Diabetes Distilled: Metformin and COVID-19 mortality risk

The search continues for drugs that may reduce the risk of serious disease and mortality in those with COVID-19, particularly those with pre-existing diabetes and obesity, two conditions that are known to involve chronic inflammation and which are significant risk factors for poor outcomes with COVID-19.

Metformin is widely prescribed as first-line glucose-lowering therapy in type 2 diabetes and was also used in people with obesity in the diabetes prevention studies. It is known to decrease inflammation and pro-inflammatory cytokine levels in those with obesity and in those with type 2 diabetes, and some studies have suggested the reduction in inflammation effects may be greater in females.

In this nationwide, retrospective analysis of a US insurance claims database in 6256 people with type 2 diabetes or BMI >25 kg/m², the primary aim was to identify whether pre-treatment with metformin (n=2333) had any impact on prognosis in people who developed COVID-19 and, secondly, to identify whether previously proposed sex differences in effects could be replicated.

Anonymised claims data for those with type 2 diabetes or obesity admitted to hospital with PCR-confirmed COVID-19 during the first half of 2020 were identified. Those with type 1 diabetes were not included. The primary outcome was in-hospital mortality (other outcomes such as intubation and ventilator use were not available from this database). Of the total cohort, 3302 (just over 50%) were female and 2333 were prescribed metformin prior to their COVID-19 infection. Metformin pre-treatment was associated with significantly decreased mortality in women, with a hazard ratio (HR) of 0.785 (95% confidence interval [CI], 0.650–0.951), but not in men (HR, 0.957; 95% CI, 0.82–1.14). There was no significant association between metformin use and mortality in the cohort as a whole.

Potential mechanisms by which metformin may result in lower mortality are discussed, including reduction of levels of TNF-alpha and other inflammatory cytokines such as IL-6, and boosting levels of the beneficial IL-10; these effects were already known to be greater in females in some studies. The authors propose several possible mechanisms for the sex-specific effect they identified, including increased inhibition of mast cell activation and increased ACE2 expression; changes to the ACE2 receptor shape resulting in decreased binding by SARS-CoV-2; and increased IL-10 in females.

The authors conclude that their study appears to support the preventative use of metformin prior to contracting COVID-19 to help reduce severity of the disease in women, but they warn there may still be residual confounding and that prospective studies are needed to confirm these findings.

Analysis

In an accompanying comment, Dardano and Del Prato (2021) urge caution in interpreting these findings. They highlight small differences between the metformin and non-metformin cohorts in this study, including a higher proportion aged <75 years and a lower prevalence of cardiovascular disease, heart failure, chronic kidney disease and end-stage renal disease in the metformin-treated group; all of these factors may impact mortality risk in COVID-19. They also highlight that there was no way to identify whether those prescribed metformin actually adhered to the drug.

Previously, Lalau et al (2020) evaluated the effects of metformin treatment prior to COVID-19 infection in a post hoc analysis of the observational CORONADO study of outcomes in those with diabetes who were admitted to hospital with COVID-19 early in the pandemic in France. There was no difference in the primary outcome of intubation and/or death within 7 days of admission between the nearly 1500 treated with metformin compared to the 953 without metformin; however, there was a significantly lower death rate at 7 days, which persisted to 28 days, in those treated with metformin. Metformin use, therefore, appeared to reduce the risk of COVID-19 mortality in both men and women with type 2 diabetes in this study.

Prospective studies are needed to identify whether metformin has any effect on preventing COVID-19, to identify the duration and optimal dose of metformin treatment required to accrue benefits and, thus, whether there is value in starting metformin treatment when people test positive, in order to reduce the severity of the subsequent disease and improve in-hospital prognosis. Whether treatment should be continued in hospital, when possible, and whether those without type 2 diabetes may also gain benefit also require further study.

The search is ongoing for cheap, effective drugs that, if taken by those with type 2 diabetes or obesity before or during COVID-19 hospitalisation, will make a significant impact on serious disease or death. In some observational studies, DPP-4 inhibitors and statins have also been associated with lower COVID-19 mortality (Scheen, 2020; Zhang et al, 2020). However, until prospective studies are published, changes in prescribing practice are felt to be premature.

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