Does metformin (metformin hydrochloride) reduce the risk of cancer in individuals with a strong family history of cancer, but without diabetes mellitus?

From the Guidelines

Metformin is not currently recommended to lower cancer risk in people with a strong family history of cancer who do not have diabetes. While some observational studies have suggested that metformin might have anti-cancer properties in diabetic patients, there is insufficient evidence from randomized controlled trials to support its use specifically for cancer prevention in non-diabetic individuals 1. The potential cancer-preventive mechanisms of metformin include activation of AMP-activated protein kinase (AMPK), which may inhibit cancer cell growth, and reduction of insulin levels, which could slow the growth of insulin-responsive tumors. However, these benefits remain theoretical for non-diabetic individuals.

Some studies have shown that metformin is associated with a reduced risk of adenoma and colorectal cancer in patients with type 2 diabetes 1. For example, a meta-analysis of 5 observational studies found that metformin was associated with a 20% reduced adenoma risk in patients with type 2 diabetes 1. Additionally, a meta-analysis of 14 observational studies found that patients with type 2 diabetes who used metformin had a 27% reduction in CRC incidence compared with those who did not use metformin 1. However, these findings are not generalizable to average-risk individuals or those without diabetes.

If you're concerned about hereditary cancer risk, more established prevention strategies include:

• Regular cancer screenings appropriate for your specific family history
• Maintaining a healthy weight
• Regular physical activity
• Limiting alcohol consumption
• Avoiding tobacco
• In some high-risk cases, genetic counseling to consider targeted preventive measures. Using metformin off-label for cancer prevention could expose you to side effects like gastrointestinal issues, vitamin B12 deficiency, and rarely lactic acidosis, without proven benefit.

From the Research

Metformin and Cancer Risk

• Metformin is a well-tolerated oral biguanide hypoglycemic agent that has been shown to have potential in preventing breast cancer, particularly in women with a high risk of developing the disease 2.
• The mechanisms of action of metformin involve secondary lowering of circulating insulin, which can drive biologically aggressive breast cancer and predict poor survival in women with breast cancer 2.
• However, there is limited evidence on the effectiveness of metformin in reducing cancer risk in individuals with a strong family history but without diabetes.

Family History and Cancer Risk

• Women with a family history of breast cancer have several treatment options, including tamoxifen, raloxifene, and hormone therapy, which should be based on each woman's risk to develop breast cancer, menopausal symptoms, preferences, and risks for other conditions 3.
• A personalized risk assessment and genetic counseling intervention can help women with a first-degree relative with breast cancer make informed decisions about their treatment options 3.
• A polygenic risk score (PRS) can also be used to stratify lifetime risks of breast cancer and inform prevention and screening strategies, particularly for women treated with selective estrogen receptor modulators (SERMs) such as tamoxifen or raloxifene 4.

Chemoprevention and Cancer Risk

• Tamoxifen and raloxifene have been shown to reduce breast cancer risk in women with BRCA1/2 mutations, with a similar chemoprevention efficacy for both BRCA1 and BRCA2 carriers 5.
• Metformin has been proposed as a potential chemopreventive agent for breast cancer, particularly for women with a high risk of developing the disease, due to its ability to lower circulating insulin levels and inhibit cancer cell growth 2.
• However, further research is needed to validate the findings and optimize the use of metformin and other chemopreventive agents in high-risk populations.

Metformin and Diabetes Prevention

• Metformin has been shown to reduce the risk of developing type 2 diabetes in individuals with impaired glucose tolerance, particularly in younger, heavier subjects 6.
• The Diabetes Prevention Program (DPP) and its follow-up study, the DPP Outcomes Study (DPPOS), demonstrated that metformin can reduce the risk of diabetes by 31% over 3 years and 18% over 10-22 years, respectively 6.
• Metformin has also been shown to have long-term weight loss and cardioprotective effects, although its impact on long-term clinical outcomes in people with non-diabetic hyperglycemia is still being researched 6.