Diabetes Medications and Cancer Risk: Review of the Literature

Diabetes mellitus is one of the fastest growing epidemics in the United States and worldwide. According to the International Diabetes Federation atlas, there were approximately 366 million people worldwide with diabetes in 2011, and this number is expected to increase to 552 million by 2030.¹ Currently, the Centers for Disease Control and Prevention (CDC) estimates that more than 25.8 million Americans (8.3% of the population) have diabetes.² The CDC also estimates that approximately 7 million of these individuals are undiagnosed and are therefore untreated.² Type 2 diabetes (90%-95% of diagnosed diabetes cases in the United States) has been largely attributed to an increase in obesity.^2,3 It is estimated that approximately one third of the US population is obese.³ The rates of increase in obesity and diabetes have mirrored each other over the past 2 decades.³ The complications of diabetes, which include heart disease, kidney disease, blindness, and increased risk for amputations, are as serious as they are diverse.²

In general, diabetes has been shown to increase the risk for heart disease by 2-fold4 and has been shown to carry the same risk for myocardial infarction (MI) as for nondiabetic individuals who have previously had an MI.⁵ Emerging data are now correlating diabetes with an increased risk of certain types of cancer.⁶ With cancer already making a large impact on mortality in our population, and with type 2 diabetes on the rise, research specific to these 2 disease states is becoming even more important.

The Link between Cancer and Diabetes

Several studies have revealed a relatively strong correlation between some types of cancer and diabetes. A study conducted by Davila and colleagues looking at the risk of hepatocellular carcinoma in diabetic patients versus nondiabetic patients in the United States showed an increased relative risk of 3.08 in those with diabetes.⁷ A study by Wang and colleagues showed an increased risk (odds ratio [OR], 1.5) of developing pancreatic cancer in patients with type 2 diabetes among randomly selected patients in the San Francisco Bay Area.⁸ There is also an increased risk of developing several other types of cancers, including kidney, endometrial, colorectal, non- Hodgkin lymphoma (NHL), bladder, and breast.⁹ By contrast, the risk for prostate cancer appears to be decreased among diabetic patients.⁶

The presence of type 2 diabetes has also been shown to increase mortality in patients who already have cancer.¹⁰ Data collected by more than 350 primary care physicians on patients in the United Kingdom have shown that patients with a diagnosis of breast cancer who developed type 2 diabetes had a 1.32 increased mortality risk compared with patients with breast cancer without diabetes.¹⁰

The Cancer Prevention Study-II evaluated more than 2200 patient records of those diagnosed with nonmetastatic colon or rectal cancer and showed a 1.53 increased risk of mortality among patients with type 2 diabetes.¹¹ Even with the decreased risk of prostate cancer in diabetic patients, they experience higher mortality rates.¹²

Bladder cancer is the fourth most common cancer and the ninth leading cause of cancer death among US men.^13,14 Bladder cancer is estimated to occur in approximately 21 per 100,000 persons annually in the United States and is thought to be higher in diabetic patients.¹⁵

Mechanisms involved in the association between diabetes mellitus and cancer are not completely understood, but they are likely associated with hyperinsulinemia, which is a result of insulin resistance characteristic of type 2 diabetes. Insulin’s role in cell proliferation, through the action of insulin-like growth factor 1, as well as inhibition of apoptosis, could play a significant role in the development of cancerous tissues.³ Although these systemic responses are reasonably well understood, the current literature does not adequately explain organ-specific cancer risk.

Despite the lack of a complete understanding of the mechanisms, the correlation between diabetes and cancer is strong, as suggested by the literature. Therefore, it is logical to inquire whether the treatment of diabetes can affect the risk of these patients developing cancer. Recently, studies have been emerging that evaluate the risk of developing cancer in diabetic patients who are being treated for their disease versus those who are not receiving antidiabetes medications.

There are currently 14 classes of drugs used in the treatment of diabetes, as discussed below. This article reviews the mechanism of action and the effect on cancer risk of each class of medication for the treatment of diabetes.

Antidiabetic Drugs and Cancer Risk

Biguanides(Metformin)

Metformin’s mechanism of action in the treatment of diabetes has been elucidated for quite some time; however, all of its actions are not fully understood. Its main effect is to improve hepatic insulin resistance via decreasing the hepatic glucose output. Metformin also improves peripheral glucose uptake by sensitizing insulin receptors in the muscles.¹⁶ Several studies in the past few years have identified additional benefits of metformin, such as lowering cancer risk and improving survival of those diagnosed with cancer among the diabetic population.

