Patients with type 1 and type 2 diabetes have increased mortality. This mortality is often associated with the elevated cardiovascular risk, i.e., the risk of suffering a heart attack or stroke.
In 1996, the risk of cardiovascular death for patients with diabetes was 2.7% higher than for patients without diabetes. By 2011, this difference had decreased to only 0.5%. The reason for this is prevention through improved pharmacological treatment. Medical therapies and guidelines have proven successful in reducing the increased risk of cardiovascular death in patients with diabetes. At the same time, excess mortality among diabetic patients has also declined.
As a result of this reduction in excess mortality, cardiovascular death is no longer the most common cause of death in patients with diabetes.
The most common cause of death in patients with type 2 diabetes mellitus is cancer. Therefore, cancer is the most important comorbidity in diabetes mellitus. If additional risk factors such as obesity and alcohol consumption are present, the risk of dying from cancer increases significantly. From 2001 to 2018 in England, the risk of cardiovascular death decreased from 44% to 24%. At the same time, the risk of dying from cancer increased from 22% to 28%.
Patients with type 2 diabetes mellitus have a 2–3 times higher risk of pancreatic cancer, a twofold increased risk of liver and bile duct cancer, a 20% increased risk of breast cancer, a twofold increased risk of endometrial cancer, and a 50% increased risk of colon and rectal cancer (Tsilidis KK et al.: Type 2 diabetes and cancer: Umbrella review of meta-analyses of observational studies. BMJ 350:g7607, 2015).
The most important measure is prevention: all patients with type 2 diabetes mellitus should regularly participate in cancer screening programs and should be examined at least once a year by their general practitioner or diabetologist.
Many studies have shown that patients taking metformin develop cancer less frequently compared to patients treated with other antidiabetic medications.
Based on these observations, studies have been and are being conducted in patients without diabetes to determine whether metformin reduces the risk of cancer. The risk of developing colorectal cancer is reduced by taking metformin. In cases of existing colorectal cancer, additional treatment with metformin (adjuvant therapy) is beneficial. Other carcinomas that occur less frequently with metformin treatment include cancers of the liver, bile ducts, and pancreas. For breast cancer and prostate cancer, the evidence is not clear, as studies show inconsistent results.
The well-known aging researcher David Sinclair takes 1 g of metformin daily. He does not have diabetes. Should we all take metformin for cancer prevention? This question has not yet been conclusively answered. Currently, studies are being conducted with participants without diabetes to determine whether metformin is suitable for cancer prevention. On the other hand, metformin is inexpensive and, when contraindications are observed, has few side effects.
How metformin leads to a reduction in cancer risk is not yet fully understood. However, there is evidence that a protein complex plays an important role in the development of cancer.
Patients with type 2 diabetes mellitus have elevated insulin levels. Insulin receptors on the cell surface are increasingly activated, triggering a signaling cascade inside the cell that activates mTORC1. mTORC1 (mechanistic Target of Rapamycin Complex 1) is a protein complex present in every mammalian cell and regulates growth, energy balance, and cell division. If mTORC1 activity is inhibited, cell proliferation and growth are reduced.
Metformin increases insulin sensitivity and leads to lower insulin levels. As a result, the insulin receptor is less stimulated, which in turn leads to reduced stimulation of mTORC1. Metformin also directly inhibits mTORC1 and affects AMPK. AMPK (AMP-activated protein kinase) inhibits phosphorylation and thereby suppresses energy-intensive biosynthetic processes. AMPK also stimulates mTORC1; since it is inhibited by metformin, the activity of mTORC1 decreases. When mTORC1 activity decreases, cell division and growth are reduced—meaning less cancer develops.
These metabolic processes within the cell are currently being studied in detail, and it is expected that drugs will be developed that inhibit cell proliferation even more specifically than metformin.
Since it may still take time to develop more effective medications for preventing the leading cause of death in diabetes, metformin should remain the basic therapy for every patient with type 2 diabetes mellitus.
Pearson-Stuttard, J., Bennett, J. E., Cheng, Y. J., Vamos, E. P., Cross, A. J., Ezzati, M., & Gregg, E. W. (2021). Trends in predominant causes of death in individuals with and without diabetes in England from 2001 to 2018. The Lancet Diabetes & Endocrinology, 9(3), 165–173. https://doi.org/10.1016/S2213-8587(20)30431-9
Demonstrates that cancer became the leading cause of death in people with diabetes in England (Imperial College London)
Ling, S., Zaccardi, F., Issa, E., Davies, M. J., Khunti, K., & Brown, K. (2023). Inequalities in cancer mortality trends in people with type 2 diabetes: A population-based cohort study. Diabetologia. Advance online publication. https://doi.org/10.1007/s00125-023-05868-6
Shows that cancer may have overtaken cardiovascular disease as the leading cause of death (Diabetologia)
Pradhan, R., Yin, H., Yu, O. H. Y., & Azoulay, L. (2022). Long-term patterns of cancer incidence among patients with type 2 diabetes: A population-based study. Journal of Diabetes and Its Complications, 36(5), 108145. https://doi.org/10.1016/j.jdiacomp.2022.108145
Notes that with declining cardiovascular mortality, cancer has become the foremost cause of death in this population (ScienceDirect)
Laurberg, T., Witte, D. R., & Sandbæk, A. (2024). Trends in cause-specific mortality among people with type 2 diabetes. The Lancet Regional Health – Europe. Advance online publication.
