What is the role of metformin (biguanide oral hypoglycemic agent) in patients with diabetes who contract COVID-19 (Coronavirus disease 2019)?

Metformin Use in COVID-19 Patients with Diabetes

Metformin should be discontinued in patients with severe COVID-19 symptoms to prevent lactic acidosis, but can be safely continued in outpatients with mild disease or those without symptoms. 1

Key Management Principles

For Outpatients with Mild or No COVID-19 Symptoms

• Continue metformin in diabetic patients who are asymptomatic or have mild COVID-19 symptoms without contraindications 1
• Do not discontinue metformin prophylactically in outpatients with diabetes who have no symptoms of infection 1
• Monitor renal function carefully during illness due to high risk of chronic kidney disease or acute kidney injury 1
• Patients should follow sick day rules if they become dehydrated 1

For Hospitalized Patients with Severe COVID-19

• Discontinue metformin immediately in patients with severe COVID-19 symptoms to reduce risk of acute metabolic decompensation 1
• Stop metformin in patients at risk for lactic acidosis, including those with:
  • Sepsis, hypoxia, or shock 1
  • Acute kidney injury (eGFR <30 mL/min per 1.73 m²) 1
  • Liver failure 1
  • Anaerobic metabolism 1
• Transition to insulin therapy when metformin is discontinued 1

Evidence on Clinical Outcomes

Mortality Benefits

Recent research suggests potential protective effects of metformin in COVID-19 patients with diabetes:

• A retrospective Chinese study of 283 hospitalized diabetic COVID-19 patients found significantly lower in-hospital mortality in the metformin group (2.9% vs 12.3%, P=0.01) 2
• The length of hospital stay did not differ between metformin users and non-users 2
• A systematic review found that 9 out of 14 studies revealed positive effects of metformin on COVID-19 prognosis in diabetic patients 3

Safety Profile

• A UK propensity score-matched cohort study (29,558 metformin users vs 10,271 non-users) found metformin was not associated with increased risk of COVID-19 infection or COVID-19-related mortality 4
• However, inpatient metformin use in Chinese COVID-19 patients was associated with increased lactic acidosis (adjusted HR 4.46,95% CI 1.11-18.0), particularly with higher doses, worse kidney function, and greater COVID-19 severity 1

Specific Risk Factors for Lactic Acidosis

Monitor and discontinue metformin if the following are present:

• eGFR <30 mL/min per 1.73 m² (discontinue); reduce dose if eGFR 30-45 mL/min per 1.73 m² 1
• Elevated lactate concentrations in fragile patients 1
• Severe COVID-19 disease requiring intensive care 1
• More than 2 daily metformin doses in hospitalized patients 5

Proposed Mechanisms of Benefit

While the clinical evidence is evolving, metformin may offer benefits through:

• Decreasing insulin resistance and improving glycemic control 3
• Reducing inflammatory cytokines (IL-6, TNF-α) 3
• Modulating ACE2 receptor expression 3
• Improving neutrophil-to-lymphocyte ratio 3
• Attenuating endothelial dysfunction 6

Critical Caveats

The key distinction is disease severity: metformin appears safe and potentially beneficial in mild-to-moderate COVID-19 but poses significant lactic acidosis risk in severe disease with organ dysfunction 1. The decision hinges on assessing for dehydration, renal function, tissue hypoxia, and overall COVID-19 severity rather than simply the presence of COVID-19 infection 1.