Health & Science
Metformin: A Pharmaceutical Dark Horse in the Face of COVID-19
An old drug with new tricks?
In 1957, Dr. Jean Strene, a French physician, discovered that Gallega officinalis, a herbal plant in medieval Europe, was capable of treating diabetes effectively. Goats hate this plant, so it is also colloquially known as “goat’s rue”. The herbal plant contains a unique biguanide compound, which is what we commonly know today as metformin, the anti-diabetic medication.
Metformin is an orally administered blood glucose lowering agent for non-insulin dependent diabetes mellitus (i.e., T2DM) by decreasing the cells’ insulin resistance and improving insulin sensitivity. Presently, it is the most commonly prescribed anti-diabetic medication worldwide, being the most preferred first-line of management for T2DM, after lifestyle modification.
Given the recent pandemic, scientists and physicians are looking at drugs — both new and old — that may stand a chance against the deadly virus. Surprisingly, metformin has been making rounds not only for its glucose-lowering abilities, but also its anti-inflammatory properties, which are the main points of discussion in this article.
What do we know so far? 💡
As metformin is widely known for its anti-hyperglycemic effects, let’s look at some of its mechanisms:
- Decreases glucose production
By inhibiting mitochondrial enzyme (mGDP), which decreases gluconeogenesis (the generation of glucose from non-carbohydrate substances) in the liver. Inhibition of this enzyme activates AMP-activated protein kinase (AMPK enzyme), further decreasing glucose production. - Enhances insulin sensitivity
Metformin inhibits SHIP2 (a phosphatase enzyme abundantly present in skeletal muscles); by doing so, it induces glucose uptake, while enhancing insulin sensitivity. Recent studies also postulated that metformin may decrease the occurrence of diabetic nephropathy (kidney injury as a complication of diabetes) by inhibiting oxidative stress via AMPK activation in a T2DM rat model, while inhibiting SHIP2 activity. These mechanisms work together to prevent podocyte apoptosis (the death of specialized cells in the kidney). - Increases glucose utilization
By influencing the host’s microbiome composition, metformin is capable of modifying the composition of intestinal microbiota groups, which is linked to a reduction in both hyperglycemia and hyperlipidemia in insulin-resistant mice models. Additionally, metformin increases the production of intestinal GLP-1, an incretin hormone that regulates appetite and enhances the release of insulin. - Suppresses inflammation
Hyperglycemia predisposes one’s body to inflammation via inducing oxidative stress. By regulating one’s blood glucose levels using metformin, it invariably reduces inflammatory events from occurring.
When I first saw headlines reporting the use of metformin reducing COVID-19 mortality, I had an inkling it might be related to some form of inflammatory modulation, as COVID-19 is notorious for inducing cytokine storms leading to multi-organ failure. If that could be managed (or prevented), logically it would save COVID-19 patients from their demise. Additionally, the use of dexamethasone (a type of steroid medication) has been shown to reduce mortality in patients with severe COVID-19 disease, which further strengthened the notion surrounding immunomodulation.
As metformin improves glycemic control by maintaining normoglycemia, it abates some of the pathogeneses that contribute to COVID-19 disease severity, indirectly decreasing mortality. On the other hand, it is arguable that diabetic patients on metformin might be in their early stages of the disease; hence, they have less severe symptoms and would sustain fewer complications from COVID-19. In order to unravel the extent of metformin’s impact on diabetic patients with COVID-19, further investigations should be carried out.
Leaving that thought-provoking possibility aside, let’s look at the immunomodulatory effects of metformin.
How metformin mitigates COVID-19 💊
Several studies have reported lower mortality associated with COVID-19 patients with T2DM using metformin. A retrospective study in Alabama, America, analyzed over 25,000 participants of various ethnicities, observed a significant 67% reduction in mortality in comparison to COVID-19 patients with T2DM without metformin use. This finding is further supported by a meta-analysis, revealing its benefits of decreasing mortality associated with metformin use. Interestingly, a previous meta-analysis investigating the outcomes of diabetic patients with sepsis (a life-threatening condition secondary to a dysregulated immune response to an infection that damages tissues and organs) also reported similar findings.
With these results in mind, repurposing metformin in COVID-19 patients no longer seems like a far-fetched idea. However, the extent of mortality benefits from metformin use in non-diabetic COVID-19 patients, as well as repurposing it for its anti-inflammatory properties, still warrant further investigation.
