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Metformin for COVID-19: real-time meta analysis of 84 studies

@CovidAnalysis, February 2024, Version 71V71
 
0 0.5 1 1.5+ All studies 29% 84 264,872 Improvement, Studies, Patients Relative Risk Mortality 34% 60 197,144 Ventilation 31% 12 55,447 ICU admission 17% 11 83,745 Hospitalization 17% 22 86,559 Cases 3% 7 70,125 Viral clearance 26% 3 1,437 RCTs 45% 4 1,431 RCT mortality 45% 3 1,411 Peer-reviewed 29% 78 233,360 Prophylaxis 26% 75 236,423 Early 58% 3 27,730 Late 53% 6 719 Metformin for COVID-19 c19early.org February 2024 after exclusions Favorsmetformin Favorscontrol
Abstract
Statistically significant lower risk is seen for mortality, ventilation, ICU admission, hospitalization, progression, and recovery. 53 studies from 50 independent teams in 17 countries show statistically significant improvements.
Meta analysis using the most serious outcome reported shows 29% [25‑33%] lower risk. Results are similar for higher quality and peer-reviewed studies and better for Randomized Controlled Trials.
Results are robust — in exclusion sensitivity analysis 64 of 84 studies must be excluded to avoid finding statistically significant efficacy in pooled analysis.
Most studies analyze existing use with diabetic patients, and many results may be 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 TOGETHER RCT shows 27% lower mortality. While not statistically significant, p = 0.53, this is consistent with the mortality results from all studies, 34% [29‑39%].
No treatment or intervention is 100% effective. 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.
All data to reproduce this paper and sources are in the appendix. Other meta analyses show significant improvements with metformin for mortality Hariyanto, Kan, Kow, Li, Lukito, Ma, Oscanoa, Parveen, Petrelli, Poly, Schlesinger, Yang, hospitalization Li, progression Yang, and severity Petrelli, Schlesinger.
Evolution of COVID-19 clinical evidence Metformin p<0.0000000001 excluding prophylaxis Acetaminophen p=0.00000029 2020 2021 2022 2023 2024 Effective Harmful c19early.org February 2024 meta analysis results (pooled effects) 100% 50% 0% -50%
Highlights
Metformin reduces risk for COVID-19 with very high confidence for mortality, ventilation, ICU admission, hospitalization, progression, recovery, and in pooled analysis, and very low confidence for viral clearance.
Metformin was the 3rd treatment shown effective with ≥3 clinical studies in July 2020, now known with p < 0.00000000001 from 84 studies.
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 66 treatments.
A
0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+ TOGETHER 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 COVID-OUT 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% lower risk Abu-Jamous 65% 0.35 [0.11-0.84] death 4/23 94/168 Improvement, RR [CI] Treatment Control Tamura 97% 0.03 [0.00-0.58] death 115 (n) 73 (n) Li 76% 0.24 [0.06-0.98] death 2/37 21/94 Shaseb (RCT) 74% 0.26 [0.06-1.06] death 85 (n) 104 (n) Ventura-.. (DB RCT) 44% 0.56 [0.33-0.95] oxygen time 10 (n) 10 (n) Mehrizi 44% 0.56 [0.53-0.60] death population-based cohort Tau​2 = 0.05, I​2 = 31.6%, p < 0.0001 Late treatment 53% 0.47 [0.34-0.66] 6/270 115/449 53% lower risk Luo 75% 0.25 [0.07-0.84] death 3/104 22/179 Improvement, RR [CI] Treatment Control CORONADO Cariou 20% 0.80 [0.45-1.43] death 746 (n) 571 (n) 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 Mirani 45% 0.55 [0.27-1.11] death 25/69 13/21 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-Bel.. (PSM) -10% 1.10 [0.84-1.40] death 79/249 79/249 Bramante 12% 0.88 [0.78-1.00] death 394/2,333 791/3,923 Sourij 37% 0.63 [0.33-1.10] death 14/77 44/161 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 Ramos-Rincón 1% 0.99 [0.77-1.29] death 206/420 179/370 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) CORONADO Wargny 28% 0.72 [0.53-0.95] death 247/1,553 330/1,241 Bramante (PSM) 62% 0.38 [0.16-0.91] death 342 (n) 342 (n) COVIDENCE UK 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) Gálvez-Barrón -16% 1.16 [0.73-1.49] death 20 (n) 83 (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-Fern.. (PSM) 16% 0.84 [0.79-0.89] death 1,476/6,556 1,787/6,556 Fu 72% 0.28 [0.09-0.84] no recov. 4/49 9/31 OT​1 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 Ma (PSW) 74% 0.26 [0.07-0.89] death 3/361 40/995 Yeh 44% 0.56 [0.45-0.71] progression n/a n/a Cousins (PSM) 50% 0.50 [0.29-0.85] ventilation 2,463 (n) 2,463 (n) Shestakova 22% 0.78 [0.67-0.91] death population-based cohort 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) Zaccardi 34% 0.66 [0.60-0.72] death population-based cohort Yip (PSM) 7% 0.93 [0.72-1.22] death/hosp. 8,604 (n) 3,727 (n) Ouchi 10% 0.90 [0.77-1.05] death 6,168 (n) 9,875 (n) Morrison (PSM) 41% 0.59 [0.41-0.84] death 2,684 (n) 2,684 (n) Mannucci 38% 0.62 [0.41-0.93] death n/a n/a Milosavljevic 33% 0.67 [0.47-0.95] severe case 377 (n) 356 (n) Miao (PSM) 1% 0.99 [0.85-1.15] death 233/796 236/796 Servais 49% 0.51 [0.34-0.78] death n/a n/a Pinchera 15% 0.85 [0.71-0.96] severe case 5/19 14/24 OT​1 Sandhu 3% 0.97 [0.95-0.99] hosp. population-based cohort Yen (PSM) 25% 0.75 [0.63-0.89] death 232/20,894 295/20,894 Araldi 60% 0.40 [0.32-0.50] death 107/2,598 263/2,598 Alieva 15% 0.85 [0.49-1.48] hosp. 375 (n) 388 (n) Obiri-Yeboah -1% 1.01 [0.54-1.87] death 148 (n) 381 (n) Piarulli 53% 0.47 [0.20-1.08] death/ICU 1,444 (n) 1,009 (n) Greco 22% 0.78 [0.57-1.05] hosp. OT​1 Guo 62% 0.38 [0.15-0.92] death/int. 241 (n) 330 (n) Zihono 49% 0.51 [0.28-0.93] death 11/56 31/81 Farah -3% 1.03 [0.83-1.28] cases 267/821 69/218 Bidari 10% 0.90 [0.65-1.23] severe case 29/80 132/326 Miguel 37% 0.63 [0.29-1.36] ICU 49 (n) 40 (n) Mamari 50% 0.50 [0.29-0.86] death 11/34 22/34 OT​1 Al-kuraishy 78% 0.22 [0.06-0.77] death 3/60 9/40 Jang 60% 0.40 [0.18-0.85] death 461 (n) 95 (n) Tau​2 = 0.02, I​2 = 91.4%, p < 0.0001 Prophylaxis 26% 0.74 [0.70-0.78] 5,813/96,973 11,005/139,450 26% lower risk All studies 29% 0.71 [0.67-0.75] 5,900/101,822 12,669/163,050 29% lower risk 84 metformin COVID-19 studies c19early.org February 2024 Tau​2 = 0.03, I​2 = 92.7%, 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+ TOGETHER Reis (DB RCT) 27% death impossible data Improvement Relative Risk [CI] Hunt 67% death COVID-OUT Bramante (DB RCT) 3% death OT​1 Tau​2 = 0.12, I​2 = 33.5%, p = 0.0046 Early treatment 58% 58% lower risk Abu-Jamous 65% death Tamura 97% death Li 76% death Shaseb (RCT) 74% death Ventura.. (DB RCT) 44% oxygen therapy Mehrizi 44% death Tau​2 = 0.05, I​2 = 31.6%, p < 0.0001 Late treatment 53% 53% lower risk Luo 75% death CORONADO Cariou 20% death Choi (PSM) -120% progression Wang 58% death Chen 33% death Kim 64% death Li 78% death Mirani 45% death Goodall 3% death Gao -225% progression Pérez-Be.. (PSM) -10% death Bramante 12% death Sourij 37% death Lalau (PSM) 22% death Huh -1% progression Ramos-Rincón 1% death Crouse 61% death Lally 52% death Oh -26% death CORONADO Wargny 28% death Bramante (PSM) 62% death COVIDENCE UK Holt -27% case Khunti 23% death Jiang (PSM) 46% death Ghany 66% death Alamgir 27% death Gálvez-Barrón -16% 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-Fer.. (PSM) 16% death Fu 72% recovery OT​1 Usman 60% death Wong 51% death Wong (PSW) 59% death MacFadden 1% case Ma (PSW) 74% death Yeh 44% progression Cousins (PSM) 50% ventilation Shestakova 22% death Loucera 30% death Chan 59% death Zaccardi 34% death Yip (PSM) 7% death/hosp. Ouchi 10% death Morrison (PSM) 41% death Mannucci 38% death Milosavljevic 33% severe case Miao (PSM) 1% death Servais 49% death Pinchera 15% severe case OT​1 Sandhu 3% hospitalization Yen (PSM) 25% death Araldi 60% death Alieva 15% hospitalization Obiri-Yeboah -1% death Piarulli 53% death/ICU Greco 22% hospitalization OT​1 Guo 62% death/intubation Zihono 49% death Farah -3% case Bidari 10% severe case Miguel 37% ICU admission Mamari 50% death OT​1 Al-kuraishy 78% death Jang 60% death Tau​2 = 0.02, I​2 = 91.4%, p < 0.0001 Prophylaxis 26% 26% lower risk All studies 29% 29% lower risk 84 metformin C19 studies c19early.org February 2024 Tau​2 = 0.03, I​2 = 92.7%, p < 0.0001 Protocol pre-specified/rotate for details1 OT: comparison with other treatment Favors metformin Favors control
B
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C
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D
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Figure 1. A. Random effects meta-analysis. This plot shows pooled effects, see the specific outcome analyses for individual outcomes, and the heterogeneity section for discussion. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix. B. Scatter plot showing the most serious outcome in all studies, and for studies within each stage. Diamonds shows the results of random effects meta-analysis. C. Results within the context of multiple COVID-19 treatments. 0.6% of 6,686 proposed treatments show efficacy c19early.org. D. Timeline of results in metformin studies. The marked dates indicate the time when efficacy was known with a statistically significant improvement of ≥10% from ≥3 studies for pooled outcomes, one or more specific outcome, and pooled outcomes in RCTs. Efficacy based on RCTs only was delayed by 25.0 months, compared to using all studies.
