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Metformin and Cancer: Solutions to a Real-World Evidence Failure
Oriana Hoi Yun Yu1,2,3, Samy Suissa1,3,4
11Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada.
Abstract:
The quest to repurpose metformin, an antidiabetes drug, as an agent for cancer prevention and treatment, which began in 2005 with an observational study that reported a reduction in cancer incidence among metformin users, generated extensive experimental, observational, and clinical research. Experimental studies revealed that metformin has anticancer effects via various pathways, potentially inhibiting cancer cell proliferation. Concurrently, multiple nonrandomized observational studies reported remarkable reductions in cancer incidence and outcomes with metformin use. However, these studies were shown, in 2012, to be affected by time-related biases, such as immortal time bias, which tend to greatly exaggerate the benefit of a drug. The observational studies that avoided these biases did not find an association. Subsequently, the randomized trials of metformin for the treatment of type 2 diabetes and as adjuvant therapy for the treatment of various cancers, advanced or metastatic, did not find reductions in cancer incidence or outcomes. Most recently, the largest phase 3 randomized trial of metformin as adjuvant therapy for breast cancer, which enrolled 3,649 women with a 5-year follow-up, found no benefit for disease-free survival or overall survival with metformin. This major failure of observational real-world evidence studies in correctly assessing the effects of metformin on cancer incidence and outcomes was caused by preventable biases which, surprisingly, are still prominent in 2022. Rigorous approaches for observational studies that emulate randomized trials, such as the incident and prevalent new-user designs along with propensity scores, avoid these biases and can provide more accurate real-world evidence for the repurposing of drugs such as metformin.
Insights
Metformin, an antidiabetes drug, does not reduce cancer incidence or improve outcomes, despite early observational studies suggesting it might. Rigorous trials and bias-aware observational studies confirm no significant anticancer benefits.
Area of Science:
- Oncology
- Pharmacology
- Epidemiology
Background:
- Metformin, a common antidiabetes medication, was investigated for cancer prevention and treatment due to early observational findings.
- Initial studies suggested metformin use was associated with reduced cancer incidence and improved outcomes.
- Concerns about time-related biases, like immortal time bias, emerged, potentially exaggerating metformin's observed benefits.
Purpose of the Study:
- To evaluate the efficacy of metformin as a cancer prevention and treatment agent.
- To reconcile conflicting evidence from observational studies and randomized controlled trials regarding metformin's anticancer effects.
- To highlight the impact of biases in observational studies and the importance of rigorous methodologies.
Main Methods:
- Review of experimental, nonrandomized observational, and randomized controlled trial data.
- Analysis of studies specifically designed to avoid time-related biases (e.g., new-user designs, propensity scores).
- Inclusion of results from large-scale randomized trials, including a phase 3 breast cancer adjuvant therapy trial.
Main Results:
- Experimental studies indicated potential anticancer mechanisms for metformin.
- Early nonrandomized observational studies reported significant benefits, but were later found to be affected by biases.
- Randomized trials, including a large breast cancer trial, did not demonstrate metformin's efficacy in reducing cancer incidence or improving survival outcomes.
- Observational studies avoiding biases did not find a significant association between metformin and cancer outcomes.
Conclusions:
- Metformin does not appear to offer significant benefits for cancer prevention or treatment.
- Time-related biases in observational studies can lead to erroneous conclusions about drug efficacy.
- Rigorous study designs, emulating randomized trials, are crucial for generating reliable real-world evidence on drug repurposing.
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