Libby and colleagues designed an observational cohort study that compared 4000 subjects with diabetes who had taken metformin with 4000 diabetic subjects who had not received the drug.¹⁷ Cancer was diagnosed in 7.3% of metformin users compared with 11.6% of those who did not take the medication.¹⁷ In a nested case-control study conducted by Monami and colleagues, 112 of 1340 diabetic patients (average followup, 75.9 months) developed cancer.¹⁸ Those who developed cancer had less exposure to metformin compared with a control group of diabetic patients.¹⁸

Jiralerspong and colleagues compared the pathologic complete response (pCR) rates—pCR is the absence of tumor in tissue removed during surgery, and it correlates with improved survival rates—between diabetic patients with early-stage breast cancer who received neoadjuvant therapy as well as metformin with diabetic patients with similar cancer characteristics but who were not taking metformin.¹⁹ Of 2529 patients identified in the study with early-stage breast cancer treated with neoadjuvant therapy, 68 patients also had diabetes and were taking metformin and 87 patients had diabetes but were not taking metformin. The pCR rates in the metformin group were 3 times (24%) higher compared with the nonmetformin group. This finding suggests a protective factor of metformin in diabetic patients who develop breast cancer.¹⁹

In another case-control study, Li and colleagues evaluated 973 patients with pancreatic adenocarcinoma who were receiving antidiabetic therapy.²⁰ The investigators compared 259 diabetic patients and 109 diabetic controls (who had no pancreatic adenocarcinoma). The results showed that diabetic patients receiving metformin had a significantly lower risk for pancreatic cancer compared with those who had not taken metformin (OR, 0.38; 95% confidence interval [CI], 0.22-0.69; P = .001), with adjustments for potential confounders. Those who received metformin had a 62% reduction in the risk for pancreatic cancer.²⁰

Wright and colleagues analyzed 1001 patients with prostate cancer versus 942 controls for diabetes and cancer risk.²¹ Of these, 97 of the patients with cancer and 101 of the controls had diabetes. The use of metformin was more frequent in the control group compared with the group of patients with cancer (4.8% vs 4.0%, respectively). The investigators calculated that prostate cancer risk was reduced by 44% with metformin use.²¹ The results showed that the use of metformin for >5 years reduced the risk for breast cancer compared with the use of metformin or any other antidiabetic drugs for <5 years.²²

Furthermore, He and colleagues reviewed the records of 233 patients diagnosed with prostate cancer who were taking antidiabetic medications.²³ The investigators concluded that treatment with metformin was a positive predictor of improved survival time by nearly a year compared with those patients who did not receive metformin.²³

Several of the studies cited above have suggested that the anticancer properties of metformin are likely a result of AMP-activated protein kinase (AMPK). AMPK phosphorylates proteins, which leads to inhibition of cell growth and possible reduction in cancer.²⁴

Based on the present review of the most recent literature, there appears to be a negative relationship between metformin use and cancer. The mechanisms by which metformin decreases cancer risk and improves survivability with cancer, possibly through decreased protein synthesis or maintaining normal insulin levels, are not clear. All of the clinical studies reviewed are retrospective studies, which may be subject to bias and confounding issues. Further research, especially prospective studies, should be conducted to better assess the relationship between metformin and cancer.

Second-Generation Sulfonylureas (Glyburide, Glipizide, Glimepiride)

Sulfonylureas work by stimulating endogenous insulin secretion through inhibition of potassium channels in the pancreatic cells. They are most effective during the early stages of diabetes when insulin secretion is still working.²⁵

Cancer risk associated with sulfonylureas has not been extensively studied in comparison with other antidiabetic drugs; however, the limited studies that have been completed indicate that there may be a higher incidence of cancer among those who receive them. The nested case-control study by Monami and colleagues mentioned above included 1340 diabetic patients who were followed up for an average of 75.9 months. The 112 patients who developed cancer also had a greater length of exposure to a sulfonylurea compared with the control group of diabetic patients.¹⁸

Similarly, in the case-control study by Li and colleagues, compared with the nondiabetic patients, there was a nonsignificant increased risk for pancreatic cancer detected among the patients with diabetes who were using a sulfonylurea.²⁰ A cohort study by Bowker and colleagues identified 10,309 new users of metformin or sulfonylureas. 26 The mean follow-up for the study was approximately 5 years. Its results showed that the cancerrelated mortality for patients receiving sulfonylureas was 4.9% compared with 3.5% for metformin.²⁶ No control group was used in this study, so it is unclear if this finding is a protective effect of metformin or a worsening effect associated with the use of sulfonylureas.

A cohort study by Yang and colleagues involving 6103 patients with type 2 diabetes identified a decreased cancer risk among patients taking glibenclamide and gliclazide.²⁷ Furthermore, the cancer risk reduction was found to be dose dependent with these 2 drugs. Of note, there was no benefit in terms of cancer risk with the use of glipizide.²⁷ Finally, Chang and colleagues evaluated the use of insulin secretagogues among diabetic patients in a retrospective study carried out in China.²⁸ Of the 108,920 subjects included in the study, 8194 cancer cases were identified. Results showed significantly increased risk for liver and pancreatic cancers with the use of first- and second-generation sulfonylureas, but not with third-generation sulfonylureas. Chang and colleagues do note that there was no dose-response measured in evaluating the risk of cancer with the first- and second-generation drugs.²⁸

The increased risk of cancer seen with sulfonylureas is concerning. These case-control studies support the hypothesis that increasing insulin levels has a positive effect on cancer development. Sulfonylureas, like other antidiabetic drugs, have only been evaluated in a retrospective manner, leading to incomplete assessments and invalidated conclusions.

