Metformin - Can a Diabetes Drug Fight Cancer?

What is Metformin?

In this issue, we take on an unusual topic for a naturopathic publication: the novel, anticancer activity of a prescription medication, metformin. Metformin is best known as a diabetes medication; it is commonly used as the first-line medication for type 2 diabetes, as well as conditions of prediabetes, such as polycystic ovary syndrome (PCOS). There is increasing interest in metformin in the treatment and prevention of cancer, including among naturopathic physicians specializing in oncology. In this article, we will review initial research that raised awareness in this area, followed by proposed mechanisms that may explain proposed anticancer effects, and lastly, we will review the current clinical data in this area, based on human clinical trials.

Metformin is first and foremost an antihyperglycemic and insulin sensitizer.^{[1, 2]} This means that it improves the action of insulin and regulates high blood glucose levels (also known as blood sugar) in the body. As such, metformin is a first-line therapy for type 2 diabetes. In type 2 diabetes, there is loss of sensitivity to the effects of insulin, the hormone responsible for regulating blood glucose. Under normal conditions, insulin is secreted by the pancreas in response to an increase in blood glucose, such as after a meal. Insulin circulates in the blood and binds to insulin receptors on the surface of cells. Activation of the insulin receptor signals a cascade of events that results in the cell moving more glucose receptors, called GLUT-4, to the cell surface, in order to take up glucose from the blood. The end result is a lowering of blood glucose levels to normal, and intracellular storage of glucose, as glycogen or as fat.

In patients with type 2 diabetes, or in patients with prediabetes including polycystic ovary syndrome, the insulin receptor on the cell surface stops responding properly to insulin. This results in the body producing more insulin, increasing blood insulin levels, in order to produce a stronger signal. This is important, because elevated insulin levels can contribute to worsening hormone balance in other areas, such as polycystic ovary syndrome (PCOS), and may be important in the development of cancer (stay tuned!). In the early stages of prediabetes, this may be enough to overcome reduced insulin sensitivity, returning blood glucose levels to within normal; with progression to diabetes, this ceases to be sufficient, and enough insulin can no longer be produced in order to overcome insulin receptor dysfunction. At this point, metformin may be prescribed.

Metformin acts by decreasing blood glucose levels through effects on the liver, including targeting the liver enzyme AMP-activated protein kinase (AMPK), and by indirectly increasing the responsiveness of the insulin receptor.^[1] Metformin decreases liver production of glucose (hepatic gluconeogenesis), and has positive effects on insulin receptor expression.^{[1, 2]} In general, metformin has a good safety profile, with the most commonly reported side effects being digestive upset and depletion of vitamin B12 levels.^[3]

Diabetes and Cancer Risk

The association of cancer with diabetes is a well-documented phenomenon. Patients with diabetes have increased risk of developing cancer. For instance, a Japanese study of over 30,000 participants found that among participants with diabetes there was a modest increase in risk of cancer.^[4] There was a nonsignificant trend towards increased total cancer risk, 9% increase, among men with diabetes. Among women with diabetes, there was a significant 35% increased risk of cancer. This was also significant for site-specific cancers, including liver cancer, bile duct cancer, stomach cancer, and laryngeal cancer.

Another study found that there was increased risk of cancer among diabetic patients medicated with non-metformin diabetes drugs.^[5] The study included over 10,000 patients who were new users of various diabetes drugs. After only 5.4 years of follow-up, there was already a significantly higher risk of developing cancer among patients treated with the drug class sulfonylureas, and a significantly increased risk of dying from cancer among patients treated with insulin, compared to patients treated with metformin. It is unclear whether these observations reflect harmful effects of sulfonylureas and insulin, or whether this reflects risk reduction by metformin.

Other data have identified the presence of diabetes as a risk factor for colorectal cancer,^[6] lung cancer,^[7] and breast cancer.^[8] The presence of diabetes has also been linked to worse outcomes in cancer treatment. For instance, in a study of prostate cancer patients who had surgical treatment (radical prostatectomy), obese men with diabetes had four-fold increased risk of metastasis (distant spread of the cancer), despite having more aggressive anticancer treatments.^[9] In another study, diabetes at the time of diagnosis independently predicted death from colorectal cancer.^[10] What has emerged more recently is that patients with diabetes who take metformin may have a reduced risk of developing cancer compared to their “peers,” patients with similar characteristics including a diagnosis of diabetes, but who have not been treated with metformin. The mechanism for this effect is actively under study…

