Diabetes and cancer are common diseases that have a tremendous impact on health worldwide. Epidemiologic evidence suggests that people with diabetes are at a significantly higher risk of many forms of cancer. Type 2 diabetes and cancer share many risk factors, but to our knowledge, potential biologic links between the 2 diseases are incompletely understood. Moreover, evidence from observational studies suggests that some medications used to treat hyperglycemia are associated with either an increased or reduced risk of cancer. Against this backdrop, the American Diabetes Association and the American Cancer Society convened a consensus development conference in December 2009. After a series of scientific presentations by experts in the field, the writing group independently developed this consensus report to address the following questions:
- 1Is there a meaningful association between diabetes and cancer incidence or prognosis?
- 2What risk factors are common to both diabetes and cancer?
- 3What are possible biologic links between diabetes and cancer risk?
- 4Do diabetes treatments influence the risk of cancer or cancer prognosis?
For each area, the authors were asked to address the current gaps in evidence and potential research and epidemiologic strategies for developing more definitive evidence in the future. Table 1 includes a summary of their findings and recommendations. Recommendations in this report are solely the opinions of the authors and do not represent the official position of the American Diabetes Association or the American Cancer Society.
Table 1. Summary and Recommendations
|• Diabetes (primarily type 2) is associated with an increased risk of some cancers (liver, pancreas, endometrium, colon/rectum, breast, and bladder). Diabetes is associated with a reduced risk of prostate cancer. For some other cancer sites, there appears to be no association or the evidence is inconclusive.|
|• The association between diabetes and some cancers may be due in part to shared risk factors between the 2 diseases such as aging, obesity, diet, and physical inactivity.|
|• Possible mechanisms for a direct link between diabetes and cancer include hyperinsulinemia, hyperglycemia, and inflammation.|
|• Healthful diet, physical activity, and weight management reduce the risk and improve outcomes of type 2 diabetes and some forms of cancer and should be promoted for all.|
|• Patients with diabetes should be strongly encouraged by their health care professionals to undergo appropriate cancer screenings as recommended for all people of their age and sex.|
|• The evidence for specific drugs affecting cancer risk is limited, and observed associations may have been confounded by indications for specific drugs, effects on other cancer risk factors such as body weight and hyperinsulinemia, and the complex progressive nature of hyperglycemia and pharmacotherapy in type 2 diabetes.|
|• Although still limited, early evidence suggests that metformin is associated with a lower risk of cancer and that exogenous insulin is associated with an increased cancer risk. Further research is needed to clarify these issues and evaluate if insulin glargine is more strongly associated with cancer risk compared with other insulins.|
|• Cancer risk should not be a major factor when choosing between available diabetes therapies for the average patient. For selected patients with a very high risk of cancer occurrence (or for recurrence of specific cancer types), these issues may require more careful consideration.|
|• Many research questions remain.|
1) Is There a Meaningful Association Between Diabetes and Cancer Incidence or Prognosis?
Both diabetes and cancer are prevalent diseases whose incidence is increasing globally. Worldwide, the prevalence of cancer has been difficult to establish because many areas do not have cancer registries, but in 2008 there were an estimated 12.4 million new cancer cases diagnosed. The most commonly diagnosed cancers are those of the lung/bronchus, breast, and colorectum, whereas the most common causes of cancer deaths are lung, stomach, and liver cancer.1 In the United States, the most commonly diagnosed cancers are those of the prostate, lung/bronchus, and colon/rectum in men and the breast, lung/bronchus, and colon/rectum in women. Of the world population between the ages of 20 and 79 years, an estimated 285 million people, or 6.6%, have diabetes.2 In 2007, diabetes prevalence in the United States was 10.7% of persons aged 20 years and older (23.6 million individuals), with an estimated 1.6 million new cases reported each year. Type 2 diabetes is the most common form, accounting for approximately 95% of prevalent cases.3 Worldwide, cancer is the 2nd and diabetes is the 12th leading cause of death.4 In the United States, cancer is the 2nd and diabetes is the 7th leading cause of death; the latter is likely an underestimate, because diabetes is under-reported on death certificates as both a cause and comorbid condition.3
Cancer and diabetes are diagnosed within the same individual more frequently than would be expected by chance, even after adjusting for age. Both diseases are complex, with multiple subtypes. Diabetes is typically divided into 2 major subtypes, type 1 and type 2, along with less common types, whereas cancer is typically classified by its anatomic origin (of which there are more than 50 [eg, lymphoma, leukemia, lung, and breast cancer]), within which there may be multiple subtypes (eg, leukemia). Furthermore, the pathophysiologies underlying both cancer and diabetes are (with rare exceptions) incompletely understood.
For more than 50 years, clinicians have reported the occurrence of patients with concurrent diabetes and cancer. However, as early as 1959, Joslin et al5 stated that although studies examining the association between diabetes and cancer have been conducted over several years, there is no conclusive evidence of a positive association. Subsequently, an association between the 2 diseases was identified in the 1960s in population-based studies. More recently, the results of several studies have been combined for meta-analytic study,6 indicating that some cancers develop more commonly in patients with diabetes (predominantly type 2), whereas prostate cancer occurs less often in men with diabetes. The relative risks imparted by diabetes are greatest (approximately 2-fold or higher) for cancers of the liver, pancreas, and endometrium, and lesser (approximately 1.2-fold to 1.5- fold) for cancers of the colon/rectum, breast, and bladder. Other cancers (eg, those of the lung) do not appear to be associated with an increased risk in diabetes, and the evidence for others (eg, kidney and non-Hodgkin lymphoma) is inconclusive. To the best of our knowledge, few studies to date have explored links with type 1 diabetes.
