Table 7c. Metformin: Selected Clinical Trial Data
Last Updated: December 20, 2023
The Panel’s recommendations for metformin are based on data from the clinical trials described in this table.
Table 7c. Metformin: Selected Clinical Trial Data Methods | Results | Limitations and Interpretation |
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TOGETHER: RCT of Metformin in Nonhospitalized Patients With COVID-19 in Brazil1 |
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.
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COVID-OUT: RCT of Metformin, Ivermectin, and Fluvoxamine in Nonhospitalized Adults With COVID-19 in the United States2 |
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.
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References
- 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.
- 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.