Grace E. Ching Sun, DO

In Reply: Dr. Fountas et al highlight further data on insulin therapy and cancer risk, specifically in regard to insulin detemir and insulin degludec. Detemir first gained US Food and Drug Administration (FDA) approval in 2005 as a basal insulin, dosed once or twice daily.¹ Compared with regular human insulin, detemir has demonstrated proliferative and antiapoptotic activities in vitro in various cancer cell lines—eg, HCT-116 (colorectal cancer), PC-3 (prostate cancer), and MCF-7 (breast adenocarcinoma).² But clinically, detemir has not demonstrated increased cancer risk compared with other basal insulins in randomized controlled trials or cohort studies.^3–5

Degludec (U-200 insulin) is equal to twice the concentration of the usual U-100 insulin therapies presently available. In February 2013, the drug application for insulin degludec failed to obtain FDA approval, and the FDA requested additional data on cardiovascular safety. Thus, degludec is not currently available in the United States.⁶

Besides ameliorating nocturnal hypoglycemia,⁷ U-200 insulin may mitigate potential mitogenic effects.⁸ However, there are still very few data on degludec compared with the amount of data on insulin glargine. Insulin analogues with a decreased dissociation rate from the insulin receptor are associated with higher mitogenic potency than metabolic potency compared with human insulin.^9,10 Degludec, like detemir, has an elevated dissociation rate from the insulin receptor, a low affinity for IGF-1 receptors, and a low mitogenic activity in vitro.⁸

At this juncture, neither detemir nor degludec has been associated with higher cancer risk, but these therapies are relatively new. And as Dr. Fountas et al indicated, their safety, particularly in regard to cancer risk in diabetes patients, should continue to be assessed.

In Reply: Dr. Fountas et al highlight further data on insulin therapy and cancer risk, specifically in regard to insulin detemir and insulin degludec. Detemir first gained US Food and Drug Administration (FDA) approval in 2005 as a basal insulin, dosed once or twice daily.¹ Compared with regular human insulin, detemir has demonstrated proliferative and antiapoptotic activities in vitro in various cancer cell lines—eg, HCT-116 (colorectal cancer), PC-3 (prostate cancer), and MCF-7 (breast adenocarcinoma).² But clinically, detemir has not demonstrated increased cancer risk compared with other basal insulins in randomized controlled trials or cohort studies.^3–5

Degludec (U-200 insulin) is equal to twice the concentration of the usual U-100 insulin therapies presently available. In February 2013, the drug application for insulin degludec failed to obtain FDA approval, and the FDA requested additional data on cardiovascular safety. Thus, degludec is not currently available in the United States.⁶

Besides ameliorating nocturnal hypoglycemia,⁷ U-200 insulin may mitigate potential mitogenic effects.⁸ However, there are still very few data on degludec compared with the amount of data on insulin glargine. Insulin analogues with a decreased dissociation rate from the insulin receptor are associated with higher mitogenic potency than metabolic potency compared with human insulin.^9,10 Degludec, like detemir, has an elevated dissociation rate from the insulin receptor, a low affinity for IGF-1 receptors, and a low mitogenic activity in vitro.⁸

At this juncture, neither detemir nor degludec has been associated with higher cancer risk, but these therapies are relatively new. And as Dr. Fountas et al indicated, their safety, particularly in regard to cancer risk in diabetes patients, should continue to be assessed.

In Reply: Dr. Fountas et al highlight further data on insulin therapy and cancer risk, specifically in regard to insulin detemir and insulin degludec. Detemir first gained US Food and Drug Administration (FDA) approval in 2005 as a basal insulin, dosed once or twice daily.¹ Compared with regular human insulin, detemir has demonstrated proliferative and antiapoptotic activities in vitro in various cancer cell lines—eg, HCT-116 (colorectal cancer), PC-3 (prostate cancer), and MCF-7 (breast adenocarcinoma).² But clinically, detemir has not demonstrated increased cancer risk compared with other basal insulins in randomized controlled trials or cohort studies.^3–5

Degludec (U-200 insulin) is equal to twice the concentration of the usual U-100 insulin therapies presently available. In February 2013, the drug application for insulin degludec failed to obtain FDA approval, and the FDA requested additional data on cardiovascular safety. Thus, degludec is not currently available in the United States.⁶

