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Metformin for COVID-19: real-time meta analysis of 48 studies
Covid Analysis, October 3, 2022, DRAFT
https://c19early.com/mfmeta.html
 
0 0.5 1 1.5+ All studies 27% 48 182,278 Improvement, Studies, Patients Relative Risk Mortality 33% 36 120,678 Ventilation 40% 6 6,366 ICU admission 21% 4 34,611 Hospitalization 20% 8 24,275 Progression 27% 9 20,493 Recovery 38% 2 4,008 Cases 0% 6 27,298 Viral clearance 1% 1 418 RCTs 24% 2 1,222 RCT mortality 24% 2 1,222 Peer-reviewed 26% 43 135,980 Prophylaxis 24% 44 154,360 Early 58% 3 27,730 Late 97% 1 188 Metformin for COVID-19 c19early.com/mf Oct 2022 Favorsmetformin Favorscontrol after exclusions
Statistically significant improvements are seen for mortality, ventilation, ICU admission, and hospitalization. 28 studies from 27 independent teams in 10 different countries show statistically significant improvements in isolation (24 for the most serious outcome).
Meta analysis using the most serious outcome reported shows 27% [21‑32%] improvement. Results are similar for Randomized Controlled Trials, similar after exclusions, and similar for peer-reviewed studies. Clinical outcomes suggest benefit while viral and case outcomes do not, consistent with an intervention that aids recovery but is not antiviral.
Results are robust — in exclusion sensitivity analysis 29 of 48 studies must be excluded to avoid finding statistically significant efficacy in pooled analysis.
0 0.5 1 1.5+ All studies 27% 48 182,278 Improvement, Studies, Patients Relative Risk Mortality 33% 36 120,678 Ventilation 40% 6 6,366 ICU admission 21% 4 34,611 Hospitalization 20% 8 24,275 Progression 27% 9 20,493 Recovery 38% 2 4,008 Cases 0% 6 27,298 Viral clearance 1% 1 418 RCTs 24% 2 1,222 RCT mortality 24% 2 1,222 Peer-reviewed 26% 43 135,980 Prophylaxis 24% 44 154,360 Early 58% 3 27,730 Late 97% 1 188 Metformin for COVID-19 c19early.com/mf Oct 2022 Favorsmetformin Favorscontrol after exclusions
Most studies analyze existing use with diabetic patients. Many results are subject to confounding by indication — metformin is typically used early in the progression of type 2 diabetes. Prophylaxis results typically include continuing use after infection and hospitalization, and greater benefit is seen for more serious outcomes. The beneficial effect of metformin may be more related to later stages of COVID-19. The TOGETHER RCT shows 27% lower mortality. While not statistically significant, p = 0.53, this is consistent with the mortality results from all studies, 33% [28‑39%].
No treatment, vaccine, or intervention is 100% effective and available. All practical, effective, and safe means should be used based on risk/benefit analysis. Multiple treatments are typically used in combination, and other treatments are more effective. None of the metformin studies show zero events with treatment.
All data to reproduce this paper and sources are in the appendix. Other meta analyses for metformin can be found in [Hariyanto, Kow, Lukito, Yang], showing significant improvements for mortality and progression.
Highlights
Metformin reduces risk for COVID-19 with very high confidence for mortality, ventilation, hospitalization, and in pooled analysis, high confidence for ICU admission, low confidence for progression, and very low confidence for recovery.
We show traditional outcome specific analyses and combined evidence from all studies, incorporating treatment delay, a primary confounding factor in COVID-19 studies.
Real-time updates and corrections, transparent analysis with all results in the same format, consistent protocol for 47 treatments.
