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99 metformin COVID-19 controlled studies, 4 RCTs
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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 TOGETHER Reis (DB RCT) 6% 0.94 [0.55-1.61] hosp. 24/215 24/203 impossible data, see notes TOGETHER Reis (DB RCT) 39% 0.61 [0.26-1.41] hosp. 8/168 14/179 impossible data, see notes TOGETHER Reis (DB RCT) -14% 1.14 [0.73-1.81] hosp./ER 34/215 28/203 impossible data, see notes TOGETHER Reis (DB RCT) 12% 0.88 [0.45-1.71] hosp./ER 14/168 17/179 impossible data, see notes TOGETHER Reis (DB RCT) 31% 0.69 [0.28-1.68] progression 8/216 11/205 impossible data, see notes TOGETHER Reis (DB RCT) 26% 0.74 [0.29-1.90] progression 7/171 10/181 impossible data, see notes TOGETHER Reis (DB RCT) 1% 0.99 [0.88-1.11] viral+ 215 (n) 203 (n) impossible data, see notes 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 OT1 COVID-OUT Bramante (DB RCT) -197% 2.97 [0.12-72.7] death 1/408 0/396 OT1 COVID-OUT Bramante (DB RCT) 52% 0.48 [0.20-1.11] death/hosp. 8/652 18/655 OT1 COVID-OUT Bramante (DB RCT) 40% 0.60 [0.37-0.94] progression 27/652 48/655 OT1 COVID-OUT Bramante (DB RCT) 12% 0.88 [0.73-1.06] progression 154/652 179/653 OT1 COVID-OUT Bramante (DB RCT) 37% 0.63 [0.48-0.83] viral+ 72/504 112/495 OT1 COVID-OUT Bramante (DB RCT) 9% 0.91 [0.81-1.03] viral+ 251/504 270/495 OT1 Abu-Jamous 65% 0.35 [0.11-0.84] death 4/23 94/168 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) Shaseb (RCT) 79% 0.21 [0.04-0.99] ventilation 85 (n) 104 (n) Shaseb (RCT) 63% 0.37 [0.13-1.09] ICU 85 (n) 104 (n) Shaseb (RCT) 5% 0.95 [0.82-1.11] hosp. time 85 (n) 104 (n) Ventura-.. (DB RCT) 44% 0.56 [0.33-0.95] oxygen time 10 (n) 10 (n) Ventura-.. (DB RCT) 10% 0.90 [0.72-1.12] hosp. time 10 (n) 10 (n) Ventura-.. (DB RCT) 41% 0.59 [0.37-0.95] viral time 10 (n) 10 (n) Mehrizi 44% 0.56 [0.53-0.60] death population-based cohort Sugimoto 40% 0.60 [0.53-0.66] death population-based cohort Sugimoto 41% 0.59 [0.51-0.68] misc. population-based cohort He 74% 0.26 [0.20-0.34] death 53,030 (all patients) He 72% 0.28 [0.19-0.40] death 53,030 (all patients) He 74% 0.26 [0.18-0.39] death 53,030 (all patients) Luo 75% 0.25 [0.07-0.84] death 3/104 22/179 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) Kim 52% 0.48 [0.19-1.24] progression 113 (n) 122 (n) Li 78% 0.22 [0.09-0.54] death 2/37 21/94 Li -27% 1.27 [0.12-13.6] ventilation 1/37 2/94 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 Bramante 21% 0.79 [0.65-0.95] death 1,129 (n) 2,173 (n) Bramante 4% 0.96 [0.82-1.14] death 1,204 (n) 1,750 (n) 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) Lalau (PSM) 18% 0.82 [0.61-1.11] death/int. 671 (n) 419 (n) Lalau (PSM) 7% 0.93 [0.64-1.35] ventilation 671 (n) 419 (n) Huh -1% 1.01 [0.81-1.23] progression 104/272 774/2,533 Huh 4% 0.96 [0.82-1.12] cases case control 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) Oh (PSM) 28% 0.72 [0.63-0.81] cases 390/5,946 541/5,946 CORONADO Wargny 28% 0.72 [0.53-0.95] death 247/1,553 330/1,241 CORONADO Wargny 15% 0.85 [0.74-0.97] no disch. 690/1,553 702/1,241 Bramante (PSM) 62% 0.38 [0.16-0.91] death 342 (n) 342 (n) Bramante 68% 0.32 [0.15-0.66] death 676 (n) 8,879 (n) Bramante (PSM) -9% 1.09 [0.62-1.91] ICU 342 (n) 342 (n) Bramante 32% 0.68 [0.45-1.02] ICU 676 (n) 8,879 (n) Bramante 22% 0.78 [0.58-1.04] hosp. 676 (n) 8,879 (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 Jiang (PSM) 80% 0.20 [0.05-0.77] progression 8/74 17/74 Ghany 66% 0.34 [0.19-0.59] death 392 (n) 747 (n) Ghany 29% 0.71 [0.52-0.86] hosp. 392 (n) 747 (n) Ghany 68% 0.32 [0.22-0.45] ARDS 392 (n) 747 (n) Alamgir 27% 0.73 [0.63-0.84] death 11,062 (n) 11,062 (n) Alamgir 34% 0.66 [0.49-0.90] death 5,369 (n) 5,369 (n) Alamgir 30% 0.70 [0.53-0.95] death 2,525 (n) 2,525 (n) Gálvez-Barrón -16% 1.16 [0.73-1.49] death 20 (n) 83 (n) Gálvez-Barrón -16% 1.16 [0.73-1.49] severe case 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 Blanc -44% 1.44 [1.00-2.07] cases 11/16 78/163 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 Wander 2% 0.98 [0.92-1.06] ICU Wander 3% 0.97 [0.94-1.01] hosp. 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 Ong 24% 0.76 [0.50-1.10] death 28/109 57/169 Ong 85% 0.15 [0.04-0.55] death 2/40 57/169 Ong 76% 0.24 [0.07-0.68] death 3/37 57/169 Bliden 60% 0.40 [0.12-1.37] death 3/34 9/41 Bliden 76% 0.24 [0.06-1.03] ventilation 2/34 10/41 Al-Salameh 55% 0.45 [0.17-0.94] death/ICU 9/47 22/50 Al-Salameh -68% 1.68 [1.12-2.05] death/ICU 34/43 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 Ojeda-Fern.. (PSM) 22% 0.78 [0.72-0.84] death 968/6,556 1,261/6,556 Ojeda-Fern.. (PSM) 22% 0.78 [0.64-0.95] ICU 166/6,556 212/6,556 Ojeda-Fern.. (PSM) 3% 0.97 [0.94-1.00] hosp. 3,551/6,556 3,670/6,556 Ojeda-Fern.. (PSM) 8% 0.92 [0.84-1.00] death 793/3,297 876/3,297 Ojeda-Fern.. (PSM) 16% 0.84 [0.75-0.94] death 512/3,297 618/3,297 Ojeda-Fern.. (PSM) 39% 0.61 [0.44-0.82] ICU 64/3,297 102/3,297 Ojeda-Fern.. (PSM) -2% 1.02 [0.97-1.07] hosp. 1,822/3,297 1,792/3,297 Fu 72% 0.28 [0.09-0.84] no recov. 4/49 9/31 OT1 Usman 60% 0.40 [0.12-1.37] death 3/34 9/41 Usman 76% 0.24 [0.06-1.03] ventilation 2/34 10/41 Usman 34% 0.66 [0.39-1.13] hosp. time 34 (n) 41 (n) Wong 51% 0.49 [0.43-0.57] death Wong 41% 0.59 [0.52-0.66] ventilation Wong 40% 0.60 [0.57-0.63] hosp. Wong (PSW) 59% 0.41 [0.22-0.80] death 786 (n) 428 (n) Wong (PSW) 61% 0.39 [0.21-0.75] no recov. 