Note: This is the second in a 2-part series on whether metformin has a place in natural medicine. Find the first installment here.
Higurashi T, Hosono K, Takahashi H, et al. Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial. Lancet Oncol. 2016;17(4):475-483.
A 1-year multicenter, double-blind, placebo-controlled, randomized phase 3 clinical trial was conducted to assess the safety and chemopreventive effects of metformin on sporadic colorectal cancer (assessed by adenoma and polyp recurrence) in patients with a high risk of adenoma recurrence.
One hundred and fifty-one nondiabetic adult patients who had previously had single or multiple colorectal adenomas or polyps resected by endoscopy were enrolled in the study from 5 hospitals in Japan. Seventy-nine were assigned to the metformin group and 72 to the placebo group. After 1 year, 71 patients in the metformin group and 62 in the placebo group underwent a 1-year follow-up colonoscopy.
Study Medication and Dosage
Metformin 250 mg per day
Number and prevalence of adenomas or polyps
The prevalence of both adenomas and total polyps (hyperplastic polyps plus adenomas) in the metformin group was significantly lower than in the placebo group. In the metformin group there were 27 polyps (38.0%) in 71 patients. In the placebo group, 35 polyps (56.5%) occurred in 62 patients (risk ratio [RR]:0.67; P=0.034). The metformin group had 22 adenomas in 71 patients (30.6%) and the placebo group had 32 in 62 patients (51.6%; RR: 0.60; P=0.016). Adverse events, which were all grade 1, were seen in 15 (11%) patients. Low-dose metformin reduced the prevalence and number of metachronous adenomas or polyps after polypectomy.
These results suggest metformin may be of significant benefit in patients who have had a polyp or adenoma removed during routine colonoscopy. The findings stand out for 2 reasons: first, these were nondiabetic patients; and second, these patients received relatively small doses of metformin. Diabetics are typically prescribed 1,000 mg or more per day of metformin.
Colorectal cancer (CRC) arises from a collection of DNA mutations within normal cells, proceeding through polyps to cancer. The mechanisms of metformin appear to stall this process. Thus metformin should be added to the list of agents that forestall polyp formation and thereby forestall colorectal cancer.
Several earlier papers by Higurashi and colleagues (authors of this present study) preceded this clinical trial of metformin for CRC prevention. Those demonstrated the chemopreventive effect of metformin in 2 rodent models and 1 human study of colorectal carcinogenesis. In a 2008 study they showed that metformin suppressed the development of intestinal polyps in a mouse model of familial adenomatous polyposis.1 In 2010 they reported that metformin suppressed azoxymethane-induced formation of colorectal aberrant crypt foci (ACF) by activating adenosine monophosphate-activated protein kinase (AMPK).2
To reduce the burden of colon cancer, the authors of a 2007 study suggest a paradigm shift—turning from the current focus on early detection of cancer toward efforts to actually lower the incidence of (ie, prevent) cancer. They point out, “Several large epidemiologic and/or clinical studies have evaluated the possible preventive effects of more than 200 agents, including fiber, calcium, and nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin and selective cyclooxygenase-2 (COX-2) inhibitors, in protecting against CRC development.”3 The NSAIDs and COX-2 inhibitors have shown the most promise, though the latter are associated with increased risk of cardiovascular events.4 In contrast to COX-2 inhibitors, metformin appears remarkably safe.
Curcumin has been on our list of supplements to consider for preventing CRC because it has effectively inhibited polyp formation in mice fed a high-fat diet.5 While curcumin also activates AMPK as metformin does, it does not have the human data to support its use. Because the authors of the present study believe that metformin’s mechanism of action is through activation of AMPK, we might ponder whether other AMPK activators could have similar preventive action.
These results stand out for two reasons: first, these were nondiabetic patients; and second, these patients received relatively small doses of metformin.
