Metformin is a bigua nide drug (also known as N′,N′-dimethylbiguanide or 1,1-dimethyl-biguanide) and the number one prescribed insulin-sensitizing drug in the world [1–5]. Metformin is primarily available as a generic medication and it was originally derived from a “natural source”—the French Lilac or Galega officinalis. This is the herbal prototype of the biguanides and also is known by the names “goat’s rue” or “Italian fitch” or “professor-weed.” Galega officinalis derives from “gale” (milk) and “ega” (to bring on) because Galega has been utilized as a galactagogue in small domestic animals, which is how the name “goat’s rue” originated.

Metformin has actually been available in Europe since the 1950s but was not approved by the US FDA until December 30, 1994 [1–5]. An extended release (XR metformin) version was approved in October 2000. Metformin was actually first synthesized and found to lower blood sugar in rabbits in the 1920s, and then put aside for decades because of an increase in insulin synthesizing/utilization research based on the discovery of insulin. A 1957 published clinical trial of diabetes (by French physician Jean Sterne—who coined the name of metformin as the glucose eater or “Glucophage”) was then completed and the UK introduced it in 1958, and Canada in 1972.

Metformin is somewhat similar in structure to the drug “phenformin” (phenethylbiguanide), which in 1977 was removed from the US market because of an increased risk of lactic acidosis [1–5]. And it is also similar to the drug “buformin” (synthesized as an oral antidiabetic in 1957), which was withdrawn from the market in many countries because of an increased risk of lactic acidosis. It was never sold in the USA and still sells in some countries such as Romania.

Metformin is now considered a first-line pharmacological treatment along with diet and exercise for adult and pediatric patients with type 2 mellitus because of its favorable overall profile (glucose control, weight loss, and low risk of hypoglycemia) [6, 7].

It is arguably the only drug proven to prevent prediabetes (high-risk diabetes patients) from becoming diabetes and is a primary treatment in patients with metabolic syndrome. Overall, few drugs in medicine cost less with such a long-term safety profile and even added potential heart health benefits [6].

Metformin works by reducing hepatic glucose production (inhibiting gluconeogenesis) and increasing skeletal muscle tissue uptake of glucose [1–5]. Metformin suppresses gluconeogenesis by 0.6 mg/kg per minute, which essentially leads to a maximum 75 % reduction in liver glucose production. It also reduces blood insulin levels (not directly), increases insulin sensitivity, suppresses synthesis of proteins, fatty acids and cholesterol, and increases the utilization of free fatty acids. Metformin has also demonstrated some evidence of reduced intestinal glucose absorption. Metformin increases insulin sensitivity by activating hepatic and muscle AMP-activated protein kinase (AMPK—“metabolic master switch”), which results in reduction of fatty acid synthesis and stimulation of fatty acid oxidation in the liver and increase in muscle glucose absorption.

Metformin is generally available in 500-, 850-, and 1000-mg tablets [1–5]. The starting dose is 500 mg BID or 850 QD, given with meals. The rec ommended maximum daily dose is 2550 mg (using 850 mg tablets) or 2500 mg/day (using 500 mg tablets) divided and given three times daily [1–5]. For example, the dosage utilized in the United Kingdom Prospective Diabetes Study (UKPDS) was 850 mg TID [8, 9]. The most common dosage utilized in the Diabetes Prevention Program (DPP) was 850 mg BID [10, 11]. In general, clinical experience suggests 500 mg QD with a meal and increasing dose in 500 mg increments every 2–4 weeks until maximum dosage is achieved. Metformin XR can be prohibitively expensive and available in 500- and 750-mg tablets utilized with the evening meal. The maximum recommended dosage is 2000 mg QD [1, 2, 12].

The half-life of metformin is on av erage 5–6-h in plasma (longer retention in red blood cells or blood—up to 18 h), which suggests 94 % of the drug is removed by the body in 24 h [1–5]. This short half-life emphasizes the need for daily compliance whether it is for patients or when measuring glucose and other parameters in clinical trials.

