Metformin - a wonder drug with ANTI-diabetes, aging, cancer, Covid, and influenza effects?

Another Examined deep dive.

Feb 22, 2025

A patient recently asked me if I would start him on a diabetes medication called metformin. I reviewed his chart. He did not have diabetes. I asked him why he wanted metformin. He replied that he had been reading a lot about metformin on his own. Diabetes prevention, antiviral effects, anti-aging effects, maybe longevity benefits. He’s also been keeping up with my Covidlandia series in which I’ve highlighted studies showing that metformin helps prevent long Covid. Like most of us he expects to get Covid again in the future. More importantly, he does actually have prediabetes. Metformin can be used to help prevent the full blown onset of type 2 diabetes.

We talked about how metformin is generally safe, cheap, and well-tolerated except for some common GI side effects. It commonly causes diarrhea, nausea, bloating, and loss of appetite, though these symptoms typically improve over days to weeks and can be minimized by taking the medication with food. More in depth information and clinical pearls can be found here.

I said sure. The prediabetes was sufficient. But what about the rest of the claims?

Metformin: from medieval herb to modern medicine

The story of metformin is a fascinating journey, from a medieval herbal remedy to what is now considered one of the most important medications of the modern era. This remarkable drug continues to surprise researchers with its diverse therapeutic potential beyond its primary use in diabetes treatment.

Ancient roots and modern discovery

The foundation of metformin lies in the humble French lilac (Galega officinalis), known in medieval Europe for treating diabetes-like symptoms. One of the plant's active compounds, guanidine, was later identified as responsible for its blood glucose-lowering properties. In the 1920s, researchers synthesized several guanidine derivatives, including dimethylbiguanide - what we now know as metformin. However, the discovery of insulin around the same time initially overshadowed these developments.

The modern chapter of metformin's story began in 1957 when French physician Jean Sterne conducted the first clinical trials and coined the name "Glucophage" (literally, "glucose eater"). Sterne's work demonstrated metformin's effectiveness in treating diabetes without the dangerous risk of severe hypoglycemia that accompanied other treatments. This remains one of the best features of the medicine.

Here’s a timeline I made with AI tools:

Mechanisms of action: a multi-talented compound

What makes metformin particularly interesting is its diverse mechanisms of action. The drug works through several pathways. For non-medical folks reading, the overall gist is fine, so don’t worry about memorizing the specifics:

The primary mechanism involves reducing the liver’s innate glucose production while improving insulin sensitivity and enhancing peripheral glucose uptake from the bloodstream and into cells.

However, recent research has revealed additional mechanisms, including modification of the gut microbiome, and activation of AMP-activated protein kinase (AMPK), a crucial cellular energy sensor.

Perhaps most intriguingly, metformin exhibits antiviral and anti-inflammatory properties through its inhibition of mitochondrial complex I. This reduces ATP production and alters cellular redox states, creating an environment less favorable for viral replication. The drug's activation of AMPK also suppresses mTOR signaling, further disrupting viral protein synthesis.

Nothing in pharmacology is ever simple it seems. You think a medicine works from point A to point B, but if you really dive in, you find most medicines work from point A to the rest of the alphabet.

Diabetes treatment (and prevention)

Metformin is still the first line medication recommended for treating type 2 diabetes several decades after it was first approved. It is sometimes used for diabetes prevention in those who are borderline.

Treatment

I’ll review this quickly, since not much is overlooked and pretty much everyone is on board with this metformin indication. Metformin is recommended as first-line therapy for type 2 diabetes due to its proven efficacy, safety profile, and long-term outcome data. It reduces HbA1c by 1-2%, decreases hepatic glucose production, and improves insulin sensitivity. The landmark UK Prospective Diabetes Study showed metformin reduces diabetes-related death by 42%, all-cause mortality by 36%, and heart attack risk by 39% compared to conventional treatment over the 10 years studied. Additionally, metformin is weight-neutral or promotes modest weight loss, has a low risk of hypoglycemia, is inexpensive, and may have anti-cancer properties. Long-term observational studies continue to support its cardiovascular benefits and safety profile.

