Metformin and Cancer – Is There Value for the Non-Diabetic Patient? by Gillian Flower, ND

Abstract

Observational studies of metformin use among individuals with diabetes suggest an anti-cancer effect of this drug. Its effects, if any, in a cancer-affected but non-diabetic population are uncertain. A literature review was conducted. Twenty-three clinical trials and one case report were identified. Metformin use was associated with improved clinical presentation in precancerous conditions including aberrant crypt foci, adenomas and dysplasia. In patients with invasive cancers, metformin decreased the proliferation marker Ki-67. This effect was enhanced in some studies by stratification of patients by hormone receptor status, human epidermal growth factor receptor 2 status, body mass index and insulin responsiveness. Weight, insulin resistance and fasting blood glucose were all improved under metformin treatment. Concerning cancer-related outcomes, studies of progression-free, disease-free and overall survival have yielded inconclusive results. Some benefit was demonstrated in colorectal, prostate, ovarian, and endometrial cancers with mixed results in breast and lung cancers, and neutral results in pancreatic cancer. Future prospective research should explore the use of metformin in both diabetic and non-diabetic individuals to hone the utility of this agent in the context of cancer-related outcomes.

Introduction

Metformin has been the mainstay of diabetic treatment for almost 100 years (Ahmed et al 2021). This biguanide is generally well-tolerated (Nasri and Rafieian-Kopaei 2014), with a side effect profile that can include gastrointestinal disturbances and, rarely, lactic acidosis. For many diabetic patients, this medication is taken for prolonged periods until it is no longer effective or until adverse effects necessitate a change in medication.

Individuals with a diagnosis of diabetes are at higher risk of subsequently developing cancer (Ling et al 2021). This fact may be explained in part by significant overlap in the risk factors for both cancer and diabetes, which include obesity, a sedentary lifestyle, dietary factors, and high blood levels of insulin and glucose (Jee et al 2005).

In 2005, Evans published a study that would intertwine cancer and diabetes from that point forward. This report put forth the notion that metformin may not only manage diabetes but could reduce the risk of developing various cancers.

In the sixteen years that have elapsed since the publication of this pivotal study, a flurry of research has explored the nature of the relationship between metformin, cancer risk and cancer outcomes. This paper seeks to describe the current evidence for this association, focusing on prospective trials in non-diabetic patients to evaluate a potential anti-cancer effect in this population.

Methods

Searches were conducted in PubMed in February and March of 2021. Results were screened and limited to human trials and case reports investigating metformin use in non-diabetic individuals diagnosed with a cancerous or pre-cancerous condition.

Observational studies, both prospective and retrospective, were incidentally reviewed during screening. These publications evaluated the impact of metformin use among patients with diabetes upon cancer-related outcomes. As metformin use has historically been restricted to diabetic individuals, no observational studies of metformin use in non-diabetic patients were identified.

Results

A total of twenty-three clinical trials and one case series pertaining to non-diabetic individuals were identified.

Premalignant Conditions

Four papers discussed the impact of metformin use in precancerous conditions, with a fifth (DeCensi et al 2015) commenting upon precancerous lesions found adjacent to invasive cancer. Diagnoses included aberrant crypt foci (ACFs), ductal carcinoma in situ (DCIS), colonic adenomas and dysplastic lesions associated with head and neck cancers.

Benefit was seen in two controlled trials that reported significant reductions in the number or risk of ACFs, adenomas and polyps following treatment with metformin (Higurashi et al 2016, Hosono et al 2010). A third study assessed effects on the proliferation marker Ki-67 and is described below (DeCensi et al 2015). Conversely, a single-arm study found no benefit from 12 weeks of 2000mg of metformin on this same marker of proliferation (Zell et al 2020).

A single case series was included and described three patients given metformin to treat dysplastic lesions. These patients, with histories of oral or laryngeal cancer, all experienced partial or complete responses to metformin and required no further surgical intervention (Lerner et al 2017).

Invasive Cancers

The remaining 20 publications evaluated individuals with a diagnosis of invasive cancer and examined changes in metabolic, biological and clinical outcomes.

Metabolic Parameters

In patients with diabetes, metformin improves insulin sensitization (Lange et al 2021), reduces blood glucose, and decreases body mass (Attiya 2020). Similar effects are noted in a non-diabetic population taking metformin.