Metformin is limited by gastrointestinal complications (soft stool, diarrhea, flatulence, abdominal pain, and more rarely nausea and vomiting) in up to 50 % of patients, but these adverse effects are usually transient and resolve within days to weeks of initiating treatment [1–5]. Additionally, GI side effects are reduced greatly by titrating increasing dosages of the d rug every 2–4 weeks (for example 500 or 850 QD for 2 weeks and then 500 mg additional) and when it is consumed with food. Although food has been reported to reduce the rate and extent of metformin absorption by increasing the time to peak plasma concentration by approximately 40 min, but this appears to be a small issue especially compared to the overall importance of long-term compliance. Less than 5 % of patients in clinical trial are not able to tolerate the drug due to side effects. Extended-release (XR) metformin appears to improve gastrointestinal tolerability and can be given once a day but is more expensive [12].

Metformin can reduce vitamin B12 and/or potentially magnesium levels so these should be monitored in patients [13, 14]. It has been known that this drug interferes with B12 absorption in the distal ileum and can lower B12 in 10–30 % of patients [13]. The reduction of B12 by metformin appears to dose-dependent. The clinical significance of this cha nge is unknown since megaloblastic anemia has been rarely reported. Metformin increases the risk of vitamin B12 deficiency (serum level <150 pmol/L) and borderline-deficient vitamin B12 (serum level 150–220 pmol/L). Patients should use one multivitamin pill a day with the current recommended daily allowance of B12 (2.4 μg/day for individuals beyond 14 years of age). Abnormally high serum levels of homocysteine and methylmalonic acid (MMA) are also utilized to indicate a B12 deficiency. The impact on magnesium is a more controversial issue in the literature [14], but metformin is at least associated with lower blood magnesium levels and should still be monitored since this could also impact cardiovascular disease status.

Rarely, patients complain of a “metallic taste” with the drug, which has been more commonly found with similar medications such as buformin [1–5]. Regardless, “metallic taste” has been reported in clinical trials in approximately 3–11 % of patients. It al so appears to be self-limiting with only 0.5 % of patients complain of metallic taste after 3 months of treatment. Regardless, a reduction in dose (again my clinical experience) appears to resolve this issue almost immediately in patients distressed by this issue.

The most serious concerning adverse event with metformin is lactic acidosis, where a low pH in body tissues and blood (acidosis) along with incr eases in lactate is problematic [1–5]. This situation usually occurs when cells are exposed to minimal amounts of oxygen (hypoxia), and then cells metabolize glucose anaerobically, which increases lactate levels. Increased lactate is symbolic of tissue damage from hypoxia and hypoperfusion. Liver lactate uptake is reduced with metformin because lactate is a substrate for hepatic gluconeogenesis, which is blocked by metformin. In healthy individuals this slight increase in lactate is simply cleared by healthy kidneys and no increase in blood lactate is observed. However, any condition that exacerbates lactic acidosis is a contraindication of the use of metformin including: alcoholism, heart failure, and/or respiratory disease (inadequate oxygenation of tissues), and the most common cause is kidney disease.

The overall incidence of lactic acid osis on metformin has been estimated to be 0–0.08 per 1000 patient years [15]. A Cochrane review of 347 trials and observational studies found no greater risk of lactic acidosis with metformin compared to other type 2 diabetic drugs [16]. Again, phenformin (another biguanide) was withdrawn in 1977 because of the risk of lactic acidosis [1–5]. And it is also similar to the drug “buformin” (synthesized as an oral antidiabetic in 1957), which was withdrawn from the market in many countries because of an increased risk of lactic acidosis, but it was never sold in the USA.

Metformin is excreted by the kidneys, and it theoretically could accumulate with reduced renal function and increase the risk of lactic acidosis. Metformin was approved in 1994 and the FDA established strict prescribing criteria based on kidney function which remains today and includes the following: Metformin is contraindicated in those with renal issues as suggested by serum creatinine levels of 1.5 mg/dl or greater in males and 1.4 mg/dl or greater in females and should not be used in patients 80 years or older unless creatinine clearance reveals that renal function is not reduced [17].

“The overall incidence of lactic acidosis in metformin users varies across studies from approximately 3 per 100,000 person-years to 10 per 100,000 person-years and is generally indistinguishable from the background rate in the overall population with diabetes” [18]. Still, metformin is contraindicated in some individuals because of impaired kidney function and the potential concerns of lactic acidosis. Yet recent research from a systematic review of 65 past studies suggest despite metformin being renally cleared, drug concentrations usually remain within the therapeutic range and lactate concentrations are not significantly changed when utilized in patients with mild to moderate chronic kidney disease (CKD) (estimated glomerular filtration rates, 30–60 mL/min per 1.73 m²) [18]. These authors suggested individuals with chronic kidney disease (CKD) stage 1 (90 or higher eGFR mL/min) and stage 2 (60–90 eGFR) can receive a maximum dose of 2550 mg of metformin a day for example. And stage 3A (45–< 60) or 3B (30–< 45) CKD could also receive 2000 or 1000 mg metformin depending on stable CKD. And stage 4 (15–< 30) and stage 5 (<15) should not receive metformin. These were only suggestions based on their analyses but are still intriguing and evidence-based.