SARS-CoV-2 infection primarily begins in the upper respiratory tract and may progress to the lower respiratory tract, other tissues, and the nervous and cardiovascular systems, which may lead to cytokine storm, pneumonia, ARDS, neurological issues Scardua-Silva, Yang (B), cardiovascular complications Eberhardt, organ failure, and death. Minimizing replication as early as possible is recommended.
SARS-CoV-2 infection and replication involves the complex interplay of 50+ host and viral proteins and other factors Note A, Malone, Murigneux, Lv, providing many therapeutic targets for which many existing compounds have known activity. Scientists have predicted that over 6,000 compounds may reduce COVID-19 risk c19early.org (B), either by directly minimizing infection or replication, by supporting immune system function, or by minimizing secondary complications.
A systematic review and meta-analysis of 15 non-COVID-19 preclinical studies showed that metformin inhibits pulmonary inflammation and oxidative stress, minimizes lung injury, and improves survival in animal models of acute respiratory distress syndrome (ARDS) or acute lung injury (ALI) Wang. Metformin inhibits SARS-CoV-2 in vitro Parthasarathy, Ventura-López, minimizes LPS-induced cytokine storm in a mouse model Taher, minimizes lung damage and fibrosis in a mouse model of LPS-induced ARDS Miguel, may protect against SARS-CoV-2-induced neurological disorders Yang (B), may be beneficial via inhibitory effects on ORF3a-mediated inflammasome activation Zhang, reduces UUO and FAN-induced kidney fibrosis Miguel, increases mitochondrial function and decreases TGF-β-induced fibrosis, apoptosis, and inflammation markers in lung epithelial cells Miguel, and may improve outcomes via modulation of immune responses with increased anti-inflammatory T lymphocyte gene expression and via enhanced gut microbiota diversity Petakh.
Efficacy with metformin has been shown for influenza A Lee.
We analyze all significant controlled studies 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, studies within each treatment stage, individual outcomes, peer-reviewed studies, Randomized Controlled Trials (RCTs), and higher quality studies.
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.
A systematic review and meta-analysis of 15 non-COVID-19 preclinical studies showed that metformin inhibits pulmonary inflammation and oxidative stress, minimizes lung injury, and improves survival in animal models of acute respiratory distress syndrome (ARDS) or acute lung injury (ALI) Wang. Metformin inhibits SARS-CoV-2 in vitro Parthasarathy, Ventura-López, minimizes LPS-induced cytokine storm in a mouse model Taher, minimizes lung damage and fibrosis in a mouse model of LPS-induced ARDS Miguel, may protect against SARS-CoV-2-induced neurological disorders Yang (B), may be beneficial via inhibitory effects on ORF3a-mediated inflammasome activation Zhang, reduces UUO and FAN-induced kidney fibrosis Miguel, and increases mitochondrial function and decreases TGF-β-induced fibrosis, apoptosis, and inflammation markers in lung epithelial cells Miguel.
4 In Vitro studies support the efficacy of metformin Miguel, Parthasarathy, Ventura-López, Yang (B).
2 In Vivo animal studies support the efficacy of metformin Miguel, Taher.
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.
Table 1 summarizes the results for all stages combined, with different exclusions, and for specific outcomes. Table 2 shows results by treatment stage. Figure 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 show forest plots for 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.
Table 1. Random effects meta-analysis for all stages combined, with different exclusions, and for specific outcomes. Results show the percentage improvement with treatment and the 95% confidence interval. * p<0.05  ** p<0.01  *** p<0.001  **** p<0.0001.
Improvement Studies Patients Authors
All studies29% [25‑33%]
****
84 264,872 1,014
After exclusions30% [26‑34%]
****
77 246,896 920
Peer-reviewed studiesPeer-reviewed29% [24‑33%]
****
78 233,360 944
Randomized Controlled TrialsRCTs45% [14‑64%]
**
4 1,431 66
Mortality34% [29‑39%]
****
60 197,144 771
VentilationVent.31% [13‑45%]
**
12 55,447 144
ICU admissionICU17% [7‑26%]
**
11 83,745 117
HospitalizationHosp.17% [11‑23%]
****
22 86,559 233
Recovery41% [13‑60%]
**
4 4,176 78
Cases3% [-6‑12%]7 70,125 89
Viral26% [-9‑49%]3 1,437 40
RCT mortality45% [-19‑74%]3 1,411 52
RCT hospitalizationRCT hosp.7% [-6‑17%]3 627 63
Table 2. Random effects meta-analysis results by treatment stage. Results show the percentage improvement with treatment, the 95% confidence interval, and the number of studies for the stage.treatment and the 95% confidence interval. * p<0.05  ** p<0.01  *** p<0.001  **** p<0.0001.
Early treatment Late treatment Prophylaxis
All studies58% [23‑77%]
**
53% [34‑66%]
****
26% [22‑30%]
****
After exclusions58% [23‑77%]
**
53% [34‑66%]
****
27% [23‑31%]
****
Peer-reviewed studiesPeer-reviewed58% [23‑77%]
**
52% [30‑67%]
***
26% [21‑30%]
****
Randomized Controlled TrialsRCTs24% [-89‑70%]49% [17‑69%]
**
Mortality58% [23‑77%]
**
63% [34‑79%]
***
31% [26‑35%]
****
VentilationVent.79% [1‑96%]
*
29% [11‑44%]
**
ICU admissionICU63% [-9‑87%]16% [6‑25%]
**
HospitalizationHosp.6% [-61‑45%]7% [-6‑18%]19% [11‑25%]
****
Recovery41% [13‑60%]
**
Cases3% [-6‑12%]
Viral19% [-25‑48%]41% [5‑63%]
*
RCT mortality24% [-89‑70%]74% [-6‑94%]
RCT hospitalizationRCT hosp.6% [-61‑45%]7% [-6‑18%]
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Figure 3. Random effects meta-analysis for all studies with pooled effects. This plot shows pooled effects, see the specific outcome analyses for individual outcomes, and the heterogeneity section for discussion. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix.
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Figure 4. Random effects meta-analysis for mortality results.
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Figure 5. Random effects meta-analysis for ventilation.
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Figure 6. Random effects meta-analysis for ICU admission.
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Figure 7. Random effects meta-analysis for hospitalization.
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Figure 8. Random effects meta-analysis for progression.
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Figure 9. Random effects meta-analysis for recovery.
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Figure 10. Random effects meta-analysis for cases.
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Figure 11. Random effects meta-analysis for viral clearance.
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Figure 12. Random effects meta-analysis for peer reviewed studies. Effect extraction is pre-specified, using the most serious outcome reported, see the appendix for details. Zeraatkar et al. analyze 356 COVID-19 trials, finding no significant evidence that preprint results are inconsistent with peer-reviewed studies. They also show extremely long peer-review delays, with a median of 6 months to journal publication. A six month delay was equivalent to around 1.5 million deaths during the first two years of the pandemic. Authors recommend using preprint evidence, with appropriate checks for potential falsified data, which provides higher certainty much earlier. Davidson et al. also showed no important difference between meta analysis results of preprints and peer-reviewed publications for COVID-19, based on 37 meta analyses including 114 trials.
Figure 13 shows a comparison of results for RCTs and non-RCT studies. Figure 14, 15, and 16 show forest plots for random effects meta-analysis of all Randomized Controlled Trials, RCT mortality results, and RCT hospitalization results. RCT results are included in Table 1 and Table 2.
Bias in clinical research may be defined as something that tends to make conclusions differ systematically from the truth. RCTs help to make study groups more similar and can provide a higher level of evidence, however they are subject to many biases Jadad, and analysis of double-blind RCTs has identified extreme levels of bias Gøtzsche. For COVID-19, the overhead may delay treatment, dramatically compromising efficacy; they may encourage monotherapy for simplicity at the cost of efficacy which may rely on combined or synergistic effects; the participants that sign up may not reflect real world usage or the population that benefits most in terms of age, comorbidities, severity of illness, or other factors; standard of care may be compromised and unable to evolve quickly based on emerging research for new diseases; errors may be made in randomization and medication delivery; and investigators may have hidden agendas or vested interests influencing design, operation, analysis, and the potential for fraud. All of these biases have been observed with COVID-19 RCTs. There is no guarantee that a specific RCT provides a higher level of evidence.
RCTs are expensive and many RCTs are funded by pharmaceutical companies or interests closely aligned with pharmaceutical companies. For COVID-19, this creates an incentive to show efficacy for patented commercial products, and an incentive to show a lack of efficacy for inexpensive treatments. The bias is expected to be significant, for example Als-Nielsen et al. analyzed 370 RCTs from Cochrane reviews, showing that trials funded by for-profit organizations were 5 times more likely to recommend the experimental drug compared with those funded by nonprofit organizations. For COVID-19, some major philanthropic organizations are largely funded by investments with extreme conflicts of interest for and against specific COVID-19 interventions.
High quality RCTs for novel acute diseases are more challenging, with increased ethical issues due to the urgency of treatment, increased risk due to enrollment delays, and more difficult design with a rapidly evolving evidence base. For COVID-19, the most common site of initial infection is the upper respiratory tract. Immediate treatment is likely to be most successful and may prevent or slow progression to other parts of the body. For a non-prophylaxis RCT, it makes sense to provide treatment in advance and instruct patients to use it immediately on symptoms, just as some governments have done by providing medication kits in advance. Unfortunately, no RCTs have been done in this way. Every treatment RCT to date involves delayed treatment. Among the 66 treatments we have analyzed, 63% of RCTs involve very late treatment 5+ days after onset. No non-prophylaxis COVID-19 RCTs match the potential real-world use of early treatments (they may more accurately represent results for treatments that require visiting a medical facility, e.g., those requiring intravenous administration).
RCTs have a bias against finding an effect for interventions that are widely available — patients that believe they need the intervention are more likely to decline participation and take the intervention. RCTs for metformin are more likely to enroll low-risk participants that do not need treatment to recover, making the results less applicable to clinical practice. This bias is likely to be greater for widely known treatments, and may be greater when the risk of a serious outcome is overstated. This bias does not apply to the typical pharmaceutical trial of a new drug that is otherwise unavailable.
Evidence shows that non-RCT trials can also provide reliable results. Concato et al. found that well-designed observational studies do not systematically overestimate the magnitude of the effects of treatment compared to RCTs. Anglemyer et al. summarized reviews comparing RCTs to observational studies and found little evidence for significant differences in effect estimates. Lee (B) et al. showed that only 14% of the guidelines of the Infectious Diseases Society of America were based on RCTs. Evaluation of studies relies on an understanding of the study and potential biases. Limitations in an RCT can outweigh the benefits, for example excessive dosages, excessive treatment delays, or Internet survey bias could have a greater effect on results. Ethical issues may also prevent running RCTs for known effective treatments. For more on issues with RCTs see Deaton, Nichol.