Among non-diabetic patients, five of six studies reporting on metabolic parameters found statistically significant improvements in plasma insulin, insulin-like growth factor 1, IGF binding protein 7, body mass index (BMI), weight, the homeostatic model assessment of insulin resistance (HOMA-IR), fasting blood glucose (FBG) and cholesterol (El-Haggar et al 2016, Kalinsky et al 2014, Laskov et al 2014, Niraula et al 2012, Rothermundt et al 2014). Only one study (Petschsila et al 2020) showed no significant change in metabolic parameters.

Ki-67 Index/Labeling Index

Ki-67 is a marker of proliferation that has been investigated for its utility as a prognostic indicator of pathological complete response to treatment (pCR) (Fasching et al 2011). Nine included publications reviewed the effect of metformin treatment on Ki-67. These studies included women with breast or endometrial cancer and compared Ki-67 results from biopsy samples to those from tumours retrieved from the same patients through surgery at a later date. Metformin was administered from time of diagnosis through to the day before or the day of surgery.

With the exception of three studies (Bonanni et al 2012, Cazzaniga et al 2013, Kalinsky et al 2014) statistically significant decreases in Ki-67 were universally identified (DeCensi et al 2014, DeCensi et al 2015, Hadad et al 2015, Laskov et al 2014, Niraula et al 2012, Petchsila et al 2020). An interaction between estrogen receptor (ER) status and human epidermal growth factor receptor 2 status (Her2) was reported by DeCensi and colleagues (2015), as the decrease in Ki-67 was only significant in women with ER+/Her2+ disease. Results in ER- or Her2-disease were non-significant.

An earlier publication by the same team (DeCensi et al 2014) reported a similar interaction with ER+ disease and Ki-67 percentages. Additionally, this group noted a parallel effect in women who were insulin resistant (HOMA-IR >2.8) or had elevated inflammatory markers (highly sensitive C-reactive protein (hs-CRP)). Other groups reported that changes in Ki-67 LI were independent of BMI (Hadad et al 2015), FBG and hemoglobin A1c (Petschsila et al 2020).

AMP-Activated Protein Kinase (AMPK) and Cancer Stem Cells (CSCs)

AMPK is a regulator of energy homeostasis in the body (Choi and Park 2013). Metformin is believed to activate AMPK-mediated pathways, increasing fat oxidation in the liver and promoting hepatic insulin sensitivity (Rena et al 2017). In addition, AMPK may have anti-proliferative effects in the context of cancer (Choi and Park 2013).

Two trials examined the effects of metformin therapy on AMPK levels, and both identified an increase in the studied population (Godara et al 2020, Hadad et al 2015), suggesting an activation of this kinase by metformin in non-diabetic patients. One paper (Godara et al 2020) described an association between increased AMPK levels and stable disease, but statistical significance was not reported.

Cancer stem cells (CSCs), thought to play an essential role in the initiation of cancer and the development of treatment resistance (Zhang et al 2021), may be a further target of metformin treatment. Brown and colleagues (2020) report decreases in ovarian CSCs compared to tumour samples from historical controls following 24 weeks of treatment with metformin. This decrease was further associated with survival that was “better than expected” when compared to historical controls.

Adverse Effects of Treatment

Metformin has also been investigated for its impact on adverse effects experienced by patients undergoing treatment for cancer. Patients receiving concurrent metformin and chemotherapy had less nausea (Sayed et al 2015) and fewer high-grade incidents of neutropenia (Nanni et al 2019) than their counterparts in control groups. Conversely, individuals receiving a tyrosine kinase inhibitor (TKI) alongside metformin reported more diarrhea with the combination than without (Li et al 2019).

Outcomes Relating to Disease Progression and Survival

Survival outcomes are undoubtedly the most desirable yet elusive targets of treatment. Eleven studies investigated the association between metformin treatment and impacts on overall survival (OS), cancer-specific survival (CSS) and progression free survival (PFS), while one assessed prostate specific antigen (PSA) as a marker of disease progression. These publications included patients with cancers of the breast, digestive tract, prostate, lung and ovary with daily metformin doses ranging from 500-2000mg per day.

Positive Studies

Five papers report positive effects of metformin on survival outcomes and progression of disease. These included OS that was “better than expected” in an uncontrolled trial (Brown et al 2020), and a report of disease control in 55% of the treated sample in a crossover study (Godara et al 2020) (no p-value expressed). A second uncontrolled trial found a decrease in PSA and an increase in PSA doubling time (Rothermundt et al 2014), suggesting a possible impact of metformin on disease progression.