Besides ameliorating nocturnal hypoglycemia,⁷ U-200 insulin may mitigate potential mitogenic effects.⁸ However, there are still very few data on degludec compared with the amount of data on insulin glargine. Insulin analogues with a decreased dissociation rate from the insulin receptor are associated with higher mitogenic potency than metabolic potency compared with human insulin.^9,10 Degludec, like detemir, has an elevated dissociation rate from the insulin receptor, a low affinity for IGF-1 receptors, and a low mitogenic activity in vitro.⁸

At this juncture, neither detemir nor degludec has been associated with higher cancer risk, but these therapies are relatively new. And as Dr. Fountas et al indicated, their safety, particularly in regard to cancer risk in diabetes patients, should continue to be assessed.

In Reply: In regard to Dr. Weiss’s first point, the Kaiser Permanente Northern California diabetes registry study aimed to assess the association between bladder cancer and pioglitazone in 193,099 patients. In their 2011 interim 5-year analysis, Lewis et al reported a modest but statistically significant increased risk of bladder cancer in patients with type 2 diabetes mellitus who used pioglitazone for 2 or more years.¹

We appreciate Dr. Weiss’s comment on the 10-year study conclusion data. As Dr. Weiss has indicated, the recent Takeda news release² showed that the primary analysis found no association between pioglitazone use and bladder cancer risk. Furthermore, no association was found between bladder cancer risk and duration of use, higher cumulative doses, or time since initiation of pioglitazone.²

Regarding Dr. Weiss’s second point, we agree that at this time the cumulative data are not supportive of pancreatitis as per Egan et al.³ Recent publication of the SAVOR-TIMI trial⁴ of saxagliptin documented no increased risk of pancreatitis or pancreatic cancer over 2.1 years of follow-up in more than 16,000 patients over the age of 40 with type 2 diabetes. However, since amylase and lipase levels were not routinely checked in study participants, subclinical and asymptomatic cases may not have been recognized.⁴ Therefore, we stand by our statement that pancreatitis is a potential side effect.

It is important to recognize that although the observational data reviewed by both agencies (the US Food and Drug Administration and European Medicine Agency) in the publication by Egan et al³ are reassuring, we cannot yet say with absolute certainty that there is no associated risk. In fact, the concluding statements of the publication are as follows: “Although the totality of the data that have been reviewed provides reassurance, pancreatitis will continue to be considered a risk associated with these drugs until more data are available; both agencies continue to investigate this safety signal.”³

On September 18, 2014, the newest approved GLP-1 receptor agonist, dulaglutide, was approved with a boxed warning that it causes thyroid C-cell tumors in rats, that whether it causes thyroid C-cell tumors including medullary thyroid carcinoma (MTC) in humans is unknown, and that since relevance to humans could not be determined from clinical or nonclinical studies, dulaglutide is contraindicated in patients with a personal or family history of MTC, as well as in patients with multiple endocrine neoplasia syndrome type 2.⁵

It is important to recognize that despite these controversies, which have not been well-supported to date, incretin-based therapies have numerous metabolic benefits, including favorable glycemic and weight effects.

In regard to Dr. Weiss’s last point, we would like to point out the study by Gier et al⁶ in which GLP-1 receptor expression was found in 3 of 17 cases of human papillary thyroid cancer. The implication is that abnormal thyroid tissue does not behave the same way as normal tissue.

Furthermore, Dr. Weiss brings up the point that patients with thyroid cancer, if it is adequately treated, should have no remnant thyroid tissue. Certainly, adequate treatment would be an easy call to make if a stimulated thyroglobulin level is below the assay’s detection limit and there is no imaging evidence of residual thyroid cancer. For example, in someone with a history of thyroid cancer diagnosed more than 10 years ago without biochemical or imaging evidence of disease, any potential concerns of GLP-1 receptor agonist use in regards to thyroid cancer would be nominal. But not everyone with thyroid cancer falls into this category.

We do not suggest that these potential risks preclude the use of these agents in all patients, but rather that a discussion should occur between physician and patient. Diabetes therapy, as in treatment of other medical conditions, should be tailored to the individual patient, and all potential risk and benefits should be disclosed and considered.