Because insulin is produced by pancreatic β cells and then transported via the portal vein to the liver, both the liver and the pancreas are exposed to high concentrations of endogenously produced insulin. Diabetes-related factors including steatosis, nonalcoholic fatty liver disease, and cirrhosis may also enhance susceptibility to liver cancer. With regard to pancreatic cancer, interpretation of the causal nature of the association is complicated by the fact that abnormal glucose metabolism may be a consequence of pancreatic cancer (so-called “reverse causality”). However, a positive association between diabetes and pancreatic cancer risk has been found when restricted to diabetes that precedes the diagnosis of pancreatic cancer by at least 5 years; therefore, reverse causation does not likely account for the entirety of the association.
Diabetes is associated with a lower risk of prostate cancer only. This association has been observed both before and after the advent of screening with prostate-specific antigen (PSA), and therefore detection bias due to differential PSA utilization does not account for this finding. Some metabolic factors associated with diabetes, such as reduced testosterone levels, may be involved (although circulating testosterone levels have not been found to be consistently associated with prostate cancer incidence). Although obesity has not been found to be associated, and in some studies is even reported to be inversely associated, with prostate cancer incidence, obese men with prostate cancer have higher cancer mortality rates than those of normal weight.7 In addition to metabolic factors such as hyperinsulinemia, obesity may be associated with clinical factors (such as delayed diagnosis and poorer treatment) that may underlie the worsened prostate cancer prognosis.
Results of some, but not all, epidemiological studies suggest that diabetes may significantly increase mortality in patients with cancer.8 For example, in one study, 5-year mortality rates were significantly higher (hazard ratio, 1.39) in patients diagnosed with both breast cancer and diabetes than in comparable breast cancer patients without diabetes.9 Because diabetes is associated with excess age-adjusted mortality, whether the apparent excess mortality associated with diabetes in cancer patients is any greater than the excess mortality observed among diabetic patients without cancer is unclear. It is interesting to note that higher prediagnosis C-peptide levels (an indirect marker of insulin resistance) have been associated with a poorer disease-specific survival for patients with prostate cancer7 and colorectal cancer.10
Diabetes has been consistently associated with an increased risk of several of the more common cancers, but for many, especially the less common cancers, data are limited or absent,6 and more research is needed. Uncertainty is even greater regarding the issue of diabetes and cancer prognosis or cancer-specific mortality. It remains unclear whether the association between diabetes and cancer is direct (eg, due to hyperglycemia), whether diabetes is a marker of underlying biologic factors that alter cancer risk (eg, insulin resistance and hyperinsulinemia), or whether the association between cancer and diabetes is indirect and due to common risk factors such as obesity. Whether cancer risk is influenced by the duration of diabetes is a critical and complex issue and may be complicated further by the multidrug therapy often necessary for diabetes treatment. What is also required is a better understanding of whether diabetes influences cancer prognosis above and beyond the prognosis conferred by each disease state independently.
To adequately address these questions, prospective population-based studies with high-quality databases are needed to compare the incidence of specific cancers between individuals with high circulating insulin levels with or without diabetes and nondiabetic individuals with normal insulin sensitivity (and therefore low insulin levels). Examining other diabetes-related biomarkers (eg, adiponectin, hyperglycemia) is also critical. Importantly, common confounders (such as body weight and physical activity) must also be more readily available and assessed. Better characterization of aspects of diabetes (diabetes duration, therapy, and degree of glycemic control) in relation to cancer risk is needed. In view of the variable associations between diabetes and cancer risk at specific sites, we discourage studies exploring links between diabetes and risk of all cancers combined. For example, because lung cancer does not appear to be meaningfully linked with diabetes, including this common cancer in studies will dilute observed associations, should they exist.
2) What Risk Factors Are Common to Both Cancer and Diabetes?
Potential risk factors (modifiable and nonmodifiable) common to both cancer and diabetes include age, sex, obesity, physical activity, diet, alcohol, and smoking.
Nonmodifiable Risk Factors
Although the incidence of some cancers peaks in childhood or young adulthood, the incidence of most cancers increases with age. In economically developed countries, approximately 78% of all newly diagnosed cancer occurs among individuals aged 55 years and older.11 Diabetes also becomes increasingly common with age, with a prevalence of 2.6% in American adults ages 20 to 39 years and 10.8% in those ages 40 to 59 years, and increases to 23.8% in those aged 60 years or older.3 In parallel with the obesity epidemic, type 2 diabetes is becoming more frequent among adolescents and young adults,12, 13 potentially adding years of additional risk from diabetes to the population.
Although certain cancers are sex-specific (eg, cervical, uterine, testicular, and prostate malignancies) or nearly so (breast cancer), overall, cancer occurs more frequently in men. Men also have a slightly higher age-adjusted risk of diabetes than women.3
The age-standardized incidence of cancer and diabetes varies significantly among different populations. Factors that may contribute to this variability include differences in the prevalence of major risk factors, genetic factors, medical practices such as screening, and completeness of reporting. In the United States, African Americans are more likely to develop and die of cancer than other racial or ethnic groups. After African Americans are non-Hispanic whites, with Hispanics, Native Americans, and Asian Americans/Pacific Islanders having lower cancer incidence and mortality.14 Similar to findings worldwide, the racial/ethnic variability in cancer incidence in the United States is attributed, at least in part, to socioeconomic and other disparities, but biological factors, such as levels of hormones that vary by race,15 also may play a role.