PFS was 47% in a randomized controlled trial (RCT) in patients with lung cancer treated with chemotherapy and metformin, compared to a PFS of 15% in a historical control group (Marrone et al 2018) – PFS was 9.6 months in the treatment arm and 6.7 months in the control arm (p=0.024). A second controlled trial found that metformin treatment was associated with improved PFS (p=0.044) and fewer metastatic events at six months (p=0.05) in women with breast cancer (El-Haggar et al 2016). This difference was no longer statistically significant at 12 months, owing perhaps to the small size of the study.

Neutral and Negative Studies

Three RCTs in patients with breast and lung cancers found no change in survival outcomes with metformin treatment (Pimentel et al 2019, Nanni et al 2019, Sayed et al 2015). The remaining three included trials, conducted in patients with advanced lung or pancreatic cancers, found non-significant trends towards poorer outcomes with the combination of metformin with a TKI or chemotherapy (Kordes et al 2015, Li et al 2019, Reni et al 2016).

Discussion

Hundreds of observational studies have investigated the link between metformin use among individuals with diabetes and cancer-related outcomes since the association was first described in the literature (Evans et al 2005). Systematic reviews summarizing the outcomes of these studies generally report the following:

• Metformin use in patients with diabetes may be associated with lower rates of cancer incidence (Ng et al 2020).
• Metformin may be associated with improved OS and PFS in those with diabetes and cancer (Cao et al 2017).

These positive effects are not seen in every study (Danker et al 2019) or even in every systematic review (Hevroni et al 2020), and some authors wisely advise caution in interpreting the results of these studies for prospective application (Gandini et al 2014).

Treatment by Cancer Site

One important question that results from this somewhat inconclusive research is whether there are cancer sites that are more susceptible to metformin therapy than others. Prospective trial data is discussed below by cancer site.

Colorectal Cancer

Studies in colorectal cancer and its precursors were among those to report the most consistent benefit. As described above, trials in patients with previous ACFs and colonic adenomas experienced clinical regression of their conditions with metformin therapy (Higurashi et al 2016, Hosono et al 2010). Disease stabilization was seen in 55% of participants with invasive gastrointestinal cancers in a later study (Godara et al 2020). More than half of the participants in this crossover trial had colorectal cancer.

These few studies seem to suggest a possible role for metformin in the management of colorectal cancer in non-diabetic patients. This impression is supported by a 2021 practice guideline released by the American Gastroenterological Association, encouraging the use of metformin for its possible anti-neoplastic effects in patients with diabetes (Liang et al 2021).

Encouraging Trends – Ovarian, Endometrial and Prostate Cancer

With such a limited pool of trial data, it is impossible to draw clear conclusions regarding the disease sites that are most susceptible to any anti-cancer impacts of metformin. However, promising results were seen in:

• Ovarian cancer, where a decrease in the number of CSCs was noted, alongside improved overall survival compared to historical controls (Brown et al 2020).
• Endometrial cancer, where decreases in proliferation markers and improvements in metabolic parameters were demonstrated (Laskov et al 2014, Petschsila et al 2020).
• Prostate cancer, where the single uncontrolled trial reported decreased PSA activity in advanced and metastatic disease (Rothermundt et al 2014).

Mixed Results – Breast and Lung Cancer

Clinical trials in breast cancer principally evaluated the effects of metformin on Ki-67, BMI, and insulin resistance. Of the studies assessing survival outcomes, one study found very encouraging reductions in metastatic spread six months after the initiation of hormone therapy. Unfortunately, these differences were not statistically significant by the 12-month time point, somewhat complicating interpretation (El-Haggar et al 2016). Other authors reported no measurable effect in PFS, OS or risk of recurrence (Nanni et al 2019, Pimentel et al 2019).

Studies in lung cancer offer equally contradictory results, with one trial presenting remarkable outcomes – a tripling in the rate of PFS at one year compared to historical controls (Marrone et al 2018) – and the other finding no significant between-group-differences in PFS or OS (Li et al 2019). Larger studies are certainly required to evaluate the significance of these findings.

Neutral Studies – Pancreatic Cancer

The two clinical trials in pancreatic cancer may present a more cohesive, albeit negative picture (Kordes et al 2015, Reni et al 2016). These placebo-controlled trials, both using 2000 mg/day of metformin, showed no evidence of benefit in either PFS or OS and in fact, resulted in non-significant trends to poorer outcomes in the treatment group. While their outcomes may align neatly, it is impossible to make a clinical judgment on the strength of two studies. Further efforts to understand the ideal sites of metformin action are urgently required.

