Metformin is the most commonly prescribed first-line treatment for Type 2 diabetes mellitus (T2DM) and is an inexpensive, readily accessible medication with a well-known safety profile.
Metformin was explored as a promising drug repurposing candidate for the prevention and treatment of severe COVID-19 and Long COVID-19 due to its hypothesized anti-inflammatory and even antiviral properties.
Several randomised trials have evaluated the use of metformin during the acute phase of COVID-19 among a broad at-risk population, summarized in a recent meta-analysis. The analysis concludes that metformin has little to no effect on mortality, some (but uncertain) effect on severe COVID-19 and a potential effect in reducing the risk of Long COVID. This is in contrast to most results from observational studies and meta-analyses thereof. There are several possible explanations: First, people with T2DM were largely excluded from the randomized trials since randomising such patients to metformin or placebo is likely unfeasible and unethical. T2DM is an important risk factor for severe COVID-19 and appropriate blood glucose control with metformin (or other antidiabetic treatments) could itself impact the course of the disease. Second, most patients in observational studies were admitted to hospital - while patients from the randomized trials were recruited in the primary care setting, presenting with non-severe COVID-19. Third, most observational studies used a prevalent-user design comparing people receiving (long-term) metformin. This design is addressing a causal question of “being on metformin vs not being on metformin”, which cannot be translated to clinical decision-making nor how a randomized trial investigating the effect of metformin on COVID outcomes would be designed. It also may introduce bias under certain circumstances. Fourth, other design-related and confounding biases in the observational studies could be an explanation.
Following the target trial emulation framework, we aim to estimate the effect of starting metformin versus not starting metformin in the primary care setting, among adults living with T2DM in England, on COVID-19 related hospitalisations or death, SARS-CoV-2 infection, and Long COVID diagnoses, and explore different study design approaches.
Details of the purpose and any published outputs from this project can be found at the link above.
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