Protection by metformin against severe Covid-19: An in-depth mechanistic analysis.

Since the outbreak of Covid-19, several observational studies on diabetes and Covid-19 have reported a favourable association between metformin and Covid-19-related outcomes in patients with type 2 diabetes mellitus (T2DM). This is not surprising since metformin affects many of the pathophysiological mechanisms implicated in SARS-CoV-2 immune response, systemic spread and sequelae. A comparison of the multifactorial pathophysiological mechanisms of Covid-19 progression with metformin's well-known pleiotropic properties suggests that the treatment of patients with this drug might be particularly beneficial. Indeed, metformin could alleviate the cytokine storm, diminish virus entry into cells, protect against microvascular damage as well as prevent secondary fibrosis. Although our in-depth analysis covers many potential metformin mechanisms of action, we want to highlight more particularly its unique microcirculatory protective effects since worsening of Covid-19 disease clearly appears as largely due to severe defects in the structure and functioning of microvessels. Overall, these observations confirm that metformin is a unique, pleiotropic drug that targets many of Covid-19's pathophysiology processes in a diabetes-independent manner.

La metformine est associée à une moindre mortalité chez les patients diabétiques hospitalisés pour la COVID-19

Résumé Les effets anti-inflammatoires et modulateurs de l’immunité de la metformine légitimaient la recherche d’un meilleur pronostic chez les diabétiques hospitalisés pour la maladie à coronavirus 2019 (COVID-19) traités par metformine, comparativement à ceux qui ne le sont pas. Une telle recherche a pu être menée à partir de la cohorte nationale CORONADO, qui a inclus les patients diabétiques de type 2 hospitalisés pour la COVID-19, entre le 10 mars et le 10 avril 2020 et avec une méthodologie robuste : un critère de jugement principal combinant à J7 l’intubation trachéale et le décès ;une courbe de survie Kaplan–Meier ;et, surtout, une analyse de régression logistique pondérée par un score de propension. Ce sont, au total, près de 2500 patients qui ont été étudiés, dont près des deux-tiers traités par metformine. Ces derniers avaient globalement moins de comorbidités, liées au diabète ou non, mais, en revanche, des signes de la COVID-19 plus francs. Parmi les résultats, le fait plus marquant a été une mortalité nettement moindre dans le groupe traité par metformine que dans le groupe non traité par metformine, et ce, dès J7 (8,2 % versus 16,1 %, respectivement). Ce différentiel persistait à J28 (16,0 % versus 28,6 %, respectivement). L’hypothèse d’un bénéfice lié à la metformine doit maintenant être confirmée par une étude d’intervention, dont dans la population générale. Summary Metformin exerts anti-inflammatory and immunosuppressive effects. We addressed the impact of prior metformin use on the prognosis of patients with type 2 diabetes hospitalised for COVID-19. We used data from the nationwide observational CORONADO cohort that included patients with diabetes hospitalised for COVID-19 between March 10 and April 10, 2020 in 68 French centres. The primary outcome was combined tracheal intubation and/or death within 7 days of admission. A Kaplan–Meier survival curve was reported for death up to day 28. The association between metformin use and outcomes was then estimated in a logistic regression analysis after applying propensity score weighting approach to account for treatment allocation. Among the 2449 patients included, 1496 were metformin users and 953 were not. Compared with non-users, metformin users were younger with a lower prevalence of diabetic complications, but had more severe features of COVID-19 at admission. The most striking feature was a lower mortality rate in metformin users vs. non-users on day 7 (8.2 % vs. 16.1 %, respectively;P<0.0001) and on day 28 (16.0 % vs. 28.6 %, respectively: P<0.0001), even after propensity score weighting was applied. Randomised, controlled studies are now needed in order to confirm the benefits associated with metformin and to establish to what extent these protective effects, if any, can be generalised to non-diabetic patients with COVID-19.

Metformin use is associated with a reduced risk of mortality in patients with diabetes hospitalised for COVID-19.

AIMS: Metformin exerts anti-inflammatory and immunosuppressive effects. We addressed the impact of prior metformin use on prognosis in patients with type 2 diabetes hospitalised for COVID-19. METHODS: CORONADO is a nationwide observational study that included patients with diabetes hospitalised for COVID-19 between March 10 and April 10, 2020 in 68 French centres. The primary outcome combined tracheal intubation and/or death within 7 days of admission. A Kaplan-Meier survival curve was reported for death up to day 28. The association between metformin use and outcomes was then estimated in a logistic regression analysis after applying a propensity score inverse probability of treatment weighting approach. RESULTS: Among the 2449 patients included, 1496 were metformin users and 953 were not. Compared with non-users, metformin users were younger with a lower prevalence of diabetic complications, but had more severe features of COVID-19 on admission. The primary endpoint occurred in 28.0% of metformin users (vs 29.0% in non-users, P = 0.6134) on day 7 and in 32.6% (vs 38.7%, P = 0.0023) on day 28. The mortality rate was lower in metformin users on day 7 (8.2 vs 16.1%, P < 0.0001) and on day 28 (16.0 vs 28.6%, P < 0.0001). After propensity score weighting was applied, the odds ratios for primary outcome and death (OR [95%CI], metformin users vs non-users) were 0.838 [0.649-1.082] and 0.688 [0.470-1.007] on day 7, then 0.783 [0.615-0.996] and 0.710 [0.537-0.938] on day 28, respectively. CONCLUSION: Metformin use appeared to be associated with a lower risk of death in patients with diabetes hospitalised for COVID-19.