Currently, 44 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. Of the 44 treatments with statistically significant efficacy/harm, 28 have been confirmed in RCTs, with a mean delay of 5.7 months. When considering only low cost treatments, 23 have been confirmed with a delay of 6.9 months. For the 16 unconfirmed treatments, 3 have zero RCTs to date. The point estimates for the remaining 13 are all consistent with the overall results (benefit or harm), with 10 showing >20%. The only treatments showing >10% efficacy for all studies, but <10% for RCTs are sotrovimab and aspirin.
We need to evaluate each trial on its own merits. RCTs for a given medication and disease may be more reliable, however they may also be less reliable. For off-patent medications, very high conflict of interest trials may be more likely to be RCTs, and more likely to be large trials that dominate meta analyses.
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Figure 13. Results for RCTs and non-RCT studies.
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Figure 14. Random effects meta-analysis for all Randomized Controlled Trials. This plot shows pooled effects, see the specific outcome analyses for individual outcomes, and the heterogeneity section for discussion. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix.
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Figure 15. Random effects meta-analysis for RCT mortality results.
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Figure 16. Random effects meta-analysis for RCT hospitalization results.
To avoid bias in the selection of studies, we analyze all non-retracted studies. Here we show the results after excluding studies with major issues likely to alter results, non-standard studies, and studies where very minimal detail is currently available. Our bias evaluation is based on analysis of each study and identifying when there is a significant chance that limitations will substantially change the outcome of the study. We believe this can be more valuable than checklist-based approaches such as Cochrane GRADE, which may underemphasize serious issues not captured in the checklists, overemphasize issues unlikely to alter outcomes in specific cases (for example, lack of blinding for an objective mortality outcome, or certain specifics of randomization with a very large effect size), and can be easily influenced by potential bias.
The studies excluded are as below. Figure 17 shows a forest plot for random effects meta-analysis of all studies after exclusions.
Al-kuraishy, unadjusted results with significant baseline differences.
Alieva, unadjusted results with no group details.
Bidari, unadjusted results with no group details.
Bliden, unadjusted results with minimal group details.
Farah, unadjusted results with no group details.
Holt, significant unadjusted confounding possible.
Ravindra, minimal details provided.
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Figure 17. Random effects meta-analysis for all studies after exclusions. This plot shows pooled effects, see the specific outcome analyses for individual outcomes, and the heterogeneity section for discussion. Effect extraction is pre-specified, using the most serious outcome reported. For details of effect extraction see the appendix.
Heterogeneity in COVID-19 studies arises from many factors including:
The time between infection or the onset of symptoms and treatment may critically affect how well a treatment works. For example an antiviral may be very effective when used early but may not be effective in late stage disease, and may even be harmful. Oseltamivir, for example, is generally only considered effective for influenza when used within 0-36 or 0-48 hours McLean, Treanor. Baloxavir studies for influenza also show that treatment delay is critical — Ikematsu report an 86% reduction in cases for post-exposure prophylaxis, Hayden show a 33 hour reduction in the time to alleviation of symptoms for treatment within 24 hours and a reduction of 13 hours for treatment within 24-48 hours, and Kumar report only 2.5 hours improvement for inpatient treatment.
Table 3. Studies of baloxavir for influenza show that early treatment is more effective.
Treatment delayResult
Post exposure prophylaxis86% fewer cases Ikematsu
<24 hours-33 hours symptoms Hayden
24-48 hours-13 hours symptoms Hayden
Inpatients-2.5 hours to improvement Kumar
Figure 18 shows a mixed-effects meta-regression for efficacy as a function of treatment delay in COVID-19 studies from 66 treatments, showing that efficacy declines rapidly with treatment delay. Early treatment is critical for COVID-19.
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Figure 18. Early treatment is more effective. Meta-regression showing efficacy as a function of treatment delay in COVID-19 studies from 66 treatments.
Details of the patient population including age and comorbidities may critically affect how well a treatment works. For example, many COVID-19 studies with relatively young low-comorbidity patients show all patients recovering quickly with or without treatment. In such cases, there is little room for an effective treatment to improve results (as in López-Medina).
Efficacy may differ significantly depending on the effect measured, for example a treatment may be very effective at reducing mortality, but less effective at minimizing cases or hospitalization. Or a treatment may have no effect on viral clearance while still being effective at reducing mortality.
There are many different variants of SARS-CoV-2 and efficacy may depend critically on the distribution of variants encountered by the patients in a study. For example, the Gamma variant shows significantly different characteristics Faria, Karita, Nonaka, Zavascki. Different mechanisms of action may be more or less effective depending on variants, for example the viral entry process for the omicron variant has moved towards TMPRSS2-independent fusion, suggesting that TMPRSS2 inhibitors may be less effective Peacock, Willett.
Effectiveness may depend strongly on the dosage and treatment regimen.
The use of other treatments may significantly affect outcomes, including anything from supplements, other medications, or other kinds of treatment such as prone positioning.
The quality of medications may vary significantly between manufacturers and production batches, which may significantly affect efficacy and safety. Williams analyze ivermectin from 11 different sources, showing highly variable antiparasitic efficacy across different manufacturers. Xu analyze a treatment from two different manufacturers, showing 9 different impurities, with significantly different concentrations for each manufacturer.
We present both pooled analyses and specific outcome analyses. Notably, pooled analysis often results in earlier detection of efficacy as shown in Figure 19. For many COVID-19 treatments, a reduction in mortality logically follows from a reduction in hospitalization, which follows from a reduction in symptomatic cases, etc. An antiviral tested with a low-risk population may report zero mortality in both arms, however a reduction in severity and improved viral clearance may translate into lower mortality among a high-risk population, and including these results in pooled analysis allows faster detection of efficacy. Trials with high-risk patients may also be restricted due to ethical concerns for treatments that are known or expected to be effective.
Pooled analysis enables using more of the available information. While there is much more information available, for example dose-response relationships, the advantage of the method used here is simplicity and transparency. Note that pooled analysis could hide efficacy, for example a treatment that is beneficial for late stage patients but has no effect on viral replication or early stage disease could show no efficacy in pooled analysis if most studies only examine viral clearance. While we present pooled results, we also present individual outcome analyses, which may be more informative for specific use cases.
Currently, 44 of the treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0% increased risk from ≥3 studies. 88% of treatments showing statistically significant efficacy/harm with pooled effects have been confirmed with one or more specific outcomes, with a mean delay of 3.6 months. When restricting to RCTs only, 50% of treatments showing statistically significant efficacy/harm with pooled effects have been confirmed with one or more specific outcomes, with a mean delay of 6.1 months.
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Figure 19. The time when studies showed that treatments were effective, defined as statistically significant improvement of ≥10% from ≥3 studies. Pooled results typically show efficacy earlier than specific outcome results. Results from all studies often shows efficacy much earlier than when restricting to RCTs. Results reflect conditions as used in trials to date, these depend on the population treated, treatment delay, and treatment regimen.
The distribution of studies will alter the outcome of a meta analysis. Consider a simplified example where everything is equal except for the treatment delay, and effectiveness decreases to zero or below with increasing delay. If there are many studies using very late treatment, the outcome may be negative, even though early treatment is very effective. This may have a greater effect than pooling different outcomes such as mortality and hospitalization. For example a treatment may have 50% efficacy for mortality but only 40% for hospitalization when used within 48 hours. However efficacy could be 0% when used late.
All meta analyses combine heterogeneous studies, varying in population, variants, and potentially all factors above, and therefore may obscure efficacy by including studies where treatment is less effective. Generally, we expect the estimated effect size from meta analysis to be less than that for the optimal case. Looking at all studies is valuable for providing an overview of all research, important to avoid cherry-picking, and informative when a positive result is found despite combining less-optimal situations. However, the resulting estimate does not apply to specific cases such as early treatment in high-risk populations. While we present results for all studies, we also present treatment time and individual outcome analyses, which may be more informative for specific use cases.
Efficacy with metformin has also been shown for influenza A Lee.
Publishing is often biased towards positive results, however evidence suggests that there may be a negative bias for inexpensive treatments for COVID-19. Both negative and positive results are very important for COVID-19, media in many countries prioritizes negative results for inexpensive treatments (inverting the typical incentive for scientists that value media recognition), and there are many reports of difficulty publishing positive results Boulware, Meeus, Meneguesso. For metformin, there is currently not enough data to evaluate publication bias with high confidence.
One method to evaluate bias is to compare prospective vs. retrospective studies. Prospective studies are more likely to be published regardless of the result, while retrospective studies are more likely to exhibit bias. For example, researchers may perform preliminary analysis with minimal effort and the results may influence their decision to continue. Retrospective studies also provide more opportunities for the specifics of data extraction and adjustments to influence results.
Figure 20 shows a scatter plot of results for prospective and retrospective studies. 63% of retrospective studies report a statistically significant positive effect for one or more outcomes, compared to 67% of prospective studies, showing similar results. The median effect size for retrospective studies is 38% improvement, compared to 35% for prospective studies, showing similar results.
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Figure 20. Prospective vs. retrospective studies. The diamonds show the results of random effects meta-analysis.
Funnel plots have traditionally been used for analyzing publication bias. This is invalid for COVID-19 acute treatment trials — the underlying assumptions are invalid, which we can demonstrate with a simple example. Consider a set of hypothetical perfect trials with no bias. Figure 21 plot A shows a funnel plot for a simulation of 80 perfect trials, with random group sizes, and each patient's outcome randomly sampled (10% control event probability, and a 30% effect size for treatment). Analysis shows no asymmetry (p > 0.05). In plot B, we add a single typical variation in COVID-19 treatment trials — treatment delay. Consider that efficacy varies from 90% for treatment within 24 hours, reducing to 10% when treatment is delayed 3 days. In plot B, each trial's treatment delay is randomly selected. Analysis now shows highly significant asymmetry, p < 0.0001, with six variants of Egger's test all showing p < 0.05 Egger, Harbord, Macaskill, Moreno, Peters, Rothstein, Rücker, Stanley. Note that these tests fail even though treatment delay is uniformly distributed. In reality treatment delay is more complex — each trial has a different distribution of delays across patients, and the distribution across trials may be biased (e.g., late treatment trials may be more common). Similarly, many other variations in trials may produce asymmetry, including dose, administration, duration of treatment, differences in SOC, comorbidities, age, variants, and bias in design, implementation, analysis, and reporting.
Figure 21. Example funnel plot analysis for simulated perfect trials.
Pharmaceutical drug trials often have conflicts of interest whereby sponsors or trial staff have a financial interest in the outcome being positive. Metformin for COVID-19 lacks this because it is off-patent, has multiple manufacturers, and is very low cost. In contrast, most COVID-19 metformin trials have been run by physicians on the front lines with the primary goal of finding the best methods to save human lives and minimize the collateral damage caused by COVID-19. While pharmaceutical companies are careful to run trials under optimal conditions (for example, restricting patients to those most likely to benefit, only including patients that can be treated soon after onset when necessary, and ensuring accurate dosing), not all metformin trials represent the optimal conditions for efficacy.