To date, the following is a list of metformin’s protective properties that may potentially mitigate COVID-19 disease:
- ACE2 receptor phosphorylation via the AMPK pathway
As metformin inhibits mGDP mitochondrial enzymes, it indirectly activates AMPK enzymes, leading to conformational changes of ACE2 receptors. These changes are known to disrupt the RBD (receptor binding domain) of SARS-CoV-2, which in turn inhibits its binding to the ACE2 receptors, overall reducing viral entry. Although the activation of AMPK enzymes also upregulates ACE2, it is unlikely to worsen infectivity due to the ACE2 conformational changes. Besides, a higher expression of ACE2 also prevents an imbalanced RAAS, avoiding the adverse inflammatory and fibrotic pathways. - Inhibition of the mTOR (the mechanistic target of rapamycin) signaling cascade
According to previous research on MERS-CoV coronavirus, the mTOR pathway plays a crucial role in its pathogenesis. It has been observed that inhibition of this pathway stops MERS-CoV from replicating in vitro. Coincidentally, metformin is able to indirectly inhibit this pathway via AMPK activation. Given its mechanism of action (and that both MERS-CoV and SARS-CoV-2 are very similar, belonging to the same family, Coronaviridae), metformin may play a therapeutic role in COVID-19. - Clinically reduces inflammation
With increasing recognition of metformin’s anti-inflammatory properties, investigations revealed that metformin is capable of suppressing markers of inflammation such as NLR (neutrophil-lymphocyte ratio), which is a prognostic indicator for COVID-19 severity, is used to detect early sepsis and systemic inflammation in ICU patients. Although neutrophils (a specific type of white blood cell) make up the first line of defense against infections, an uncontrolled neutrophilic response may trigger inflammatory cascades, leading to fatal outcomes. - Reduction of NETosis
Neutrophils kill microbes by releasing NETs (neutrophil extracellular traps) that contain compounds associated with inflammation. Despite it being a beneficial response against microbes, uncontrolled NETosis may propagate cytokine storms, microvascular thrombosis and ARDS, which are features observed in severe COVID-19 disease. With metformin use, the occurrence of NETosis is significantly reduced in patients with diabetes. - Modulates immune cells
Metformin increases the production of specific white blood cells: M2 macrophages and Treg cells (regulatory T cells). Treg cells are dysregulated in patients with diabetes, which result in uncontrolled immune responses and elevated T cell proliferation and cytokine release, contributing to inflammation and autoimmunity (a condition where the immune system attacks the body’s own tissues and organs). M2 macrophages are specialized immune cells that mainly secrete anti-inflammatory cytokines such as IL-10, IL-1ra and TGF-beta, which collectively reduce inflammation. Metformin has been shown to increase M2 macrophage polarization while decreasing the production of M1 macrophages (which are mainly associated with inflammation) in wound healing studies. - Downregulates pro-inflammatory gene expression
Metformin suppresses the transcription activity of NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells, a protein complex involved in the expression of pro-inflammatory genes that produce cytokines); this has been shown to significantly reduce levels of TNF-alpha (tumor necrosis factor) and other inflammatory mediators (i.e., IL-6, IL-8 and IL-1beta). - Reduces oxidative stress
As mentioned previously, hyperglycemia induces ROS production and metformin does the opposite: it suppresses mitochondria-induced ROS by inhibiting mitochondrial complex 1. This also disrupts macrophages from releasing inflammatory IL-6, as ROS is required to activate this mechanism. A primary research highlights that metformin provides antioxidative protective effects regardless of glycemic control, hinting at the potential benefits of adding metformin to T1DM treatment, as well as the management of autoimmune diseases.
Although metformin has a plethora of complex mechanisms of action that are capable of influencing multiple cell signaling pathways, it is assuring to note that they have been extensively researched prior to the pandemic. Presently, metformin is recognized for its therapeutic potential in managing diseases other than diabetes, such as PCOS (polycystic ovarian syndrome) and psoriasis (an autoimmune disease affecting the skin). For the past decade, it has also been clinically trialed as an adjunct in cancer treatment.
Repurposing existing drugs is not as uncommon as we think. Needless to say, thorough studies must be done rigorously to ensure its therapeutic efficacy, short-term and long-term adverse effects, as well as to elucidate its molecular mechanisms in SARS-CoV-2.
As a matter of fact, several randomized clinical trials are underway as we speak. Though it will take some time to procure substantial data, currently metformin is not approved for hospital use to manage patients with COVID-19. Still, knowing this brings hope — as one of these “old” drugs may very well be the next dark horse in our battle against COVID-19.
For now, get vaccinated, follow national healthcare guidelines, wash your hands, and don’t start taking metformin without your doctor’s advice!😉
Take care and stay safe.❤️
Love, Alice
