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Metformin Reduced Long COVID Incidence by 43%
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Outpatient Treatment of COVID-19 and the Development of Long COVID Over 10 Months: A Multi-Center, Quadruple-Blind, Parallel Group Randomized Phase 3 Trial
6 Mar 2023
A 42% relative decrease and 4.3% absolute decrease in the Long COVID incidence occurred in participants who received early outpatient COVID-19 treatment with metformin compared to exact-matching placebo.
When started within <4 days of symptom onset, the effect of metformin preventing Long Covid was potentially greater (Hazard Ratio = 0.37; 95% CI, 0.15 to 0.95) as compared with those who started metformin >4 days (Hazard Ratio = 0.64; 95% CI, 0.40 to 1.03).
Experimentally, metformin has in vitro activity at a physiologically relevant dose against SARS-CoV-2 in cell culture and in human lung tissue, ex vivo.27,33-35 Larger effects for therapies started earlier in the course of infection support an anti-viral mechanism. In addition to in vitro and in vivo activity against SARS-CoV-2, metformin has been extensively studied for actions relevant to oxidative stress and inflammation.36
Among those randomized to metformin, the cumulative incidence for developing Long Covid was 6.3% (95% CI 4.2% to 8.2%) as compared with 10.6% (8.0% to 13.1) in the blinded, identical-matched placebo controls.
Abstract
Background: Post-acute sequelae of COVID, termed "Long COVID", is an emerging chronic illness potentially affecting ~10% of those with COVID-19. We sought to determine if outpatient treatment with metformin, ivermectin, or fluvoxamine could prevent Long COVID.
Methods: COVID-OUT (NCT04510194) was a decentralized, multi-site trial in the United States testing three medications (metformin, ivermectin, fluvoxamine) using a 2x3 parallel treatment factorial randomized assignment to efficiently share placebo controls. Participants, investigators, care providers, and outcomes assessors were masked to randomized treatment assignment. Inclusion criteria included: age 30 to 85 years with overweight or obesity, symptoms <7 days, enrolled within <=3 days of documented SARS-CoV-2 infection. Long COVID diagnosis from a medical provider was a pre-specified secondary outcome assessed by monthly surveys through 300 days after randomization and confirmed in medical records.
Findings: Of 1323 randomized trial participants, 1125 consented for long-term follow up, and 95.1% completed >9 months of follow up. The median age was 45 years (IQR, 37 to 54), and 56% were female (7% pregnant). The median BMI was 30 kg/m2 (IQR, 27 to 34).
Overall, 8.4% reported a medical provider diagnosed them with Long COVID; cumulative incidence: 6.3% with metformin and 10.6% with matched placebo. The hazard ratio (HR) for metformin preventing Long COVID was 0.58 (95%CI, 0.38 to 0.88; P=0ยท009) versus placebo. The metformin effect was consistent across subgroups, including viral variants. When metformin was started within <4 days of symptom onset, the HR for Long COVID was 0.37 (95%CI, 0.15 to 0.95). No statistical difference in Long COVID occurred in those randomized to either ivermectin (HR=0.99; 95%CI, 0.59 to 1.64) or fluvoxamine (HR=1.36; 95%CI, 0.78 to 2.34).
Interpretations: A 42% relative decrease and 4.3% absolute decrease in the Long COVID incidence occurred in participants who received early outpatient COVID-19 treatment with metformin compared to exact-matching placebo.
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