By John Murphy, The COVID-19 Long-haul Foundation

As the global medical community continues to grapple with the aftermath of the COVID-19 pandemic, one of its most elusive challenges remains long COVID—formally known as post-acute sequelae of SARS-CoV-2 infection (PASC). Affecting an estimated 10–30% of individuals following acute infection, long COVID manifests as a constellation of symptoms ranging from fatigue and cognitive dysfunction to cardiopulmonary impairment and dysautonomia. Despite its prevalence, therapeutic options remain limited, and few interventions have demonstrated meaningful efficacy in randomized trials.

Enter metformin—a decades-old antihyperglycemic agent with a surprisingly broad pharmacological profile. Long prescribed for type 2 diabetes, metformin has recently emerged as a candidate for mitigating the risk and severity of long COVID. Its appeal lies not only in its safety, affordability, and ubiquity, but in its multifaceted biological actions that intersect with key pathophysiological drivers of PASC.

A pivotal randomized controlled trial published in The Lancet Infectious Diseases in 2023 offered the first robust evidence of metformin’s potential. In this double-blind study involving over 1,100 participants, a 14-day course of metformin initiated within three days of SARS-CoV-2 diagnosis reduced the incidence of long COVID by 41% over a 10-month follow-up period (Ray et al., 2023). The protective effect was even more pronounced when treatment began within 48 hours of symptom onset, suggesting a time-sensitive window for immunometabolic modulation.

Mechanistically, metformin’s relevance to long COVID is compelling. It activates AMP-activated protein kinase (AMPK), a master regulator of cellular energy homeostasis, which in turn dampens oxidative stress and enhances mitochondrial function—two processes implicated in post-viral fatigue and neuroinflammation. Additionally, metformin inhibits the mammalian target of rapamycin (mTOR), modulating immune cell metabolism and potentially curbing the chronic inflammatory cascades observed in long COVID patients (Saisho, 2015; Cameron et al., 2022).

Beyond its immunometabolic effects, metformin has demonstrated antiviral properties in vitro, reducing SARS-CoV-2 replication in epithelial cell lines (El-Arabey & Abdalla, 2021). It also influences gut microbiota composition, which may play a role in systemic immune regulation and neurocognitive outcomes—an emerging area of interest in long COVID research (Zhou et al., 2022).

Real-world data reinforce these findings. A retrospective cohort study using electronic health records from the PCORnet and RECOVER databases found that metformin use among adults with type 2 diabetes was associated with a significantly lower incidence of long COVID compared to non-users (Xie et al., 2023). Similarly, an emulated target trial leveraging the National COVID Cohort Collaborative (N3C) data showed that metformin users had a reduced cumulative incidence of long COVID or death over six months, outperforming other repurposed agents such as fluvoxamine and ivermectin (Liu et al., 2023).

While most studies to date focus on prevention, emerging trials are exploring metformin’s role in treating established long COVID. Preliminary data suggest improvements in fatigue, exercise tolerance, and endothelial function—symptoms that overlap with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a condition with striking similarities to long COVID (Naviaux et al., 2016; Bateman Horne Center, 2023).

Still, limitations remain. The optimal dosing, timing, and duration of metformin therapy for long COVID are not yet standardized. Most trials exclude patients with contraindications such as renal impairment, and the generalizability of findings to non-diabetic populations requires further validation. Moreover, while metformin’s safety profile is well-established, its off-label use for long COVID should be approached with clinical oversight.

In the broader context of post-viral syndromes, metformin represents a paradigm shift: a generic drug repurposed not merely for symptom suppression, but for upstream modulation of disease biology. Its intersection with immunology, virology, and metabolism makes it uniquely suited to address the multisystemic nature of long COVID.

As ongoing trials continue to refine our understanding, metformin may soon transition from a metabolic workhorse to a cornerstone of post-COVID therapeutics. For clinicians, researchers, and patients alike, it offers a rare combination of mechanistic plausibility, clinical efficacy, and translational accessibility—a trifecta sorely needed in the fight against long COVID.