Prevention of type 2 diabetes

There is some mixed evidence for using metformin to prevent type 2 diabetes. In the U.S. a staggering 38% of adults over 18 years of age have prediabetes; among those aged 65 years or older 49% have prediabetes. Earlier in my career (yikes, that’s been two decades already!) we used to use this more often. But this article published in the Journal of Family Practice sums up the nuance quite well:

To treat, or not? Studies have shown that interventions such as lifestyle modification and use of metformin by patients with prediabetes can decrease their risk for Type 2 Diabetes (T2D).⁵^,⁶ In the Diabetes Prevention Program (DPP) study, progression from prediabetes to T2D was reduced to 14% with lifestyle modification and 22% with metformin use, vs 29% with placebo.⁷
However, there is disagreement about whether to treat prediabetes, particularly with medication. Some argue that metformin is a safe, effective, and cost-saving treatment to prevent T2D and its associated health consequences.⁸ The current American Diabetes Association (ADA) guidelines suggest that metformin be considered in certain patients with prediabetes and high-risk factors, especially younger age, obesity or hyperglycemia, or a history of gestational diabetes.⁹ However, only an estimated 1% to 4% of adults with prediabetes are prescribed metformin.¹⁰
Others argue that treating a preclinical condition is not a patient-centered approach, especially since not all patients with prediabetes progress to T2D and the risk for development or progression of retinopathy and microalbuminuria is extremely low if A1C levels remain < 7.0%.¹¹ By this standard, pharmacologic treatment should be initiated only if, or when, a patient develops T2D, with a focus on intensive lifestyle intervention for high-risk patients in the interim.¹¹
Given the conflicting viewpoints, ongoing long-term studies on T2D prevention will help guide treatment decisions for patients with prediabetes

Beyond diabetes: expanding applications?

While metformin remains the first-line medication for type 2 diabetes management, its therapeutic potential extends far beyond glucose control. Current applications and research areas include:

Polycystic Ovary Syndrome (PCOS): Metformin has become a valuable tool in PCOS treatment, helping manage insulin resistance, improve ovulation, and reduce androgen levels.

Cancer prevention and treatment: Emerging research suggests potential anti-cancer properties, with studies investigating metformin's role in both prevention and as an adjunct to traditional cancer treatments. Since this statement is quite loaded, I’m going to let my subscription to UpToDate unpack it. Once again, sorry this is technically written:

Metformin — Metformin has been associated with reduced incidence of several types of cancer in patients with type 2 diabetes.
A systematic review and meta-analysis included 11 independent studies contributing 4042 cases of cancer and 529 deaths in patients with diabetes [187]. Both cancer incidence and cancer mortality were reduced by 30 percent among users of metformin. Reductions in the incidence of pancreatic and liver cancer as well as nonsignificant reductions for breast, colon, and prostate cancer were observed. There was a trend toward a dose-response relationship. In two subsequent meta-analyses in patients with diabetes, there was an association between metformin use and a decrease in colorectal cancer risk [188] and a decrease in risk of colorectal, liver, and lung cancers [189].
In an observational study of 4085 patients in the United Kingdom who used metformin for type 2 diabetes from 1994 to 2003, cancer incidence was 40 percent lower than among diabetic patients who did not take metformin (7.3 versus 11.6 percent) [185].
In a prospective study of 1353 patients with type 2 diabetes in the Netherlands, during 9.6 years of follow-up, cancer mortality was reduced in those who used metformin. [186].
In a registry-based case control study in the United Kingdom, metformin use was associated with a substantial decrease in pancreatic cancer risk among women but had no effect on cancer risk among men [190].
Among postulated mechanisms for such a benefit are the inhibition of cancer cell growth and suppression of HER2 overexpression and inhibition of mTOR [191-193]. Alternatively, these results may reflect increased risk due to use of other regimens for diabetes rather than decreased risk due to use of metformin.

The bold-faced emphasis on patients with diabetes was added by me.

What about anti-cancer effects in people without diabetes? A fair answer to this question could further balloon the word count here, so I’ll summarize in about 1 paragraph, and point you towards these references in Perplexity if you want a deeper dive.