In the United States, type 2 diabetes and its complications disproportionately affect several specific populations, including African Americans, Native Americans, Hispanics, and Asian Americans/Pacific Islanders compared with non-Hispanic whites.3 Although incompletely understood, genetic, socioeconomic, lifestyle, and other environmental factors are believed to contribute to these disparities.
Modifiable Risk Factors
Overweight, Obesity, and Weight Change
Overweight (defined as a body mass index [BMI] ≥25 kg/m2 and <30 kg/m2) or obese (BMI ≥30 kg/m2) individuals have a higher risk of many types of cancer compared with individuals whose BMI is considered within the normal range (18.5 to <25 kg/m2).16, 17 The cancers most consistently associated with overweight and obesity are those of the breast (in postmenopausal women), colon/rectum, endometrium, pancreas, adenocarcinoma of the esophagus, kidney, gallbladder, and liver. Obesity may also increase the risk of mortality from some cancers, such as prostate.7 A growing body of evidence suggests that weight gain is associated with an increased risk of some cancers, breast cancer in particular.17 Increases in body weight during adulthood largely reflect increases in adipose tissue rather than lean mass, and therefore total body fat may be a better measure of the risk of cancer than BMI.
Studies conducted over decades have consistently demonstrated a strong association between obesity and both insulin resistance and type 2 diabetes incidence,18 with risk of diabetes and earlier age at onset reported to be directly linked to obesity severity.19 For type 2 diabetes20 as well as certain cancers (eg, colon),21 some studies suggest that waist circumference, waist-to-hip ratio, or direct measures of visceral adiposity are associated with risk independently of BMI.
The case for a causal relation between obesity and disease is strengthened by evidence that weight loss lowers disease risk. In the case of diabetes, numerous studies have shown that weight loss decreases diabetes incidence and restores euglycemia in a significant percentage of individuals with type 2 diabetes. In the randomized, prospective, multicenter Diabetes Prevention Program trial, an intensive lifestyle intervention of diet (targeting 5–7% weight loss) and physical activity was associated with a 58% reduction in diabetes incidence in high-risk individuals,22 and weight loss accounted for the majority of the effect.23 In addition, weight loss may also limit the risk of developing gestational diabetes.24
The association between weight loss and subsequent cancer risk is less clear. Most evidence has been derived from breast cancer studies, in which weak or null associations were observed. Because the weight loss definition and the referent groups differed across studies, these studies are difficult to compare. Weight loss categories tend to have small numbers, and many women who do lose weight do not maintain their weight loss beyond 1 year. In the Nurses' Health Study, a statistically significant inverse association between adult weight loss and postmenopausal breast cancer was found only when the weight loss had been maintained for 2 survey cycles, or 4 years.25 Observational studies of weight loss and cancer risk require extremely large sample sizes with long-term follow-up and careful monitoring of weight change. One concern of all observational studies of weight loss and subsequent cancer risk is that weight loss may be a sign of undiagnosed cancer. As a practical matter, a randomized clinical trial to study the effect of weight loss on cancer risk is unlikely to be feasible; such a study would have to be very large and would likely be stopped early due to a protective effect on diabetes and heart disease before enough cancer endpoints would accumulate.
The significant amount of weight lost achieved with bariatric surgery may also provide clarity to this issue. However, a recent summary26 noted the limited evidence of the effects of bariatric surgery on cancer incidence. Among the studies published to date, 3 found that obese women who underwent bariatric surgery were at lower risk of cancer (relative risks range, 0.58-0.62) compared with untreated obese women. The inverse associations appeared to be due in large part to a protective effect on breast and endometrial cancer. In the 2 studies that included men, no association between bariatric surgery and cancer risk was observed.
Bariatric surgery is a very effective treatment for patients with type 2 diabetes, with a meta-analysis demonstrating that type 2 diabetes resolved in 78% and resolved or improved in 87% of patients after bariatric surgery.27 In contrast to the known effects of bariatric surgery in the treatment of diabetes, its role in preventing diabetes would appear likely but to our knowledge has not been established through prospective trials.