Summary statistics from meta analysis necessarily lose information. As with all meta analyses, studies are heterogeneous, with differences in treatment delay, treatment regimen, patient demographics, variants, conflicts of interest, standard of care, and other factors. We provide analyses by specific outcomes and by treatment delay, and we aim to identify key characteristics in the forest plots and summaries. Results should be viewed in the context of study characteristics.
Some analyses classify treatment based on early or late administration, as done here, while others distinguish between mild, moderate, and severe cases. Viral load does not indicate degree of symptoms — for example patients may have a high viral load while being asymptomatic. With regard to treatments that have antiviral properties, timing of treatment is critical — late administration may be less helpful regardless of severity.
Details of treatment delay per patient is often not available. For example, a study may treat 90% of patients relatively early, but the events driving the outcome may come from 10% of patients treated very late. Our 5 day cutoff for early treatment may be too conservative, 5 days may be too late in many cases.
Comparison across treatments is confounded by differences in the studies performed, for example dose, variants, and conflicts of interest. Trials affiliated with special interests may use designs better suited to the preferred outcome.
In some cases, the most serious outcome has very few events, resulting in lower confidence results being used in pooled analysis, however the method is simpler and more transparent. This is less critical as the number of studies increases. Restriction to outcomes with sufficient power may be beneficial in pooled analysis and improve accuracy when there are few studies, however we maintain our pre-specified method to avoid any retrospective changes.
Studies show that combinations of treatments can be highly synergistic and may result in many times greater efficacy than individual treatments alone Alsaidi, Andreani, Biancatelli, De Forni, Gasmi, Jeffreys, Jitobaom, Jitobaom (B), Ostrov, Thairu. Therefore standard of care may be critical and benefits may diminish or disappear if standard of care does not include certain treatments.
This real-time analysis is constantly updated based on submissions. Accuracy benefits from widespread review and submission of updates and corrections from reviewers. Less popular treatments may receive fewer reviews.
No treatment, vaccine, or intervention is 100% available and effective for all current and future variants. Efficacy may vary significantly with different variants and within different populations. All treatments have potential side effects. Propensity to experience side effects may be predicted in advance by qualified physicians. We do not provide medical advice. Before taking any medication, consult a qualified physician who can compare all options, provide personalized advice, and provide details of risks and benefits based on individual medical history and situations.
5 of the 84 studies compare against other treatments, which may reduce the effect seen. Other meta analyses show significant improvements with metformin for mortality Hariyanto, Kan, Kow, Li, Lukito, Ma, Oscanoa, Parveen, Petrelli, Poly, Schlesinger, Yang, hospitalization Li, progression Yang, and severity Petrelli, Schlesinger.
Multiple reviews cover metformin for COVID-19, presenting additional background on mechanisms and related results, including De Jesús-González, Halma, Petakh (B), Tseng, Zhang.
Statistically significant lower risk is seen for mortality, ventilation, ICU admission, hospitalization, progression, and recovery. 53 studies from 50 independent teams in 17 countries show statistically significant improvements. Meta analysis using the most serious outcome reported shows 29% [25‑33%] lower risk. Results are similar for higher quality and peer-reviewed studies and better for Randomized Controlled Trials. Results are robust — in exclusion sensitivity analysis 64 of 84 studies must be excluded to avoid finding statistically significant efficacy in pooled analysis.
Most studies analyze existing use with diabetic patients, and many results may be 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 TOGETHER RCT shows 27% lower mortality. While not statistically significant, p = 0.53, this is consistent with the mortality results from all studies, 34% [29‑39%].
Other meta analyses show significant improvements with metformin for mortality Hariyanto, Kan, Kow, Li, Lukito, Ma, Oscanoa, Parveen, Petrelli, Poly, Schlesinger, Yang, hospitalization Li, progression Yang, and severity Petrelli, Schlesinger.
0 0.5 1 1.5 2+ Mortality 65% Improvement Relative Risk Metformin  Abu-Jamous et al.  LATE TREATMENT Is late treatment with metformin beneficial for COVID-19? Retrospective 191 patients in the United Kingdom (Jan - May 2020) Lower mortality with metformin (p=0.044) c19early.org Abu-Jamous et al., medRxiv, August 2020 Favors metformin Favors control
Abu-Jamous: Retrospective diabetes patients in the UK, showing lower mortality for metformin treatment (administered within 21 days after a positive PCR test).
0 0.5 1 1.5 2+ Mortality 78% Improvement Relative Risk Clinical score 41% CT score 84% Metformin  Al-kuraishy et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Prospective study of 100 patients in Iraq (March - June 2020) Lower mortality (p=0.012) and improved recovery (p=0.0002) c19early.org Al-kuraishy et al., European Review fo.., Dec 2023 Favors metformin Favors control
Al-kuraishy: Prospective study of 60 hospitalized type 2 diabetes patients with COVID-19 on metformin monotherapy compared to 40 patients on other diabetes treatments, showing significantly lower inflammatory biomarkers, oxidative stress, and mortality, and improvements in radiological and clinical outcomes with metformin. Confounding due to differences in baseline characteristics may be significant.
0 0.5 1 1.5 2+ Death/ICU 55% Improvement Relative Risk Death/ICU (b) -68% Metformin for COVID-19  Al-Salameh et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 97 patients in France Lower death/ICU with metformin (p=0.04) c19early.org Al-Salameh et al., Diabetes & Metabolism, Nov 2021 Favors metformin Favors control
Al-Salameh: Retrospective 140 diabetic patients in France, showing lower mortality for patients where metformin use was continued after hospitalization.
0 0.5 1 1.5 2+ Mortality 27% Improvement Relative Risk Mortality (b) 34% Mortality (c) 30% Metformin for COVID-19  Alamgir et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 22,124 patients in the USA Lower mortality with metformin (p=0.000022) c19early.org Alamgir et al., medRxiv, April 2021 Favors metformin Favors control
Alamgir: In Silico study followed by PSM analysis of the National COVID Cohort Collaborative data in the USA, showing 27% lower mortality with metformin use.
0 0.5 1 1.5 2+ Hospitalization 15% Improvement Relative Risk Metformin for COVID-19  Alieva et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 763 patients in Uzbekistan (April - December 2020) Lower hospitalization with metformin (not stat. sig., p=0.56) c19early.org Alieva et al., Obesity and metabolism, Jun 2023 Favors metformin Favors control
Alieva: Retrospective 763 COVID-19 patients with type 2 diabetes in Uzbekistan, showing lower hospitalization with metformin use in unadjusted results, without statistical significance.
0 0.5 1 1.5 2+ Hospitalization 39% Improvement Relative Risk Metformin for COVID-19  Ando et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 28,093 patients in the USA (January - November 2020) Lower hospitalization with metformin (p=0.044) c19early.org Ando et al., Scientific Reports, September 2021 Favors metformin Favors control
Ando: Retrospective 28,093 COVID+ patients in the USA, showing lower risk of hospitalization with metformin use.
0 0.5 1 1.5 2+ Mortality 60% Improvement Relative Risk Metformin for COVID-19  Araldi et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 43,610 patients in the United Kingdom Lower mortality with metformin (p<0.000001) c19early.org Araldi et al., medRxiv, May 2023 Favors metformin Favors control
Araldi: UK Biobank retrospective including 43,610 type 2 diabetes patients, showing lower mortality with metformin use within matched type 2 diabetes patients.
0 0.5 1 1.5 2+ Severe case 10% Improvement Relative Risk Metformin for COVID-19  Bidari et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 406 patients in Iran (February - April 2020) Lower severe cases with metformin (not stat. sig., p=0.53) c19early.org Bidari et al., Cureus, October 2023 Favors metformin Favors control
Bidari: Retrospective 406 COVID-19 patients in Iran, showing lower risk of severe cases with metformin use in unadjusted results, without statistical significance.
0 0.5 1 1.5 2+ Mortality 79% Improvement Relative Risk Case -44% Metformin for COVID-19  Blanc et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 179 patients in France Lower mortality (p=0.058) and more cases (p=0.12), not sig. c19early.org Blanc et al., GeroScience, July 2021 Favors metformin Favors control
Blanc: Retrospective 179 patients in France exposed to COVID-19 showing, without statistical significance, a higher risk of cases, and a lower risk of mortality among cases with existing metformin treatment.
0 0.5 1 1.5 2+ Mortality 60% Improvement Relative Risk Ventilation 76% Metformin for COVID-19  Bliden et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 75 patients in the USA Lower mortality (p=0.21) and ventilation (p=0.054), not sig. c19early.org Bliden et al., Circulation, 144:A12228, Nov 2021 Favors metformin Favors control
Bliden: Retrospective 75 diabetes patients, 34 on metformin, showing lower mortality with treatment in unadjusted results with minimal group details.
0 0.5 1 1.5 2+ Hospitalization 10% Improvement Relative Risk Metformin for COVID-19  Boye et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 9,531 patients in the USA Lower hospitalization with metformin (p=0.0000028) c19early.org Boye et al., Diabetes Therapy, July 2021 Favors metformin Favors control
Boye: Retrospective 9531 COVID+ diabetes patients in the USA, showing lower risk of hospitalization with existing biguanides treatment (defined as mainly metformin in the abstract and entirely metformin in the text).
0 0.5 1 1.5 2+ Mortality, PSM 62% Improvement Relative Risk Mortality, MV 68% ICU admission, PSM -9% ICU admission, MV 32% Hospitalization, MV 22% Metformin for COVID-19  Bramante et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 9,555 patients in the USA (March - December 2020) Lower mortality with metformin (p=0.029) c19early.org Bramante et al., J. Medical Virology, Mar 2021 Favors metformin Favors control
Bramante (B): Retrospective 17,396 PCR+ patients in the USA, showing lower mortality with metformin use.
0 0.5 1 1.5 2+ Mortality, all 12% Improvement Relative Risk Mortality, women 21% Mortality, men 4% Metformin for COVID-19  Bramante et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 6,256 patients in the USA No significant difference in mortality c19early.org Bramante et al., The Lancet Healthy Lo.., Dec 2020 Favors metformin Favors control
Bramante (C): Retrospective 6,256 COVID-19+ diabetes patients in the USA, showing lower mortality with existing metformin treatment, statistically significant only for women.
0 0.5 1 1.5 2+ Mortality, day 28 3% Improvement Relative Risk Mortality, day 14 -197% Death/hospitalization 52% Progression 40% Progression (b) 12% primary Viral clearance, day 10 37% Viral clearance, day 5 9% Metformin  COVID-OUT  EARLY TREATMENT  DB RCT Is early treatment with metformin beneficial for COVID-19? Double-blind RCT 1,307 patients in the USA Trial compares with control (including fluvoxamine and ivermectin) Lower progression (p=0.033) and improved viral clearance (p=0.00079) c19early.org Bramante et al., NEJM, August 2022 Favors metformin Favors control (inc..
