Metformin for COVID-19: real-time meta analysis of 65 studies

• Statistically significant improvements are seen for mortality, ventilation, ICU admission, hospitalization, and progression. 42 studies from 39 independent teams in 11 different countries show statistically significant improvements in isolation (38 for the most serious outcome).• Meta analysis using the most serious outcome reported shows 28% [23‑32%] improvement. Results are similar for Randomized Controlled Trials, similar after exclusions, and similar for peer-reviewed studies. Clinical outcomes suggest benefit while viral and case outcomes do not, consistent with an intervention that aids recovery but is not antiviral. • Results are robust — in exclusion sensitivity analysis 48 of 65 studies must be excluded to avoid finding statistically significant efficacy in pooled analysis.• Most studies analyze existing use with diabetic patients. Many results are subject to confounding by indication — metformin is typically used early in the progression of type 2 diabetes. Prophylaxis results typically include continuing use after infection and hospitalization, and greater benefit is seen for more serious outcomes. The beneficial effect of metformin may be more related to later stages of COVID-19. The TOGETHER RCT shows 27% lower mortality. While not statistically significant, p = 0.53, this is consistent with the mortality results from all studies, 32% [27‑37%].• No treatment, vaccine, or intervention is 100% effective and available. All practical, effective, and safe means should be used based on risk/benefit analysis. Multiple treatments are typically used in combination, and other treatments are more effective. None of the metformin studies show zero events with treatment. • All data to reproduce this paper and sources are in the appendix. Other meta analyses for metformin can be found in [Hariyanto, Kow, Li, Lukito, Ma, Parveen, Schlesinger, Yang], showing significant improvements for mortality, hospitalization, progression, and severity.

Percentage improvement with metformin (more)

	All studies	Prophylaxis	Early treatment	Studies	Patients	Authors
All studies	28% [23‑32%]****	26% [22‑30%]****	58% [23‑77%]**	65	256,116	783
Randomized Controlled TrialsRCTs	24% [-89‑70%]	-	24% [-89‑70%]	2	1,222	26
Mortality	32% [27‑37%]****	30% [25‑34%]****	58% [23‑77%]**	49	193,729	623
RCT mortality	24% [-89‑70%]	-	24% [-89‑70%]	2	1,222	26