Confirms cancer as a predominant cause of death in several diabetes cohorts (The Lancet)
Bjornsdottir, H. H., Rawshani, A., Rawshani, A., Franzén, S., Svensson, A.-M., Eliasson, B., & Gudbjörnsdottir, S. (2020). A national observational study of cancer incidence and mortality in type 2 diabetes. Scientific Reports, 10, 1734. https://doi.org/10.1038/s41598-020-73668-y
Demonstrates increased cancer mortality risk in type 2 diabetes populations (Nature)
Suh, S., & Kim, K. W. (2011). Diabetes and cancer: Is diabetes causally related to cancer? Diabetes & Metabolism Journal, 35(3), 193–198. https://doi.org/10.4093/dmj.2011.35.3.193
Reviews epidemiological links between diabetes and cancer mortality
Swerdlow, A. J., Laing, S. P., Qiao, Z., Slater, S. D., Burden, A. C., Botha, J. L., Waugh, N. R., Morris, A. D., Gatling, W., Gale, E. A. M., Patterson, C. C., & Keen, H. (2005). Cancer incidence and mortality in patients with insulin-treated diabetes: A UK cohort study. British Journal of Cancer, 92(11), 2070–2075. https://doi.org/10.1038/sj.bjc.6602611
Barone, B. B., Yeh, H. C., Snyder, C. F., Peairs, K. S., Stein, K. B., Derr, R. L., Wolff, A. C., & Brancati, F. L. (2008). Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: A systematic review and meta-analysis. JAMA, 300(23), 2754–2764. https://doi.org/10.1001/jama.2008.824
Meta-analyses & Systematic Reviews (strongest evidence base)
Gandini, S., Puntoni, M., Heckman-Stoddard, B. M., Dunn, B. K., Ford, L., DeCensi, A., & Szabo, E. (2014). Metformin and cancer risk and mortality: A systematic review and meta-analysis taking into account biases and confounders. Cancer Prevention Research, 7(9), 867–885. https://doi.org/10.1158/1940-6207.CAPR-13-0424
Reports reduced cancer incidence and mortality associated with metformin use (PMC)
Soranna, D., Scotti, L., Zambon, A., Bosetti, C., Grassi, G., Catapano, A., La Vecchia, C., & Mancia, G. (2012). Cancer risk associated with use of metformin and sulfonylureas in type 2 diabetes: A meta-analysis. The Oncologist, 17(6), 813–822.
Found lower overall cancer risk in metformin users compared with other antidiabetics (PMC)
O’Connor, L. E., et al. (2024). Association of metformin use and cancer incidence: A systematic review and meta-analysis. Cancer Epidemiology, Biomarkers & Prevention.
Shows reduced risk of several cancer types, though with heterogeneity (PMC)
Kasznicki, J., et al. (2014). Metformin in cancer prevention and therapy. Annals of Translational Medicine.
Summarizes meta-analytic evidence supporting reduced cancer risk (PMC)
Observational Cohort Studies (large real-world evidence)
Evans, J. M. M., Donnelly, L. A., Emslie-Smith, A. M., Alessi, D. R., & Morris, A. D. (2005). Metformin and reduced risk of cancer in diabetic patients. BMJ, 330(7503), 1304–1305. https://doi.org/10.1136/bmj.38415.708634.F7
Landmark cohort study showing ~23% reduced cancer incidence (PMC)
Lee, M. S., Hsu, C. C., Wahlqvist, M. L., Tsai, H. N., Chang, Y. H., & Huang, Y. C. (2011). Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences. Diabetes Research and Clinical Practice, 94(1), 87–94.
Demonstrates reduced incidence of multiple cancers with metformin (gavinpublishers.com)
Kim, Y. S., et al. (2020). Metformin use reduced the overall risk of cancer in diabetic patients: A population-based cohort study. Diabetes Research and Clinical Practice.
Shows lower overall cancer risk in metformin users (ScienceDirect)
Murff, H. J., et al. (2018). Metformin use and incidence cancer risk: Evidence from observational studies. Cancer Epidemiology, Biomarkers & Prevention.
Summarizes multiple cohort studies suggesting reduced cancer incidence (PMC)
Prospective & Longitudinal Cohort Studies (higher-quality observational evidence)
Seo, H. J., & Oh, H. S. (2021). Effects of early medication treatment and metformin use for cancer prevention in diabetes patients: A nationwide cohort study. Epidemiology and Health, 43, e2021103. https://doi.org/10.4178/epih.e2021103
Prospective cohort: ~25–34% reduced cancer risk with metformin (kci.go.kr)
Additional Supporting Reviews / Mechanistic & Epidemiological Evidence
Najafi, F., et al. (2023). The relationship between metformin consumption and cancer incidence: A systematic review. Frontiers in Oncology.
Indicates protective effect, particularly for colorectal cancer (~39% reduction) (PMC)
Sirtori, C. R., et al. (2024). Metformin: From diabetes to cancer prevention. Pharmacological Research.
Suggests reduced frequency of specific cancers (e.g., breast cancer) (ScienceDirect)
Rangraze, I., et al. (2025). Metformin as a dual-role agent in cancer prevention and therapy. Medicina.
Highlights reduced cancer risk but emphasizes need for randomized trials (MDPI)
Interpretation of the Evidence
Key Conclusion