COVID-OUT remotely operated RCT, showing lower combined ER/hospitalization/death with metformin. Results for other treatments are listed separately - ivermectin, fluvoxamine.
The "control" group includes patients receiving active treatments fluvoxamine and ivermectin.
Control arm results are very different between treatments, for example considering hospitalization/death, this was 1.0% for ivermectin vs. 2.7% for overall control, however it was 1.3% for the ivermectin-specific control. 394 control patients are shared. The rate for the non-shared 261 metformin control patients is 5%, compared to 1.3% for ivermectin control patients. The metformin arm started earlier, however it is unclear why the difference in outcomes is so large.
Results were delayed for 6 months with no explanation, with followup ending Feb 14, 2022.
Adherence was very low, with 77% overall reporting 70+% adherence. Numbers for 100% adherence are not provided.
Multiple outcomes are missing, for example time to recovery (where ACTIV-6 showed superiority of ivermectin).
Treatment was 14 days for metformin and fluvoxamine, but only 3 days for ivermectin.
Trial outcomes were changed on January 20, 2022 clinicaltrials.gov, and again on March 2, 2022 clinicaltrials.gov (B). COVIDOUT.
Medication delivery varied significantly over the trial. In this presentation vimeo.com, author indicates that delivery was initially local, later via FedEx, was much slower in August, there were delays due to team bandwidth issues, and they only realized they could use FedEx same day delivery in September.
0 0.5 1 1.5 2+ Mortality 20% Improvement Relative Risk Metformin for COVID-19  CORONADO  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 1,317 patients in France (March - April 2020) Lower mortality with metformin (not stat. sig., p=0.46) c19early.org Cariou et al., Diabetologia, May 2020 Favors metformin Favors control
Cariou: Analysis of 1,317 hospitalized COVID-19 patients with diabetes showing lower mortality with metformin use, without statistical significance.
0 0.5 1 1.5 2+ Mortality, prediabeties 59% Improvement Relative Risk Severe case, prediabeties 54% Progression, prediabeties 42% Progression, prediabe.. (b) 37% Progression, PCOS 41% Progression, PCOS (b) 34% Metformin for COVID-19  Chan et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 3,136 patients in the USA Lower severe cases (p=0.37) and progression (p=0.37), not sig. c19early.org Chan et al., medRxiv, August 2022 Favors metformin Favors control
Chan: Retrospective 3,136 patients with prediabetes and 282 with PCOS, showing metformin associated with reduced COVID-19 severity.
0 0.5 1 1.5 2+ Mortality 33% Improvement Relative Risk Metformin for COVID-19  Chen et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 120 patients in China Lower mortality with metformin (not stat. sig., p=0.46) c19early.org Chen et al., Diabetes Care, July 2020 Favors metformin Favors control
Chen: Retrospective 120 COVID-19 diabetes patients, showing non-statistically significantly lower mortality with existing metformin treatment.
0 0.5 1 1.5 2+ Mortality -65% Improvement Relative Risk Metformin for COVID-19  Cheng et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? PSM retrospective 1,213 patients in China Higher mortality with metformin (not stat. sig., p=0.25) c19early.org Cheng et al., Cell Metabolism, August 2021 Favors metformin Favors control
Cheng: Retrospective 1,213 hospitalized diabetic COVID-19 patients in China, showing no significant difference in mortality with pre-existing metformin use.
0 0.5 1 1.5 2+ Progression -120% Improvement Relative Risk Metformin for COVID-19  Choi et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? PSM retrospective 72 patients in South Korea (Mar - Mar 2020) Higher progression with metformin (not stat. sig., p=0.26) c19early.org Choi et al., J. Clinical Medicine, Jun 2020 Favors metformin Favors control
Choi: Retrospective 293 patients in South Korea, showing higher risk of progression with metformin use, without statistical significance.
0 0.5 1 1.5 2+ Ventilation 50% Improvement Relative Risk ICU admission 51% Metformin for COVID-19  Cousins et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? PSM retrospective 64,349 patients in the USA Lower ventilation (p=0.014) and ICU admission (p<0.0001) c19early.org Cousins et al., Cell Reports Methods, Jul 2022 Favors metformin Favors control
Cousins: PSM retrospective 64,349 COVID-19 patients in the USA, showing metformin associated with lower ICU admission and mechanical ventilation.
0 0.5 1 1.5 2+ Mortality 61% Improvement Relative Risk Metformin for COVID-19  Crouse et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 220 patients in the USA Lower mortality with metformin (p=0.021) c19early.org Crouse et al., Front. Endocrinol., Jan 2021 Favors metformin Favors control
Crouse: Retrospective 219 COVID-19+ diabetes patients in the USA, showing lower mortality with existing metformin treatment.
0 0.5 1 1.5 2+ Case -3% Improvement Relative Risk Metformin for COVID-19  Farah et al.  Prophylaxis Does metformin reduce COVID-19 infections? Retrospective 1,039 patients in Jordan No significant difference in cases c19early.org Farah et al., J. Int. Medical Research, Sep 2023 Favors metformin Favors control
Farah: Retrospective 1,039 diabetes patients in Jordan, showing no significant difference in COVID-19 cases with metformin use in unadjusted results. Severity outcomes are not provided for metformin.
0 0.5 1 1.5 2+ Unfavorable outcome 72% Improvement Relative Risk Metformin for COVID-19  Fu et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 80 patients in China (January - March 2020) Study compares with other diabetes medications Improved recovery with metformin (p=0.026) c19early.org Fu et al., Int. J. Endocrinology, January 2022 Favors metformin Favors other diabet..
Fu: Retrospective 108 T2D patients hospitalized with COVID-19, showing lower risk of unfavorable outcomes with metformin use vs. other diabetic medications.
0 0.5 1 1.5 2+ Progression -225% Improvement Relative Risk Metformin for COVID-19  Gao et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 110 patients in China (January - March 2020) Higher progression with metformin (p=0.045) c19early.org Gao et al., Clinical and Translational.., Oct 2020 Favors metformin Favors control
Gao: Retrospective 110 hospitalized COVID-19 patients with diabetes in China, showing increased risk of severity with metformin.
0 0.5 1 1.5 2+ Mortality 66% Improvement Relative Risk Hospitalization 29% ARDS 68% Metformin for COVID-19  Ghany et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 1,139 patients in the USA Lower mortality (p=0.00021) and hospitalization (p=0.0076) c19early.org Ghany et al., Diabetes & Metabolic Syn.., Mar 2021 Favors metformin Favors control
Ghany: Retrospective 1,139 elderly COVID+ patients in the USA, 392 with pre-existing metformin use, showing significantly lower mortality, hospitalization, and ARDS with treatment.
0 0.5 1 1.5 2+ Mortality 3% Improvement Relative Risk Metformin for COVID-19  Goodall et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 981 patients in the United Kingdom (Mar - Apr 2020) No significant difference in mortality c19early.org Goodall et al., Epidemiology and Infec.., Oct 2020 Favors metformin Favors control
Goodall: Retrospective 981 hospitalized patients in the UK, showing no significant difference with metformin use.
0 0.5 1 1.5 2+ Hospitalization, DPP-4is 22% Improvement Relative Risk Hospitalization, insulin or.. 26% Hospitalization, GLP-1 RAs 17% Metformin for COVID-19  Greco et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 44,977 patients in Italy (January 2020 - December 2021) Study compares with DPP-4is, results vs. placebo may differ Lower hospitalization with metformin (not stat. sig., p=0.11) c19early.org Greco et al., Biomedicines, August 2023 Favors metformin Favors DPP-4is
Greco: Retrospective 76,764 diabetes patients in Italy, showing that patients on metformin had lower rates of COVID-19 hospitalization compared to those on insulin/insulin secretagogues, GLP-1 receptor agonists, and DPP-4 inhibitors. Metformin vs. no metformin results are not provided. The most relevant result for COVID-19 and metformin may be the DPP-4i comparison, based on the DPP-4i group being the most similar to the metformin group in terms of baseline COVID-19 risk and confounders. Patients on insulin/secretagogues may have more severe or advanced diabetes.
0 0.5 1 1.5 2+ Death/intubation 62% Improvement Relative Risk Progression, severe respir.. 81% Progression, ARDS 80% Metformin for COVID-19  Guo et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 571 patients in China (February - April 2020) Lower death/intubation (p=0.032) and progression (p=0.0029) c19early.org Guo et al., Diabetes, Metabolic Syndro.., Aug 2023 Favors metformin Favors control
Guo: Retrospective 571 type 2 diabetes patients with COVID-19 in China, showing lower combined mortality/mechanical ventilation with metformin.
0 0.5 1 1.5 2+ Mortality -16% Improvement Relative Risk Severe case -16% Metformin  Gálvez-Barrón et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 103 patients in Spain (March - May 2020) Higher mortality (p=0.46) and severe cases (p=0.46), not sig. c19early.org Gálvez-Barrón et al., Gerontology, Apr 2021 Favors metformin Favors control
Gálvez-Barrón: Analysis of 103 elderly hospitalized COVID-19 patients in Spain, showing higher mortality with metformin, without statistical significance.
0 0.5 1 1.5 2+ Case -27% Improvement Relative Risk Metformin for COVID-19  COVIDENCE UK  Prophylaxis Does metformin reduce COVID-19 infections? Prospective study of 15,227 patients in the United Kingdom (May 2020 - Feb 2021) More cases with metformin (not stat. sig., p=0.42) c19early.org Holt et al., Thorax, March 2021 Favors metformin Favors control
Holt: Prospective survey-based study with 15,227 people in the UK, showing lower risk of COVID-19 cases with vitamin A, vitamin D, zinc, selenium, probiotics, and inhaled corticosteroids; and higher risk with metformin and vitamin C. Statistical significance was not reached for any of these. Except for vitamin D, the results for treatments we follow were only adjusted for age, sex, duration of participation, and test frequency. NCT04330599. COVIDENCE UK.
0 0.5 1 1.5 2+ Progression -1% Improvement Relative Risk Case 4% Metformin for COVID-19  Huh et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 44,046 patients in South Korea No significant difference in outcomes seen c19early.org Huh et al., Int. J. Infectious Diseases, Dec 2020 Favors metformin Favors control
Huh: Retrospective database analysis showing no significant differences with pre-existing metformin use.
0 0.5 1 1.5 2+ Mortality 67% Improvement Relative Risk Metformin for COVID-19  Hunt et al.  EARLY TREATMENT Is early treatment with metformin beneficial for COVID-19? Retrospective 26,508 patients in the USA (March - September 2020) Lower mortality with metformin (p<0.000001) c19early.org Hunt et al., J. General Internal Medic.., Jun 2022 Favors metformin Favors control
Hunt: Retrospective 26,508 consecutive COVID+ veterans in the USA, showing lower mortality with multiple treatments including metformin. Treatment was defined as drugs administered ≥50% of the time within 2 weeks post-COVID+, and may be a continuation of prophylactic treatment in some cases, and may be early or late treatment in other cases. Further reduction in mortality was seen with combinations of treatments.