A
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Reis (DB RCT) 27% 0.73 [0.28-1.94] death 7/215 9/203 impossible data, see notes Improvement, RR [CI] Treatment Control Hunt 67% 0.33 [0.25-0.43] death 73/3,956 1,539/22,552 Bramante (DB RCT) 3% 0.97 [0.06-15.5] death 1/408 1/396 OT​1 Tau​2 = 0.12, I​2 = 33.5%, p = 0.0046 Early treatment 58% 0.42 [0.23-0.77] 81/4,579 1,549/23,151 58% improvement Tamura 97% 0.03 [0.00-0.58] death 115 (n) 73 (n) Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.019 Late treatment 97% 0.03 [0.00-0.58] 0/115 0/73 97% improvement Luo 75% 0.25 [0.07-0.84] death 3/104 22/179 Improvement, RR [CI] Treatment Control Choi (PSM) -120% 2.20 [0.51-9.58] progression case control Wang 58% 0.42 [0.01-1.98] death 1/9 13/49 Chen 33% 0.67 [0.20-1.78] death 4/43 15/77 Kim 64% 0.36 [0.10-1.23] death 113 (n) 122 (n) Li 78% 0.22 [0.09-0.54] death 2/37 21/94 Goodall 3% 0.97 [0.75-1.25] death 74/210 280/771 Gao -225% 3.25 [1.03-7.41] progression 16/56 4/54 Pérez-Belm.. (PSM) -10% 1.10 [0.84-1.40] death 79/249 79/249 Kolin -30% 1.30 [0.97-1.73] cases n/a n/a Bramante 7% 0.93 [0.81-1.06] death 394/2,333 791/3,923 Lalau (PSM) 22% 0.78 [0.55-1.10] death 671 (n) 419 (n) Huh -1% 1.01 [0.75-1.37] progression 104/272 774/2,533 Crouse 61% 0.39 [0.16-0.87] death 8/76 34/144 Lally 52% 0.48 [0.28-0.84] death 16/127 144/648 Oh -26% 1.26 [0.81-1.95] death 5,946 (n) 5,946 (n) Wargny 28% 0.72 [0.53-0.95] death 247/1,553 330/1,241 Holt -27% 1.27 [0.72-2.22] cases 12/429 434/14,798 Khunti 23% 0.77 [0.73-0.81] death population-based cohort Jiang (PSM) 46% 0.54 [0.13-2.26] death 3/74 10/74 Ghany 66% 0.34 [0.19-0.59] death 392 (n) 747 (n) Alamgir 27% 0.73 [0.63-0.84] death 11,062 (n) 11,062 (n) Ravindra 30% 0.70 [0.28-1.56] death 5/53 57/313 Blanc 79% 0.21 [0.03-1.46] death 1/14 25/75 Boye 10% 0.90 [0.86-0.94] hosp. 2,067/4,250 3,196/5,281 Cheng (PSM) -65% 1.65 [0.71-3.86] death 678 (n) 535 (n) Wang 12% 0.88 [0.81-0.97] ICU 6,504 (n) 10,000 (n) Ando 39% 0.61 [0.38-0.99] hosp. Wander 15% 0.85 [0.80-0.90] death Saygili (PSM) 42% 0.58 [0.37-0.92] death 120 (n) 120 (n) Ong 47% 0.53 [0.31-0.87] death 33/186 57/169 Bliden 60% 0.40 [0.12-1.37] death 3/34 9/41 Al-Salameh 55% 0.45 [0.17-0.94] death/ICU 9/47 22/50 Wallace (PSW) 72% 0.28 [0.21-0.37] death 103/1,203 1,536/6,970 Ojeda-Ferná.. (PSM) 16% 0.84 [0.79-0.89] death 1,476/6,556 1,787/6,556 Usman 60% 0.40 [0.12-1.37] death 3/34 9/41 Wong 51% 0.49 [0.43-0.57] death Wong (PSW) 59% 0.41 [0.22-0.80] death 786 (n) 428 (n) MacFadden 1% 0.99 [0.96-1.01] cases n/a n/a Cousins (PSM) 54% 0.46 [0.25-0.82] ventilation 2,498 (n) 2,497 (n) Shestakova 22% 0.78 [0.67-0.91] death Loucera 30% 0.70 [0.61-0.80] death 1,896 (n) 14,072 (n) Chan 59% 0.41 [0.12-1.44] death 400 (n) 2,736 (n) Yip (PSM) 7% 0.93 [0.72-1.22] death/hosp. 8,604 (n) 3,727 (n) Tau​2 = 0.02, I​2 = 92.1%, p < 0.0001 Prophylaxis 24% 0.76 [0.71-0.81] 4,663/57,619 9,649/96,741 24% improvement All studies 27% 0.73 [0.68-0.79] 4,744/62,313 11,198/119,965 27% improvement 48 metformin COVID-19 studies c19early.com/mf Oct 2022 Tau​2 = 0.03, I​2 = 92.3%, p < 0.0001 Effect extraction pre-specified(most serious outcome, see appendix) 1 OT: comparison with other treatment Favors metformin Favors control
