Is metformin (a biguanide oral hypoglycemic agent) effective for treating long-COVID (post-acute coronavirus disease 2019)?

Metformin for Long COVID: Current Evidence and Recommendations

Based on current evidence, metformin shows promise in reducing the risk of developing long COVID when used during acute COVID-19 infection, with a 41% relative risk reduction demonstrated in the highest quality trial, but it is not recommended specifically for treating established long COVID symptoms.

Evidence for Metformin in Long COVID Prevention

The most compelling evidence comes from a high-quality randomized controlled trial (COVID-OUT) that evaluated metformin for preventing long COVID:

• The COVID-OUT trial showed that outpatient treatment with metformin during acute COVID-19 reduced long COVID incidence by approximately 41% compared to placebo, with an absolute risk reduction of 4.1% 1
• This benefit was most pronounced when metformin was started within 3 days of symptom onset (HR 0.37,95% CI 0.15-0.95) 1
• A systematic review and meta-analysis found that metformin might decrease the development of long COVID (risk ratio 0.6,95% CI 0.4-0.9), though this was based primarily on the COVID-OUT trial data 2

However, more recent data from the ACTIV-6 trial showed:

• No significant reduction in COVID-19 symptoms at day 180 with metformin compared to placebo (adjusted risk ratio 0.79,95% CrI 0.474 to 1.230) 3
• The posterior probability of efficacy (0.83) did not meet the pre-specified threshold (0.975) for declaring efficacy 3
• Metformin did not significantly shorten time to symptom resolution in acute COVID-19 4

Safety Considerations

When considering metformin use during COVID-19, important safety considerations include:

• Discontinue metformin in patients with severe COVID-19 to reduce the risk of acute metabolic decompensation, particularly lactic acidosis 5, 6
• Risk factors for lactic acidosis include:
  • eGFR <45 mL/min/1.73m²
  • Acute kidney injury
  • Liver disease
  • Heart failure
  • Hypoxic states 6
• The ACTIV-6 trial reported minimal safety concerns with metformin in outpatients with mild-to-moderate COVID-19 4

Practical Recommendations

For patients with acute COVID-19:

1. Consider metformin (titrated to 1500 mg daily for 14 days) for non-hospitalized adults with acute COVID-19, particularly those with risk factors for long COVID
2. Initiate treatment as early as possible, ideally within 3 days of symptom onset
3. Monitor for adverse effects, particularly gastrointestinal symptoms
4. Discontinue metformin if the patient develops severe COVID-19 requiring hospitalization

For patients with established long COVID:

1. There is insufficient evidence to recommend metformin specifically for treating established long COVID symptoms
2. The ESCMID rapid guidelines for long COVID do not mention metformin as a treatment option 5
3. Focus on symptom-specific management and rehabilitation approaches

Limitations and Caveats

• The evidence for metformin in preventing long COVID comes primarily from one high-quality trial (COVID-OUT) 1
• The more recent ACTIV-6 trial did not confirm these findings 3, 4
• Most studies were conducted before widespread vaccination and during earlier SARS-CoV-2 variants
• The definition and assessment of long COVID varies between studies
• The mechanism by which metformin might prevent long COVID remains unclear, though its anti-inflammatory and metabolic effects may play a role

In conclusion, while metformin shows promise for preventing long COVID when used during acute infection, particularly when started early, there is insufficient evidence to recommend it for treating established long COVID symptoms. Further research is needed to confirm these findings and determine optimal timing, dosing, and patient selection.