A common diabetes medication could offer significant protection against Long COVID for millions of overweight and obese individuals, according to a large-scale UK study that analyzed real-world data from over 624,000 patients.
The retrospective analysis, published in Clinical Infectious Diseases, found that overweight or obese adults who initiated metformin within 90 days of COVID-19 infection experienced a 64% reduction in their likelihood of developing Long COVID compared to those who did not receive the medication.
Real-World Evidence from UK Primary Care Data
Researchers from University College London analyzed anonymized primary care data from the UK's Clinical Practice Research Datalink Aurum database, which covers nearly 25% of England's population. The study included 624,308 adults with clinically validated overweight or obesity (BMI ≥25 kg/m²) who were diagnosed with COVID-19 between March 2020 and July 2023.
Of these patients, 2,976 with an average age of 50 years initiated metformin within three months after their COVID-19 diagnosis. The study employed a statistical method called "sequential target trial emulation" to simulate the design of a randomized controlled trial while using observational data.
Substantial Risk Reduction Across Patient Groups
The intention-to-treat analysis revealed a hazard ratio of 0.36 (95% CI, 0.32-0.41), representing the 64% risk reduction. This translates to an absolute risk difference of -12.58% at one year, suggesting that approximately eight overweight or obese individuals need to be treated with metformin to prevent one Long COVID case.
"These findings emphasize the role of using metformin in early COVID-19 treatment plans for overweight/obesity individuals to help lower the risk of developing PCC," the researchers wrote.
The protective effect remained consistent across multiple subgroups, including different age groups, genders, BMI categories, and diabetes status. Notably, 51.9% of metformin users in the study had type 2 diabetes. The association also held during periods dominated by both Delta and Omicron variants.
Mechanisms and Clinical Implications
While metformin is best known for its glucose-lowering effects in diabetes treatment, the drug demonstrates powerful anti-inflammatory properties that may contribute to its protective effects against Long COVID. The medication has been shown to activate AMP-activated protein kinase (AMPK), a key cellular energy sensor that may interfere with viral replication, though the precise mechanisms remain unclear.
"Beyond its glucose-lowering effects, metformin has anti-inflammatory properties," the study authors noted. "These properties contribute to its protective effects against conditions such as cardiovascular disease, chronic kidney disease, and polycystic ovary syndrome."
Study Limitations and Future Directions
The researchers emphasized that as an observational study, their results indicate association but cannot prove causation. The findings build upon previous research, including the COVID-OUT randomized trial, which reported similar protective effects in overweight and obese individuals.
A negative control analysis revealed no association between metformin use and cancer risk (HR 1.13), supporting the robustness of the findings. However, the authors cautioned that the results may not apply to individuals with normal BMI.
Global Health Impact
With more than 1.9 million people in the UK (2.9% of the population) reported to have Long COVID as of March 2023, according to WHO definitions, the potential for an inexpensive, widely available medication to reduce this burden could have significant public health implications.
Long COVID, officially termed post-COVID-19 condition by the WHO, encompasses over 200 possible symptoms including persistent fatigue, cognitive impairment, shortness of breath, and insomnia. The condition is defined as symptoms lasting at least two months, typically starting within three months of initial infection.
The researchers concluded that "further randomized controlled trials are needed to confirm the causal relationship between metformin use and its efficacy in treating PCC in overweight/obesity individuals."