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Reis (DB RCT) 27% death impossible data, see notes Improvement Relative Risk [CI] Hunt 67% death Bramante (DB RCT) 3% death OT​1 Tau​2 = 0.12, I​2 = 33.5%, p = 0.0046 Early treatment 58% 58% improvement Tamura 97% death Tau​2 = 0.00, I​2 = 0.0%, p = 0.019 Late treatment 97% 97% improvement Luo 75% death Choi (PSM) -120% progression Wang 58% death Chen 33% death Kim 64% death Li 78% death Goodall 3% death Gao -225% progression Pérez-Belm.. (PSM) -10% death Kolin -30% case Bramante 7% death Lalau (PSM) 22% death Huh -1% progression Crouse 61% death Lally 52% death Oh -26% death Wargny 28% death Holt -27% case Khunti 23% death Jiang (PSM) 46% death Ghany 66% death Alamgir 27% death Ravindra 30% death Blanc 79% death Boye 10% hospitalization Cheng (PSM) -65% death Wang 12% ICU admission Ando 39% hospitalization Wander 15% death Saygili (PSM) 42% death Ong 47% death Bliden 60% death Al-Salameh 55% death/ICU Wallace (PSW) 72% death Ojeda-Ferná.. (PSM) 16% death Usman 60% death Wong 51% death Wong (PSW) 59% death MacFadden 1% case Cousins (PSM) 54% ventilation Shestakova 22% death Loucera 30% death Chan 59% death Yip (PSM) 7% death/hosp. Tau​2 = 0.02, I​2 = 92.1%, p < 0.0001 Prophylaxis 24% 24% improvement All studies 27% 27% improvement 48 metformin COVID-19 studies c19early.com/mf Oct 2022 Tau​2 = 0.03, I​2 = 92.3%, p < 0.0001 Protocol pre-specified/rotate for details1 OT: comparison with other treatment Favors metformin Favors control
Figure 1. A. Random effects meta-analysis. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix. B. Scatter plot showing the distribution of effects reported in studies. C. History of all reported effects (chronological within treatment stages).
Introduction
We analyze all significant studies concerning the use of metformin for COVID-19. Search methods, inclusion criteria, effect extraction criteria (more serious outcomes have priority), all individual study data, PRISMA answers, and statistical methods are detailed in Appendix 1. We present random effects meta-analysis results for all studies, for studies within each treatment stage, for individual outcomes, for peer-reviewed studies, for Randomized Controlled Trials (RCTs), and after exclusions.
Figure 2 shows stages of possible treatment for COVID-19. Prophylaxis refers to regularly taking medication before becoming sick, in order to prevent or minimize infection. Early Treatment refers to treatment immediately or soon after symptoms appear, while Late Treatment refers to more delayed treatment.
Figure 2. Treatment stages.
Preclinical Research
An In Vitro study supports the efficacy of metformin [Parthasarathy].
Preclinical research is an important part of the development of treatments, however results may be very different in clinical trials. Preclinical results are not used in this paper.
Results
Figure 3 shows a visual overview of the results, with details in Table 1 and Table 2. Figure 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13 show forest plots for a random effects meta-analysis of all studies with pooled effects, mortality results, ventilation, ICU admission, hospitalization, progression, recovery, cases, viral clearance, and peer reviewed studies.
