Table 7c. Metformin: Selected Clinical Trial Data

Key Inclusion Criteria

• Aged ≥50 years or aged ≥18 years with ≥1 comorbidities
• Positive rapid antigen test result for SARS-CoV-2 infection
• ≤7 days of COVID-19 symptoms

Key Exclusion Criteria

• Acute respiratory symptoms that required hospitalization
• Receipt of a COVID-19 vaccine

Interventions

• Extended-release metformin 750 mg PO twice daily for 10 days (n = 215)
• Placebo PO twice daily for 10 days (n = 203)

Primary Endpoint

• Composite of ED observation >6 hours or hospitalization for COVID-19 by Day 28 

Key Secondary Endpoints

• Clinical improvement by Day 28
• Viral clearance by Day 7
• Time to hospitalization or death
• Occurrence of AEs
• Study adherence

Participant Characteristics

• Median age 52 years; 57% women; 91% self-identified as mixed race
• 45% with BMI ≥30; 40% with HTN; 15% with DM
• 44% had COVID-19 symptoms for 0–3 days at enrollment

Primary Outcome

• Study was stopped early by DSMB for futility. At the time the study was stopped, primary endpoint had occurred in 16% in metformin arm vs. 14% in placebo arm (relative risk 1.14; 95% CI, 0.73–1.81; probability of superiority 28%).

Secondary Outcomes

• No difference between arms in:
• Clinical improvement by Day 28 (OR 1.05; 95% CI, 0.71–1.56) 
• Viral clearance by Day 7 (OR 0.99; 95% CI, 0.88–1.11)
• Time to hospitalization or death (P = 0.53)
• Occurrence of treatment-emergent, grade 3 AEs: 9.8% in metformin arm vs. 4.4% in placebo arm (relative risk 2.11; 95% CI, 1.05–4.61)
• Did not complete all phases of the study: 22% in metformin arm vs. 12% in placebo arm

   

Key Limitations

• The >6-hour ED observation endpoint has not been used in other studies of interventions for nonhospitalized patients who are at high risk of hospitalization and death.
• Study was stopped early for futility.
• Vaccinated individuals were excluded from trial.

Interpretation

• This trial demonstrated no clinical benefit of metformin in nonhospitalized patients with COVID-19.
• The use of metformin was associated with more grade 3 AEs than placebo.

Key Inclusion Criteria

• Aged 30–85 years
• BMI ≥25 or ≥23 if Asian or Latinx
• Laboratory-confirmed SARS-CoV-2 infection within 3 days of randomization
• ≤7 days of COVID-19 symptoms

Key Exclusion Criteria

• Immunocompromised
• Hepatic impairment
• Stage 4–5 chronic kidney disease or eGFR of <45 mL/min/1.73m²

Interventions

• Immediate-release metformin 500 mg PO on Day 1, 500 mg twice daily on Days 2–5, and 500 mg in morning and 1,000 mg in evening on Days 6–14 (n = 663) in the following arms:
• Metformin alone (n = 284) 
• Metformin plus IVM 390–470 µg/kg PO once daily for 3 days (n = 204)
• Metformin plus fluvoxamine 50 mg PO twice daily for 14 days (n = 175)
• Control (n = 655), which included the following arms:
  • Placebo alone (n = 293)
  • IVM or fluvoxamine alone (n = 362)

Primary Endpoints

• Composite of hypoxemia (SpO₂ ≤93%, as measured by a home pulse oximeter), ED visit, hospitalization, or death by Day 14
• A prespecified secondary analysis evaluated the occurrence of ED visits, hospitalization, or death by Day 14.

Key Secondary Endpoints

• Total symptom severity score by Day 14, as measured by a symptom severity scale
• Drug discontinuation or interruption
• Hospitalization or death by Day 28

Participant Characteristics

• Median age 46 years; 56% women; 82% White
• Median BMI 30 
• 27% with CVD
• 52% received primary COVID-19 vaccination series
• Mean duration of symptoms was 4.8 days 
• Approximately 66% enrolled while Delta was the dominant variant; approximately 22% enrolled while Omicron was dominant

Primary Outcomes

• Composite of hypoxemia, ED visit, hospitalization, or death by Day 14: 154 (24%) in metformin arm vs. 179 (27%) in control arm (aOR 0.84; 95% CI, 0.66–1.09; P = 0.19)
• No difference between metformin alone arm and placebo alone arm in occurrence of primary endpoint (aOR 0.91; 95% CI, 0.62–1.33)
• ED visit, hospitalization, or death by Day 14 in a prespecified secondary analysis: 27 (4.1%) in metformin arm vs. 48 (7.3%) in control arm (aOR 0.58; 95% CI, 0.35–0.94)
• Hospitalization or death by Day 14 in a prespecified secondary analysis: 8 (1.2%) in metformin arm vs. 18 (2.7%) in control arm (aOR 0.47; 95% CI, 0.20–1.11)

Secondary Outcomes

• No difference between arms in total symptom severity score by Day 14
• Drug discontinuation or interruption: 29% in metformin arm vs. 25% in control arm
• Hospitalization or death by Day 28: 8 of 596 (1.3%) in metformin arm vs. 19 of 601 (3.2%) in control arm

Key Limitations

• Analyses of secondary endpoints were not adjusted for multiple comparisons.
• Study included SpO₂ measurements using home pulse oximeters as 1 of the composite measures of the primary endpoint. However, the FDA has issued a statement concerning the accuracy of these home pulse oximeters, making this study endpoint less reliable. 

Interpretation

• The use of metformin did not prevent the occurrence of the primary composite endpoint of hypoxemia, ED visit, hospitalization, or death by Day 14.
• Although the results of the prespecified secondary analyses of ED visits, hospitalization, or death by Day 14 and the secondary endpoint of hospitalization or death by Day 28 suggest a potential benefit of metformin, these results are not considered definitive.