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Table 7c. Metformin: Selected Clinical Data

Last Updated: December 1, 2022

The Panel’s recommendations for metformin are based on data from the clinical trials described in this table.

Table 7c. Metformin: Selected Clinical Data
Methods Results Limitations and Interpretation
COVID-OUT: RCT of Metformin, Ivermectin, and Fluvoxamine in Nonhospitalized Adults With COVID-19 in the United States1

Key Inclusion Criteria

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

Key Exclusion Criteria

  • Immunocompromised
  • Hepatic impairment
  • Stage 4–5 chronic kidney disease or eGFR <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 = 660), which included the following arms:
    • Placebo alone (n = 293)
    • IVM or fluvoxamine alone (n = 367)

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 risk of ED visit, hospitalization, or death by Day 14

Key Secondary Endpoints

  • Total symptom score by Day 14, as measured by a symptom severity scale
  • Drug discontinuation

Participant Characteristics

  • Median age 46 years; 56% women; 82% White
  • Median BMI 30
  • 27% with CVD
  • 52% received primary COVID-19 vaccination series
  • Mean number of days of symptoms: 4.8 days
  • Approximately 66% enrolled during Delta-predominant period; approximately 23% enrolled during Omicron-predominant period

Primary Outcomes

  • Proportion of patients who met the composite endpoint 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 those who received metformin alone vs. placebo alone 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 score by Day 14
  • Drug discontinuation or interruption: 29% in metformin arm vs. 25% in placebo alone 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 composite outcome of COVID-19–related hypoxemia, ED visit, hospitalization, or death.
  • Although the impact of metformin on the occurrence of ED visit, hospitalization, or death suggests a possible positive effect, these results cannot be considered definitive.
TOGETHER: RCT of Metformin in Nonhospitalized Patients With COVID-19 in Brazil2

Key Inclusion Criteria

  • Aged ≥50 years or aged ≥18 years with at least 1 comorbidity
  • 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 retention in ED for >6 hours or hospitalized for progression of 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 symptom onset within 0–3 days

Primary Outcome

  • Study was stopped early by DSMB for futility. At the time the study was stopped, primary endpoint had occurred in 13% in metformin arm vs. 15% 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 AEs: 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 retention endpoint has not been used in other studies of patients who are at high risk of hospitalization or 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.

References

  1. Bramante CT, Huling JD, Tignanelli CJ, et al. Randomized trial of metformin, ivermectin, and fluvoxamine for COVID-19. N Engl J Med. 2022;387(7):599-610. Available at: https://www.ncbi.nlm.nih.gov/pubmed/36070710.
  2. Reis G, Dos Santos Moreira Silva EA, Medeiros Silva DC, et al. Effect of early treatment with metformin on risk of emergency care and hospitalization among patients with COVID-19: the TOGETHER randomized platform clinical trial. Lancet Reg Health Am. 2022;6:100142. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34927127.