In Reply: In regard to Dr. Weiss’s first point, the Kaiser Permanente Northern California diabetes registry study aimed to assess the association between bladder cancer and pioglitazone in 193,099 patients. In their 2011 interim 5-year analysis, Lewis et al reported a modest but statistically significant increased risk of bladder cancer in patients with type 2 diabetes mellitus who used pioglitazone for 2 or more years.¹

We appreciate Dr. Weiss’s comment on the 10-year study conclusion data. As Dr. Weiss has indicated, the recent Takeda news release² showed that the primary analysis found no association between pioglitazone use and bladder cancer risk. Furthermore, no association was found between bladder cancer risk and duration of use, higher cumulative doses, or time since initiation of pioglitazone.²

Regarding Dr. Weiss’s second point, we agree that at this time the cumulative data are not supportive of pancreatitis as per Egan et al.³ Recent publication of the SAVOR-TIMI trial⁴ of saxagliptin documented no increased risk of pancreatitis or pancreatic cancer over 2.1 years of follow-up in more than 16,000 patients over the age of 40 with type 2 diabetes. However, since amylase and lipase levels were not routinely checked in study participants, subclinical and asymptomatic cases may not have been recognized.⁴ Therefore, we stand by our statement that pancreatitis is a potential side effect.

It is important to recognize that although the observational data reviewed by both agencies (the US Food and Drug Administration and European Medicine Agency) in the publication by Egan et al³ are reassuring, we cannot yet say with absolute certainty that there is no associated risk. In fact, the concluding statements of the publication are as follows: “Although the totality of the data that have been reviewed provides reassurance, pancreatitis will continue to be considered a risk associated with these drugs until more data are available; both agencies continue to investigate this safety signal.”³

On September 18, 2014, the newest approved GLP-1 receptor agonist, dulaglutide, was approved with a boxed warning that it causes thyroid C-cell tumors in rats, that whether it causes thyroid C-cell tumors including medullary thyroid carcinoma (MTC) in humans is unknown, and that since relevance to humans could not be determined from clinical or nonclinical studies, dulaglutide is contraindicated in patients with a personal or family history of MTC, as well as in patients with multiple endocrine neoplasia syndrome type 2.⁵

It is important to recognize that despite these controversies, which have not been well-supported to date, incretin-based therapies have numerous metabolic benefits, including favorable glycemic and weight effects.

In regard to Dr. Weiss’s last point, we would like to point out the study by Gier et al⁶ in which GLP-1 receptor expression was found in 3 of 17 cases of human papillary thyroid cancer. The implication is that abnormal thyroid tissue does not behave the same way as normal tissue.

Furthermore, Dr. Weiss brings up the point that patients with thyroid cancer, if it is adequately treated, should have no remnant thyroid tissue. Certainly, adequate treatment would be an easy call to make if a stimulated thyroglobulin level is below the assay’s detection limit and there is no imaging evidence of residual thyroid cancer. For example, in someone with a history of thyroid cancer diagnosed more than 10 years ago without biochemical or imaging evidence of disease, any potential concerns of GLP-1 receptor agonist use in regards to thyroid cancer would be nominal. But not everyone with thyroid cancer falls into this category.

We do not suggest that these potential risks preclude the use of these agents in all patients, but rather that a discussion should occur between physician and patient. Diabetes therapy, as in treatment of other medical conditions, should be tailored to the individual patient, and all potential risk and benefits should be disclosed and considered.

In Reply: In regard to Dr. Weiss’s first point, the Kaiser Permanente Northern California diabetes registry study aimed to assess the association between bladder cancer and pioglitazone in 193,099 patients. In their 2011 interim 5-year analysis, Lewis et al reported a modest but statistically significant increased risk of bladder cancer in patients with type 2 diabetes mellitus who used pioglitazone for 2 or more years.¹

We appreciate Dr. Weiss’s comment on the 10-year study conclusion data. As Dr. Weiss has indicated, the recent Takeda news release² showed that the primary analysis found no association between pioglitazone use and bladder cancer risk. Furthermore, no association was found between bladder cancer risk and duration of use, higher cumulative doses, or time since initiation of pioglitazone.²

Regarding Dr. Weiss’s second point, we agree that at this time the cumulative data are not supportive of pancreatitis as per Egan et al.³ Recent publication of the SAVOR-TIMI trial⁴ of saxagliptin documented no increased risk of pancreatitis or pancreatic cancer over 2.1 years of follow-up in more than 16,000 patients over the age of 40 with type 2 diabetes. However, since amylase and lipase levels were not routinely checked in study participants, subclinical and asymptomatic cases may not have been recognized.⁴ Therefore, we stand by our statement that pancreatitis is a potential side effect.