0 0.5 1 1.5+ ALL STUDIES MORTALITY VENTILATION ICU ADMISSION HOSPITALIZATION PROGRESSION RECOVERY CASES VIRAL CLEARANCE RANDOMIZED CONTROLLED TRIALS RCT MORTALITY PEER-REVIEWED After Exclusions ALL STUDIES All Prophylaxis Early Late Metformin for COVID-19 C19EARLY.COM/MF OCT 2022
Figure 3. Overview of results.
Treatment timeNumber of studies reporting positive effects Total number of studiesPercentage of studies reporting positive effects Random effects meta-analysis results
Early treatment 3 3 100% 58% improvement
RR 0.42 [0.23‑0.77]
p = 0.0046
Late treatment 1 1 100% 97% improvement
RR 0.03 [0.00‑0.58]
p = 0.019
Prophylaxis 36 44 81.8% 24% improvement
RR 0.76 [0.71‑0.81]
p < 0.0001
All studies 40 48 83.3% 27% improvement
RR 0.73 [0.68‑0.79]
p < 0.0001
Table 1. Results by treatment stage.
Studies Early treatment Late treatment Prophylaxis PatientsAuthors
All studies 4858% [23‑77%]97% [42‑100%]24% [19‑29%] 182,278 603
With exclusions 4558% [23‑77%]97% [42‑100%]24% [19‑30%] 166,610 546
Peer-reviewed 4358% [23‑77%]97% [42‑100%]23% [17‑29%] 135,980 552
Randomized Controlled TrialsRCTs 224% [-89‑70%] 1,222 26
Table 2. Results by treatment stage for all studies and with different exclusions.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Reis (DB RCT) 27% 0.73 [0.28-1.94] death 7/215 9/203 impossible data, see notes Improvement, RR [CI] Treatment Control Hunt 67% 0.33 [0.25-0.43] death 73/3,956 1,539/22,552 Bramante (DB RCT) 3% 0.97 [0.06-15.5] death 1/408 1/396 OT​1 Tau​2 = 0.12, I​2 = 33.5%, p = 0.0046 Early treatment 58% 0.42 [0.23-0.77] 81/4,579 1,549/23,151 58% improvement Tamura 97% 0.03 [0.00-0.58] death 115 (n) 73 (n) Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.019 Late treatment 97% 0.03 [0.00-0.58] 0/115 0/73 97% improvement Luo 75% 0.25 [0.07-0.84] death 3/104 22/179 Improvement, RR [CI] Treatment Control Choi (PSM) -120% 2.20 [0.51-9.58] progression case control Wang 58% 0.42 [0.01-1.98] death 1/9 13/49 Chen 33% 0.67 [0.20-1.78] death 4/43 15/77 Kim 64% 0.36 [0.10-1.23] death 113 (n) 122 (n) Li 78% 0.22 [0.09-0.54] death 2/37 21/94 Goodall 3% 0.97 [0.75-1.25] death 74/210 280/771 Gao -225% 3.25 [1.03-7.41] progression 16/56 4/54 Pérez-Belm.. (PSM) -10% 1.10 [0.84-1.40] death 79/249 79/249 Kolin -30% 1.30 [0.97-1.73] cases n/a n/a Bramante 7% 0.93 [0.81-1.06] death 394/2,333 791/3,923 Lalau (PSM) 22% 0.78 [0.55-1.10] death 671 (n) 419 (n) Huh -1% 1.01 [0.75-1.37] progression 104/272 774/2,533 Crouse 61% 0.39 [0.16-0.87] death 8/76 34/144 Lally 52% 0.48 [0.28-0.84] death 16/127 144/648 Oh -26% 1.26 [0.81-1.95] death 5,946 (n) 5,946 (n) Wargny 28% 0.72 [0.53-0.95] death 247/1,553 330/1,241 Holt -27% 1.27 [0.72-2.22] cases 12/429 434/14,798 Khunti 23% 0.77 [0.73-0.81] death population-based cohort Jiang (PSM) 46% 0.54 [0.13-2.26] death 3/74 10/74 Ghany 66% 0.34 [0.19-0.59] death 392 (n) 747 (n) Alamgir 27% 0.73 [0.63-0.84] death 11,062 (n) 11,062 (n) Ravindra 30% 0.70 [0.28-1.56] death 5/53 57/313 Blanc 79% 0.21 [0.03-1.46] death 1/14 25/75 Boye 10% 0.90 [0.86-0.94] hosp. 2,067/4,250 3,196/5,281 Cheng (PSM) -65% 1.65 [0.71-3.86] death 678 (n) 535 (n) Wang 