Metformin, a widely prescribed medication, is primarily recognized for its role in managing type 2 diabetes. It helps regulate blood sugar levels, particularly in individuals who are overweight. As the COVID-19 pandemic unfolded, scientific interest grew regarding metformin’s potential to treat or prevent severe effects of the virus, leading to extensive research beyond glucose control.
Metformin’s Potential Role in COVID-19
The investigation into metformin’s relevance for COVID-19 stemmed from its established properties beyond diabetes management. Metformin has demonstrated anti-inflammatory effects, relevant because severe COVID-19 often involves an overactive immune response known as a “cytokine storm.” It can influence cellular pathways to dampen excessive inflammatory reactions.
COVID-19 can disrupt glucose metabolism, leading to elevated blood sugar levels even in individuals without pre-existing diabetes. Metformin’s ability to improve insulin sensitivity and reduce glucose production in the liver could counteract these metabolic disturbances, which are associated with worse outcomes in COVID-19 patients. It may also influence cellular entry of the SARS-CoV-2 virus by activating AMP-activated protein kinase (AMPK) and altering the ACE2 receptor, a key binding site for the virus.
Research Findings and Clinical Evidence
Numerous studies, including both observational analyses and randomized controlled trials, have explored metformin’s impact on COVID-19 outcomes. Several retrospective analyses noted improved clinical outcomes among type 2 diabetes patients who were already taking metformin when hospitalized with COVID-19. These benefits included reduced admissions to intensive care and lower mortality rates in subgroups receiving metformin treatment. One meta-analysis found a 0.62 odds ratio for mortality in metformin users compared to non-users within this population.
Beyond patients with diabetes, research has also investigated metformin’s effects in broader populations. A large randomized controlled trial involving 1,300 adults, many without type 2 diabetes, found that metformin reduced the subsequent diagnosis of long COVID by over 40% (hazard ratio 0.59). This effect was even more pronounced, over 60%, if metformin treatment began within four days of symptom onset (hazard ratio 0.37). Another study indicated that metformin use was associated with a lower incidence of death or post-acute sequelae of SARS-CoV-2 (PASC) in adults with type 2 diabetes.
While some evidence suggests metformin might reduce hospital admissions related to COVID-19, the certainty of this evidence remains low to very low across different analyses. A systematic review of randomized controlled trials found metformin had little to no impact on mortality, with a risk ratio of 0.76 (95% CI 0.30 to 1.90). Effects on hospital admission were also uncertain, with a risk ratio of 0.74 (95% CI 0.28 to 1.95). However, the same review indicated that metformin decreased the incidence of long COVID, with a risk ratio of 0.6 (95% CI 0.4 to 0.9), based on low certainty evidence from a single trial.
Current Recommendations and Considerations
Based on current evidence, medical recommendations regarding metformin for COVID-19 focus primarily on specific patient populations. The Canadian Post-COVID-19 Condition Collaborative suggests using short-course metformin in adults with acute COVID-19, particularly for those who are overweight or obese. This recommendation is conditional and based on low certainty evidence, drawing from trials where participants had a body mass index (BMI) of 25 or higher (or 23 for individuals identifying as Asian or Latino) and presented with symptoms for fewer than seven days.
It is important to understand that metformin is not a standalone treatment for everyone with COVID-19 and should always be used under medical supervision. Doses used in trials varied, with some studies employing 750 mg twice daily for 10 days, while others used an escalating dose regimen up to 1000 mg in the evening by day 6. Potential side effects, such as gastrointestinal issues, can be mitigated by starting with a lower dose, for example, 250 mg twice daily. While metformin is considered safe, it is important to discuss its use with a healthcare provider, considering existing medical conditions or other medications.