Meglitinides (Repaglinide, Nateglinide) Meglitinide is an insulin secretagogue that stimulates insulin release by inhibiting potassium channels in the pancreas on a different site from sulfonylureas. These medications work much faster than other secretagogues and can be taken more effectively before meals. They can lower postprandial blood glucose levels and thus avoid the risk of hypoglycemia between mealtimes.²⁹ Only 1 study was found in a literature search that evaluated the effect of meglitinide on cancer risk. The retrospective study by Chang and colleagues discussed earlier showed that any use of a meglitinide had a significantly increased risk for developing cancer, but mainly liver cancer.²⁸ As discussed with sulfonylureas, elevated insulin levels can possibly increase cancer risk. A correlation between meglitinide use and cancer risk cannot be determined at this time, because there was only 1 study evaluating this effect, and it was based on a retrospective analysis.

Glucosidase Inhibitors (Acarbose, Miglitol)

Glucosidase inhibitors act by delaying the absorption of complex carbohydrates from the digestive tract, therefore reducing the body’s glucose load.³⁰ It is used in conjunction with other antidiabetic medications to attain better blood glucose control.³⁰ There are no current studies evaluating glucosidase inhibitors and cancer.

Thiazolidinediones (Rosiglitazone, Pioglitazone)

Thiazolidinediones (TZDs) improve metabolic control in patients with type 2 diabetes through the improvement of peripheral tissue insulin sensitivity. TZDs activate a group of receptor molecules inside the cell nucleus known as peroxisome proliferator-activated receptors (PPARs), specifically PPARγ, to increase peripheral insulin sensitivity and potentially reduce hepatic gluconeogenesis. Although not all the actions of TZDs are known, these agents still have the potential to benefit the full “insulin resistance syndrome” that is associated with diabetes.³¹

In June 2011, the US Food and Drug Administration (FDA) issued a safety announcement that the use of pioglitazone for more than 1 year may be associated with an increased risk of bladder cancer.32 This announcement was based on studies conducted by the drug manufacturer, which included a 10-year, observational cohort study, as well as a nested case-control study in patients with diabetes who are members of the Kaiser Permanente Northern California (KPNC) health plan. This study included 193,099 patients in the KPNC Diabetes Registry who were aged ≥40 years. A planned 5-year interim analysis was performed with data collected from January 1, 1997, through April 30, 2008. The median duration of therapy among patients treated with pioglitazone was 2 years (range, 0.2-8.5 years).32 The results showed no significant increase in the risk for bladder cancer in patients ever exposed to pioglitazone compared with those who were never exposed to pioglitazone (hazard ratio [HR], 1.2; 95% CI, 0.9-1.5). However, the risk for bladder cancer was greater with increasing dose and duration of pioglitazone use compared with never being exposed to pioglitazone. In this study, the HRs were 0.8 for <1 year of pioglitazone treatment and 1.4 for 1 to 2 years and for >2 years of therapy.³²

In a post hoc analysis, the HR was even higher for those patients with >36 months of exposure and for those with >48 months of exposure, with a trend for increasing risk with longer duration of exposure.33 The use of pioglitazone therapy for 12 months was associated with a 40% increase in risk (HR, 1.4; 95% CI, 0.9-2.1), whereas the HR after >24 months of treatment with pioglitazone was 1.4 (95% CI, 1.03-2.0). Based on these data, the FDA calculated that duration of therapy >12 months was associated with 27.5 additional cases of bladder cancer per 100,000 person-years of follow-up compared with patients having never received pioglitazone.³²

In a retrospective cohort study using data from the French National Health Insurance Plan, approximately 1.5 million patients with diabetes who were aged 40 to 79 years were followed for up to 42 months (2006-2009).^32,34 The study showed a statistically significant increase in the risk of bladder cancer in patients exposed to pioglitazone compared with patients exposed to other antidiabetic agents (HR, 1.22; 95% CI, 1.05-1.43). There was an increased bladder cancer risk observed with a larger cumulative dose of ≥28,000 mg (HR, 1.75; 95% CI, 1.22- 2.50) and for longer duration of exposure between 12 to 23 months (HR, 1.34; 95% CI, 1.02-1.75).^32,34