A majority of studies (despite different study designs and differing study populations) suggest that diets low in red and processed meats and higher in vegetables, fruits, and whole grains are associated with a lower risk of many types of cancer.17, 28, 29 Diets that are low in red and processed meat but high in monounsaturated fatty acids, fruits, vegetables, whole-grain cereals, and dietary fiber may protect against type 2 diabetes, possibly through improving insulin sensitivity.30, 31 Low-carbohydrate diets (which often include a greater consumption of red meats and fat) have also been associated with weight loss and improvements in insulin sensitivity and glycemic control. However, to the best of our knowledge, randomized controlled trial evidence of dietary interventions and diabetes prevention exists only for low-fat, low-calorie, plus/minus high-fiber diets.22, 32
Several studies have suggested that diets high in foods with a high glycemic index or load are associated with an increased risk of type 2 diabetes.28, 33 However, evidence of their associations with cancer risk is mixed.28, 34, 35 Regardless, to the extent that energy-dense and sugary foods contribute to overweight and obesity, the American Cancer Society, the World Cancer Research Fund, and the American Institute for Cancer Research recommend limiting consumption of these foods.17, 29
Evidence from observational epidemiologic studies consistently demonstrates that higher levels of physical activity are associated with a lower risk of colon, postmenopausal breast, and endometrial cancer.17, 36, 37 Physical activity may also help prevent other cancers, including lung and aggressive prostate cancer, but a clear link has not been established to date. Some evidence also suggests that physical activity after diagnosis may improve survival for some cancers, including those of the breast38 and colorectum.39
A protective role for increased physical activity in diabetes metabolism and outcomes has been demonstrated. Data from observational and randomized trials suggest that approximately 30 minutes of moderate-intensity physical activity, such as walking, at least 5 days per week substantially reduces (approximately 25-36%) the risk of developing type 2 diabetes.40 Analyses of the effects of different components of the intensive lifestyle intervention in the Diabetes Prevention Program have suggested that those who did not reach weight loss goals still significantly reduced their risk of diabetes if they achieved the physical activity goals, although weight loss was the only component found to be independently associated with diabetes prevention on multivariate analyses.23
It is estimated that worldwide, tobacco smoking accounts for 71% of all trachea, bronchus, and lung cancer deaths.41 Other cancers strongly associated with smoking are those of the larynx, upper digestive tract, bladder, kidney, pancreas, leukemia, liver, stomach, and uterine cervix. Studies suggest that smoking is also an independent risk factor for the development of diabetes.42, 43 In addition, because of the effect of smoking on increasing the risk of cardiovascular disease, retinopathy, and other complications of diabetes, smoking has an adverse effect on diabetes-related health outcomes.44
Alcoholic beverage consumption, even in moderate amounts, increases the risk of many types of cancer including those of the oral cavity, pharynx, larynx, esophagus, liver, colon/rectum, and female breast.45 Although excess alcohol consumption is also a risk factor for diabetes, moderate alcohol consumption has been associated with reduced diabetes incidence in both men and women.46, 47
A critical question is whether the association between diabetes and the risk of certain cancers is largely due to shared risk factors (obesity, poor diet, physical inactivity, and aging), or whether diabetes itself, and the specific metabolic derangements typical of diabetes (eg, hyperglycemia, insulin resistance, and hyperinsulinemia), increases the risk of some types of cancer. Although it is clear that lower levels of adiposity, a healthy diet, and regular physical activity are associated with a reduced risk of type 2 diabetes and several common types of cancer, these factors are generally interrelated, making the contribution of each factor difficult to assess. More research is needed to understand the role of specific components of a healthy lifestyle independent of others (eg, diet quality independent of body weight). In addition, further study of those who are of normal body weight but have hyperinsulinemia or are sedentary and those who are obese but have normal metabolic parameters is necessary to better understand the relation between diabetes and cancer risk. To the best of our knowledge, little is known regarding how modifiable lifestyle factors influence prognosis in cancer patients. The question of how genetic variants that influence diverse aspects of diabetes (eg, insulin resistance and β-cell depletion) affect cancer risk may provide insights into the nature of the association between diabetes and cancer. Addressing these questions will require large, long-term observational studies, with their inherent limitations. Although not powered for cancer outcomes, long-term trials such as the Look AHEAD trial of the effects of weight loss on cardiovascular outcomes in patients with diabetes,48 and follow-up of cohorts in lifestyle studies such as the Diabetes Prevention Program, may provide further evidence of the impact of lifestyle improvements on cancer incidence.
3) What Are Possible Biologic Links Between Diabetes and Cancer Risk?
Carcinogenesis is a complex process. Normal cells must undergo multiple genetic “hits” before the full neoplastic phenotype of growth, invasion, and metastasis occurs. This process of malignant transformation can be divided into multiple steps: initiation (irreversible first step toward cancer), promotion (stimulation of the growth of initiated cells), and progression (development of a more aggressive phenotype of promoted cells). Factors that affect one or more steps of this pathway could be associated with cancer incidence or mortality. Diabetes may influence the neoplastic process by several mechanisms, including hyperinsulinemia (either endogenous due to insulin resistance or exogenous due to administered insulin or insulin secretogogues), hyperglycemia, or chronic inflammation.
The Insulin/Insulin-Like Growth Factor Axis
Insulin and insulin-like growth factor (IGF) receptors form a complex network of cell surface receptors; homodimers and heterodimers have been described, and all function to mediate insulin and IGF responses.49 The majority of cancer cells express insulin and IGF-I receptors; the A isoform of the insulin receptor is commonly expressed. The A receptor isoform can stimulate insulin-mediated mitogenesis, even in cells deficient in IGF-I receptors.50 In addition to its metabolic functions, the insulin receptor is also capable of stimulating cancer cell proliferation and metastasis. Because most glucose uptake in cancer cells is constitutively high and independent of insulin binding to its receptor,51 the effects of insulin receptor activation on neoplastic cells may relate more to cell survival and mitogenesis than to enhanced glucose uptake.
Multiple signaling pathways are activated after insulin receptors or IGF-I receptors interact with their ligands. By phosphorylating adaptor proteins, most notably the insulin receptor substrate family, the initial kinase event is linked to downstream signaling pathways.52 Once activated, these signaling pathways may stimulate multiple cancer phenotypes including proliferation, protection from apoptotic stimuli, invasion, and metastasis, potentially enhancing the promotion and progression of many types of cancer cells. It is also clear that insulin/IGF may stimulate normal cells that are involved in cancer progression. For example, hyperglycemia allows IGF-I to stimulate vascular smooth muscle cell proliferation and migration.53 Although this process has been linked to the pathophysiology of atherosclerosis, abnormal vasculature growth is also a hallmark of cancer.
