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Updated on April 28, 2016.
While postmenopausal women with type 2 diabetes may have a heightened risk for invasive cancers and cancer mortality, use of metformin — particularly long-term use — may lower the risk for dying from cancer, according to results from a large prospective study.
Researchers from Roswell Park Cancer Institute and the University of Buffalo analyzed information from 145 826 postmenopausal women aged 50 to 79 years from 40 US clinical centers who participated in the Women’s Health Initiative (WHI) between 1993 and 1998.
They found that women with diabetes were more likely to die from invasive cancer when compared with women without diabetes. In addition, among women with diabetes, the risk for cancer death differed significantly between metformin users and nonusers. The researchers also noted that risk for cancer death tended to decrease with longer metformin use.
“As expected, in this large cohort of postmenopausal women, we found that women with diabetes are at higher risk to develop cancer and are at greater risk of death from these diseases,” said study author Zhihong Gong, PhD, assistant professor of oncology in the department of cancer prevention and control at Roswell Park Cancer Institute in Buffalo, New York.
“However, our results did suggest that long-term metformin use was related to a lower risk of developing certain cancers. We also found that women with diabetes who were treated with metformin were at lower risk of dying from cancer compared to non-metformin users, suggesting that metformin may be associated with better survival in diabetes patients with cancer.”
Metformin and Cancer Risks in Diabetes
Overall, the researchers found that women with diabetes had a 13% higher risk for developing invasive cancer when compared with those without diabetes (hazard ratio [HR]=1.13; 95% CI, 1.07-1.19).1
In terms of cancer types, women with diabetes faced a 37% higher risk for cancers of the digestive organs and peritoneum (HR=1.37; 95% CI, 1.23-1.53), including a 24% increased risk for colon cancer (HR=1.24; 95% CI, 1.06-1.46) and a more than 2-fold increased risk for liver and pancreas cancers, as compared with women without diabetes. Risk for reproductive tract cancer was also 22% higher for women with diabetes vs those without diabetes (HR=1.22; 95% CI, 1.05-1.42), especially endometrial cancer (HR=1.36; 95% CI, 1.12-1.65). The researchers also observed a suggestion of a higher risk for malignant neoplasms of lymphatic and hematopoietic tissue, particularly non-Hodgkin lymphoma (HR=1.26; 95% CI, 1.02-1.55).
Breast cancer risk was elevated among women with diabetes only after BMI and waist-to-hip ratio were included as covariates (HR=1.11; 95% CI, 1.01-1.20).
Women with diabetes also had a 46% increased risk for death from invasive cancer overall (HR=1.46; 95% CI, 1.34-1.60) and a 44% increased risk for death from colorectal cancer (HR=1.44; 95% CI, 1.06-1.96).
In women with diabetes vs those without the disease, risk for total invasive cancer was not significantly different between metformin users (HR=1.13; 95% CI, 1.04-1.23) and users of other medications (HR=1.10; 95% CI, 1.00-1.21), according to the data. However, metformin use was associated with better survival. Women with diabetes who used metformin had a significantly lower risk for dying of cancer (HR=1.09; 95% CI, 0.91-1.28) than those using other medications (HR=1.45; 95% CI, 1.25-1.69), relative to women without diabetes. Data also showed that women taking metformin were less likely to die from breast cancer (HR=0.50; 95% CI, 0.22-1.13) than those taking other medications (HR=1.29; 95% CI, 0.71-2.33).
The researchers noted that metformin was also linked to better survival in diabetes patients diagnosed with ovarian and colorectal cancers.
“Our findings from this large cohort of postmenopausal women with long-term follow-up suggest that diabetes remains a risk factor for cancer and cancer-related death, and metformin therapy, compared to other diabetes medications, may have an important role in the prevention or management of diabetes-associated cancer,” said Dr Gong.
While metformin use did not appear to affect invasive cancer risk overall, longer use was associated with a decreased risk for breast cancer (P– trend=.04). Furthermore, results revealed a trend of decreasing risk for cancer death with increasing duration of metformin use, but a trend of increasing risk for use other antidiabetes medications (P<.001).
“I think although more studies are necessary, such as clinical trials, to further address whether or how metformin is associated with decreased risk of certain cancers and cancer death, our findings from this large study may provide more evidence that postmenopausal women with diabetes and cancer may benefit from metformin therapy compared to other antidiabetes therapy,” Dr Gong told Endocrinology Advisor, highlighting the study’s strengths. “We had a long-term follow-up with a median follow-up of 15 years among these women. In this study, we collected detailed data on various factors, and collected information on medication use not only at baseline and updated during the entire follow-up period, limiting issues from potential bias.”
Nevertheless, the researchers noted that the analyses were limited by the small number of certain rarer cancers occurring in women with diabetes, especially when stratified by medication use. In addition, they reported that the findings may not be the same in premenopausal women or men.
Clinical Perspectives
Janet McGill, MD, professor of medicine and director of fellowship in endocrinology, diabetes, and metabolism at Washington University School of Medicine in St. Louis, Missouri, said this is a well done analysis and confirms prior reports, albeit with somewhat different findings relative to the strength of the association for each type of cancer and effects on mortality vs incidence.
Epidemiologic studies such as this study conducted by Gong and colleagues are hypothesis-generating, she noted.
“These findings should be confirmed by both preclinical models of human disease and by randomized clinical trials. Whether metformin would benefit women without diabetes who develop breast or other cancer is not known and would be best served by clinical trials,” Dr McGill told Endocrinology Advisor. “Given the overall safety of metformin when used within prescribing guidelines for kidney function, the practical message for providers taking care of patients with diabetes may be to continue metformin therapy, and add on other antidiabetes therapies rather than replace metformin, for as long as possible. This is our current practice, which now has support from this Nurses Health Initiative Study.”
Iris Romero, MD, MS, associate professor of obstetrics and gynecology at The University of Chicago Medicine in Illinois, said this paper makes an important contribution to a longstanding question regarding the relationship between diabetes and cancer, and sheds light on a new question of whether or not a common diabetes medication — metformin — protects against cancer.
“The study had unique strengths that other studies that have tried to answer these questions did not have, including a large samples size, long follow-up, and detailed information about medication use,” Dr Romero told Endocrinology Advisor.
“However, even with a dataset as large as the WHI and this rigorous statistical analysis, several ongoing questions remain unanswered. First, are there specific cancers where the effect of diabetes and metformin are more important? Because of the limited number of each individual cancer types, we would not be able to use these findings to advise patients about risk or survival of specific cancer. Second, what would be the effect of metformin in patients without diabetes?”
Ultimately, she noted, the role of metformin in cancer can only be answered by prospective clinical trials in patients without diabetes. These trials are underway in several cancers including breast cancer and a trial in ovarian cancer, which Dr Romero is helping conduct.
Cynthia Stuenkel, MD, clinical professor of medicine at the University of California, San Diego in LaJolla, California, said the study was “interesting” and “well powered.” However, she noted that it was limited by its observational design.
“Right now it would seem reasonable to counsel women with diabetes who were already taking or about to take metformin that some studies suggest that cancer mortality might be reduced in women taking metformin compared to other diabetes drugs, but this finding was preliminary and had not been proven in properly conducted randomized controlled trials,” she told Endocrinology Advisor. “It would be premature, based on this observational data, to recommend metformin for cancer prevention or mortality benefit.”
UPDATE: This article has been updated to correct Dr Stuenkel’s comments. A previous version misquoted Dr Stuenkel as calling the study “excellent.” The updated version more accurately reflects Dr Stuenkel’s statements.