It is important to recognize that although the observational data reviewed by both agencies (the US Food and Drug Administration and European Medicine Agency) in the publication by Egan et al³ are reassuring, we cannot yet say with absolute certainty that there is no associated risk. In fact, the concluding statements of the publication are as follows: “Although the totality of the data that have been reviewed provides reassurance, pancreatitis will continue to be considered a risk associated with these drugs until more data are available; both agencies continue to investigate this safety signal.”³

On September 18, 2014, the newest approved GLP-1 receptor agonist, dulaglutide, was approved with a boxed warning that it causes thyroid C-cell tumors in rats, that whether it causes thyroid C-cell tumors including medullary thyroid carcinoma (MTC) in humans is unknown, and that since relevance to humans could not be determined from clinical or nonclinical studies, dulaglutide is contraindicated in patients with a personal or family history of MTC, as well as in patients with multiple endocrine neoplasia syndrome type 2.⁵

It is important to recognize that despite these controversies, which have not been well-supported to date, incretin-based therapies have numerous metabolic benefits, including favorable glycemic and weight effects.

In regard to Dr. Weiss’s last point, we would like to point out the study by Gier et al⁶ in which GLP-1 receptor expression was found in 3 of 17 cases of human papillary thyroid cancer. The implication is that abnormal thyroid tissue does not behave the same way as normal tissue.

Furthermore, Dr. Weiss brings up the point that patients with thyroid cancer, if it is adequately treated, should have no remnant thyroid tissue. Certainly, adequate treatment would be an easy call to make if a stimulated thyroglobulin level is below the assay’s detection limit and there is no imaging evidence of residual thyroid cancer. For example, in someone with a history of thyroid cancer diagnosed more than 10 years ago without biochemical or imaging evidence of disease, any potential concerns of GLP-1 receptor agonist use in regards to thyroid cancer would be nominal. But not everyone with thyroid cancer falls into this category.

We do not suggest that these potential risks preclude the use of these agents in all patients, but rather that a discussion should occur between physician and patient. Diabetes therapy, as in treatment of other medical conditions, should be tailored to the individual patient, and all potential risk and benefits should be disclosed and considered.

In the last quarter century, many new drugs have become available for treating type 2 diabetes mellitus. The American Association of Clinical Endocrinologists incorporated these new agents in its updated glycemic control algorithm in 2013.¹ Because diabetes affects 25.8 million Americans and can lead to blindness, renal failure, cardiovascular disease, and amputation, agents that help us treat it more effectively are valuable.²

One of the barriers to effective treatment is the side effects of the agents. Because some of these drugs have been in use for only a short time, concerns of potential adverse effects have arisen. Cancer is one such concern, especially since type 2 diabetes mellitus by itself increases the risk of cancer by 20% to 50% compared with no diabetes.³

Type 2 diabetes has been linked to risk of cancers of the pancreas,⁴ colorectum,^5,6 liver,⁷ kidney,^8,9 breast,¹⁰ bladder,¹¹ and endometri-um,¹² as well as to hematologic malignancies such as non-Hodgkin lymphoma.¹³ The risk of bladder cancer appears to depend on how long the patient has had type 2 diabetes. Newton et al,¹⁴ in a prospective cohort study, found that those who had diabetes for more than 15 years and used insulin had the highest risk of bladder cancer. On the other hand, the risk of prostate cancer is actually lower in people with diabetes,¹⁵ particularly in those who have had diabetes for longer than 4 years.¹⁶

Cancer and type 2 diabetes share many risk factors and underlying pathophysiologic mechanisms. Nonmodifiable risk factors for both diseases include advanced age, male sex, ethnicity (African American men appear to be most vulnerable to both cancer and diabetes),^17,18 and family history. Modifiable risk factors include lower socioeconomic status, obesity, and alcohol consumption. These common risk factors lead to hyperinsulinemia and insulin resistance, changes in mitochondrial function, low-grade inflammation, and oxidative stress,³ which promote both diabetes and cancer. Diabetes therapy may influence several of these processes.

Several classes of diabetes drugs, including exogenous insulin,^19–22 insulin secretagogues,^23–25 and incretin-based therapies,^26–28 have been under scrutiny because of their potential influences on cancer development in a population already at risk (Table 1).