786 (n) 428 (n) Wong (PSW) 64% 0.36 [0.18-0.76] improv. 786 (n) 428 (n) Wong (PSW) 56% 0.44 [0.24-0.81] no disch. 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 Ma (PSM) 25% 0.75 [0.36-1.56] ventilation 12/360 16/360 Yeh 44% 0.56 [0.45-0.71] progression n/a n/a Yeh 37% 0.63 [0.53-0.75] hosp. n/a n/a Cousins (PSM) 50% 0.50 [0.29-0.85] ventilation 2,463 (n) 2,463 (n) Cousins (PSM) 51% 0.49 [0.35-0.68] ICU 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) Chan 54% 0.46 [0.18-1.14] severe case 400 (n) 2,736 (n) Chan 42% 0.58 [0.17-1.91] progression 51/400 798/2,736 Chan 37% 0.63 [0.23-1.71] progression 400 (n) 2,736 (n) Chan 41% 0.59 [0.31-1.13] progression 196 (n) 86 (n) Chan 34% 0.66 [0.39-1.09] progression 196 (n) 86 (n) Zaccardi 34% 0.66 [0.60-0.72] death population-based cohort Zaccardi 31% 0.69 [0.65-0.73] hosp. population-based cohort Yip (PSM) 7% 0.93 [0.72-1.22] death/hosp. 8,604 (n) 3,727 (n) Yip (PSM) 15% 0.85 [0.68-1.07] progression 8,604 (n) 3,727 (n) Yip (PSM) 15% 0.85 [0.68-1.05] progression 8,604 (n) 3,727 (n) Ouchi 10% 0.90 [0.77-1.05] death 6,168 (n) 9,875 (n) Ouchi 8% 0.92 [0.82-1.02] death/hosp. 6,168 (n) 9,875 (n) Morrison (PSM) 41% 0.59 [0.41-0.84] death 2,684 (n) 2,684 (n) Morrison (PSM) -16% 1.16 [0.76-1.76] ventilation 2,684 (n) 2,684 (n) Morrison (PSM) 3% 0.97 [0.72-1.31] ICU 2,684 (n) 2,684 (n) Morrison (PSM) -4% 1.04 [0.84-1.28] hosp. 2,684 (n) 2,684 (n) Mannucci 38% 0.62 [0.41-0.93] death n/a n/a Mannucci 15% 0.85 [0.64-1.12] hosp. 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 Miao (PSM) 5% 0.95 [0.88-1.03] hosp. time 796 (n) 796 (n) 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 OT1 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 Yen (PSM) 25% 0.75 [0.60-0.95] ventilation 133/20,894 168/20,894 Yen (PSM) 19% 0.81 [0.70-0.94] ICU 332/20,894 390/20,894 Yen (PSM) 15% 0.85 [0.81-0.89] hosp. 2,820/20,894 3,139/20,894 Yen (PSM) -2% 1.02 [0.94-1.10] cases 1,467/20,894 1,364/20,894 Araldi 60% 0.40 [0.32-0.50] death 107/2,598 263/2,598 Akinosoglou 37% 0.63 [0.35-1.13] death 147 (n) 207 (n) Akinosoglou -39% 1.39 [0.79-2.45] ICU 147 (n) 207 (n) Akinosoglou -3% 1.03 [0.62-1.69] ARDS 147 (n) 207 (n) 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) Obiri-Yeboah -4% 1.04 [0.67-1.59] ventilation 148 (n) 381 (n) Obiri-Yeboah 8% 0.92 [0.60-1.43] ICU 148 (n) 381 (n) Piarulli 53% 0.47 [0.20-1.08] death/ICU 1,444 (n) 1,009 (n) Piarulli 15% 0.85 [0.39-1.83] death/ICU 209 (n) 180 (n) Piarulli 45% 0.55 [0.40-0.75] hosp. 