A cohort study of pioglitazone and cancer incidence in patients with diabetes explored whether treatment with pioglitazone was associated with a risk of incident cancer at the 10 most common sites (ie, prostate, female breast, lung/bronchus, endometrial, colon, NHL, pancreas, kidney/renal pelvis, rectal, and melanoma).35 This study evaluated 252,467 patients aged ≥40 years from the KPNC Diabetes Registry. The HR for each cancer associated with the ever-use of pioglitazone ranged from 0.7 to 1.3, with all 95% CIs including 1.0. Increased risks of melanoma (HR, 1.3; 95% CI, 0.9-2.0) and NHL (HR, 1.3; 95% CI, 1.0-1.8) were suggested, and a decreased risk of kidney/renal pelvis cancers (HR, 0.7; 95% CI, 0.4-1.1) was associated with the ever-use of pioglitazone. These associations were not affected by increasing dose, duration, or time since first use. The power of the study was somewhat limited, given the relatively small number of cases for NHL, kidney/renal pelvis cancers, and melanoma. There was no clear evidence of an association between the use of pioglitazone and the risk of incident cancer at the sites examined. This study of relatively short-term use could miss effects that require longer-term exposure or follow-up to become evident.³⁵

A recent retrospective cohort study using a nested case-control analysis was done to determine if the use of pioglitazone is associated with an increased risk of incident bladder cancer in patients with type 2 diabetes.³⁶ Azoulay and colleagues analyzed data from a large UK general practice database from January 1988 to December 2009. The cohort included 115,727 new users of oral hypoglycemic agents, with a mean patient age of 64 years and a mean follow-up duration of 4.6 years. A total of 0.5% of patients were taking pioglitazone or rosiglitazone as monotherapy, with a mean duration of use of approximately 2.2 years. A total of 470 patients were diagnosed with bladder cancer during follow-up (rate, 89.4 per 100,000 person-years). The 376 cases of bladder cancer that were diagnosed beyond 1 year of follow-up were matched to 6699 controls. Overall, the ever-use of pioglitazone was associated with an increased rate of bladder cancer by 83% (rate ratio [RR], 1.83; 95% CI, 1.10-3.05). The rate of bladder cancer increased with longer use of pioglitazone, with those taking the drug for >2 years having a 2-fold increase in risk (RR, 1.99; 95% CI, 1.14- 3.45), and in those with a cumulative dosage >28,000 mg (RR, 2.54; 95% CI, 1.05-6.14). Rosiglitazone did not have an elevated risk, even with duration of use and cumulative dosage (RR, 1.14; 95% CI, 0.78-1.68). The authors hypothesized that the possible mechanism for the bladder cancer risk is chronic irritation of the bladder from crystal formation, which needs further research.^36,37

Based on these studies, pioglitazone use for longer duration and exposure to the highest cumulative dose are associated with an increased risk of bladder cancer, whereas no increased risk was observed with rosiglitazone. The potential for increasing melanoma or NHL risk and decreasing kidney/renal pelvis cancer risk associated with an ever-use of pioglitazone was observed in one study³⁸; however, the power of the study was limited.³⁸

Bromocriptine Mesylate Bromocriptine mesylate, an ergot derivative, is a sympatholytic dopamine D₂ receptor agonist that can exert inhibitory effects on serotonin turnover in the central nervous system. Bromocriptine mesylate was FDA approved for type 2 diabetes in adults in 2009. It has been proposed that bromocriptine can reverse many of the metabolic alterations associated with insulin resis - tance and obesity by resetting central (hypothalamic) circadian organization of monoamine neuronal activities. Bromocriptine has been shown to reduce hemoglobin A_1c levels (by 0.4-0.8), fasting and postprandial glucose, and fasting and postprandial triglycerides.39

Bromocriptine is used in the treatment of pituitary prolactinomas.⁴⁰ In September 2000, a preliminary study conducted in Italy showed that low-dose bromocriptine is sufficient to acutely normalize prolactin in patients with metastatic breast cancer and in those with prostate carcinoma.⁴⁰

It is unknown whether bromocriptine affects cancer risk in diabetic patients. On the other hand, it is used in the treatment of prolactinomas and paraneoplastic processes of certain cancers where prolactin levels are elevated.

Colesevelam (Welchol)

The mechanism by which colesevelam exerts its antihyperglycemic effect is unknown; however, speculated actions include enhanced meal-induced incretin secretion and/or altered farnesoid X receptor signaling.⁴¹ Because of a lack of data regarding colesevelam and cancer, its effect on cancer risk is unknown.

