January 23, 2025

Metformin Could Reduce Risk for Skin Cancer, New Study

Written by our expert

Ava

Avanthika Nityanand

M.Sc Human Genetics, B.Sc Plant Biology & Plant Biotechnology

Metformin Could Reduce Risk for Skin Cancer, New Study
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Non-melanoma skin cancers (NMSC), which include both squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), are among the most frequently diagnosed malignancies worldwide.

Despite their often lower mortality rate compared to melanomas, they represent a considerable burden to healthcare systems and patients due to high treatment costs, morbidity, and potential disfigurement. Against this backdrop, the findings of the retrospective study using data from the All of Us research database are both timely and intriguing.

A new study published in December 2024 suggests that metformin, a widely prescribed and generally well-tolerated antihyperglycemic drug used primarily in the treatment of type 2 diabetes, may reduce the risk of developing SCC and BCC.

Metformin’s putative protective effect against cancer has greatly interested clinicians and researchers for over a decade.

Its antineoplastic properties are hypothesized to stem from several mechanisms. Chief among these is metformin’s known ability to reduce circulating insulin and insulin-like growth factor (IGF) levels, which can lower oncogenic signaling cascades.

Additionally, metformin appears to activate the adenosine monophosphate-activated protein kinase (AMPK) pathway, potentially inhibiting cancer cell proliferation.

These biologic underpinnings have fueled investigations into metformin’s effect on various tumor types, from breast and colon cancers to liver and pancreatic malignancies.

This study extends that scope to non-melanoma skin cancers, shedding new light on a possible chemopreventive role in dermatological oncology.

Metformin can reduce the risk for NMSC and BCC

One of the major strengths of this study lies in the data source: the All of Us research database.

This initiative was designed to gather health data from a diverse cross-section of the U.S. population. This addresses a historical shortcoming of many large-scale databases that underrepresented minority groups.

Using the data from this resource, the authors performed a careful study comparing people who had a particular condition with those who did not (a retrospective case-control analysis). They used techniques like propensity score matching and multivariable regression to factor in differences such as age, sex, ethnicity, and other health conditions.

By using these methods, they reduced the chances of bias, strengthened the reliability of their findings, and made it easier to draw clear conclusions about the relationships they observed.

Understanding the Results

The results demonstrated that individuals exposed to metformin had a generally lower risk of developing NMSC. Specifically, BCC risk was reduced across all examined sex and ethnic groups, underscoring the drug’s potentially broad protective effect.

Similar associations emerged for SCC, though one caveat was that the protective effect was not observed in African American patients.

This differential finding hints at the possibility of genetic or environmental factors influencing metformin’s mechanism of action in SCC. Or, alternatively, the need for more targeted subgroup analyses with larger numbers of African American participants.

Given that the All of Us database is designed to reflect a more diverse population, these results underscore the complexity of personalized medicine and indicate that not every population may experience the same degree of benefit from metformin for SCC prevention.

Metformin makes it hard for tumors to grow

From a pathophysiological standpoint, metformin’s beneficial effect on skin carcinogenesis can be rationalized by several mechanisms.

Its impact on insulin resistance and lowered insulin levels is thought to create a less favorable environment for tumor growth, given insulin’s role in cell proliferation. Meanwhile, metformin’s activation of AMPK may downregulate mTOR signaling, an important pathway for cell growth and proliferation.

Additionally, emerging research suggests that metformin has anti-inflammatory effects, which could mitigate the chronic inflammation that often contributes to tumorigenesis in the skin.

Moreover, the finding that metformin use was associated with a protective effect for BCC “across all sex and ethnicity groups” is compelling.

This broad applicability suggests the drug’s mechanism might be more universally applicable for BCC prevention than for SCC.

However, the observation that African American patients did not see a significant association in SCC prevention highlights the need for deeper explorations into genetic or molecular mechanisms specific to SCC in individuals with darker skin tones. It is also possible that environmental exposures, skin biology, or other unmeasured confounders vary in this population.

Metformin: A potential chemopreventative agent

If future studies confirm and expand these findings, metformin could be considered as a chemopreventive agent, especially for high-risk populations.

For instance, individuals with a history of organ transplantation or those receiving immunosuppressive therapy are known to have elevated rates of NMSC. It is conceivable that clinicians might investigate metformin in these populations as part of a broader strategy to reduce skin cancer incidence.

Understanding the side effects

That said, caution is warranted. Metformin is not free from side effects—most notably gastrointestinal upset—and any strategy of broad prescription for cancer prevention would need thorough risk-benefit evaluations.

Currently, the best prevention against NMSC includes sun protection measures, regular skin screenings, and careful management of other risk factors like immunosuppression.

Metformin’s role, should it become validated in randomized clinical trials, would likely be adjunctive rather than a standalone preventive measure.

Prospective research

The authors are correct to call for prospective research. Observational studies, even those carefully adjusted for confounders, cannot fully rule out residual confounding or reverse causation.

Prospective trials or at least well-designed cohort studies could help clarify whether metformin use truly lowers NMSC risk and define any population-based differences in response.

Specifically, prospective work might parse out the duration of metformin therapy needed, the dose-response relationship, and potential synergistic effects with other interventions.

How this affects people of colour

Lastly, the mention that “metformin exposure was associated with a significantly lower risk of skin cancer, particularly in patients with skin of color” deserves attention.

Traditionally, there has been a narrative that darker-skinned individuals have a lower risk for certain skin cancers. While that may hold true in terms of absolute incidence, when skin cancers do occur in these populations, they are often diagnosed at later stages, leading to worse outcomes.

Therefore, a chemopreventive strategy that serves these groups effectively could have substantial clinical relevance in reducing morbidity.

Conclusion

This study contributes important preliminary evidence that metformin may offer protective benefits against non-melanoma skin cancers, notably BCC, across diverse groups and SCC in certain populations. By leveraging the expansive and diverse All of Us research database, the investigators underscore how population diversity can reveal nuanced outcomes and highlight unmet needs in specific subgroups. While further investigation is warranted—particularly prospective trials to establish causality and define clinical protocols firmly—these findings open the door to repurposing a well-established diabetes medication for skin cancer prevention. Such a development could mark a meaningful advance in reducing the public health burden of non-melanoma skin cancers and improving dermatologic care in high-risk and underserved communities.

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