INSULIN ANALOGUES: MIXED EVIDENCE

Insulin promotes cell division by binding to insulin receptor isoform A and insulin-like growth factor 1 receptors.²⁹ Because endogenous hyperinsulinemia has been linked to cancer risk, growth, and proliferation, some speculate that exogenous insulin may also increase cancer risk.

In 2009, a retrospective study by Hemkens et al linked the long-acting insulin analogue glargine to risk of cancer.¹⁹ This finding set off a tumult of controversy within the medical community and concern among patients. Several limitations of the study were brought to light, including a short duration of follow-up, and several other studies have refuted the study’s findings.^20,21

More recently, the Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial²² found no higher cancer risk with glargine use than with placebo. This study enrolled 12,537 participants from 573 sites in 40 countries. Specifically, risks with glargine use were as follows:

• Any cancer—hazard ratio 1.00, 95% confidence interval (CI) 0.88–1.13, P = .97
• Cancer death—hazard ratio 0.94, 95% CI 0.77–1.15, P = .52.

However, the study was designed to assess cardiovascular outcomes, not cancer risk. Furthermore, the participants were not typical of patients seen in clinical practice: their insulin doses were lower (the median insulin dose was 0.4 units/kg/day by year 6, whereas in clinical practice, those with type 2 diabetes mellitus often use more than 1 unit/kg/day, depending on duration of diabetes, diet, and exercise regimen), and their baseline median hemoglobin A_1c level was only 6.4%. And one may argue that the median follow-up of 6.2 years was too short for cancer to develop.²²

In vitro studies indicate that long-acting analogue insulin therapy may promote cancer cell growth more than endogenous insulin,³⁰ but epidemiologic data have not unequivocally substantiated this.^20–22 There is no clear evidence that analogue insulin therapy raises cancer risk above that of human recombinant insulin, and starting insulin therapy should not be delayed because of concerns about cancer risk, particularly in uncontrolled diabetes.

INSULIN SECRETAGOGUES

Sulfonylureas: Higher risk

Before 1995, only two classes of diabetes drugs were approved by the US Food and Drug Administration (FDA)—insulin and sulfonylureas.

Sulfonylureas lower blood sugar levels by binding to sulfonylurea receptors and inhibiting adenosine triphosphate-dependent potassium channels. The resulting change in resting potential causes an influx of calcium, ultimately leading to insulin secretion.

Sulfonylureas are effective, and because of their low cost, physicians often pick them as a second-line agent after metformin.

The main disadvantage of sulfonylureas is the risk of hypoglycemia, particularly in patients with renal failure, the elderly, and diabetic patients who are unaware of when they are hypoglycemic. Other potential drawbacks are that they impair cardiac ischemic preconditioning³¹ and possibly increase cancer risk.^21,32 (Ischemic preconditioning is the process in which transient episodes of ischemia “condition” the myocardium so that it better withstands future episodes with minimal anginal pain and tissue injury.³³) Of the sulfonylureas, glyburide has been most implicated in cardiovascular risk.³²

In a retrospective cohort study of 62,809 patients from a general-practice database in the United Kingdom, Currie et al²¹ found that sulfonylurea monotherapy was associated with a 36% higher risk of cancer (95% CI 1.19–1.54, P < .001) than metformin monotherapy. Prescribing bias may have influenced the results: practitioners are more likely to prescribe sulfonylureas to leaner patients, who have a greater likelihood of occult cancer. However, other studies also found that the cancer death rate is higher in those who take a sulfonylurea alone than in those who use metformin alone.^23,24

Some evidence indicates that long-acting sulfonylurea formulations (eg, glyburide) likely hold the most danger, certainly in regard to hypoglycemia, but it is less clear if this translates to cancer concerns.³¹

Meglitinides: Limited evidence

Meglitinides, the other class of insulin secretagogues, are less commonly used but are similar to sulfonylureas in the way they increase endogenous insulin levels. The data are limited regarding cancer risk and meglitinide therapy, but the magnitude of the association is similar to that with sulfonylurea therapy.²⁵

INSULIN SENSITIZERS

There are currently two classes of insulin sensitizers: biguanides and thiazolidinediones (TZDs, also known as glitazones). These drugs show less risk of both cancer incidence and cancer death than insulin secretagogues such as sulfonylureas.^21,23,24 In fact, they may decrease cancer potential by alteration of signaling via the AKT/mTOR (v-akt murine thymoma viral oncogene homolog 1/mammalian target of rapamycin) pathway.³⁴