Intravascular iodinated contr ast media administration could result in lactic acidosis in a patient utilizing metformin [19–21]. However, this rare adverse effect occurs if the contrast causes renal failure. Metformin is excreted primarily by the kidneys so continued utilization of metformin after the initiation of renal failure causes toxic concentrations of the drug and subsequent lactic acidosis. In order to avoid this complication metformin should be withheld after the administration of contrast agent for 48 h, and if renal function is normal after 48 h from receiving contrast then metformin can be reinitiated. However, despite what the package insert recommends, which is also to withhold metformin 48 h before contrast medium is given, others have argued there is no justification for this before and then after procedure (for 48 h). Interestingly, large variations exist for metformin and contrast administration from five international guidelines, which is due to a low amount of evidence within the guidelines themselves [20]. Overall, most guidelines suggest that a patient with normal creatinine and renal function (estimated glomerular filtration rate or eGFR greater than 60 mL/min/1.73 m²) and without comorbidities can continue metformin use after receiving contrast medium. Yet despite a lack of good evidence it also seems prudent to stop metformin 2 days before and after contrast in any patient with a hint of renal insufficiency simply because the benefit exceeds the risk in my opinion, even though in many patients with mild to moderate chronic kidney disease it has been shown to be safe to take metformin.

Regardless, for a good overview or summary of the contraindications to metformin treatment please refer to Table 6.1. It should be reiterated to patients that even alcohol consumption should be minimized on metformin treatment because it has the potential to create insulin surges and potentiate hypoglycemia [1–5], and one mechanism it accomplishes this task appears to be a direct shift in pancreatic microcirculation from exocrine to the endocrine cells with an increase in nitric oxide concentrations and vagal stimuli [22]. Additionally, the caloric content of alcohol and not just insulin alterations can often result in weight gain and inhibit the metabolic benefits of metformin.

Drug and supplement interactions are minimal with metformin because it is not protein bound (negligible binding to plasma proteins), not metabolized hepatically, and accumulates in the gastrointestinal tract, salivary glands and kidneys [1–5]. Metformin is eventually excreted unchanged in the urine. Since metformin is excreted primarily via renal tubular secretion medications that compete with this pathway or interfere with renal function should not be used with metformin. Cationic drugs such as: amiloride, cimetidine, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin are discarded via this renal tubular pathway. However, only cimetidine and metformin has been adequately accessed where a 50 % increase in plasma levels (AUC) of metformin and a 27 % reduction in the 24-h renal excretion of metformin occurred in healthy volunteers [3]. Interestingly, phenformin undergoes hepatic aromatic hydroxylation, which could lead to increased concentration of the drug in those with minimal hydroxylation ability. This is one method whereby phenformin may increase lactic acidosis.

One dietary fiber supplement, guar gum has been preliminarily found to potentially reduce plasma levels of metformin [3, 23]. Still, it is theore tically possible that most fiber supplements would have a similar impact and could also potentiate the glucose lowering effects of this drug. There is a growing list of glucose reducing and/or insulin sensitizing supplements that should either not be combined with metformin or the patient should be monitored more closely when utilizing them initially and these include fiber dietary supplements. A partial listing of these supplements can be found in Table 6.2 [24, 25]. For example, there is some evidence that psyllium fiber (one of the most popular commercial sources in the world) may synergistically reduce glucose levels in diabetics but in my opinion should be taken several hours before or after metformin ideally to prevent absorption or bioavailability issues with the drug.