Metformin has actually shown intriguing potential in cancer prevention and treatment for non-diabetic patients. Research has demonstrated promising results across various cancer types. In colorectal cancer, low-dose metformin reduced adenomas and polyps in non-diabetic patients after polypectomy. Studies in breast cancer showed that preoperative metformin use led to significant changes in cancer-related proteomic markers in overweight patients, while also helping control glucose levels in non-diabetic breast cancer patients. The drug's anti-cancer mechanisms appear to work through multiple pathways, including direct tumor growth inhibition, insulin level reduction, and selective elimination of cancer stem cells. Head and neck cancer patients have also shown regression of mucosal lesions with metformin treatment. While these findings are encouraging, researchers emphasize the need for larger, long-term studies to definitively establish metformin's role in cancer prevention and treatment for non-diabetic patients, including determining optimal dosing and identifying which populations would benefit most.

Anti-aging properties: One always has to be careful with medicines, potions, and tricks that purport to reverse the laws of thermodynamics. And yet metformin does some unique stuff under the hood. The drug's ability to activate AMPK and inhibit mTOR contributes to potential anti-aging effects by improving energy homeostasis, reducing oxidative stress, and mitigating chronic inflammation - key drivers of the aging process.

Metformin research that goes beyond biochemical markers and instead focuses on outcomes related to anti-aging effects has produced mixed results across different studies. Animal research shows variable outcomes: while some mice studies demonstrated increased lifespan with low-dose metformin, higher doses proved toxic, and other studies failed to replicate these benefits. In diabetic humans, observational studies and trials like UKPDS-34 suggest potential longevity benefits, showing reduced mortality rates. However, there's currently no definitive evidence that metformin extends lifespan in healthy humans. Major clinical trials like TAME are ongoing to investigate metformin's potential anti-aging effects in non-diabetic populations, which may provide more conclusive answers.

Cardiovascular protection: Studies indicate potential benefits in cardiovascular disease prevention, though the exact mechanisms are still under investigation. See above proven benefits in diabetic patients, but these are hard to extrapolate to the rest of the population.

Neurodegenerative disorders: Research on metformin's effects on neurodegenerative conditions shows mixed results. While some studies indicate potential benefits for Alzheimer's disease and cognitive function, particularly in early intervention, others suggest neutral or negative effects. Notably concerning is data showing increased Parkinson's disease risk. The drug's mechanisms include anti-inflammatory properties and insulin sensitivity improvement, but it may also increase harmful amyloid beta proteins. More research is needed for definitive conclusions.

Current research frontiers

Modern research continues to uncover new potential applications for metformin. Recent studies have explored its effects on:

The gut microbiome: Research suggests metformin may positively modify gut bacteria composition, potentially contributing to its therapeutic effects. Specifically it affects gut microbiota by increasing beneficial bacteria like Akkermansia muciniphila and short chain fatty acid-producing species. These microbial changes may improve glucose tolerance, strengthen gut barrier function, and reduce inflammation, potentially contributing to metformin's antidiabetic effects. While research shows consistent increases in specific beneficial bacteria, metformin's impact on overall microbial diversity remains unclear and requires further study.

Viral infections: Studies indicate potential benefits against various RNA viruses, including influenza and SARS-CoV-2, through its antiviral and immunomodulatory properties. As regular readers know by now, I am long on finding ways to kill viruses more quickly and completely in our bodies when infected, and I really hope this keeps showing long game benefits. It’s hard to find good research on the long game, so the art of medicine kind of kicks in here.

I’ve written extensively in my Covidlandia series about using metformin for Covid treatment, specifically for long Covid risk reduction. I’ll point to my previous post on a self-treatment plan, and include the following quite convincing compendium of studies in support of this practice:

According to research examining Metformin's effects on Covid, data from 103 studies involving 1,246 scientists and 350,869 patients across 29 countries has shown promising results. The studies indicate significantly lower risks for several outcomes including mortality, ventilation, ICU admission, hospitalization, disease progression, and recovery among patients treated with Metformin. Further supporting these findings, 67 studies conducted by 62 independent research teams across 22 countries demonstrated significant benefits, with particularly notable improvements in late treatment (55% improvement) and RCT mortality (45% improvement). The study data ranges from 5% improvement in case numbers to 37% reduction in overall mortality.

A reader and good friend asked me a really interesting question about a month ago. Since metformin really does seem to have beneficial effects in terms of Covid treatment, what about with influenza?