0 0.5 1 1.5 2+ Mortality 60% Improvement Relative Risk Ventilation 72% ICU admission 39% Oxygen therapy 30% Hospitalization -27% Metformin for COVID-19  Jang et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 556 patients in South Korea Lower mortality (p=0.018) and ventilation (p=0.008) c19early.org Jang et al., Endocrinology and Metabol.., Jan 2024 Favors metformin Favors control
Jang: Retrospective 556 diabetic patients in South Korea with COVID-19 showing lower risk of mechanical ventilation and death with metformin, lower risks of oxygen treatment and death with DPP-4 inhibitors, and increased risk of mechanical ventilation with sulfonylureas. The study used nationwide data to analyze the impact of common antidiabetic medications on COVID-19 outcomes. Authors note that South Korea had a policy early in the pandemic of hospitalizing nearly all confirmed COVID-19 patients regardless of severity.
0 0.5 1 1.5 2+ Mortality 46% Improvement Relative Risk ARDS 80% Metformin for COVID-19  Jiang et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? PSM retrospective 148 patients in China Lower progression with metformin (p=0.017) c19early.org Jiang et al., Diabetes Research and Cl.., Mar 2021 Favors metformin Favors control
Jiang: Retrospective 328 COVID-19 patients with type 2 diabetes in China, showing significantly lower risk of ARDS with existing metformin use.
0 0.5 1 1.5 2+ Mortality 23% Improvement Relative Risk Metformin for COVID-19  Khunti et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 2,851,465 patients in the United Kingdom Lower mortality with metformin (p<0.000001) c19early.org Khunti et al., The Lacent Diabetes & E.., Mar 2021 Favors metformin Favors control
Khunti: Retrospective 2,851,465 people with type 2 diabetes in the UK, showing lower mortality with existing metformin use. Results are subject to confounding by indication because metformin is typically used early in the progression of type 2 diabetes.
0 0.5 1 1.5 2+ Mortality 64% Improvement Relative Risk Progression 52% Metformin for COVID-19  Kim et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 235 patients in South Korea Lower mortality (p=0.1) and progression (p=0.13), not sig. c19early.org Kim et al., Diabetes & Metabolism J., Aug 2020 Favors metformin Favors control
Kim: Retrospective 235 hospitalized diabetes patients in South Korea, showing lower mortality and lower progression to severe disease with metformin.
0 0.5 1 1.5 2+ Mortality 22% Improvement Relative Risk Death/intubation 18% primary Ventilation 7% Metformin for COVID-19  Lalau et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? PSM retrospective 1,090 patients in France (March - April 2020) Lower mortality (p=0.16) and death/intubation (p=0.21), not sig. c19early.org Lalau et al., Diabetes & Metabolism, Dec 2020 Favors metformin Favors control
Lalau: Retrospective 2,449 hospitalized COVID-19 diabetes patients in France, 1,496 with existing metformin use, showing lower mortality with treatment. Statistical significance was reached in model 1 but not in models 2-4 which also adjust for HbA1c, eGFR, and diabetes duration, but have a lower number of patients. CORONADO (Coronavirus SARS-CoV-2 and Diabetes Outcomes).
0 0.5 1 1.5 2+ Mortality 52% Improvement Relative Risk Metformin for COVID-19  Lally et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 775 patients in the USA Lower mortality with metformin (p=0.0088) c19early.org Lally et al., J. the American Medical .., Jan 2021 Favors metformin Favors control
Lally: Retrospective 775 nursing home residents in the USA, showing lower mortality with existing metformin use.
0 0.5 1 1.5 2+ Mortality 78% Improvement Relative Risk Ventilation -27% Metformin for COVID-19  Li et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 131 patients in China (January - March 2020) Lower mortality with metformin (p=0.02) c19early.org Li et al., Endocrine Practice, October 2020 Favors metformin Favors control
Li (C): Retrospective 131 type II diabetes patients with COVID pneumonia, showing lower mortality with existing metformin use. Acarbose (commonly used in China as an initial therapy for diabetes) did not have a similar association with mortality, suggesting that the result may not be explained by metformin being used early in type II diabetes.
0 0.5 1 1.5 2+ Mortality 76% Improvement Relative Risk Metformin for COVID-19  Li et al.  LATE TREATMENT Is late treatment with metformin beneficial for COVID-19? Retrospective 131 patients in China Lower mortality with metformin (p=0.022) c19early.org Li et al., Endocrinology, Diabetes & M.., Sep 2021 Favors metformin Favors control
Li (B): Retrospective 131 hospitalized COVID-19 patients with type 2 diabetes, showing lower mortality with metformin treatment and acarbose treatment.
0 0.5 1 1.5 2+ Mortality 30% Improvement Relative Risk Metformin for COVID-19  Loucera et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 15,968 patients in Spain (January - November 2020) Lower mortality with metformin (p<0.000001) c19early.org Loucera et al., Virology J., August 2022 Favors metformin Favors control
Loucera: Retrospective 15,968 COVID-19 hospitalized patients in Spain, showing lower mortality with existing use of several medications including metformin, HCQ, azithromycin, aspirin, vitamin D, vitamin C, and budesonide. Since only hospitalized patients are included, results do not reflect different probabilities of hospitalization across treatments.
0 0.5 1 1.5 2+ Mortality 75% Improvement Relative Risk Metformin for COVID-19  Luo et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 283 patients in China Lower mortality with metformin (p=0.02) c19early.org Luo et al., The American J. Tropical M.., May 2020 Favors metformin Favors control
Luo: Retrospective 283 COVID-19+ diabetes patients in China, showing lower mortality with existing metformin treatment.
0 0.5 1 1.5 2+ Mortality 74% Improvement Relative Risk Ventilation 25% Metformin for COVID-19  Ma et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 1,356 patients in the USA (March 2020 - February 2021) Lower mortality with metformin (p=0.034) c19early.org Ma et al., Scientific Reports, April 2022 Favors metformin Favors control
Ma (B): PSM/IPTW retrospective 1,356 hospitalized COVID-19 patients with type 2 diabetes in China, showing lower mortality/hospice with metformin use.
0 0.5 1 1.5 2+ Case 1% Improvement Relative Risk Metformin for COVID-19  MacFadden et al.  Prophylaxis Does metformin reduce COVID-19 infections? Retrospective study in Canada (January - December 2020) No significant difference in cases c19early.org MacFadden et al., Open Forum Infectiou.., Mar 2022 Favors metformin Favors control
MacFadden: Retrospective 26,121 cases and 2,369,020 controls ≥65yo in Canada, showing no significant difference in cases with chronic use of metformin.
0 0.5 1 1.5 2+ Mortality 50% Improvement Relative Risk Metformin for COVID-19  Mamari et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 109 patients in Syria Study compares with sulfonylureas, results vs. placebo may differ Lower mortality with metformin (p=0.015) c19early.org Mamari et al., Research J. Pharmacy an.., Nov 2023 Favors metformin Favors sulfonylureas
Mamari: Retrospective 109 hospitalized COVID-19 patients in Syria, 68 with diabetes, showing significantly lower mortality with metformin vs. sulfonylureas, and significantly higher mortality with discontinuation of metformin.
0 0.5 1 1.5 2+ Mortality 38% Improvement Relative Risk Hospitalization 15% Metformin for COVID-19  Mannucci et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective study in Italy (March - December 2020) Lower mortality with metformin (p=0.02) c19early.org Mannucci et al., Diabetes, Metabolic S.., Oct 2022 Favors metformin Favors control
Mannucci: Retrospective 54,009 diabetes patients in Italy, showing lower mortality with metformin use.
0 0.5 1 1.5 2+ Mortality 44% Improvement Relative Risk Metformin for COVID-19  Mehrizi et al.  LATE TREATMENT Is late treatment with metformin beneficial for COVID-19? Retrospective 917,198 patients in Iran (February 2020 - March 2022) Lower mortality with metformin (p<0.000001) c19early.org Mehrizi et al., Frontiers in Public He.., Dec 2023 Favors metformin Favors control
Mehrizi: Retrospective study of 917,198 hospitalized COVID-19 cases covered by the Iran Health Insurance Organization over 26 months showing that antithrombotics, corticosteroids, and antivirals reduced mortality while diuretics, antibiotics, and antidiabetics increased it. Confounding makes some results very unreliable. For example, diuretics like furosemide are often used to treat fluid overload, which is more likely in ICU or advanced disease requiring aggressive fluid resuscitation. Hospitalization length has increased risk of significant confounding, for example longer hospitalization increases the chance of receiving a medication, and death may result in shorter hospitalization. Mortality results may be more reliable.

Confounding by indication is likely to be significant for many medications. Authors adjustments have very limited severity information (admission type refers to ward vs. ER department on initial arrival). We can estimate the impact of confounding from typical usage patterns, the prescription frequency, and attenuation or increase of risk for ICU vs. all patients.

0 0.5 1 1.5 2+ Mortality 1% Improvement Relative Risk Hospitalization time 5% Metformin for COVID-19  Miao et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? PSM retrospective 4,462 patients in the USA (Jan - May 2020) No significant difference in outcomes seen c19early.org Miao et al., Frontiers in Endocrinology, Nov 2022 Favors metformin Favors control
Miao: Retrospective 4,462 COVID+ diabetes patients in the USA, showing no significant difference in outcomes with metformin use.
0 0.5 1 1.5 2+ ICU admission, both cohor.. 37% Improvement Relative Risk ICU admission, cohort 1 43% ICU admission, cohort 2 31% Metformin for COVID-19  Miguel et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 132 patients in Spain (March - June 2020) Lower ICU admission with metformin (not stat. sig., p=0.24) c19early.org Miguel et al., Redox Biology, November 2023 Favors metformin Favors control
Miguel: Mouse models showing reduced lung and kidney injury with metformin. Metformin minimized lung damage and fibrosis in a mouse model of LPS-induced ARDS, and reduced UUO and FAN-induced kidney fibrosis. In Vitro study showing that metformin increased mitochondrial function and decreased TGF-β-induced fibrosis, apoptosis, and inflammation markers in lung epithelial cells.

Authors also include a retrospective study showing lower ICU admission with metformin without statistical significance.
0 0.5 1 1.5 2+ Severe case 33% Improvement Relative Risk Metformin  Milosavljevic et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 733 patients in the USA (March - December 2020) Lower severe cases with metformin (p=0.025) c19early.org Milosavljevic et al., J. Community Hos.., Nov 2022 Favors metformin Favors control
Milosavljevic: Retrospective 733 hospitalized COVID-19 patients with diabetes in the USA, showing lower risk of severity with metformin use.