Apart from the direct effects of insulin on cancer cells, it is possible that hyperinsulinemia could promote carcinogenesis indirectly through its effects on IGF-I.54 Insulin reduces the hepatic production of IGF binding protein (IGFBP)-155, 56 and possibly IGFBP-2,57 with resultant increases in the levels of circulating free, bioactive IGF-I. IGF-I has more potent mitogenic and antiapoptotic activities than insulin58 and could act as a growth stimulus in preneoplastic and neoplastic cells that express insulin, IGF-I, and hybrid receptors.49 Human tumors commonly overexpress these receptors, and many cancer cell lines have been shown to be responsive to the mitogenic action of physiological concentrations of IGF-I.
As has been found in other cancers, insulin receptors are frequently expressed by breast cancer cells.59 Compared with the ligand (ie, insulin), higher levels of insulin receptor have been found to be associated with a favorable breast cancer prognosis in some studies.60, 61 Although these findings may appear to be contradictory, they are consistent with other hormone-dependent pathways in breast cancer. Elevated serum levels of estradiol are weakly associated with increased breast cancer risk,62 whereas the expression of estrogen receptor (ER)-α is a favorable prognostic factor.63 Similar to ER, insulin receptor may be a marker of breast cancer cell differentiation and identify cells with a potentially less aggressive phenotype. Conversely, a recent larger study64 concluded that high insulin receptor levels are correlated with adverse prognosis; however, further research is needed. Moreover, the relation between serum levels of insulin and the regulation of insulin receptor levels in neoplastic tissues has to the best of our knowledge never been established. Because growth factors may downregulate the expression of their cognate receptors, it is possible that tumors with low insulin receptor levels are the most stimulated by insulin. Thus, there are biologically plausible models and correlative human clinical studies suggesting that insulin acting through insulin receptors might affect breast cancer risk and progression.
Effect of Hyperinsulinemia on Other Hormones
Increased circulating insulin has several indirect effects, including a reduction in the hepatic synthesis and blood levels of sex hormone-binding globulin, leading to increases in bioavailable estrogen in both men and women and increased levels of bioavailable testosterone in women but not in men.65 Androgen synthesis in the ovaries and possibly the adrenal glands is increased by hyperinsulinemia in premenopausal women. Elevated endogenous sex steroid levels are associated with a higher risk of postmenopausal breast, endometrial, and possibly other cancers.
Hyperglycemia and Cancer
When considering the complexity of interactions between diabetes, diabetes treatments, and cancer, it is important not to overlook glucose as a potentially relevant mediator. The recent resurgence of interest in the Warburg hypothesis and cancer energetics66 emphasizes the dependence of many cancers on glycolysis for energy, creating a high requirement for glucose (or even “glucose addiction”) because ATP generation by glycolysis requires far more glucose than oxidative phosphorylation. Indeed, this forms the basis for 18F-fluorodeoxyglucose (FDG)-positron emission tomography of cancers, which detects tissues with high rates of glucose uptake. The possibility that untreated hyperglycemia facilitates neoplastic proliferation therefore deserves consideration. Direct data concerning dose-response characteristics of cancers to glucose are sparse, but it is relevant that most cancers have highly effective upregulated, insulin-independent glucose uptake mechanisms67 and therefore may not derive a further growth advantage from hyperglycemia.
In vivo models demonstrating reduced tumor growth in the setting of type 1 diabetes68 suggest that hyperglycemia does not lead to increased neoplastic growth, at least in the setting of insulin deficiency. Studies correlating hyperglycemia with cancer do not necessarily indicate that glucose mediates the correlation; rather, hyperglycemia may serve as a surrogate for a causative factor such as hyperinsulinemia. Given the molecular heterogeneity of cancers, one cannot at this point exclude the possibility that there exists a subset of tumors for which hyperglycemia confers a growth advantage and therefore appropriate therapy for diabetes limits tumor growth, but the aggregate data suggest that insulin receptor activation may be a more important variable than hyperglycemia in determining tumor growth.
Inflammatory Cytokines, Diabetes, and Cancer Risk
In addition to the direct effects of insulin, type 2 diabetes and/or the related obesity might enhance other pathways, resulting in malignant progression. As recently reviewed, adipose tissue is an active endocrine organ, producing free fatty acids, interleukin-6 (IL-6), monocyte chemoattractant protein, plasminogen activator inhibitor-1 (PAI-1), adiponectin, leptin, and tumor necrosis factor-α.69 Each of these factors might play an etiologic role in regulating malignant transformation or cancer progression. In some cases, the role of these molecules is well known. For example, the plasminogen system has been linked to cancer, with expression of PAI-1 linked to poor outcome in patients with breast cancer.70 Activation of signal transducer and activator of transcription protein (STAT) signaling, via cytokines such as IL-6, is known to enhance cancer cell proliferation, survival, and invasion while also suppressing host antitumor immunity.71
Similarly, animal studies of energy balance support epidemiologic results correlating obesity with cancer mortality. Certain experimental cancers tend to behave more aggressively when animals overeat and less aggressively when animals are calorically restricted.72–74 These studies provide evidence that diet-induced changes in IL-6 and/or insulin may mediate the effect of diet on neoplasia and indicate that differences between tumors with respect to specific signaling pathways determine the extent to which diet influences tumor behavior.75
Major Unanswered Questions
As previously outlined, there is a growing body of epidemiologic evidence supporting a link between diabetes and the incidence and/or prognosis of some cancers. It is recognized the association may not be causal; diabetes and cancer may be associated simply because they share common predisposing risk factors such as obesity. However, several plausible biologic mechanisms have been described that may account for this link, including the effects of hyperglycemia, hyperinsulinemia, and inflammation on cancer etiology and progression. Mechanisms by which these factors interact with cancer risk require further study. Another important area for investigation concerns the issue of insulin resistance in type 2 diabetes in cells of nonclassic insulin target organs, such as the breast, colon, or prostate. The assumption that in the setting of insulin resistance in classic insulin target organs (liver, muscle, and adipose tissue) at least a subset of cancers remain insulin sensitive, or that insulin insensitivity to metabolic pathways does not extend to resistance to growth-promoting properties, needs to be examined more closely. How common is this? And what are the dose-response characteristics of insulin stimulation of such cancers?
