Metformin Use Linked to Better Survival Rates in Patients With Ovarian Cancer

Metformin use was associated with improved survival in patients with ovarian cancer, according to a study published in Neoplasia.¹

Metformin is widely used as a first-line therapy in patients with type 2 diabetes to normalize hyperglycemia.² Past studies have associated metformin use with a reduced risk of cancer in patients with diabetes.¹ Other studies suggested that metformin use after diagnosis may improve survival in patients with ovarian cancer.

However, the findings of past studies on the impact of metformin use on survival in patients with ovarian cancer are inconsistent. The researchers noted that many of these studies suffered from immortal time bias, which is a bias that occurs when patients analyzed cannot experience the outcome for a certain portion of the study timeframe³; this biases a study toward finding a survival effect of metformin.

To better understand metformin’s potential role in increasing ovarian cancer survival, the researchers conducted a population-based retrospective cohort study of all patients in British Columbia (BC), Canada, diagnosed with ovarian cancer at 30 years or older between January 1, 1997, and December 31, 2018, with follow-up through December 31, 2020.¹

Consequently, they analyzed the relationship between medication use, all-cause mortality, and ovarian cancer–specific mortality. The researchers ran Cox proportional hazard models to estimate the association between metformin and survival in both the full cohort of patients with ovarian cancer and a subgroup of diabetic patients with ovarian cancer.

The researchers identified eligible patients with ovarian cancer from the BC Cancer Registry, which contains data on all patients in BC with cancer. They included all patients with epithelial ovarian cancers diagnosed between 1997 and 2018; patients with diabetes and ovarian cancer were identified using diagnostic codes. However, the researchers excluded those with borderline tumors, those who did not survive for 12 complete months after diagnosis, and those not registered in BC at diagnosis.

Also, the researchers obtained data on medication use from BC PharmaNet, where every medication dispensed in an outpatient setting in BC must be entered by law. They grouped all patients using metformin monotherapy or a combination as the metformin-exposed group. The researchers explained that exposure was lagged by 6 months as it is “biologically implausible” that the short-duration exposure would meaningfully impact ovarian cancer survival. Therefore, patients were considered unexposed until 6 months after the lag period to remove the immortal time bias.

The study population consisted of 4951 patients diagnosed with epithelial ovarian cancer, 711 (14.4%) of whom had a diagnostic code in their health records indicating they had diabetes in the 5 years before their ovarian cancer diagnosis. Of this subpopulation, 236 (4.8%) were metformin users in the 12 months before diagnosis; nearly all metformin users had diabetes (98.7%). However, 166 (3.3%) patients were lost to follow-up after 1 year.

Overall, the mean (SD) age at diagnosis was 62.2 (12.5) years, and the median years of follow-up were 3.1 (IQR, 1.3-6.9); the follow-up time was short because 70% of patients with ovarian cancer die within 5 years of diagnosis. During the follow-up period, 2984 patients died, 2628 (88%) of whom died from ovarian cancer.

Compared with nonusers, metformin users were diagnosed at an older average age (66.1 vs 61.9 years). They were also more likely to have serous ovarian cancers (66.1% vs 58.7%) and other comorbidities, like cardiovascular disease and renal disease. Additionally, within the diabetic cohort, metformin users were more likely to have filled a prescription for β-blockers, insulin, statins, and other diabetes medications.

After adjusting for all covariates, the researchers found that metformin use was associated with a 17% better ovarian cancer survival in the full cohort (adjusted HR [aHR], 0.83; 95% CI, 0.67-1.02) and a 16% better chance of survival in the cohort of patients with serous cancers (aHR, 0.84; 95% CI, 0.66-1.07); however, both were not statistically significant. Conversely, they observed a statistically significant protective effect of metformin use on ovarian cancer–specific mortality when restricted to the diabetic (aHR, 0.71; 95% CI, 0.54-0.91) and serous cancers (aHR, 0.73; 95% CI, 0.54-0.98) cohorts.

The researchers acknowledged their limitations, one being that they had minimal information on metformin use among patients without diabetes. Similarly, the researchers were limited by the small number of metformin users; this made it impossible to conduct histotype-specific analyses for any histotypes other than serous ovarian cancer. Consequently, they suggested areas for further research.

“While we cannot rule out bias, particularly due to ovarian cancer prognosis, future research should examine whether metformin use among non-diabetic patients might improve ovarian cancer survival,” the authors concluded. “The best study design for this question is a randomized controlled trial, as it will also eliminate the confounding by prognosis that is impossible to completely address using observational research designs.”

References

1. Marolt N, Pavlič R, Kreft T, Gjogorska M, Rižner TL. Targeting estrogen metabolism in high-grade serous ovarian cancer shows promise to overcome platinum resistance. Biomed Pharmacother. Published online July 4, 2024. doi:10.1016/j.biopha.2024.117069
2. Quinn BJ, Kitagawa H, Memmott RM, Gills JJ, Dennis PA. Repositioning metformin for cancer prevention and treatment. Trends Endocrinol Metab. 2013;24(9):469-480. doi:10.1016/j.tem.2013.05.004
3. Suissa S. Immortal time bias in pharmaco-epidemiology. Am J Epidemiol. 2008;167(4):492-499. doi:10.1093/aje/kwm324