DPP-4 Inhibitors (Sitagliptin, Saxagliptin, Linagliptin)/GLP-1 Agonists (Exenatide, Liraglutide)

Glucagon-like peptide (GLP)-1 is an incretin hormone that is secreted by L-type endocrine cells in the distal ileum when food is ingested.⁴² It acts by binding to cell membrane GLP receptors, which promotes stimulation of glucose-dependent insulin secretion, as well as promotes beta-cell proliferation and survival.^43,44 GLP-1 agonists bind to GLP receptors to restore beta-cell sensitivity to glucose and to increase beta-cell mass.⁴³ Native GLP-1 is normally degraded by the enzyme dipeptidyl peptidase (DPP)-4. Drugs that inhibit DPP-4 have been developed and are currently being used as treatment for type 2 diabetes. Together, these 2 drug classes are known as the incretin family.

Type 2 diabetes and obesity are known risk factors for chronic pancreatitis and pancreatic cancer. There were 88 postmarketing cases of acute pancreatitis, including 2 cases of necrotizing hemorrhagic pancreatitis, in patients receiving sitagliptin that were reported to the FDA between October 2006 and February 2009.⁴⁵

In 2007, the FDA released a safety alert, and subsequently the manufacturer updated exenatide’s prescribing information to include the precaution of acute pancrea - titis, based on postmarketing reports of pancreatitis in patients taking exenatide.46 Because pancreatitis is a known risk factor for pancreatic cancer, there is concern that long-term use of a GLP-1 agonist increases pancreatic cancer risk. A study published in 2006 found that GLP-1 receptor stimulation did not impact the growth or survival of pancreatic cancer cells.44 However, in a study published by Elashoff and colleagues in 2011, the FDA database was used to look for associations between GLP-1 agonist use and pancreatitis, pancreatic cancer, and thyroid cancer. They found that patients taking exenatide or sitagliptin had a more than 6-fold higher event rate in pancreatitis compared with patients receiving other treatment options and a 2.9-fold higher event rate of pancreatic cancer in those patients whose diabetes was treated with exenatide compared with other therapies.⁴²

In addition to the FDA noting the suspected association, the Drug Commission of the German Medical Association has received 11 reports of pancreatic cancer associated with the use of exenatide.47,48 The time between exposure and diagnosis was 2 to 33 months, which is contrary to the thought that the time between tumor induction and diagnosis is usually >10 years.^47,48

With regard to thyroid cancer, there is a known association with liraglutide use and medullary thyroid cancer in rodents.⁴⁹ Elashoff and colleagues reviewed the FDA data for association between exenatide use and thyroid cancer and found a greater than 4-fold increase in events in the exenatide therapy group.⁴²

There is also an association between colorectal cancer and type 2 diabetes, especially in men.⁵⁰ However, in an article published in 2011, Koehler and colleagues found that activation of the GLP-1 receptor actually decreases the growth of and increases apoptosis of colon cancer cells.⁵¹ In addition, although there is a known association between obesity, type 2 diabetes, and breast cancer, there is evidence that stimulation of GLP-1 receptors leads to increased apoptosis and reduced viability of breast cancer cells without affecting noncancer cells.⁵²

GLP-1 agonists have the potential to reduce breast cancer and colon cancer risk.^51,52 Diabetes alone is a risk factor for breast and colon cancers; therefore, this particular treatment would be especially useful in diabetic individuals with or at risk for these cancers. It would likely be advisable to use caution in those patients with known risk factors for pancreatic cancer, beyond diabetes and obesity alone. The association with thyroid cancer is one that should be investigated further.

At present, there is no direct evidence to support an increase in pancreatic cancer with long-term DPP-4 inhibitor use. Long-term prospective studies are needed. Meanwhile, caution should be used when prescribing DPP-4 inhibitors in patients who are obese and have type 2 diabetes, as well as other known risk factors for pancreatic cancer.⁴²

Insulin/Insulin Analogues

Similar to endogenous insulin, exogenous insulin increases the uptake of glucose into the cells, stimulates glycogen synthesis, and inhibits glucagon. It is altered in various ways to change the onset and duration of action. For example, insulin aspart, a fast-acting insulin analogue, begins to work within minutes of administration but lasts only a few hours, whereas insulin glargine is stable enough for once-daily dosing.

A German cohort study published in 2009 investigated the association between cancer risk and insulin use.⁵³ Using malignancy diagnosis as a primary outcome, the authors analyzed data from one of the national statutory health insurance funds and included individuals without a known malignancy who received first-time treatment only with human insulin, aspart, lispro, or glargine. Of the 127,031 patients included in the study, it was noted that there was an association between incidence of malignancy and insulin dose for all insulin types; how - ever, in comparing aspart, lispro, and glargine to human insulin, only glargine was found to have a higher dosedependent risk. Although the authors found that glargine treatment involved a higher risk of the development of cancer, a specific type of cancer was not identified in the study.