Research is currently ongoing to provide a clearer understanding of these possible links, and this information may be relevant for prevention and optimal patient management. The majority of the supporting evidence regarding biologic mechanisms is derived from in vivo and in vitro studies. Because multiple prediagnostic biospecimens are rarely available from cohorts large enough for studies of cancer, many epidemiologic studies are only able to evaluate a single time point when measuring levels of insulin, glucose, or other analytes. To the best of our knowledge, the risk of long-term exposure to high levels of insulin is relatively underexplored and has direct relevance to the cancer risk associated with the duration of diabetes and use of exogenous insulin. In addition, most of the large studies have only fasting levels available; postprandial (area under the curve) insulin levels have not been adequately examined.
4) Do Diabetes Treatments Influence Cancer Risk or Cancer Prognosis?
Improved glucose control remains one of the central goals of effective diabetes management, which strives to minimize morbidity and mortality by reducing the risk of diabetes-associated complications. Several factors are considered by clinicians and patients when selecting pharmacologic diabetes therapies. These include the type of diabetes being treated, the glucose-lowering potential of a given agent, known acute and chronic adverse effects of treatment (such as weight gain, hypoglycemia, fluid retention, and gastrointestinal intolerance), treatment costs, and patient comorbidities and characteristics. To our knowledge, only recently has the issue of cancer risk with diabetes treatments been considered.
Individuals with type 1 diabetes represent approximately 5% of the diabetes population worldwide. The autoimmune destruction of pancreatic β cells results in the loss of insulin production and the need for immediate and lifelong insulin therapy. In contrast, type 2 diabetes is much more common and accounts for approximately 95% of the diabetes population. Type 2 diabetes is generally associated with overweight and obesity (in an estimated 80% of cases) and commonly advances from a prediabetic state characterized by insulin resistance (hyperinsulinemia) to frank diabetes with sustained insulin resistance accompanied by a progressive reduction in insulin secretion. The resulting relative insulin deficiency gives rise to both fasting and postmeal hyperglycemia. Ongoing loss of insulin secretory capacity, along with a diminished incretin effect and several other pathophysiologic defects,76 makes the hyperglycemia of type 2 diabetes progressive. This results in the increasing use of pharmacologic agents over time and the eventual need for insulin therapy in approximately half of all patients.77 The selection of the most appropriate pharmacologic agent(s) for each patient involves a clinical decision-making process that includes an ongoing risk/benefit analysis.78
The biguanide metformin is the most commonly used therapy in patients with type 2 diabetes, and is often prescribed as initial or combination therapy.79 Although the mechanism of action of metformin in diabetes is only partially understood, metformin treatment generally reduces levels of both circulating glucose and insulin in patients with insulin resistance and hyperinsulinemia. The primary mode of action is through reduced hepatic glucose output.80
In laboratory studies, metformin has been shown to inhibit cell proliferation, reduce colony formation, and cause partial cell cycle arrest in cancer cell lines.81–83 These studies suggest that metformin-induced activation of 5′ adenosine monophosphate-activated protein (AMP)-activated protein kinase (AMPK) in tumor cells may lead to growth inhibition, at least in part by inhibiting protein synthesis.84 It is interesting to note that in vivo studies have indicated that metformin has less antineoplastic activity in mice receiving a control diet than it does in mice receiving a high-energy diet associated with hyperinsulinemia and accelerated tumor growth.74 This suggests that the insulin-lowering action of metformin may contribute to its antineoplastic activity, and that it may have less impact on cancers occurring in less hyperinsulinemic patients. Other in vitro studies have suggested that metformin may selectively kill cancer stem cells and enhance the effectiveness of breast cancer treatment regimens.85–87 Metformin has also been shown to reduce mammary tumor growth in rodent models.88
Results of a growing number of observational human studies suggest that treatment with metformin (compared with other glucose-lowering therapies) is associated with a reduced risk of cancer89–93 or cancer mortality.94 However, these studies have generally been limited in their ability to assess an association with specific cancer types. Confounding by indication may limit the interpretation of results from observational studies because metformin is most typically prescribed to those with a short duration of diabetes and without contraindicating factors (advanced age and liver or kidney disease) that also might impact the risk of some cancers.
Additional observational data suggest that metformin might improve cancer prognosis. Metformin treatment was found to be associated with higher pathologic complete response among patients with early stage breast cancer who were receiving neoadjuvant therapy.95 The potential effect of metformin on breast cancer cell proliferation (as measured by Ki-67 index) is currently being evaluated in a clinical trial with a small number of subjects,96 and other trials of metformin therapy in patients with breast cancer are planned.
