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96 metformin COVID-19 controlled studies, 4 RCTs
58% improvement
for early treatment, RR
0.42
[0.23-0.77]
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
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
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
Metformin COVID-19 outcomes
c19 early .org
November 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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means should be used based on risk/benefit analysis.
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