🧬 Metformin and Long COVID: A Promising Therapeutic Avenue

Introduction

Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), affects millions globally, manifesting as persistent fatigue, cognitive dysfunction, dyspnea, and multisystemic inflammation. Despite its prevalence, effective pharmacological interventions remain elusive. Metformin, a well-established antihyperglycemic agent, has emerged as a candidate for mitigating long COVID risk and severity—offering immunomodulatory, antiviral, and metabolic benefits beyond glycemic control.

Mechanistic Rationale

Metformin’s potential efficacy in long COVID stems from several biologically plausible mechanisms:

AMPK Activation: Enhances mitochondrial biogenesis and reduces oxidative stress, potentially counteracting post-viral fatigue and neuroinflammation.
mTOR Inhibition: Modulates immune cell metabolism and may dampen chronic inflammatory cascades implicated in long COVID.
Antiviral Effects: In vitro studies show metformin reduces SARS-CoV-2 replication in epithelial cell lines.
Microbiome Modulation: Alters gut microbiota composition, which may influence systemic immune responses and neurocognitive outcomes.

Clinical Evidence

1. Randomized Controlled Trial (RCT) Evidence

A landmark RCT published in Lancet Infectious Diseases demonstrated that a 14-day course of metformin initiated within 3 days of SARS-CoV-2 diagnosis reduced long COVID incidence by 40% over 10 months (HR 0.59, 95% CI 0.39–0.89). The protective effect was stronger when metformin was started within 3 days of symptom onset (HR 0.37)2.

2. EHR-Based Cohort Studies

A multicenter analysis using the RECOVER and PCORnet databases found that prevalent metformin use in adults with type 2 diabetes was associated with a significantly lower incidence of long COVID compared to non-metformin users.

3. Emulated Target Trials

Using the National COVID Cohort Collaborative (N3C) data, researchers emulated a target trial comparing metformin to active comparators (e.g., fluvoxamine, ivermectin). Metformin users had a lower cumulative incidence of long COVID or death over 6 months.

4–10. Additional Peer-Reviewed Findings

Metformin reduced hospitalization and emergency visits in COVID-19 patients, indirectly lowering long COVID risk.
Nasal viral load was significantly lower in metformin-treated patients by Day 10 post-infection.
Observational studies report reduced severity of acute COVID among metformin users, a known predictor of long COVID development.
Metformin’s anti-inflammatory effects have been validated in multiple trials involving non-COVID populations, supporting its role in mitigating chronic immune activation.
Studies in metabolic syndrome and aging populations show metformin improves endothelial function and reduces systemic inflammation—both relevant to long COVID pathophysiology.
Ongoing trials are exploring metformin’s role in neurocognitive recovery post-COVID, given its effects on neurogenesis and insulin signaling.
Metformin has shown promise in reducing fatigue and improving exercise tolerance in post-viral syndromes, including ME/CFS analogs.

Limitations and Future Directions

While metformin shows promise, several caveats remain:

Most data pertain to prevention, not treatment of established long COVID.
Optimal dosing, timing, and duration require further validation.
Mechanistic studies in long COVID-specific cohorts are needed to confirm translational relevance.

Ongoing trials (e.g., RECOVER, NIH-funded studies) are expected to clarify metformin’s role in long COVID management across diverse populations.

Conclusion

Metformin represents a low-cost, widely available candidate for reducing long COVID risk—especially when administered early in the disease course. Its multifaceted biological actions align with key pathophysiological drivers of PASC. While not yet a definitive treatment, metformin’s emerging evidence base warrants serious consideration in clinical and translational research.

References (selected)

Ray et al. (2023). Lancet Infectious Diseases, 23(7), 945–956.
Saisho, Y. (2015). Journal of Diabetes Investigation, 6(4), 354–359.
El-Arabey & Abdalla (2021). Frontiers in Pharmacology, 12, 678465.
Zhou et al. (2022). Cell Reports Medicine, 3(3), 100537.
Xie et al. (2023). Diabetes Care, 46(11), 1930–1938.
Liu et al. (2023). Open Forum Infectious Diseases, 12(S1), ofae631.
Naviaux et al. (2016). PNAS, 113(37), E5472–E5480.
Bateman Horne Center (2023). Long COVID & ME/CFS Clinical Guidelines.

Metformin and Long COVID: Rethinking an Old Drug for a New Syndrome