12% 0.88 [0.81-0.97] ICU 6,504 (n) 10,000 (n) Ando 39% 0.61 [0.38-0.99] hosp. Wander 15% 0.85 [0.80-0.90] death Saygili (PSM) 42% 0.58 [0.37-0.92] death 120 (n) 120 (n) Ong 47% 0.53 [0.31-0.87] death 33/186 57/169 Bliden 60% 0.40 [0.12-1.37] death 3/34 9/41 Al-Salameh 55% 0.45 [0.17-0.94] death/ICU 9/47 22/50 Wallace (PSW) 72% 0.28 [0.21-0.37] death 103/1,203 1,536/6,970 Ojeda-Ferná.. (PSM) 16% 0.84 [0.79-0.89] death 1,476/6,556 1,787/6,556 Usman 60% 0.40 [0.12-1.37] death 3/34 9/41 Wong 51% 0.49 [0.43-0.57] death Wong (PSW) 59% 0.41 [0.22-0.80] death 786 (n) 428 (n) MacFadden 1% 0.99 [0.96-1.01] cases n/a n/a Cousins (PSM) 54% 0.46 [0.25-0.82] ventilation 2,498 (n) 2,497 (n) Shestakova 22% 0.78 [0.67-0.91] death Loucera 30% 0.70 [0.61-0.80] death 1,896 (n) 14,072 (n) Chan 59% 0.41 [0.12-1.44] death 400 (n) 2,736 (n) Yip (PSM) 7% 0.93 [0.72-1.22] death/hosp. 8,604 (n) 3,727 (n) Tau​2 = 0.02, I​2 = 92.1%, p < 0.0001 Prophylaxis 24% 0.76 [0.71-0.81] 4,663/57,619 9,649/96,741 24% improvement All studies 27% 0.73 [0.68-0.79] 4,744/62,313 11,198/119,965 27% improvement 48 metformin COVID-19 studies c19early.com/mf Oct 2022 Tau​2 = 0.03, I​2 = 92.3%, p < 0.0001 Effect extraction pre-specified(most serious outcome, see appendix) 1 OT: comparison with other treatment Favors metformin Favors control
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Reis (DB RCT) 27% death impossible data, see notes Improvement Relative Risk [CI] Hunt 67% death Bramante (DB RCT) 3% death OT​1 Tau​2 = 0.12, I​2 = 33.5%, p = 0.0046 Early treatment 58% 58% improvement Tamura 97% death Tau​2 = 0.00, I​2 = 0.0%, p = 0.019 Late treatment 97% 97% improvement Luo 75% death Choi (PSM) -120% progression Wang 58% death Chen 33% death Kim 64% death Li 78% death Goodall 3% death Gao -225% progression Pérez-Belm.. (PSM) -10% death Kolin -30% case Bramante 7% death Lalau (PSM) 22% death Huh -1% progression Crouse 61% death Lally 52% death Oh -26% death Wargny 28% death Holt -27% case Khunti 23% death Jiang (PSM) 46% death Ghany 66% death Alamgir 27% death Ravindra 30% death Blanc 79% death Boye 10% hospitalization Cheng (PSM) -65% death Wang 12% ICU admission Ando 39% hospitalization Wander 15% death Saygili (PSM) 42% death Ong 47% death Bliden 60% death Al-Salameh 55% death/ICU Wallace (PSW) 72% death Ojeda-Ferná.. (PSM) 16% death Usman 60% death Wong 51% death Wong (PSW) 59% death MacFadden 1% case Cousins (PSM) 54% ventilation Shestakova 22% death Loucera 30% death Chan 59% death Yip (PSM) 7% death/hosp. Tau​2 = 0.02, I​2 = 92.1%, p < 0.0001 Prophylaxis 24% 24% improvement All studies 27% 27% improvement 48 metformin COVID-19 studies c19early.com/mf Oct 2022 Tau​2 = 0.03, I​2 = 92.3%, p < 0.0001 Protocol pre-specified/rotate for details1 OT: comparison with other treatment Favors metformin Favors control
Figure 4. Random effects meta-analysis for all studies with pooled effects. This plot shows pooled effects, discussion can be found in the heterogeneity section, and results for specific outcomes can be found in the individual outcome analyses. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix.
