Antineoplastic Activity of Metformin

Conflicting findings on metformin’s antineoplastic activity and the drug’s possible relationship to cancer. 

Cancer is a major public health problem, and its causality is a major theme of numerous studies. Researchers have explored the use of glucose-lowering medications (GLMs) and the ability to reduce the risk of cancer. Metformin is used in the treatment of patients with diabetes and is known to have a good safety profile. The majority of studies conducted on metformin or other GLMs and their effect on cancer risk are not conclusive, with studies having heterogeneous results. The article under review attempts to account for various factors thought to cause biases in studies relating GLMs to cancer development, and to explore various findings on the relationship between cancer development and metformin.

The authors of the article relied on data from electronic health records sourced from Clalit Health Services, an organization that insures an estimated 53% of persons in Israel. All participants between the ages of 21 and 87 who were free of diabetes and were cancer-free were involved in a closed cohort study from 2002 to 2012 for incident diabetes. The analysis conducted by the authors included only those participants who developed diabetes during follow-up. The data collected during the study entailed high-quality demographic and clinical and pharmaceutical data. The authors relied on the National Cancer Registry in Israel to determine cancer morbidity.

Dankner et al. explore how metformin affects cancer development. They find that there is conflicting literature on the effect of metformin and cancer development. In their study, they included 315,000 patients in a Cox Regression Analysis for patients treated between 2002 and 2012 for diabetes using metformin. Their study concluded that metformin does not affect the development of major cancer, excluding pancreatic and prostate cancer.

Some research centers have tried to point to the ability of metformin to impede cancer development. The studies in these laboratories have demonstrated that metformin has pleiotropic anticancer effects both in vitro and in vivo (Schulten). This property of metformin was demonstrated in molecular pathways as well as metabolic processes. It is argued that metformin targets stem cells in laboratory animal models such as rats and plays a role in augmenting the benefits of anticancer drugs (Hirsch et al.). In an animal model of rats with postmenopausal breast cancer, metformin was found to prevent the formation of new tumors as well as reduce the size of existing tumors.

However, a problem with studies on the subject is that they were not replicated in human models, with the antineoplastic activity being demonstrated with surrogate markers or showing negative results. Numerous other studies have found metformin to prevent the development of cancer as well as its progression generally. Nevertheless, some studies have disputed these observations arguing that the results were due to time-related biases (Suissa and Laurent; Klil-Drori Laurent and Michael).

This study review relied on data from a large sample. The data from Clalit Health Services associations were of high quality and used data from the Israel National Cancer Registry. The registry has a coverage of about 95% of cancer diagnoses. The Cox Model negated the ill effect of time-related biases while the weighted cumulative exposure approach used allowed for the analysis of different periods. The use of a weighted cumulative exposure concept in real-time relied on special programming, and the adaptation of discrete-time periods allowed for the natural implementation of the weighted cumulative exposure approach. The use of metformin was determined as a time-dependent variable to allow researchers to capture the complexity in diabetes management to account for the various confounding factors.

From the evidence presented in the article under review, it is apparent that the methodologies in most studies that examine metformin and other GLMs and their relationship with cancer development need to be fine-tuned in the future. When the time factor was accounted for in this study, the findings of prior studies supposing metformin has an antineoplastic effect appear to be negated in some cancer types. The current study accounts for the time factor and finds a significant influence of metformin in some types of cancer. A lot remains unknown about metformin activity in reducing cancer development. There is a need for more studies to establish the actual relationship between metformin and the dynamic surrounding cancer development.  

Practice Pearls:

• In an animal model of rats with postmenopausal breast cancer, metformin was found to prevent the formation of new tumors as well as reduce the size of existing tumors.
• This study accounts for the time factor and finds the antineoplastic activity of metformin to be untrue in some cancer cases.
• Metformin therapy may be associated with a decreased risk of colorectal adenomas and colorectal cancer in type 2 diabetes mellitus patients.

References for “Antineoplastic Activity of Metformin”:
Hirsch, Heather A., et al. “Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumour growth and prolong remission.” Cancer research 69.19 (2009):7507-7511time

Klil-Drori, Adi J., Laurent Azoulay, and Michael N. Pollak. “Cancer, obesity, diabetes, and antidiabetic drugs: is the fog clearing?.” Nature reviews Clinical oncology 14.2 (2017): 85.

Schulten, Hans-Juergen. “Pleiotropic effects of metformin on cancer.” International Journal of molecular sciences 19.10 (2018): 2850.

Suissa, Samy, and Laurent Azoulay. “Metformin and the risk of cancer: time-related biases in observational studies.” Diabetes care, 35.12 (2012): 2665-2673.

 Andrew Daoud, PharmD candidate University Florida A&M University