The history of dietary suppl ements and prescription weight loss medications has been fraught with controversy and removal of products from around the globe, but it still provides an important teachable moment. This is primarily because despite helping individuals lose weight the weight loss medications also increased the risk of cardiovascular disease, cardiovascular events and even death [25]. When a drug or supplement dramatically increases metabolism the downstream implications could result in heart rate, heart rhythm, and blood pressure increases. Fenfluramine, and sibutramine were removed due to an increase in cardiovascular disease (CVD) risk, while a cannabinoid type 1 (CB1) receptor agonist, rimonabant, was removed because of serious psychiatric issues [26]. Currently, almost all of the multiple weight loss drugs and supplements on the markets appear to have some tangible controversy in terms of short and long-term safety, which could partially explain their disappointing sales numbers compared to original projections [25].

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in diabetics, which only further emphasizes the need for a “heart Healthy” drug or supp lement to be used in this population. And CVD is the number one cause of death in men and women overall and this has been the situation in the USA for over 100 years. Thus, the desire to find a medication that improves weight loss and heart health while simultaneously maintaining or improving mental health status should be paramount but could appear to be unrealistic. This is not necessarily the case.

Again, the primary mechanism whereby metformin reduces glucose and insulin is via AMP-activated protein kinase (AMPK) activation, through activation of the upstream kinase liver-kinase B1 (LKB1), and this results in gluconeogenesis inhibition [1–5, 25]. AMPK is the so-called “master metabolic switch” or central cellular energy sensor which responds to inc reases in the adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratio (cellular stress). Nutrient deprivation activates AMPK for example leading to blockage of energy-consuming processes and stimulation of pathways that generate energy, which results in increases in ATP supply. Inadequate activity of AMPK permits uncontrolled cell growth and may also accelerate the cellular aging process. Again AMPK is activated by cellular stress, which results in the restoration of energy levels via regulation of growth and metabolism. A variety of direct and indirect (with weight loss primarily adipose tissue for example) heart healthy markers are improved with metformin. Reduced food consumption with this drug has been documented and not just the potential for an anorectic effect. Improvements in glucose and lipids, but also a reduction in inflammatory markers has occurred with metformin. Endothelial dysfunction improves via improved blood flow and normoglycemia is associated with restoration of normal platelet function. Additionally, there appears to be little to no change in mental health status in patients on metformin, but B12 levels should be monitored because deficient levels could cause cognitive changes.

The impact of metformin on car diovascular outcomes or endpoints of patients with type 2 diabetes has been studied in two randomized trials [27–29]. In the UKPDS, a 39 % lower risk of myocardial infarction over 10 years was observed in overweight patients versus patients on conventional dietary therapy [27], and post-trial follow-up continues to demonstrate positive effects [28]. The second study, the HOME trial, included 390 patients with type 2 diabetes on insulin found metformin reduced the composite cardiovascular endpoint by 40 % [29]. Overall, there appears to be a reduction in all-cause mortality with metformin versus other type 2 diabetes treatment regimens, especially in regards to patients with stable coronary disease, following acute coronary syndrome, and in CHF [30, 31]. Indeed an older systematic review of 40 publications found metformin was associated with a reduced risk of cardiovascular mortality (OR = 0.74) compared with placebo or any other oral diabetes drug [32].

The limitation with metformin and CVD is little is the lack of long-term data of the cardiovascular preventive effects of this drug in the nondiabetic population. Still, a recent small randomized trial examining the effects of metformin (850 mg BID with morning and evening meals, n = 173) on progression of mean carotid intima–media thickness (cIMT) or carotid plaque score in nondiabetics with coronary heart disease and an average BMI and waist circumference of 30–31 and 105 cm found no difference compared to placebo [33]. Regardless, the metabolic effects were impressive overall and safety issues were predictable. This single-center study (Glasgow, UK) known as “CAMERA” (Carotid Atherosclerosis: MEtformin for insulin ResistAnce) was only 18 months with participants also utilizing statins. Metf ormin did significantly reduce all parameters of adiposity including bodyweight, body fat, BMI, and waist circumference at 18 months (p < 0.0001 for all). Mean weight loss in the metformin group was 3.2 kg versus 0.0 kg in the placebo group after 18 months. Interestingly, 7 % (n = 6) of placebo group developed new-onset diabetes and 2 % (n = 2) with metformin. Tissue plasminogen nonsignificantly dropped with metformin, which is consistent with past studies, which suggests that another one of its cardioprotective properties could result from a decrease in prothrombotic potential. Although 21 % (n = 18) of patients experienced diarrhea compared to 5 % (n = 4) with placebo. And 12 % (n = 10) of patients experienced nausea or vomiting versus 1 % (n = 1) with placebo. Metformin caused a significant reduction in vitamin B12 levels (−62 pmol/L; p < 0.0001) by 18 months. Interestingly, gamma-glutamyltransferase (GGT) levels also dropped in the participants on metformin versus placebo (p = 0.0002) but there were no significant changes in alanine aminotransferase (ALT).