1,444 (n) 1,009 (n) Greco 22% 0.78 [0.57-1.05] hosp. OT1 Greco 26% 0.74 [0.60-0.92] hosp. OT1 Greco 17% 0.83 [0.46-1.50] hosp. OT1 Guo 62% 0.38 [0.15-0.92] death/int. 241 (n) 330 (n) Guo 81% 0.19 [0.06-0.56] progression 241 (n) 330 (n) Guo 80% 0.20 [0.04-1.03] progression 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 64 (n) 68 (n) Miguel 43% 0.57 [0.19-1.71] ICU 3/15 14/40 Miguel 31% 0.69 [0.23-2.04] ICU 6/49 5/28 Mamari 50% 0.50 [0.29-0.86] death 11/34 22/34 OT1 Al-kuraishy 78% 0.22 [0.06-0.77] death 3/60 9/40 Al-kuraishy 41% 0.59 [0.45-0.78] no recov. 57 (n) 31 (n) Al-kuraishy 84% 0.16 [0.06-0.40] no recov. 57 (n) 31 (n) Jang 60% 0.40 [0.18-0.85] death 461 (n) 95 (n) Jang 72% 0.28 [0.11-0.72] ventilation 461 (n) 95 (n) Jang 39% 0.61 [0.33-1.13] ICU 461 (n) 95 (n) Jang 30% 0.70 [0.40-1.25] oxygen 461 (n) 95 (n) Jang -27% 1.27 [0.70-2.29] hosp. 461 (n) 95 (n) Lewandowski 23% 0.77 [0.53-1.08] death 14/101 83/329 Silverii 29% 0.71 [0.27-1.90] death 220 (n) 304 (n) Silverii 20% 0.80 [0.49-1.28] death 220 (n) 304 (n) Dimnjaković 23% 0.77 [0.64-0.92] hosp. 2,843 (n) 4,475 (n) Dimnjaković 12% 0.88 [0.77-0.99] cases 2,843 (n) 4,475 (n) Xu (PSM) 52% 0.48 [0.23-0.83] death 405 (n) 405 (n) Xu 59% 0.41 [0.24-0.70] death 466 (n) 4,456 (n) Xu 54% 0.46 [0.26-0.81] ventilation 466 (n) 4,456 (n) Xu 72% 0.28 [0.08-0.96] ARDS 466 (n) 4,456 (n) Olawore 19% 0.81 [0.55-1.20] PASC 5,596 (n) 1,451 (n) Olawore 14% 0.86 [0.56-1.32] PASC 5,596 (n) 1,451 (n) Chen 81% 0.19 [0.05-0.80] ICU 2/121 25/292 Chen 39% 0.61 [0.42-0.89] progression 25/121 99/292 Chen 17% 0.83 [0.75-0.93] hosp. time 121 (n) 292 (n) Hussein 64% 0.36 [0.12-0.87] death 30/158 60/110 OT1 Johnson 11% 0.89 [0.77-1.03] progression Johnson 21% 0.79 [0.71-0.88] progression Johnson 15% 0.85 [0.78-0.92] progression Johnson 13% 0.87 [0.66-1.14] progression Johnson -4% 1.04 [0.97-1.11] progression Harmon (PSW) 18% 0.82 [0.75-0.90] death 4,667 (n) 5,745 (n) Sakamaki 23% 0.77 [0.72-0.82] severe case population-based cohort Somasundaram 89% 0.11 [0.04-0.29] death 221 (n) 200 (n) Chertok Shacham 70% 0.30 [0.11-0.23] death 342 (n) 515 (n) Metformin COVID-19 outcomes c19 earlyDecember 2024 1 OT: comparison with other treatment Favors metformin Favors control
Figure S2. Comparison of results for RCTs versus observational studies.
For COVID-19 treatments, there is no significant difference between the results of RCTs and observational studies. Observational studies do not systematically over or underestimate efficacy. For high-cost treatments, there is a non-significant trend towards RCTs showing greater efficacy.
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