Berberine is often suggested as a botanical substitute for metformin in treating type 2 diabetes mellitus.6 Berberine also activates AMPK and inhibits colon tumor formation in mouse models.7
Metformin has a significant impact on the digestive tract, a fact patients will inform you of if they consume too large a dose. Regular metformin use shifts the gut microbiome. These shifts account for some of metformin’s effect on glucose homeostasis.8 Berberine has been shown to promote similar shifts in gut microbiome.9
Whether or not the drug metformin is within your scope of practice, or even if it is but for philosophical reasons your patients choose not to use it, the information in this current study is of interest. We can translate the results from this metformin study to suggest that other agents that have similar chemical effects on AMPK or the gut biome might bring similar, albeit unproven benefits.
Is metformin natural medicine?
Our practice at the Natural Medicine Journal is to highlight the use of natural and complementary medicines so that our primary readership, naturopathic physicians, may stay informed of current research as it impacts their clinical practices. Featuring information on the prescription drug metformin may appear as a departure from that practice. After careful consideration we have made the decision to review a pair of research papers on metformin because the information is of clinical relevance to many of our patients. Some would argue that as a prescription drug, metformin is not a natural medicine. Others would argue that as a synthetic mimic of a chemical derived from Galega officinalis, it falls in a less defined category. Prescribing metformin now falls within the scope of many of our colleagues so this distinction may be fading in relevance. Even for those of us who cannot prescribe metformin, its new potential utility in prevention and treatment of cancer is still relevant, because many natural substances and lifestyle practices we routinely prescribe patients may have similar impacts on physiology.
As of June 2016 there were nearly 2000 papers referenced on PubMed (by MeSH terms) related to metformin and cancer. Two publications published in 2016 will be discussed in this issue. The mechanisms of metformin action result in a list of anticancer benefits, including blocking the mTOR pathway, stimulating apoptosis of cancer stem cells, inhibiting angiogenesis, suppressing HER2 (human epidermal growth factor receptor 2, a protein sometimes associated with breast cancer), increasing the benefit of several chemotherapies, and enhancing radiation cell kill. There is evidence that berberine may produce some of these same effects, and while this idea generates great enthusiasm among our colleagues in regard to employing berberine for similar situations, there is far more published evidence concerning metformin. There is no discernable structural similarity between metformin and berberine molecules and the 2 substances do not always produce the same actions. So though some may speak of berberine as a botanical substitute for metformin, care should be taken with such assumptions, especially if metformin has been shown to accomplish something not yet shown for berberine.
Editor, Abstracts & Commentary
Natural Medicine Journal
- Tomimoto A, Endo H, Sugiyama M, et al. Metformin suppresses intestinal polyp growth in ApcMin/+ mice. Cancer Sci. 2008;99(11):2136-2141.
- Hosono K, Endo H, Takahashi H, et al. Metformin suppresses azoxymethane-induced colorectal aberrant crypt foci by activating AMP-activated protein kinase. Mol Carcinog. 2010;49(7):662-671.
- Das D, Arber N, Jankowski JA. Chemoprevention of colorectal cancer. Digestion. 2007;76(1):51-67.
- Meyskens FL, McLaren CE, Pelot D, et al. Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: a randomized placebo-controlled, double-blind trial. Cancer Prev Res (Phila). 2008;1(1):32-38.
- Pettan-Brewer C, Morton J, Mangalindan R, Ladiges W. Curcumin suppresses intestinal polyps in APC Min mice fed a high fat diet. Pathobiol Aging Age Relat Dis. 2011;1.
- Dong H, Wang N, Zhao L, Lu F. Berberine in the treatment of type 2 diabetes mellitus: a systemic review and meta-analysis. Evid Based Complement Alternat Med. 2012;2012:591654.
- Zhang J, Cao H, Zhang B, et al. Berberine potently attenuates intestinal polyps growth in ApcMin mice and familial adenomatous polyposis patients through inhibition of Wnt signalling. J Cell Mol Med. 2013;17(11):1484-1493.
- McCreight LJ, Bailey CJ, Pearson ER. Metformin and the gastrointestinal tract. Diabetologia. 2016;59(3):426-435.
- Bouchoucha M, Uzzan B, Cohen R. Metformin and digestive disorders. Diabetes Metab. 2011;37(2):90-96.