0 0.5 1 1.5 2+ Mortality 45% Improvement Relative Risk Metformin for COVID-19  Mirani et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 90 patients in Italy (February - April 2020) Lower mortality with metformin (not stat. sig., p=0.097) c19early.org Mirani et al., Diabetes Care, October 2020 Favors metformin Favors control
Mirani: Retrospective 90 hospitalized COVID-19 patients with diabetes in Italy, showing lower mortality with metformin use, without statistical significance.
0 0.5 1 1.5 2+ Mortality 41% Improvement Relative Risk Ventilation -16% ICU admission 3% Hospitalization -4% Metformin for COVID-19  Morrison et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? PSM retrospective 13,585 patients in the USA (Mar 2020 - Mar 2021) Lower mortality with metformin (p=0.0032) c19early.org Morrison et al., PLOS ONE, October 2022 Favors metformin Favors control
Morrison: Retrospective 13,585 COVID+ patients in the USA, showing lower mortality with metformin use, but no significant difference for ventilation, ICU admission, and hospitalization.
0 0.5 1 1.5 2+ Mortality -1% Improvement Relative Risk Ventilation -4% ICU admission 8% Metformin  Obiri-Yeboah et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 529 patients in the USA No significant difference in outcomes seen c19early.org Obiri-Yeboah et al., Endocrine Practice, Jun 2023 Favors metformin Favors control
Obiri-Yeboah: Retrospective 529 hospitalized COVID-19 patients with type 2 diabetes, showing no significant difference in outcomes with metformin use. This does not account for the different risk of being hospitalized based on metformin use.

Authors note that "there is a lower-than-expected proportion of metformin prescription in our population (28%) compared to the general US population", without noting that this may reflect the lower risk of being hospitalized for metformin patients, as shown in other studies c19early.org (C).
0 0.5 1 1.5 2+ Mortality -26% Improvement Relative Risk Case 28% Metformin for COVID-19  Oh et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 11,892 patients in the USA Fewer cases with metformin (p<0.000001) c19early.org Oh et al., Acta Diabetologica, February 2021 Favors metformin Favors control
Oh: Retrospective 27,493 type II diabetes patients in the USA, 7,204 on metformin, showing significantly lower COVID-19 cases, but no significant difference in mortality.
0 0.5 1 1.5 2+ Mortality 16% Improvement Relative Risk Mortality (b) 22% ICU admission 22% Hospitalization 3% Mortality (c) 8% Mortality (d) 16% ICU admission (b) 39% Hospitalization (b) -2% Metformin  Ojeda-Fernández et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? PSM retrospective 13,112 patients in Italy Lower mortality (p<0.0001) and ICU admission (p=0.013) c19early.org Ojeda-Fernández et al., Diabetes, Obes.., Jan 2022 Favors metformin Favors control
Ojeda-Fernández: Retrospective 31,966 COVID+ patients using anti-hyperglycemic drugs in Italy, showing lower mortality and ICU admission with metformin use.
0 0.5 1 1.5 2+ Mortality 47% Improvement Relative Risk Mortality (b) 24% Mortality (c) 85% Mortality (d) 76% Metformin for COVID-19  Ong et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 355 patients in Philippines (March - September 2020) Lower mortality with metformin (p=0.017) c19early.org Ong et al., J. the ASEAN Federation of.., Oct 2021 Favors metformin Favors control
Ong: Retrospective 355 diabetic hospitalized COVID-19 patients in the Philippines, showing lower mortality with metformin use.
0 0.5 1 1.5 2+ Mortality 10% Improvement Relative Risk Death/hospitalization 8% Metformin for COVID-19  Ouchi et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 16,043 patients in Spain (March - June 2020) No significant difference in outcomes seen c19early.org Ouchi et al., Primary Care Diabetes, Oct 2022 Favors metformin Favors control
Ouchi: Retrospective 31,006 diabetic COVID-19 patients in Spain, showing lower mortality with metformin treatment, without statistical significance. Authors provide results for metformin compared with untreated patients rather than all non-metformin patients, which may increase confounding due to higher prevalence for treatment of patients with more severe disease.
0 0.5 1 1.5 2+ Death/ICU 53% Improvement Relative Risk Death/ICU, hosp. patients 15% Hospitalization 45% Metformin for COVID-19  Piarulli et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 4,014 patients in Italy (February 2020 - February 2021) Lower hospitalization with metformin (p=0.00021) c19early.org Piarulli et al., Nutrition, Metabolism.., Jun 2023 Favors metformin Favors control
Piarulli: Retrospective diabetic COVID-19 patients in Italy, showing lower risk of hospitalization with metformin use.
0 0.5 1 1.5 2+ Severe case 15% Improvement Relative Risk Metformin for COVID-19  Pinchera et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 43 patients in Italy (November 2021 - May 2022) Study compares with insulin, results vs. placebo may differ Lower severe cases with metformin (p=0.048) c19early.org Pinchera et al., Microorganisms, January 2023 Favors metformin Favors insulin
Pinchera: Retrospective 43 diabetes patients hospitalized for COVID-19 in Italy, showing lower risk of severe cases with metformin vs. insulin.
0 0.5 1 1.5 2+ Mortality -10% Improvement Relative Risk Metformin  Pérez-Belmonte et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? PSM retrospective 498 patients in Spain No significant difference in mortality c19early.org Pérez-Belmonte et al., BMC Medicine, Nov 2020 Favors metformin Favors control
Pérez-Belmonte: Retrospective 2,666 type 2 diabetes COVID-19 patients in Spain, showing higher mortality with existing metformin use (not statistically significant).
0 0.5 1 1.5 2+ Mortality 1% Improvement Relative Risk Metformin  Ramos-Rincón et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 790 patients in Spain (March - May 2020) No significant difference in mortality c19early.org Ramos-Rincón et al., Research Square, Dec 2020 Favors metformin Favors control
Ramos-Rincón: Retrospective 790 hospitalized type 2 diabetes patients ≥80 years old in Spain, showing no significant difference in mortality with existing metformin use.
0 0.5 1 1.5 2+ Mortality 30% Improvement Relative Risk Metformin for COVID-19  Ravindra et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 366 patients in India Lower mortality with metformin (not stat. sig., p=0.42) c19early.org Ravindra et al., medRxiv, May 2021 Favors metformin Favors control
Ravindra: Retrospective 1,035 hospitalized patients in India. Of 366 diabetic patients, there was lower mortality for the 53 that were on metformin.
0 0.5 1 1.5 2+ Mortality 27% Improvement Relative Risk Hospitalization 6% Hospitalization (b) 39% Extended ER observation.. -14% primary Extended ER observat.. (b) 12% ER visit 31% ER visit (b) 26% Viral clearance 1% Metformin  TOGETHER  EARLY TREATMENT  DB RCT Is early treatment with metformin beneficial for COVID-19? Double-blind RCT 421 patients in Brazil (January - April 2021) Lower mortality (p=0.53) and progression (p=0.48), not sig. c19early.org Reis et al., The Lancet Regional Healt.., Aug 2021 Favors metformin Favors control
Reis: Data for the primary outcome in this trial appears to be impossible doyourownresearch.substack.com. For example, considering the metformin arm and the ITT population: 24 were hospitalized and 8 had an ER visit (tables S2/S3), therefore the number for combined ER or hospitalization must be between 24 and 32. However, authors report 34 events for ER/hospitalization.

RCT with 215 patients treated with metformin and 203 controls, showing no significant difference with treatment.

For multiple major issues with this trial see doyourownresearch.substack.com, doyourownresearch.substack.com (B).

The hospitalization risk for off-protocol patients was several times higher in both arms, resulting in Simpson's paradox when combining per-protocol and off-protocol patients twitter.com.

750mg twice daily for 10 days.

The TOGETHER trial has extreme COI, impossible data, blinding failure, randomization failure, uncorrected errors, and many protocol violations. Authors do not respond to these issues and they have refused to release the data as promised. Some issues may apply only to specific arms. For more details see Reis (B), Reis (C), Reis (D), Reis (E), Reis (F).
0 0.5 1 1.5 2+ Hospitalization 3% Improvement Relative Risk Metformin for COVID-19  Sandhu et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 3,974,272 patients in the USA (Jan - Dec 2020) Lower hospitalization with metformin (p=0.0042) c19early.org Sandhu et al., PLOS ONE, March 2023 Favors metformin Favors control
Sandhu: Retrospective 3,974,272 COVID-19 patients in the USA, showing 3% lower risk of hospitalization with pre-existing metformin use.
0 0.5 1 1.5 2+ Mortality 42% Improvement Relative Risk Metformin for COVID-19  Saygili et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? PSM retrospective 240 patients in Turkey Lower mortality with metformin (p=0.02) c19early.org Saygili et al., Irish J. Medical Science, Oct 2021 Favors metformin Favors control
Saygili: Retrospective 586 diabetic hospitalized COVID-19 patients in Turkey, showing lower mortality with existing metformin use.
0 0.5 1 1.5 2+ Mortality 49% Improvement Relative Risk Metformin for COVID-19  Servais et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective study in Belgium (March - May 2020) Lower mortality with metformin (p=0.0018) c19early.org Servais et al., Annals of Endocrinology, Dec 2022 Favors metformin Favors control
Servais: Retrospective 375 hospitalized diabetes patients in Belgium, showing lower risk of COVID-19 mortality with metformin use.
0 0.5 1 1.5 2+ Mortality 74% Improvement Relative Risk Ventilation 79% ICU admission 63% Hospitalization time 5% Metformin  Shaseb et al.  LATE TREATMENT  RCT Is late treatment with metformin beneficial for COVID-19? RCT 189 patients in Iran (March - April 2020) Lower ventilation with metformin (p=0.048) c19early.org Shaseb et al., Advanced Pharmaceutical.., Jul 2022 Favors metformin Favors control
Shaseb: RCT 189 hospitalized patients showing lower mortality, ICU admission, and intubation with metformin, statistically significant only for intubation. Treatment patients may have also taken metformin prior to admission. Authors note that patients receiving metformin prior to the study were not matched, and diabetes and hyperlipidemia differed between groups.
0 0.5 1 1.5 2+ Mortality 22% Improvement Relative Risk Metformin for COVID-19  Shestakova et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 189,998 patients in Russia (March 2020 - November 2021) Lower mortality with metformin (p=0.0012) c19early.org Shestakova et al., Frontiers in Endocr.., Aug 2022 Favors metformin Favors control
Shestakova: Retrospective 224,190 type 2 diabetes patients in Russia, showing lower mortality with metformin use.