Thiazolidinediones (TZDs) are insulin-sensitizing peroxisome proliferator–activated receptor (PPAR)γ agonists that do not increase insulin secretion directly or cause hypoglycemia when used alone. Two drugs in this class, pioglitazone and rosiglitazone, are currently available. Unlike metformin, TZDs may be used in patients with renal insufficiency, although fluid retention is a potential adverse effect. TZDs are contraindicated in selected patients, most notably those with liver disease or active untreated or unstable congestive heart failure.
In vitro studies indicate that PPARγ agonists have several anticancer activities, such as inhibiting growth and inducing apoptosis and cell differentiation,97 and PPARγ is currently considered a potential target for both chemoprevention and cancer therapy based on other preclinical studies.98, 99 However, because recent in vitro studies have indicated that the effects of PPARγ agonists on cell growth are often independent of the presence of PPARγ,100–102 the clinical relevance of the findings of in vitro studies is unclear. Rodent studies also indicate that PPAR agonists can potentiate tumorigenesis, and they have been considered by some to be multispecies, multisex carcinogens.103 Therefore, it is possible that TZDs may increase, decrease, or have a neutral effect on the risk of cancer or cancer progression in humans.
To the best of our knowledge, definitive human data regarding the cancer risk associated with TZDs are not available. Three epidemiologic studies conducted among patients with diabetes focused on all cancers combined or only on a limited number of cancer sites, and the results were inconsistent.104–106 Results of a recent meta-analysis of clinical trials of rosiglitazone demonstrated no statistically significant increase or decrease in the risk of cancer at all sites combined or at the more common sites, although the numbers of cancer cases at these specific sites were small.107 The epidemiologic studies and the meta-analysis of trials were able to examine only short-term exposure, largely due to the relatively recent introduction of these medications and the shorter duration of many clinical efficacy trials.
To the best of our knowledge, only a few clinical trials of TZDs for cancer treatment have been conducted to date, and results have largely been negative.108 Other clinical trials are currently in progress109 or are planned.99
Secretagogues, including sulfonylureas and the rapid-acting glinides, stimulate β cells to release insulin by binding to specific cell receptors, resulting in β- cell depolarization and the release of insulin stores. Sulfonylureas (eg, glyburide, glipizide, and glimepiride) have been used to treat type 2 diabetes for more than 50 years. Although this class of agents is one of the more effective in lowering A1C, these drugs can cause hypoglycemia and weight gain. A small number of observational studies found a higher risk of cancer or cancer death among individuals with diabetes who were treated with sulfonylureas compared with those treated with metformin or other diabetes medications.90–92, 110 However, the majority of these studies had very few cancer cases among users of sulfonylureas, and therefore power was limited to examine associations with specific cancer sites.91, 111 Studies regarding dose, duration, recency, and persistence of use are limited.
Although it is possible that the association between sulfonylureas and cancer risk is genuine, it is difficult to determine whether the findings reflect excess cancer among users of the secretagogues or a reduced risk in those using comparator drugs, which often include metformin therapy. Furthermore, if the association was to be confirmed, it remains to be determined whether the mechanism involves direct actions of the agents on transformed cells or cells at risk of carcinogenesis, compared with indirect effects mediated by increased insulin levels. To the best of our knowledge, there are no published data to date that support an association between the glinide secretagogues and cancer risk, perhaps because they are newer and the use of these agents is less common.
Two recently developed classes of drugs either enhance or mimic the effect of gut-derived incretin hormones that improve glucose-dependent insulin secretion, suppress postprandial glucagon levels, and delay gastric emptying. The first of the incretin-based therapies introduced, exenatide, has an approximately 50% homology with the incretin hormone glucagon-like peptide 1 (GLP-1), whereas the more recently approved liraglutide is an analog of human GLP-1. Both compounds bind to the GLP-1 receptor to exert agonist activity. The oral dipeptidyl peptidase-4 (DPP-4) inhibitors inhibit action of the ubiquitous enzyme that rapidly degrades many peptides, including endogenous GLP-1.
Liraglutide was found to increase the risk of medullary thyroid cancer in rats and mice in preclinical tests and was associated with slight increases in serum calcitonin in human trials (Food and Drug Administration). Exenatide, liraglutide, and DPP-4 inhibitors increased β-cell proliferation in animal studies, and in one small study of a transgenic rodent model, the DPP-4 inhibitor sitagliptin was demonstrated to increase pancreatic ductal hyperplasia.112 No impact of incretin-based agents on human cancer incidence has been reported, likely because of the fact that these newer drugs have not been used in sufficient numbers of patients or for long enough periods of time to fully assess any possible effects on cancer risk.
Insulin and Insulin Analogs
Insulin is required for all patients with type 1 diabetes. It is also necessary for many patients with type 2 diabetes to treat hyperglycemia, in part due to the progressive loss of β-cell function over time. Between 40% to 80% of individuals with type 2 diabetes will ultimately be considered for insulin therapy in an effort to achieve glycemic targets.77 Several formulations of insulin exist: short-acting human regular insulin, intermediate-acting human neutral protamine Hagedorn (NPH) insulin, and both rapid-acting and long-acting analogs of human insulin. Subcutaneous injection of insulin results in significantly higher levels of circulating insulin in the systemic circulation than endogenous insulin secretion, thereby possibly amplifying links between hyperinsulinemia and cancer risk.