Mechanism

Lab-based studies indicating that metformin may possess anticancer activity began emerging almost a decade ago.^{[11, 12, 13]} These studies indicate that metformin inhibits cancer cell growth through inhibition of AMPK, which inhibits the mammalian target of rapamycin (mTOR) pathway. The protein mTOR is important in the translation and expression of proteins within the cell, and in regulating cell proliferation.^{[11, 13, 14]} In animal models, treatment with metformin has been shown to enhance suppression of breast cancer tumor growth when used in conjunction with tamoxifen, an antiestrogen.^[15] This action was associated with effects on the AMPK / mTOR / p70 S76 pathway, as well as another cellular pathway that leads to cell death, the Bax / Bcl-2 apoptotic pathway.^[15]

Another possible, but less thoroughly investigated anticancer action of metformin may be its insulin-lowering effects. Insulin increases growth factors such as insulin-like growth factor-1 (IGF-1), which may promote cancer cell growth.^[16] A 2008 study evaluated treatment with metformin among women with early stage breast cancer without diabetes but whose insulin levels were at least 45 pmol/L.^[17] Unfortunately, this study did not follow the patients to assess cancer treatment outcomes, but the study did show a significant lowering of fasting insulin levels, improvement in insulin sensitivity, and weight reduction by almost 2 kg associated with metformin (1500 mg per day), despite the absence of diabetes.

Metformin may regulate hormone levels in breast cancer patients. A study in breast cancer patients without diabetes found that women taking 1500 mg metformin had a 25% reduction in insulin, 23% reduction in testosterone, and a reduction in free androgen index.^[18] In another study, metformin lowered both testosterone and estrogen in nondiabeteic breast cancer patients.^[19] Together, this data combined with metformin’s effects on the mTOR pathway suggest that this drug may be useful even in nondiabetic patients. This is especially relevant given the large number of individuals who may have insulin resistance (prediabetes), hence increased insulin levels, but not yet meet diagnostic criteria for diabetes.

Metformin and Cancer Risk

The first data on the anticancer effects of metformin came from a 2005 study in the British Medical Journal. This study analyzed a cohort of over 11,000 Scottish patients who had been diagnosed with type 2 diabetes.^[20] Among patients with diabetes who were treated with metformin, there was a lower risk of cancer compared to diabetic patients who were not treated with metformin, adjusted odds ratio, 0.77 (95% confidence interval 0.64–0.92). This indicates a 23% reduction in cancer risk associated with use of metformin. Interestingly, there was also a dose-response curve, indicating that patients who received a higher dose of metformin had a parallel decrease in risk. Another study found that cumulative duration of metformin use following a diagnosis of prostate cancer was associated with decreases in both all-cause death as well as prostate cancer death.^[21] Similarly, in colorectal cancer patients with diabetes, high-dose metformin use was associated with a significant reduction in death from colorectal cancer, by over 50%, compared to diabetics not treated with metformin.^[22] Another study has shown that having diabetes and not taking metformin was associated with worse cancer outcomes in patients with urothelial carcinoma compared to patients who had diabetes and took metformin, as well as nondiabetic patients.^[23] In diabetic women with breast cancer, use of metformin has been shown to increase survival.^[24]

There is a small amount of data available so far from clinical trials. One study evaluated the effect of metformin on Ki-67, a marker of cellular proliferation, in nondiabetic women about to undergo surgery for breast cancer.^[25] This study found no significant effects overall; however, when looking at those women with insulin resistance, there was a nonsignificant but notable10% decrease in Ki-67. There was also a nonsignificant 11% increase in women with good insulin sensitivity. Another pilot study of breast cancer found that there was a significant decrease in Ki-67 associated with use of metformin 1000 mg per day before surgery.^[26] Women were randomized to treatment with metformin and took metformin for two weeks prior to having a biopsy. After taking metformin, the Ki-67 proliferative index of the tumor tissue was significantly lower in patients who took metformin. Notably, these women did not have diabetes. Similar effects were found in another study.^[27] A randomized, double-blind, placebo-controlled trial that is currently in progress is evaluating the ability of metformin to prevent precancerous colorectal polyps in nondiabetic patients.^[14] A previous pilot study by the same team conducted among 26 nondiabetic patients with rectal aberrant crypt foci (ACF), a precancerous lesion of the colon.^[28] Patients were randomized to treatment with 250 mg per day of metformin or placebo. After one month, the metformin group had a significant decrease in the mean number of ACF per patient, whereas this did not change in the control group. In addition, the proliferating cell nuclear antigen index, a measure of cellular proliferation, was significantly decreased in normal colon tissue of the metformin-treated patients.

Data on the effect of metformin on risk of cancer or cancer treatment are largely based on observational data; there are a large number of trials currently underway to assess the anticancer effects in randomized, controlled trials.^[16] A question that has yet to be answered by further research is whether the anticancer effects of metformin among patients with diabetes will hold equally true among patient who do not have diabetes.