0 0.5 1 1.5 2+ Mortality 37% Improvement Relative Risk Metformin for COVID-19  Sourij et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 247 patients in Austria Lower mortality with metformin (not stat. sig., p=0.13) c19early.org Sourij et al., Diabetes, Obesity and M.., Dec 2020 Favors metformin Favors control
Sourij: Retrospective 247 hospitalized COVID-19 diabetes patients, showing lower mortality with metformin use in unadjusted results.
0 0.5 1 1.5 2+ Mortality 97% Improvement Relative Risk Metformin for COVID-19  Tamura et al.  LATE TREATMENT Is late treatment with metformin beneficial for COVID-19? Retrospective 188 patients in Brazil (March - November 2020) Lower mortality with metformin (p=0.019) c19early.org Tamura et al., Diabetology & Metabolic.., Jul 2021 Favors metformin Favors control
Tamura: Retrospective 188 hospitalized patients in Brazil, showing lower risk of mortality with metformin use. Authors note that, although pre-hospital metformin use improved clinical parameters at admission, continuous use during hospitalization is essential. Patients that used pre-hospital metformin therapy but interrupted the treatment during hospitalization showed higher mortality than those that continued metformin therapy.
0 0.5 1 1.5 2+ Mortality 60% Improvement Relative Risk Ventilation 76% Hospitalization time 34% Metformin for COVID-19  Usman et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 75 patients in the USA Lower mortality (p=0.21) and ventilation (p=0.054), not sig. c19early.org Usman et al., J. Thrombosis and Thromb.., Jan 2022 Favors metformin Favors control
Usman: Retrospective 75 diabetes patients, 34 on metformin, showing improved clinical outcomes with treatment, without statistical significance.
0 0.5 1 1.5 2+ Oxygen time 44% Improvement Relative Risk Hospitalization time 10% Time to viral- 41% Metformin  Ventura-López et al.  LATE TREATMENT  DB RCT Is late treatment with metformin beneficial for COVID-19? Double-blind RCT 20 patients in Mexico (January 2020 - August 2021) Lower need for oxygen therapy (p=0.03) and faster viral clearance (p=0.029) c19early.org Ventura-López et al., Biomedicine &amp.., Aug 2022 Favors metformin Favors control
Ventura-López: RCT 20 hospitalized COVID-19 patients showing faster viral load reduction and lower oxygen use with metformin glycinate 620mg twice daily for 14 days compared to placebo. The in vitro portion demonstrated inhibition of viral replication and cytopathic effects with metformin glycinate pretreatment.
0 0.5 1 1.5 2+ Mortality 72% Improvement Relative Risk Metformin for COVID-19  Wallace et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 8,173 patients in the USA Lower mortality with metformin (p<0.000001) c19early.org Wallace et al., BMJ Open, December 2021 Favors metformin Favors control
Wallace: Retrospective 9,532 hospitalized COVID+ veterans in the USA, showing lower mortality with metformin use. The study provides results for use before, after, and before+after. Before+after should more accurately represent prophylaxis up to COVID-19 infection (and continued use). Before included use up to 2 years before, and after included use up to 60 days later.
0 0.5 1 1.5 2+ Mortality 15% Improvement Relative Risk ICU admission 2% Hospitalization 3% Metformin for COVID-19  Wander et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 64,892 patients in the USA Lower mortality with metformin (p<0.000001) c19early.org Wander et al., Diabetes Care, October 2021 Favors metformin Favors control
Wander: Retrospective 64,892 veterans with diabetes in the USA, showing lower mortality with existing metformin use.
0 0.5 1 1.5 2+ ICU admission 12% Improvement Relative Risk Metformin for COVID-19  Wang et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 16,504 patients in the USA Lower ICU admission with metformin (p=0.0055) c19early.org Wang et al., BMJ Open Diabetes Researc.., Sep 2021 Favors metformin Favors control
Wang (B): Retrospective 16,504 COVID-19 type 2 diabetes patients, showing lower risk of ICU admission with existing metformin use.
0 0.5 1 1.5 2+ Mortality 58% Improvement Relative Risk Metformin for COVID-19  Wang et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 58 patients in the USA Lower mortality with metformin (not stat. sig., p=0.43) c19early.org Wang et al., J. Hematology & Oncology, Jul 2020 Favors metformin Favors control
Wang (C): Retrospective 58 multiple myeloma COVID-19 patients in the USA, showing non-statistically significant lower mortality with metformin treatment.
0 0.5 1 1.5 2+ Mortality 28% Improvement Relative Risk Discharge 15% Metformin for COVID-19  CORONADO  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 2,794 patients in France (March - April 2020) Lower mortality (p=0.026) and higher discharge (p=0.019) c19early.org Wargny et al., Diabetologia, February 2021 Favors metformin Favors control
Wargny: Retrospective 2,796 hospitalized diabetes patients with COVID-19 in France, showing lower mortality with metformin use.
0 0.5 1 1.5 2+ Mortality 59% Improvement Relative Risk Recovery 61% Clinical improvement 64% Discharge 56% Metformin for COVID-19  Wong et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 1,214 patients in China (January 2020 - January 2021) Lower mortality (p=0.01) and improved recovery (p=0.005) c19early.org Wong et al., Frontiers in Endocrinology, Mar 2022 Favors metformin Favors control
Wong: Retrospective 1,214 COVID+ type 2 diabetes patients in Hong Kong, showing lower mortality and improved recovery with metformin use.
0 0.5 1 1.5 2+ Mortality 51% Improvement Relative Risk Ventilation 41% Hospitalization 40% Metformin for COVID-19  Wong et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 39,616 patients in the USA Lower mortality (p<0.0001) and ventilation (p<0.0001) c19early.org Wong et al., Diabetes Care, February 2022 Favors metformin Favors control
Wong (B): N3C retrospective 39,616 COVID-19 patients with diabetes in the USA, showing lower mortality, ventilation, and hospitalization with metformin use.
0 0.5 1 1.5 2+ ICU/intubation/death 44% Improvement Relative Risk Hospitalization 37% Metformin for COVID-19  Yeh et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective study in the USA (March 2020 - February 2021) Lower progression (p<0.0001) and hospitalization (p<0.0001) c19early.org Yeh et al., BMJ Open Diabetes Research.., Jun 2022 Favors metformin Favors control
Yeh: Retrospective 4,944 COVID-19 patients with type 2 diabetes in the USA, showing lower risk of hospitalization and combined ICU/intubation/death with metformin use.
0 0.5 1 1.5 2+ Mortality 25% Improvement Relative Risk Ventilation 25% ICU admission 19% Hospitalization 15% Case -2% Metformin for COVID-19  Yen et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? PSM retrospective 123,709 patients in multiple countries (Jan 2020 - Nov 2022) Lower mortality (p=0.0011) and ventilation (p=0.014) c19early.org Yen et al., Diabetes Research and Clin.., May 2023 Favors metformin Favors control
Yen: TriNetX retrospective 123,709 vaccinated patients with type 2 diabetes, showing significantly lower risk of COVID-19 mortality, mechanical ventilation, and hospitalization with metformin use. There was no significant difference for cases. The increasing benefit for more serious outcomes matches the results of studies to date.
0 0.5 1 1.5 2+ Death/hospitalization 7% Improvement Relative Risk Progression 15% Progression (b) 15% Metformin for COVID-19  Yip et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? PSM retrospective 12,331 patients in China (February - March 2022) Lower progression with metformin (not stat. sig., p=0.16) c19early.org Yip et al., SSRN Electronic J., September 2022 Favors metformin Favors control
Yip: Retrospective 12,331 diabetes patients in Hong Kong, showing no significant difference in outcomes with metformin use.
0 0.5 1 1.5 2+ Mortality 34% Improvement Relative Risk Hospitalization 31% Metformin for COVID-19  Zaccardi et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 624,771 patients in the United Kingdom Lower mortality (p<0.0001) and hospitalization (p<0.0001) c19early.org Zaccardi et al., Diabetes, Obesity and.., Sep 2022 Favors metformin Favors control
Zaccardi: Retrospective 624,771 people with type 2 diabetes in the UK, showing lower COVID-19 mortality and hospitalization with metformin use.
0 0.5 1 1.5 2+ Mortality 49% Improvement Relative Risk Metformin for COVID-19  Zihono et al.  Prophylaxis Is prophylaxis with metformin beneficial for COVID-19? Retrospective 137 patients in Indonesia Lower mortality with metformin (p=0.024) c19early.org Zihono et al., Folia Medica Indonesiana, Sep 2023 Favors metformin Favors control
Zihono: Retrospective 137 hospitalized mild to moderate COVID-19 patients with type 2 diabetes in Indonesia, showing a significantly lower mortality with metformin treatment.
We perform ongoing searches of PubMed, medRxiv, Europe PMC, ClinicalTrials.gov, The Cochrane Library, Google Scholar, Research Square, ScienceDirect, Oxford University Press, the reference lists of other studies and meta-analyses, and submissions to the site c19early.org. Search terms are metformin and COVID-19 or SARS-CoV-2. Automated searches are performed twice daily, with all matches reviewed for inclusion. All studies regarding the use of metformin for COVID-19 that report a comparison with a control group are included in the main analysis. Sensitivity analysis is performed, excluding studies with major issues, epidemiological studies, and studies with minimal available information. This is a living analysis and is updated regularly.
We extracted effect sizes and associated data from all studies. If studies report multiple kinds of effects then the most serious outcome is used in pooled analysis, while other outcomes are included in the outcome specific analyses. For example, if effects for mortality and cases are both reported, the effect for mortality is used, this may be different to the effect that a study focused on. If symptomatic results are reported at multiple times, we used the latest time, for example if mortality results are provided at 14 days and 28 days, the results at 28 days have preference. Mortality alone is preferred over combined outcomes. Outcomes with zero events in both arms are not used, the next most serious outcome with one or more events is used. For example, in low-risk populations with no mortality, a reduction in mortality with treatment is not possible, however a reduction in hospitalization, for example, is still valuable. Clinical outcomes are considered more important than viral test status. When basically all patients recover in both treatment and control groups, preference for viral clearance and recovery is given to results mid-recovery where available. After most or all patients have recovered there is little or no room for an effective treatment to do better, however faster recovery is valuable. If only individual symptom data is available, the most serious symptom has priority, for example difficulty breathing or low SpO2 is more important than cough. When results provide an odds ratio, we compute the relative risk when possible, or convert to a relative risk according to Zhang (B). Reported confidence intervals and p-values were used when available, using adjusted values when provided. If multiple types of adjustments are reported propensity score matching and multivariable regression has preference over propensity score matching or weighting, which has preference over multivariable regression. Adjusted results have preference over unadjusted results for a more serious outcome when the adjustments significantly alter results. When needed, conversion between reported p-values and confidence intervals followed Altman, Altman (B), and Fisher's exact test was used to calculate p-values for event data. If continuity correction for zero values is required, we use the reciprocal of the opposite arm with the sum of the correction factors equal t