In another analysis published the same year, an association between insulin glargine use and cancer incidence was not identified after evaluating 31 randomized clinical trials in a drug manufacturer’s database.⁵⁴ The analyzed trials included fewer total participants (N = 10,880), and the length of the trials was, in general, approximately 6 months, except for 1 study in which participants were followed for 5 years. Furthermore, only 20 of these trials compared insulin glargine with neutral protamine Hagedorn (NPH) insulin, whereas the others included such treatments as lispro, pioglitazone, or dietary measures. Because of the concerns surrounding glargine and cancer risk, Dejgaard and colleagues conducted a metaanalysis to study the effect of insulin detemir use on diabetic patients; they found that among a group of 8693 patients with diabetes, the incidence of malignancy in those using insulin detemir was lower than or no different from the incidence in patients treated with NPH insulin or with insulin glargine.⁵⁵

A French study published in 2012, using the national healthcare insurance system database and data from 2003 to 2010, found that there was no increase in cancer risk with glargine use compared with human insulin use.⁵⁶ By contrast, using “possession rate”—which is defined as “the ratio of the number of treatments dispensed during the insulin exposure period divided by the number of 28-day periods during the follow-up period”— the authors did find an association between cancer risk and increasing mean possession rate.⁵⁶

In another study published this year with similar conclusions, Ruiter and colleagues analyzed pharmacy records linked to hospital discharge records of 2.5 million patients in the Netherlands to determine the number of first hospital admissions with a primary diagnosis of cancer (main outcome) and to identify specific cancers.⁵⁷ Of the 19,337 insulin users included in this study, 878 patients developed cancer. Use of glargine was actually associated with a lower risk of malignancy (HR, 0.75). With regard to specific malignancies, glargine use was associated with a lower risk of colon cancer, but no other cancers, when compared with human insulin use (similar results were true for other insulin analogues). However, glargine was associated with an increased risk of breast and prostate cancers (HRs, 1.58 and 2.76, respectively) in comparison with the use of human insulin. Glargine dose was not found to be related to diagnosis.⁵⁷

In another recently published study, Luo and colleagues identified an association between postmenopausal women with diabetes who were treated with insulin and lung cancer risk.⁵⁸ Using data from the Women’s Health Initiative, it was found that women who reported a diagnosis of diabetes had a higher risk of lung cancer compared with women without diabetes (HR, 1.27). Furthermore, women who reported treatment with insulin had an even greater risk of developing lung cancer (HR, 1.71). In addition, the authors noted that an association between diabetes duration and untreated diabetes was not found.⁵⁸

Although the concern regarding insulin use and cancer risk is worth noting, recent studies have not justified this concern because of the lack of correlation. Further research on insulin use and cancer is warranted, and unless a patient has a high risk for malignancy, not utilizing insulin when needed would not be appropriate. Long-term prospective studies are needed.

Amylinomimetics

Amylin is a peptide hormone that is secreted with insulin from pancreatic beta-cells, so it is therefore deficient in diabetic patients. It regulates postprandial spikes in blood glucose by slowing gastric emptying and digestion, promoting satiety, and inhibiting glucagon secretion.⁵⁹ Pramlintide, an amylinomimetic, is utilized in type 1 and type 2 diabetic patients as an adjunctive therapy to insulin therapy, hence allowing patients to use less insulin. It has no known association with cancer.

Conclusions

No conclusive data are currently available that link the use of diabetes drugs to cancer development. Of the 14 diabetes drug classes currently available, there are data suggesting a higher risk of cancer development with insulin, pioglitazone, and insulin secretagogues. Metformin seems to be protective against some cancers in diabetic patients. It is important to note that all of these data are from retrospective studies and can only suggest association rather than direct cause. Prospective studies are needed to shed light on this topic.

In the absence of clear correlation, practitioners and patients should continue to feel comfortable utilizing medications to control diabetes, because the correlation between uncontrolled diabetes and cancer is stronger than the correlation between diabetic medications and cancer. In patients with other risk factors for malignancy (such as a strong family history or personal history of cancer), providers may wish to be more thoughtful in their selection of agents to manage diabetes by utilizing the data provided in the studies mentioned.

Author Disclosure Statement

Dr QT Nguyen, Dr Sanders, Dr Michael, Mr Anderson, Dr LD Nguyen, and Mr Johnson have reported no conflicts of interest.

Dr QT Nguyen is an Endocrinologist, Carson Tahoe Physicians Clinic, Carson City, and Adjunct Associate Professor, Endocrinology and Internal Medicine, Touro University Nevada, College of Osteopathic Medicine; Dr Sanders is a Senior Medical Resident, Internal Medicine Program, University of Nevada, Reno; Dr Michael is a Senior Medical Resident, Internal Medicine Program, University of Nevada, Reno; Mr Anderson is a Senior Medical Student, University of Nevada School of Medicine, Reno; Dr LD Nguyen is Clinical Pharmacy Specialist, VA Sierra Nevada Health Care System, Reno; and Mr Johnson is a Sophomore Medical Student, University of Nevada School of Medicine, Reno.