Impact of Disease Stage

Stage of disease may impact outcomes from metformin therapy, suggesting that later stage and metastatic disease may not respond to treatment (Li et al 2017). Results from Sayed’s 2015 trial in metastatic lung cancer and the controlled trials in pancreatic cancer (Kordes et al 2015, Reni et al 2016) corroborate this perspective. This is further supported by the benefits reported in precancerous conditions (Higurashi et al 2016, Hosono et al 2010, Lerner et al 2017), suggesting optimal effect in earlier stages of disease.

However, positive outcomes have been documented in patients with advanced disease as well. Over 52% of metformin-treated patients with metastatic prostate cancer had prolonged PSA doubling time in one uncontrolled trial (Rothermundt et al 2014), while 47% of people with advanced or metastatic lung cancer (Marrone et al 2018) were progression-free at 1 year, compared to the expected 15% suggested by historical controls. These inconsistencies present other key opportunities for further research.

Effects by Patient and Cancer Characteristics

Alongside disease stage, patient characteristics such as BMI, insulin resistance and inflammation as well as tumour receptor status may profoundly impact interpretation of results. This is demonstrated in three publications on the same group of 200 women receiving metformin between biopsy and surgery for breast cancer.

The initial publication (Nanni et al 2012) reported no significant change in Ki-67 with metformin treatment but when patients were stratified by characteristic, significant changes were seen in women with ER+/Her2+ disease (DeCensi et al 2015) or inflammation and insulin resistance (DeCensi et al 2014). This knowledge may help tailor metformin trials and treatment to those who may be expected to derive the most benefit from it.

Impact of Metformin on Risk Factors and Mechanism of Action

Obesity, insulin resistance (Jee et al 2005) and elevated fasting blood glucose levels (Haseen et al 2015) have all been associated with an increase in cancer risk. Although patients in these studies were not classified as having diabetes, participants with metabolic risk factors were included.

With the exception of one paper, metformin consistently and significantly modified these risk factors. It is notable that the neutral trial (Petchsila et al 2020) used metformin for as little as 12 days at the relatively low dose of 850 mg per day. These effects suggest that metformin improves metabolic parameters in non-diabetic people and may explain its antineoplastic effects.

Additional mechanisms for metformin’s effects in cancer have been proposed and include:

• Inhibition of CSCs (as evidenced in Brown and colleagues 2020).
• Reversal of immune suppression through AMPK activation (Li et al 2018).
• Inhibition of epigenetic alterations associated with cancer progression (Tang et al 2018).

AMPK is central to the activation of these disparate pathways, highlighting the importance of studies that report increases in this compound (Godara et al 2020, Hadad et al 2015).

Future Directions for Research

As of March 2021, over 100 active clinical trials of metformin in cancer were registered at www.clinicaltrials.gov. Although the utility of metformin in a non-diabetic, cancer-affected population is still incompletely understood, there are enough signals of benefit in the current research to warrant further investigation. One of particular interest to this author is NCT01101438 (completion February 2022): “A Phase III Randomized Trial of Metformin vs Placebo in Early-Stage Breast Cancer”. To date, over 3600 participants have been recruited to take metformin or placebo alongside standard of care for five years. This large trial is expected to make a significant contribution to our understanding of the therapeutic potential of metformin in cancer.

Future directions for research should seek to understand the apparent disparity between the encouraging results seen in case control and cohort studies and the inconsistent results in disease-based outcomes in controlled trials. Have observational studies severely overestimated the impact of metformin, or have we simply not identified the populations that may benefit from this intervention? Optimal dose and treatment duration and ideal disease targets must also be established through prospective trials.

Future studies examining clinically relevant outcomes such as progression and mortality would ideally incorporate evaluations of markers of proliferation, immune activity, or biochemical changes. The inclusion of biometric data would help to illuminate the contribution of perceived improvements in risk factors (insulin resistance, BMI) to concrete outcomes like survival.

Finally, future research should also investigate the anti-neoplastic effects of metformin in its original target population, patients with Type II diabetes. While observational studies show significant promise, it is not yet clear whether metformin should be prioritized over other glucose-lowering agents for its potential effects in cancer.

Conclusion

Observational research has suggested that metformin may possess significant anti-neoplastic activity, but its action in non-diabetic patients remains uncertain. This study summarizes the available data from 23 clinical trials and one case report in non-diabetic individuals. While metformin appears to have measurable benefit in pre-cancerous conditions and may influence cancer risk factors, its effects in survival outcomes are less certain. Future investigation is required to identify the ideal parameters of metformin use in in non-diabetic individuals.

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