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ Reis (DB RCT) 27% 0.73 [0.28-1.94] 7/215 9/203 impossible data, see notes Improvement, RR [CI] Treatment Control Hunt 67% 0.33 [0.25-0.43] 73/3,956 1,539/22,552 Bramante (DB RCT) 3% 0.97 [0.06-15.5] 1/408 1/396 OT​1 Tau​2 = 0.12, I​2 = 33.5%, p = 0.0046 Early treatment 58% 0.42 [0.23-0.77] 81/4,579 1,549/23,151 58% improvement Tamura 97% 0.03 [0.00-0.58] 115 (n) 73 (n) Improvement, RR [CI] Treatment Control Tau​2 = 0.00, I​2 = 0.0%, p = 0.019 Late treatment 97% 0.03 [0.00-0.58] 0/115 0/73 97% improvement Luo 75% 0.25 [0.07-0.84] 3/104 22/179 Improvement, RR [CI] Treatment Control Wang 58% 0.42 [0.01-1.98] 1/9 13/49 Chen 33% 0.67 [0.20-1.78] 4/43 15/77 Kim 64% 0.36 [0.10-1.23] 113 (n) 122 (n) Li 78% 0.22 [0.09-0.54] 2/37 21/94 Goodall 3% 0.97 [0.75-1.25] 74/210 280/771 Pérez-Belm.. (PSM) -10% 1.10 [0.84-1.40] 79/249 79/249 Bramante 7% 0.93 [0.81-1.06] 394/2,333 791/3,923 Lalau (PSM) 22% 0.78 [0.55-1.10] 671 (n) 419 (n) Crouse 61% 0.39 [0.16-0.87] 8/76 34/144 Lally 52% 0.48 [0.28-0.84] 16/127 144/648 Oh -26% 1.26 [0.81-1.95] 5,946 (n) 5,946 (n) Wargny 28% 0.72 [0.53-0.95] 247/1,553 330/1,241 Khunti 23% 0.77 [0.73-0.81] population-based cohort Jiang (PSM) 46% 0.54 [0.13-2.26] 3/74 10/74 Ghany 66% 0.34 [0.19-0.59] 392 (n) 747 (n) Alamgir 27% 0.73 [0.63-0.84] 11,062 (n) 11,062 (n) Ravindra 30% 0.70 [0.28-1.56] 5/53 57/313 Blanc 79% 0.21 [0.03-1.46] 1/14 25/75 Cheng (PSM) -65% 1.65 [0.71-3.86] 678 (n) 535 (n) Wander 15% 0.85 [0.80-0.90] Saygili (PSM) 42% 0.58 [0.37-0.92] 120 (n) 120 (n) Ong 47% 0.53 [0.31-0.87] 33/186 57/169 Bliden 60% 0.40 [0.12-1.37] 3/34 9/41 Wallace (PSW) 72% 0.28 [0.21-0.37] 103/1,203 1,536/6,970 Ojeda-Ferná.. (PSM) 16%