References

1. Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Res Clin Pract. 2011;94:311-321.
2. Centers for Disease Control and Prevention. National diabetes fact sheet 2011. www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed July 2, 2012.
3. Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004;4:579-591.
4. Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375:2215-2222.
5. Schramm TK, Gislason GH, Kober L. Diabetes patients requiring glucose-lowering therapy and nondiabetics with a prior myocardial infarction carry the same cardiovascular risk: a population study of 3.3 million people. Circulation. 2008;117: 1945-1954.
6. Cannata D, Fierz Y, Vijayakumar A, Le Roith D. Type 2 diabetes and cancer: what is the connection? Mt Sinai J Med. 2010;77:197-213.
7. Davila JA, Morgan RO, Shaib Y, et al. Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. GUT. 2005; 54:533-539.
8. Wang F, Gupta S, Holly EA. Diabetes mellitus and pancreatic cancer in a population- based case-control study in the San Francisco Bay Area, California. Cancer Epidemiol Biomarkers Prev. 2006;15:1458-1463.
9. McFarland MS, Cripps R. Diabetes mellitus and increased risk of cancer: focus on metformin and the insulin analogs. Pharmacotherapy. 2010;30:1159-1178.
10. Currie CJ, Poole CD, Jenkins-Jones S, et al. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care. 2012;35:299-304.
11. Dehal AN, Newton CC, Jacobs EJ, et al. Impact of diabetes mellitus and insulin use on survival after colorectal cancer diagnosis: the Cancer Prevention Study-II Nutrition Cohort. J Clin Oncol. 2012;30:53-59.
12. Vigneri P, Frasca F, Sciacca L, et al. Diabetes and cancer. Endocr Relat Cancer. 2009;16:1103-1123.
13. Baylor College of Medicine. Bladder cancer. www.bcm.edu/urology/index.cfm?pmid=4973. Accessed June 17, 2012.
14. Piccinni C, Motola D, Marchesini G, Poluzzi E. Assessing the association of pioglitazone use and bladder cancer through drug adverse event reporting. Diabetes Care. 2011;34:1369-1371.
15. National Cancer Institute. SEER stat fact sheets: bladder. http://seer.cancer.gov/statfacts/html/urinb.html. Accessed June 17, 2012.
16. Bosi E. Metformin—the gold standard in type 2 diabetes: what does the evidence tell us? Diabetes Obes Metab. 2009;11(suppl 2):3-8.
17. Libby G, Donnelly LA, Donnan PT, et al. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care. 2009;32:1620-1625.
18. Monami M, Colombi C, Balzi D, et al. Metformin and cancer occurrence in insulin-treated type 2 diabetic patients. Diabetes Care. 2011;34:129-131.
19. Jiralerspong S, Palla SL, Giordano SH, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol. 2009;27:3297-3302.
20. Li D, Yeung SC, Hassan MM, et al. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology. 2009;137:482-488.
21. Wright JL, Stanford JL. Metformin use and prostate cancer in Caucasian men: results from a population-based case-control study. Cancer Causes Control. 2009;20: 1617-1622.
22. Bodmer M, Meier C, Krähenbühl S, et al. Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care. 2010;33:1304-1308.
23. He XX, Tu SM, Lee MH, Yeung SC. Thiazolidinediones and metformin associated with improved survival of diabetic prostate cancer patients. Ann Oncol. 2011; 22:2640-2645.
24. Luo Z, Zang M, Guo W. AMPK as a metabolic tumor suppressor: control of metabolism and cell growth. Future Oncol. 2010;6:457-470.
25. Hanefeld M. Pioglitazone and sulfonylureas: effectively treating type 2 diabetes. Int J Clin Pract Suppl. 2007;61(suppl 153):20-27.
26. Bowker SL, Majumdar SR, Veugelers P, Johnson JA. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care. 2006;29:254-258.
27. Yang X, So WY, Ma RC, et al. Use of sulphonylurea and cancer in type 2 diabetes— The Hong Kong Diabetes Registry. Diabetes Res Clin Pract. 2010;90:343-351.
28. Chang C, Lin J, Wu L, et al. Oral insulin secretagogues, insulin, and cancer risk in type 2 diabetes mellitus. J Clin Endocrin Metab. 2012 May 4. [Epub ahead of print.]
29. Landgraf R. Meglitinide analogues in the treatment of type 2 diabetes mellitus. Drugs Aging. 2000;17:411-425.
30. van de Laar FA. Alpha-glucosidase inhibitors in the early treatment of type 2 diabetes. Vasc Health Risk Manag. 2008;4:1189-1195.
31. Hauner H. The mode of action of thiazolidinediones. Diabetes Metab Res Rev. 2002;18(suppl 2):S10-S15.
32. US Food and Drug Administration. FDA Drug Safety Communication: update to ongoing safety review of Actos (pioglitazone) and increased risk of bladder cancer. June 5, 2011. www.fda.gov/Drugs/Drugsafety/ucm259150.htm. Accessed June 17, 2012.
