By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC
Professor of Medicine, Northeast Ohio Medical University, Rootstown, OH
SYNOPSIS: A randomized, placebo-controlled clinical trial of outpatients with COVID-19 found that metformin reduced SARS-CoV-2 viral load 3.6-fold compared to placebo, while ivermectin and fluvoxamine showed no benefit.
SOURCE: Bramante CT, Beckman KB, Mehta T, et al. Favorable antiviral effect of metformin on SARS-CoV-2 viral load in a randomized, placebo-controlled clinical trial of COVID-19. Clin Infect Dis 2024;79:354-363.
Several in vitro studies have suggested that metformin may be a beneficial treatment for COVID-19. The mechanism has been hypothesized to be inhibition of the mechanistic target of rapamycin (mTOR), which suppresses protein translation. Metformin also has anti-inflammatory activity by inhibiting interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor (TNF)-alpha. Therefore, Bramante and colleagues conducted a randomized clinical trial to elucidate whether metformin is clinically useful in treating COVID-19.
The study was a randomized, placebo-controlled, multicenter clinical trial (RCT) that enrolled patients between December 2020 and January 2022. Patients were included who were aged 30 to 85 years, overweight or obese based on body mass index (BMI), had a documented positive test for COVID-19 within three days, and had no prior COVID-19 infection. Exclusion criteria were hospitalization, symptom onset more than seven days prior, and unstable organ failure. Patients were randomized to receive metformin, fluvoxamine, ivermectin, or placebo. Pregnant women were randomized to just metformin or placebo. Metformin, fluvoxamine, and placebo were given for 14 days, while ivermectin was given for three days. Patients self-collected anterior nasal swabs on days 1, 5, and 10. Viral load was quantified by polymerase chain reaction (PCR). Viral rebound was defined as having a viral load higher at day 10 than at day 5. The primary end point of the study was severe COVID-19 by day 14. The secondary end points were hospitalization or death by day 28 and long COVID in the following 10 months.
There were 945 patients who provided a day 1 nasal sample, 871 provided a day 5 sample, and 775 provided a day 10 sample. The viral load was a median of 4.88 log10 copies/mL (range, 2.99 to 6.18) on day 1, 1.90 (range, 0 to 3.93) on day 5, and 0 (range, 0 to 1.90) on day 10. The overall mean SARS-CoV-2 viral load reduction with metformin was -0.56 log10 copies/mL greater than placebo across all follow-up (P = 0.027). Neither ivermectin nor fluvoxamine had any antivirologic affect. Furthermore, patients who received metformin were less likely to have a detectable viral load at day 10 (odds ratio [OR], 0.65) and day 5 (OR, 0.79). Compared to placebo, those who received metformin had a lower risk for viral rebound (22 of 370 [5.9%] vs. 12 of 366 [3.2%], respectively). Vaccination status, including receipt of a booster, did not significantly affect any of the results. Metformin was effective against all three of the SARS-CoV-2 strains (i.e., Alpha, Delta, and Omicron).
Regarding the secondary end points, patients who received metformin had a lower chance of being hospitalized or dying by day 28 (OR, 0.48) or developing long COVID (hazard ratio, 0.59). Finally, the antiviral effect of metformin on geometric log10 scale was greater among those with baseline viral loads < 100,000 copies/mL compared to those with viral loads > 100,000 copies/mL.
Commentary
In this multicenter RCT, metformin significantly reduced SARS-CoV-2 viral load over 10 days and led to improvement in several clinically important outcomes. Metformin is relatively inexpensive, especially compared to other COVID-19 treatments like nirmatrelvir. Given its proposed mechanism of action, the risk of metformin promoting antiviral resistance seems low, although this needs to be investigated further. Metformin is safe for pregnant women and those with and without diabetes. Furthermore, historical concerns about lactic acidosis with metformin have been disproven. While there have been a multitude of repurposed drugs such as hydroxychloroquine and azithromycin for treating COVID-19 that failed under rigorous evaluation, the positive results for metformin are indeed welcome news.
There were some limitations to the study. First, the investigators were only able to sample viral loads on days 1, 5, and 10 due to limited resources. More frequent sampling could have better characterized the dynamics of viral shedding early in the course of infection. Second, the investigators did not report on the proportion of patients with a viral load above the threshold reported with live viral shedding (i.e., > 104 copies/mL), which could have informed the potential public health implications of metformin use. Finally, subgroup analysis can be hampered by low power and sparse data bias.
At this point in the COVID-19 pandemic, more treatment options are needed, especially for outpatients. Should metformin be one? While promising and intriguing, the study by Bramante et al is a single trial. However, more evidence may be available soon in the form of another clinical trial called ACTIV6, which currently is randomizing patients with COVID-19 to placebo vs. metformin and is expected to enroll 3,000 subjects. Thus, if metformin again shows benefit, then treatment guidelines will need to be updated to recommend it.