Recently, a series of widely publicized epidemiologic analyses examined a possible association between insulin use and/or use of the long-acting insulin analog glargine91, 110, 113, 114 and an increased risk of cancer. Insulin glargine may have a disparate impact on cancer risk through its binding to IGF-1 receptors. The potential strengths and weaknesses of these studies have been broadly debated and well detailed.115–117 For example, one concern is that insulin is more commonly prescribed in patients with a longer duration of type 2 diabetes and is used more often in those with one or more comorbid conditions that preclude the use of comparator medications. To the best of our knowledge, rarely have these or other potential confounders (BMI, actual insulin dose, degree of glucose control, glucose variability, and other patient characteristics) been fully accounted for in the study designs or analyses.
Randomized clinical trial data from an open-label, 5-year trial of insulin glargine versus NPH insulin did not find evidence of excess cancer risk (all sites combined) in the insulin glargine arm,118 although among the approximately 1000 subjects randomized, there was a very small number of cancer endpoints (57 cancer cases in the glargine arm and 62 cases in the NPH arm). The ongoing randomized ORIGIN (Outcome Reduction With Initial Glargine Intervention) trial (glargine vs placebo in patients with impaired fasting glucose or newly diagnosed type 2 diabetes) is much larger (approximately 12,000 patients randomized and followed for 6–7 years).119 It is important to note that this trial was powered for cardiovascular outcomes and may still not provide definitive evidence regarding cancer incidence, especially for specific cancers.
Possible Mechanisms for the Link Between Exogenous Insulin, Insulin Analogs, and Cancer
Potential mechanisms by which the administration of insulin or insulin analogs might influence neoplastic disease include both direct and indirect actions. Direct actions have received the most attention and involve interactions of the administered ligands (or their metabolites) with cancer cells, partially transformed cells, or cells at risk of transformation. Indirect mechanisms have been less well studied but would involve interactions of signaling molecules whose levels (eg, glucagon, adiponectin, or IGFBPs) or activity are influenced by the administration of insulin into these target cells.
With respect to direct actions, one must consider not only the affinity of the administered agents for the various receptors involved, but also pharmacokinetic aspects. Substantial prior research has emphasized differences between human insulin and analog insulin with respect to binding affinity to the IGF-I receptor, including evidence that insulin glargine has much higher affinity, and higher mitogenic potency, than human insulin or other analogs.120–122 The affinity of particular analog insulins for the IGF-I receptor is an important issue in view of evidence that knockdown of the IGF-1 receptor, but not the insulin receptor, abolished the proliferation of malignant cell lines in response to insulin glargine.120 However, the implicit assumption that an insulin or analog that retains specificity for the insulin receptor over the IGF-I receptor is unlikely to have important mitogenic effects or effects on neoplasia may be simplistic in the light of recent research results64, 123 that indicate that the insulin receptor is present on neoplastic cells and may itself influence neoplastic behavior in certain contexts.
Other pharmacokinetic issues must also be considered. It is not clear whether there is a biologic difference between the exposure of neoplastic cells to fluctuating levels of endogenous insulin observed under normal physiologic conditions compared with the levels of endogenous insulin noted in obesity, type 2 diabetes, and/or after the administration of exogenous human or synthetic insulins. Classic subcutaneous therapy with subcutaneous human insulin involves transient exposures to very high insulin levels, whereas the subcutaneous administration of some synthetic insulins results (by design) in longer term exposure to higher insulin concentrations. As such, simple pharmacokinetics may not fully explain observed changes in the behavior of neoplastic tissues. It also is critical to recognize that cancer cells in patients with type 2 diabetes may be exposed to abnormally high levels of endogenous insulin for many years prior to the administration of exogenous insulin.
There are several important limitations in human studies of diabetes treatment and cancer risk that require careful consideration. First, the majority of studies have had limited power to detect modest associations, particularly for site-specific cancers. Conducting studies with all sites combined might attenuate or even mask important associations with only specific cancer sites. Another limitation of observational studies is that most diabetic patients are treated with one or more antihyperglycemic medications. Indeed, the progressive nature of type 2 diabetes, requiring changes in pharmacotherapy over time, adds complexity to studies of a long-term outcome such as cancer incidence. Therefore, it is extremely difficult to assess the independent association between a specific medication and cancer risk relative to no medication. For example, if some medications increase risk whereas others decrease or have no effect on risk, different comparator drugs will likely lead to different associations and may explain some of the observed inconsistencies across studies.
Because specific antihyperglycemic medications are associated with cancer risk factors, confounding by unmeasured or incompletely measured risk factors may explain at least in part the previously reported associations between medications and cancer. To our knowledge, few studies to date have examined the risk associated with the dose, duration, or recency of medication use, which might inform the biologic plausibility of observed associations. Many agents that affect carcinogenesis have long latencies or require a minimum exposure level, and the risk associated with some agents may return to baseline after the exposure has been terminated for a period of time. Some diabetes medications have only recently come on the market (eg, TZDs, insulin analogs, and incretin-based therapies), and therefore, studies of these agents will only assess the cancer risk associated with relatively short-term use.
It is unlikely that the effect of diabetes therapies on cancer risk and progression, particularly at specific cancer sites, will be fully addressed with randomized controlled clinical trials, due to both cost and follow-up time limitations. Such trials would also be confounded by the natural crossover and treatment escalation required to appropriately treat progressive hyperglycemia. Given these limitations, multiple well-conducted and appropriately designed prospective observational studies are needed. Results of in vitro and preclinical studies should inform design considerations for observational studies, but by themselves cannot be considered conclusive.