.

DRUG INTERACTIONS – Metformin is a substrate of organic cation transporter 1 (OCT1) and the multidrug and toxin extrusion (MATE) transporter; inhibitors of these transporters (e.g., codeine, cimetidine) can increase its serum concentrations and inducers of these transporters (e.g., metoprolol) can decrease them. Use of metformin with other products that increase the risk of lactic acidosis (e.g., alcohol, carbonic anhydrase inhibitors, iodinated contrast media) can result in additive effects. Metformin can decrease the anticoagulant effect of warfarin.

DOSAGE, ADMINISTRATION, AND COST – The dosage of metformin used in the COVID-OUT trial was 500 mg once on day 1, 500 mg twice daily on days 2-5, and 500 mg each morning and 1000 mg each evening on days 6-14.5 The cost for a 14-day supply of metformin at this dosage is about $1.50.6

CONCLUSION – In a double-blind trial, adults with SARS-CoV-2 infection who took metformin for 2 weeks were less likely than those who took placebo to later report a diagnosis of long COVID. The drug did not decrease the risk of severe COVID-19. Off-label use of metformin to prevent long COVID in high-risk patients with normal renal function is reasonable, but confimatory data from a trial more specifically focused on long COVID would be welcome.

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