Several studies have investigated the effects of metformin in the treatment of influenza, showing promising results for both short-term and long-term outcomes.

Short-term outcomes

Reduced mortality: A study using an administrative claim database demonstrated that diabetic patients with obesity who were prescribed metformin had improved overall survival after an influenza diagnosis confirmed via PCR. This suggests a potential short-term benefit of metformin in influenza treatment.
Decreased hospitalization: Patients with diabetes taking metformin were less likely to be hospitalized following an emergency department visit for influenza compared to patients with diabetes not taking metformin. This indicates that metformin may help reduce the severity of influenza symptoms in the short term.
Improved T cell function: Preclinical studies have shown that metformin can improve or restore T cell function, which could serve as a potential treatment mechanism for influenza. This suggests that metformin may enhance the immune response to influenza in the short term.

Long-term outcomes

Lower risk of influenza-related complications: A cohort study demonstrated that pre-influenza vaccination metformin use was associated with lower risks of hospitalizations for influenza, pneumonia, and cardiovascular disease. The adjusted hazard ratios (aHRs) for metformin users compared to nonusers were:
- Hospitalization for influenza: a possible 40% reduction. *HR was 0.60 (95% CI: 0.34, 1.060 which crosses 1 meaning that validity of this finding is questionable and needs a larger study to reevaluate)
- Hospitalization for pneumonia: a 37% reduction. (HR 0.63 (95% CI: 0.53, 0.75 is statistically significant)
Reduced all-cause mortality: The same cohort study showed that metformin use was associated with lower all-cause mortality in the long term.
Enhanced vaccination response: Research has shown that metformin treatment during vaccination can considerably improve outcomes after influenza infection in older adults with diabetes. This suggests that metformin may have long-term benefits by enhancing the effectiveness of influenza vaccines.
Improved immunological resilience: A pilot study in non-diabetic older adults found that metformin treatment resulted in an increase in circulating T follicular helper cells post-vaccination and decreased certain markers of T cell exhaustion. This indicates that metformin may improve overall immunological resilience in the long term.

While these studies show promising results, it's important to note that more research is needed to fully understand the effects of metformin on influenza treatment. Some studies were retrospective or had small sample sizes, and larger, prospective randomized trials are required to confirm these findings and establish metformin as a potential treatment option for influenza.

I have taken and prescribed metformin for Covid. Influenza? Not yet, but I’m open to new ideas and more expert analysis. The above sounds pretty promising to me.

Asthma: A paper came out late last year and really deserves its own deep dive, but here’s the quick version. A UK study found that metformin reduced asthma exacerbations by 30% in patients with asthma and type 2 diabetes or prediabetes. Adding GLP-1 agonists provided an additional 40% reduction. These benefits occurred regardless of body mass, blood sugar levels, or asthma severity. The exact mechanism isn't known, but could involve direct lung effects or reduced inflammation. Commentary in the NEJM correctly stated: “It is too early to manage asthma with these agents in patients without other approved indications based on these retrospective cohort studies, but randomized trials are underway.”

Conclusion

I hope this article gives you some overlooked, outside the box thinking about metformin. If you have not heard of this medicine before, you will be hearing more about it in the near future I think. Here’s what we reviewed, in a concise bullet-point summary of the key takeaways:

Metformin, originally derived from French lilac, has evolved from a medieval remedy to one of modern medicine's most versatile drugs, with its primary use being first-line treatment for type 2 diabetes.
Beyond diabetes management, metformin shows promising potential across multiple areas:
- Prevention of diabetes in prediabetic patients
- Reduction of long Covid risk
- Possible anti-cancer properties, particularly in diabetic patients
- Treatment of PCOS
- Potential anti-aging effects (though evidence is still mixed)
- Promising results in reducing influenza severity and complications
- Recent evidence suggesting benefits for asthma patients
The drug works through multiple mechanisms, including improving insulin sensitivity, modifying gut microbiome, and exhibiting antiviral and anti-inflammatory properties.
Metformin is generally safe, inexpensive, and well-tolerated, though it can cause initial GI side effects that typically improve over time.
While many of these "off-label" applications show promise, more research is needed - particularly large-scale clinical trials - to fully understand metformin's potential benefits beyond diabetes treatment.