33. Lewis JD, Ferrara A, Peng T, et al. Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care. 2011;34:916-922.
34. Neumann A, Weill A, Ricordeau P, et al. Pioglitazone and risk of bladder cancer among diabetic patients in France: a population-based cohort study. Diabetologia. 2012;55:1953-1962.
35. Ferrara A, Lewis JD, Quesenberry CP Jr, et al. Cohort study of pioglitazone and cancer incidence in patients with diabetes. Diabetes Care. 2011;34:923-929.
36. Azoulay L, Yin H, Filion KB, et al. The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study. BMJ. 2012;344:e3645.
37. Walsh N. Study affirms Actos bladder cancer risk. Med Page Today. May 31, 2012. www.medpagetoday.com/Endocrinology/Diabetes/33012. Accessed June 17, 2012.
38. Ferrara A, Lewis JD, Quesenberry CP Jr, et al. Cohort study of pioglitazone and cancer incidence in patients with diabetes. Diabetes Care. 2011;34:923-929.
39. Mikhail N. Quick-release bromocriptine for treatment of type 2 diabetes. Curr Drug Deliv. 2011;8:511-516.
40. Iyer P, Molitch M. Positive prolactin response to bromocriptine in 2 patients with cabergoline-resistant prolactinomas. Endocr Pract. 2011;17:e55-e58.
41. Younk LM, Davis SN. Evaluation of colesevelam hydrochloride for the treatment of type 2 diabetes. Expert Opin Drug Metab Toxicol. 2012;8:515-525.
42. Elashoff M, Matveyenko AV, Gier B, et al. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology. 2011;141:150-156.
43. Sun G, Kashyap SR. Cancer risk in type 2 diabetes mellitus: metabolic links and therapeutic considerations. J Nutr Metab. 2011;2011:708183.
44. Koehler JA, Drucker DJ. Activation of glucagon-like peptide-1 receptor signaling does not modify the growth or apoptosis of human pancreatic cancer cells. Diabetes. 2006;55:1369-1379.
45. US Food and Drug Administration. Sitagliptin (marketed as Januvia and Janumet)—acute pancreatitis. September 29, 2009. www.fda.gov/Safety/MedWatch/ SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm183800.htm. Accessed June 17, 2012.
46. US Food and Drug Administration. Byetta (exenatide) October 2007. August 18, 2008. www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHuman MedicalProducts/ucm150839.htm. Accessed June 17, 2012.
47. Spranger J, Gundert-Remy U, Stammschulte T. GLP-1-based therapies: the dilemma of uncertainty. Gastroenterology. 2011;141:20-23.
48. Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010;467:1114-1117.
49. Victoza (liraglutide [rDNA origin]) injection: REMS-risk of thyroid C-cell tumors, acute pancreatitis. www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm258826.htm. Accessed June 17, 2012.
50. Limburg PJ, Vierkant RA, Fredericksen ZS, et al. Clinically confirmed type 2 diabetes mellitus and colorectal cancer risk: a population-based, retrospective cohort study. Am J Gastroenterol. 2006;101:1872-1879.
51. Koehler JA, Kain T, Drucker DJ. Glucagon-like peptide-1 receptor activation inhibits growth and augments apoptosis in murine CT26 colon cancer cells. Endocrinology. 2011;152:3362-3372.
52. Ligumsky H, Wolf I, Israeli S, et al. The peptide-hormone glucagon-like peptide- 1 activates cAMP and inhibits growth of breast cancer cells. Breast Cancer Res Treat. 2012;132:449-461.
53. Hemkens LG, Grouven U, Bender R, et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia. 2009;52:1732-1744.
54. Home PD, Lagarenne P. Combined randomised controlled trial experience of malignancies in studies using insulin glargine. Diabetologia. 2009;52:2499-2506.
55. Dejgaard A, Lynggaard H, Råstam J, Krogsgaard Thomsen M. No evidence of increased risk of malignancies in patients with diabetes treated with insulin detemir: a meta-analysis. Diabetologia. 2009;52:2507-2512.
56. Blin P, Lassalle R, Dureau-Pournin C, et al. Insulin glargine and risk of cancer: a cohort study in the French National Healthcare Insurance Database. Diabetologia. 2012;55:644-653.
57. Ruiter R, Visser LE, van Herk-Sukel MP, et al. Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin: results from a large population-based follow-up study. Diabetologia. 2012; 55:51-62.
58. Luo J, Chlebowski R, Wactawski-Wende J, et al. Diabetes and lung cancer among postmenopausal women. Diabetes Care. 2012;35:1485-1491.
59. Symlin [prescribing information]. San Diego, CA: Amylin Pharmaceuticals; 2008. http://documents.symlin.com/SYMLIN_PI.pdf. Accessed June 17, 2012.