In the near future a better understanding of CVD prevention from metformin will occur. For example, there is the GLINT trial, which is a double-blind randomized trial of approximately 12,000 nondiabetic hyperglycemic and increased cardiovascular risk individuals [34]. Participants will be on metformin or placebo for 5 years. Another fascinating trial with be GIPS-III which will access left ventricular ejection fraction for 4 months after acute myocardial infarction in nondiabetic patients (NCT01217307). And the MetCAB (Metformin in Coronary Artery Bypass grafting) study will also examine the impact of metformin on cardiac injury in the setting of bypass grafting (NCT01438723). Preliminary laboratory studies suggest metformin could limit myocardial infarct size and damage.

In order to appreciate the overall heart healthy changes attributed to metformin from a variety of clinical trials Table 6.3 is provided, which are the metabolic parameter benefits of metformin [1–5].

Additionally, an appreciation of the diabetes prevention ability of metformin and/or lifestyle changes has arrived via phase-3 evidence and this is the subject of the next two sections of this chapter.

This landmark trial was published on February 7, 2002 in the New England Journal of Medicine [10]. This trial consisted of 3234 nondiabetic individuals with elevated fasting blood glucose (mean of 106 mg/dl and hemogl obin A1c of 5.9 % and 67 % with a fasting glucose of 95–109 mg/dl and 33 % with 110–125 mg/dl) were assigned to placebo, 850 mg metformin twice daily (850 mg for first month then 850 mg BID thereafter), or lifestyle changes with a goal of at least 7 % weight loss (via low-fat low caloric diet) with 150 min of physi cal activity per week. Mean age and BMI was 51 years and 34 with 68 % women, 45 % members of a minority group and 20 % 60 years of age or older. However, almost 33 % of the participants had a baseline BMI of 22–29! Approximately 70 % of the participants had a family history of diabetes and 16 % of the women had a history of gestational diabetes. The average follow-up was only 2.8 years and compared to placebo the group utilizing metformin reduced the risk of diabetes by 31 % (95 % CI 17–43) and the lifestyle intervention reduced the incidence by 58 %. In addition, and one of the key findings of this landmark publication was the “lifestyle intervention was significantly more effective than metformin.” In fact, the number needed to treat (NNT), or to prevent one-case of diabetes over 3-years for metformin was 13.9 persons for metformin and 6.9 for lifestyle-intervention. Regardless of BMI group (22–<30, 30–35 or >35) metformin or lifestyle was beneficial in reducing the incidence of diabetes regardless of gender and race or ethnic group, but metformin appeared to have a greater impact in those with a BMI of 35 or more. Overall, treatment effects did not significantly differ by gender or race or ethnic group. Daily caloric intake was reduced by 249 kcal in the placebo group, 296 in the metformin group, and 450 kcal in the lifestyle group (p < 0.001). The average weight loss was 0.1, 2.1, and 5.6 kg in the placebo, metformin, and lifestyle groups (p < 0.001). Interestingly, side effects with metformin were significantly (p < 0.02) greater than placebo in terms of gastrointestinal symptoms (diarrhea, flatulence, nausea, and vomiting), but were significantly (p < 0.02) lower with lifestyle changes compared to placebo.

In 2009, the Diabetes Prevention Program Research Group published their 10-year follow-up or outcomes study in the journal Lancet (known as “DPPOS”) [35]. A total of 88 % of the participants (2766 of 3150) enroll ed for an additional follow-up of 5.7 years. On the basis of the original findings all three groups were offered lifestyle support. During the 10-year follow-up since randomization to DPP the modest weight loss with metformin was maintained but som e weight gain occurred in the lifestyle group. Regardless, diabetes incidence in the 10 years since DPP randomization was reduced by 34 % in the lifestyle group and 18 % in the metformin group versus placebo. Interestingly, during this follow-up period the incidences of diabetes in the former placebo and metformin groups was reduced to those in the former lifestyle group, but overall and cumulatively the diabetes incidence continued to be lowest in the lifestyle intervention group. Further analysis of this study has found that diabetes risk was 56 % lower for subjects who had their glucose return to the normal range compared to those that consistently experienced prediabetes (HR = 0.44, p < 0.0001) [11]. Regardless, this follow-up demonstrated that lifestyle interventions or metformin can prevent or delay diabetes for at least 10 years [35]! Interestingly, lipid and blood pressure medication use was less in the lifestyle group and the impact on long-term cardiovascular disease risk parameters were similar for metformin and lifestyle intervention [36].

