Metformin protective against death in individuals with diabetes, COVID-19?

Metformin use in individuals with diabetes who contracted COVID-19 was associated with a dramatic reduction in mortality risk, a study has shown.

 

“This beneficial effect remained even after correcting for age, sex, race, obesity, hypertension, chronic kidney disease (CKD), and heart failure (HF),” said Dr Anath Shalev from the University of Alabama at Birmingham, Alabama, US, in a press release. “[W]hile these factors might contribute to a worse outcome, they cannot fully account for it.”

 

Records of 25,326 individuals with diabetes who were tested for COVID-19 between February 25, 2020 and June 22, 2020 were retrospectively analysed. Of these, 604 were COVID-19 positive. [Front Endocrinol (Lausanne) 2021;doi:10.3389/fendo.2020.600439]

 

Despite the significantly high mortality risk tied to diabetes (odds ratio [OR], 3.62; p<0.0001), metformin use prior to COVID-19 diagnosis was independently associated with reduced mortality after adjusting for confounders (OR, 0.33; p=0.021).

 

“These suggest that, while diabetes is an independent risk factor for COVID-19-related mortality, this risk is dramatically reduced in subjects taking metformin prior to COVID-19 diagnosis, raising the possibility that metformin may provide a protective approach in this high-risk population,” Shalev said.

 

Metformin use in COVID-19-positive men was analysed to establish whether the effect might be driven by the female sex, based on evidence showing that women specifically benefit from metformin. [MedRxiv 2020;doi:10.1101/2020.06.19.20135095] A lower likelihood of death was found in this subgroup (OR, 0.28; p=0.029).

 

Despite this benefit, male sex remains an independent mortality risk factor in diabetes, potentially due to differences in fat distribution, sex steroid concentrations, circulating pro-inflammatory cytokine levels, and innate and adaptive immune response to viral infections. [Diabetes 2020;69:1857-1863; Nat Rev Immunol 2016;16:626-638]

 

A similar mortality benefit was observed with metformin use after excluding individuals with CKD or chronic HF, which are contraindications for metformin (OR, 0.17; p=0.023). “This makes any potential confounding effects from skewing metformin users toward healthier subjects without these additional comorbidities, very unlikely,” they added.

 

Of note was the high percentage of African-Americans who tested positive for COVID-19 (52 percent), translating to a high chance of contracting COVID-19 compared with Whites (OR, 2.6; p<0.0001). “[This implies that being African-American may] primarily be a risk factor for contracting COVID-19, rather than for mortality … This suggests that any racial disparity observed is likely due to exposure risk and external socioeconomic factors, including access to proper healthcare,” Shalev said.

 

This finding is relevant as African-Americans across the US have been disproportionately affected by COVID-19, and the prevalence of diabetes among them is high. [New Engl J Med 2020;382:2534-2243; Int J Environ Res Public Health 2020;doi:10.3390/ijerph17124322; Clin Infect Dis 2021;72:703-706]

 

The protective effect of metformin may be due to its anti-inflammatory and antithrombotic effects, noted the researchers. [Circ Res 2016;119:652-665; Br J Pharmacol 2011;162:1498-1508; Sci Rep 2016;doi:10.1038/srep36222] “[E]xcessive inflammatory responses (eg, cytokine storm), as well as disseminated thromboembolic events, have been recognized as deadly complications of COVID-19,” they said. “It is therefore tempting to speculate that, by exerting some of its antifibrinolytic activities and inhibiting inflammatory cytokines … suspected to play a role in the immune response to COVID-19, metformin might improve outcome.”

 

These findings underline the value of adhering to diabetes treatment and prevention protocols, and not delaying or discontinuing metformin, especially during the pandemic wherein diabetic individuals are highly at risk. “[Metformin] might not only help with diabetes … but also reduce the risk of adverse outcomes in case of a COVID-19 infection,” they added.

 

“[Moreover,] since similar results have been obtained in different populations … [our study] suggests that the observed reduction in mortality risk associated with metformin use in subjects with type 2 diabetes and COVID-19 might be generalizable,” Shalev noted. [Am J Trop Med Hygiene 2020;103:69-72; Diabetologia 2020;63:1500-1515; Obes Med 2020;doi:10.1016/j.obmed.2020.100290]

 

Further exploration is warranted to ascertain the protective effect of metformin against COVID-19, re-evaluate its benefit-risk profile, and determine whether its indications should be adjusted in the face of the ongoing pandemic.