By Austin Ulrich, PharmD, BCACP

Clinical Pharmacist Practitioner, UpStream Pharmaceutical Care, Greensboro, NC

SYNOPSIS: Investigators found metformin use before COVID-19 hospitalization for patients with diabetes was associated with a lower risk of death.

SOURCE: Lalau JD, Al-Salameh A, Hadjadj S, et al. Metformin use is associated with a reduced risk of mortality in patients with diabetes hospitalised for COVID-19. Diabetes Metab 2020; Dec 10;101216. doi: 10.1016/j.diabet.2020.101216. [Online ahead of print].

Metformin is a first-line treatment for type 2 diabetes, one of the most common comorbidities linked to the severity of COVID-19. Historically, metformin has been studied as an agent with potential antimicrobial and immunosuppressive effects, demonstrating positive results against hepatitis B virus, tuberculosis, malaria, Legionella pneumonia, and Zika virus.1 The action of metformin on mitochondrial ROS/Ca2+ release-activated Ca2+ channels and IL-6 cascade has been theorized to mitigate the proinflammatory and prothrombotic processes of COVID-19. Additionally, researchers have observed metformin-producing antifibrosis effects in the lungs.2,3 Based on these mechanisms, it is possible metformin is useful in attenuating COVID-19 severity.

Lalau et al evaluated patients from the French nationwide CORONADO study to determine if prior metformin use was associated with improvement in prognosis for patients with diabetes who were hospitalized for COVID-19. The CORONADO study included patients hospitalized for COVID-19 from March 10, 2020, to April 10, 2020, at 68 French centers. Patients were included in the Lalau et al study if they had diabetes and had been admitted to a COVID-19 unit with confirmed COVID-19 diagnosis. The primary outcome was a composite of intubation or death within seven days of hospital admission. Secondary endpoints included the composite endpoint at 28 days of hospitalization and intubation, and death individually at seven and 28 days of hospitalization. Propensity scores were calculated and used during data analysis to minimize bias. The authors included 2,449 patients in the analysis (1,496 took metformin before hospitalization, 953 did not). Patients who took metformin were more likely to be younger and male, more likely to have a shorter duration of diabetes and higher hemoglobin A1c, and less likely to use insulin or experience complications from diabetes.

Patients who took metformin experienced a longer period between symptom onset and hospitalization (six days vs. four days) and reported more frequent symptoms related to COVID-19. There was no difference in patients who experienced the primary composite outcome for metformin non-users and metformin users (276 vs. 419, respectively; P = 0.6134). However, metformin users were less likely than non-users to experience the composite endpoint at hospital day 28 (488 vs. 369; P = 0.0023). Metformin users were less likely to die by hospital day 7 (122 vs. 153; P < 0.0001) and less likely to die by hospital day 28 (239 vs. 273; P < 0.0001). Interestingly, metformin users were more likely to be intubated by hospital day 7 (316 vs. 140; P = 0.0001) and by hospital day 28 (328 vs. 149; P = 0.0001).

The authors concluded prior use of metformin was associated with a lower rate of the composite endpoint (intubation and death) and a lower rate of death within 28 days of hospitalization for patients with diabetes.

COMMENTARY

This study adds to the current body of evidence on metformin and COVID-19 outcomes. The authors of other observational studies have reported lower hospital mortality from metformin,4 but some did not find this association.5-8 Many of these other studies did not include body mass index (BMI) as a covariate or the sample sizes were smaller. Lalau et al included BMI as well as other key variables in developing propensity scores and recruited more patients. Several questions remain about the effects of metformin on COVID-19, including optimal dose and duration of metformin to provide protective effects, whether metformin treatment should be administered in the hospital, and whether metformin effects on COVID-19 can be generalized to all patients regardless of diabetes diagnosis. Still, practitioners may benefit from an awareness of the apparent protective effects of prior metformin use against COVID-19-related death for hospitalized patients with diabetes, despite a possible increase in symptoms related to COVID-19.

REFERENCES

  1. Malik F, Mehdi SF, Ali H, et al. Is metformin poised for a second career as an antimicrobial? Diabetes Metab Res Rev 2018;34:e2975.
  2. Menendez JA. Metformin and SARS-CoV-2: Mechanistic lessons on air pollution to weather the cytokine/thrombotic storm in COVID-19. Aging 2020;12:8760-8765.
  3. Kheirollahi V, Wasnick RM, Biasin V, et al. Metformin induces lipogenic differentiation in myofibroblasts to reverse lung fibrosis. Nat Commun 2019;10:2987.
  4. Luo P, Qiu L, Liu Y, et al. Metformin treatment was associated with decreased mortality in COVID-19 patients with diabetes in a retrospective analysis. Am J Trop Med Hyg 2020;103:69-72.
  5. Cheng X, Liu YM, Li H, et al. Metformin is associated with higher incidence of acidosis, but not mortality, in individuals with COVID-19 and pre-existing type 2 diabetes. Cell Metab 2020;32:537-547.e3.
  6. Do JY, Kim SW, Park JW, et al. Is there an association between metformin use and clinical outcomes in diabetes patients with COVID-19? Diabetes Metab 2020; Nov 4;S1262-3636(20)30159-2. doi: 10.1016/j.diabet.2020.10.006. [Online ahead of print].
  7. Pérez-Belmonte LM, Torres-Peña JD, López-Carmona MD, et al. Mortality and other adverse outcomes in patients with type 2 diabetes mellitus admitted for COVID-19 in association with glucose-lowering drugs: A nationwide cohort study. BMC Med 2020;18:359.
  8. Gao Y, Liu T, Zhong W, et al. Risk of metformin in patients with type 2 diabetes with COVID-19: A preliminary retrospective report. Clin Transl Sci 2020;13:1055-1059.