Clinically, now that so much preventive data has been documented from a variety of studies it is of interest to utilize the th is type 2 diabetes risk score in clinical practice and patients can easily go on li ne and complete this test in less than 1 min [37, 38].

American Diabetes Risk Score consists of seven questions:

Total Score = _______?

Metformin is utilized as one standard of care for many patients with PCOS (polycystic ovary syndrome) [39], and still utilized in some patients with nonalcoholic steatohepatitis (NASH) [40]. Metformin in the laboratory and observationally has exhibited bone protective properties and a neutral or reduced risk of bone fractures [41]. Insulin resistance is also associated with cognitive decline and dementia and preliminary evidence suggests a reduction in this risk with metformin in type 2 diabetes patients [42, 43]. Mental health status is not significantly impacted by metformin except a profound reduction in cobalamin or B12 can occur with this drug, which can increase the risk of depression [44]. Thus, again monitoring of B12 levels is critical with long-term metformin usage. And metformin is known as a drug that down regulates inflammatory cytokines and is also being studied against a variety of other disease including autoimmune conditions [45].

Type 2 diabetes is associated with ins ulin resistance or increased insulin levels which can itself act as a cellular growth factor or mitogen. This is perhaps one of the reasons that there is a higher cancer risk and cancer-related mortality in diabetics, which includes breast cancer [46, 47]. Regardless, countless epidemiologic data has now suggested a reduced risk of cancer and cancer mortality in diabetics utilizing metformin.

Metformin is currently in well over 100 human clinical trials with and without conventional treatment for various forms of cancer [48]. It has shown an ability to not only potentially prevent various forms of cancer, slow progression, act synergistically with some conventional agents, and has already demonstrated a reduction in some conventional treatment side effects (for example weight gain from hormone suppressive medications) [6, 47–49]. A rapid appreciation of the potential role for metformin in cancer can be derived from a diversity of completed studies and their conclusions. It could simply be argued that by preventing diabetes metformin has already demonstrated an ability to prevent cancer.

After a review of 18 publications: “Our analysis support a protective effect of metformin on breast cancer risk among postmen opausal women with diabetes [50],” although not just for prevention, but as an ancillary treatment in breast, endometrial, and ovarian cancer appears promising [51, 52]. Additionally, recent laboratory evidence suggests a potential anti-cervical cancer effect [53].

“Patients with CRC and dia betes treated with metformin appear to have an improved survival outcome.” This was the conclusion of a meta-analysis of six cohort studies [54].

“Metformin repo rtedly improves the overall survival of HNSCC (head and neck squamous cell carcinoma) patients [55].”

A total of sev en studies (three cohort and four case–control) studies found “Metformin treatment was associated with reduced risk of HCC in diabetic patients [56].”

Data from the Sur veillance, Epidemiology, and End Results registry linked to Medicare claims identified 750 patients with diabetes 65–80 years of age diagnosed with stage IV NSCLC. Researchers found the following: “Metformin is associated with improved survival among patients with diabetes with stage IV NSCLC, suggesting a potential anticancer effect [57].”

A retrospective review of 1240 MM pati ents from MD Anderson found metformin is associated with improved clinical outcomes [58].

After a review of 13 stud ies including 10 cohort and three case controls, “use of metformin appears to be associated with a reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus [59].”

Metformin appears to be ass ociated with a lower incidence of prostate cancer and a reduced risk of recurrence after a meta-analysis of 21 observational studies was conducted [60]. Another rigorous systematic review and meta-analysis of 230 citations and only nine studies meeting the inclusion criteria also found the potential for a reduced risk of recurrence [61].

There are a ple thora of potential anticancer mechanisms of action attributed to metformin and a brief review is presented here [6, 62, 63]:

The number of breast cancer clinical trials now utilizing metformin at all stages of this disease from prevention to advanced carcinoma is impressive and many of these trials are summarized in Table 6.4 [71].