Metformin and Cancer Risk Among Women With Diabetes
Objective We investigated if metformin lowers breast, endometrial, and ovarian cancer risk in women with type 2 diabetes mellitus compared with women who used other antidiabetic medications.
Research design and Methods We followed a cohort of 66 778 female patients with diabetes for a maximum of 12 years (median 6 years). We examined breast, endometrial, and ovarian cancer risk, and the composite cancer risk. We examined drug categories using pharmacy records: metformin only; metformin combination regimens; non-metformin regimens; and non-users. We used χ analyses to examine categorical variables. We conducted multivariable Cox regression models with time-dependent drug use status.
Results Women who used metformin combination regimens versus metformin only had a 15% lower breast cancer risk (adjusted HR=0.85, 95% CI 0.69 to 1.04). After stratifying by glycated hemoglobin (HbA1c), the association attenuated in those who had poorly controlled HbA1c (adjusted HR=1.06, 95% CI 0.73 to 1.55). Given the small numbers of ovarian and endometrial cancer outcomes, we examined these as a composite. The risk of all cancers combined was similar in those who used metformin combination regimens versus metformin only (adjusted HR=0.92, 95% CI 0.78 to 1.10). We found no significant differences for breast cancer or all cancers combined when we compared risks in non-metformin users versus metformin only users.
Conclusions Women who used metformin and other antidiabetic drugs had a lower breast cancer risk compared with women who used metformin only, but the results were not significant. We also found no difference in overall cancer risks when we compared women who used other antidiabetic drugs (no metformin) versus metformin users.
Epidemiological studies suggest that hyperinsulinemia, insulin resistance, and diabetes are associated with increased cancer risks. Metformin improves glycemic control and is used to treat type 2 diabetes, and based on in vitro studies, the drug may have anticancer effects, particularly for breast cancer. While several studies described a lower cancer risk among patients with type 2 diabetes using metformin, other studies have disputed metformin's protective effect. One case–control study of 11 000 women with type 2 diabetes in Scotland showed that overall cancer incidence was lower in patients taking metformin, and also suggested that there was a dose–response relationship. This study was later expanded into a cohort study to confirm this overall reduction and found a lower incidence of all cancers from 11% to 8% as well as lower overall and cancer-related mortality in metformin users. Another prospective study of 1353 patients in the Netherlands similarly demonstrated lower cancer mortality among those with type 2 diabetes using metformin compared with non-users. These observations have also been generally found when analyzing the impact of metformin use on specific cancers. A case–control analysis of 22 621 women with type 2 diabetes found an adjusted OR of 0.44 for developing breast cancer in those on long-term metformin treatment when compared to women with diabetes not using metformin. In contrast, other studies have found no association with metformin, while one found an increased risk of various cancers among metformin users. However, prior studies were limited by self-reported medication use data, short follow-up duration, inclusion of patients without diabetes, or limited covariate data. With little data available on metformin use in gynecological cancers, our goal was to examine whether metformin use had an impact on breast, endometrial, or ovarian cancer incidence in a large cohort of adult women with type 2 diabetes with pharmacy and healthcare coverage.
Abstract and Introduction
Abstract
Objective We investigated if metformin lowers breast, endometrial, and ovarian cancer risk in women with type 2 diabetes mellitus compared with women who used other antidiabetic medications.
Research design and Methods We followed a cohort of 66 778 female patients with diabetes for a maximum of 12 years (median 6 years). We examined breast, endometrial, and ovarian cancer risk, and the composite cancer risk. We examined drug categories using pharmacy records: metformin only; metformin combination regimens; non-metformin regimens; and non-users. We used χ analyses to examine categorical variables. We conducted multivariable Cox regression models with time-dependent drug use status.
Results Women who used metformin combination regimens versus metformin only had a 15% lower breast cancer risk (adjusted HR=0.85, 95% CI 0.69 to 1.04). After stratifying by glycated hemoglobin (HbA1c), the association attenuated in those who had poorly controlled HbA1c (adjusted HR=1.06, 95% CI 0.73 to 1.55). Given the small numbers of ovarian and endometrial cancer outcomes, we examined these as a composite. The risk of all cancers combined was similar in those who used metformin combination regimens versus metformin only (adjusted HR=0.92, 95% CI 0.78 to 1.10). We found no significant differences for breast cancer or all cancers combined when we compared risks in non-metformin users versus metformin only users.
Conclusions Women who used metformin and other antidiabetic drugs had a lower breast cancer risk compared with women who used metformin only, but the results were not significant. We also found no difference in overall cancer risks when we compared women who used other antidiabetic drugs (no metformin) versus metformin users.
Introduction
Epidemiological studies suggest that hyperinsulinemia, insulin resistance, and diabetes are associated with increased cancer risks. Metformin improves glycemic control and is used to treat type 2 diabetes, and based on in vitro studies, the drug may have anticancer effects, particularly for breast cancer. While several studies described a lower cancer risk among patients with type 2 diabetes using metformin, other studies have disputed metformin's protective effect. One case–control study of 11 000 women with type 2 diabetes in Scotland showed that overall cancer incidence was lower in patients taking metformin, and also suggested that there was a dose–response relationship. This study was later expanded into a cohort study to confirm this overall reduction and found a lower incidence of all cancers from 11% to 8% as well as lower overall and cancer-related mortality in metformin users. Another prospective study of 1353 patients in the Netherlands similarly demonstrated lower cancer mortality among those with type 2 diabetes using metformin compared with non-users. These observations have also been generally found when analyzing the impact of metformin use on specific cancers. A case–control analysis of 22 621 women with type 2 diabetes found an adjusted OR of 0.44 for developing breast cancer in those on long-term metformin treatment when compared to women with diabetes not using metformin. In contrast, other studies have found no association with metformin, while one found an increased risk of various cancers among metformin users. However, prior studies were limited by self-reported medication use data, short follow-up duration, inclusion of patients without diabetes, or limited covariate data. With little data available on metformin use in gynecological cancers, our goal was to examine whether metformin use had an impact on breast, endometrial, or ovarian cancer incidence in a large cohort of adult women with type 2 diabetes with pharmacy and healthcare coverage.
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