Metformin, a biguanide, is the oral drug of choice

Metformin is the only biguanide currently available in the United States. It was approved by the FDA in 1995, although it had been in clinical use since the 1950s. Inexpensive and familiar, it is the oral antihyperglycemic of choice if there are no contraindications to it, such as renal dysfunction (creatinine ≥ 1.4 mg/dL in women and ≥ 1.5 mg/dL in men), acute decompensated heart failure, or pulmonary or hepatic insufficiency, all of which may lead to an increased risk of lactic acidosis.¹

Metformin lowers blood sugar levels primarily by inhibiting hepatic glucose production (gluconeogenesis) and by improving peripheral insulin sensitivity. It directly activates AMP-activated protein kinase (AMPK), which affects insulin signaling and glucose and fat metabolism.³⁵ It may exert further beneficial effects by acutely increasing glucagon-like peptide-1 (GLP-1) levels and inducing islet incretin-receptor gene expression.³⁶ Although the exact mechanisms have not been fully elucidated, metformin’s insulin-sensitizing properties are likely from favorable effects on insulin receptor expression, tyrosine kinase activity, and influences on the incretin pathway.^36,37 These effects also mitigate carcinogenesis, both directly (via AMPK and liver kinase B1, a tumor-suppressor gene) and indirectly (via reduction of hyperinsulinemia).³⁵

Overall, biguanide therapy is associated with a lower cancer incidence or, at worst, no effect on cancer incidence. In vitro studies demonstrate that metformin both suppresses cancer cell growth and induces apoptosis, resulting in fewer live cancer cells.³⁴ Several retrospective studies found lower cancer risk in metformin users than in patients receiving antidiabetes drugs other than insulin-sensitizing agents,^{21,23,25,38–40} while others have shown no effect.⁴¹ Use of metformin was specifically associated with lower risk of cancers of the liver, colon and rectum, and lung.⁴² Further, metformin users have a lower cancer mortality rate than nonusers.^24,43

Thiazolidinediones

TZDs, such as pioglitazone, work by binding to peroxisome proliferator-activated gamma receptors in the cell nucleus, altering gene transcription.⁴⁴ They reduce insulin resistance and levels of endogenous insulin levels and free fatty acids.⁴⁴

Concern over bladder cancer risk with TZD use, particularly with pioglitazone, has increased in the last few years, as various cohort studies found a statistically significant increased risk with this agent.⁴⁴ The risk appears to rise with cumulative dose.^45,46

Randomized controlled trials also found an increased risk of bladder cancer with TZD therapy, although the difference was not statistically significant.^47–49 In a mean follow-up of 8.7 years, the Prospective Pioglitazone Clinical Trial in Macrovascular Events reported 23 cases of bladder cancer in the pioglitazone group vs 22 cases in the placebo group, for rates of 0.9% vs 0.8% (relative risk [RR] 1.06, 95% CI 0.59–1.89).⁴⁹

On the other hand, the risk of cancer of the breast, colon, and lung has been found to be lower with TZD use.⁴⁷ In vitro studies support the clinical data, showing that TZDs inhibit growth of human cancer cells derived from cancers of the lung, colon, breast, stomach, ovary, and prostate.^50–53

Home et al⁵⁴ compared rosiglitazone against a sulfonylurea in patients already taking metformin in the Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes (RECORD) trial. Malignancies developed in 6.7% of the sulfonylurea group compared with 5.1% of the rosiglitazone group, for a hazard ratio of 1.33 (95% CI 0.94–1.88).

Both ADOPT (A Diabetes Outcome Progression Trial) and the RECORD trial found rosiglitazone comparable to metformin in terms of cancer risk.⁵⁴

Colmers et al⁴⁷ pooled data from four randomized controlled trials, seven cohort studies, and nine case-control studies to assess the risk of cancer with TZD use in type 2 diabetes. Both the randomized and observational data showed neutral overall cancer risk with TZDs. However, pooled data from observational studies showed significantly lower risk with TZD use in terms of:

• Colorectal cancer RR 0.93, 95% CI 0.87–1.00
• Lung cancer RR 0.91, 95% CI 0.84–0.98
• Breast cancer RR 0.89, 95% CI 0.81–0.98.

INCRETIN-BASED THERAPIES

Incretins are hormones released from the gut in response to food ingestion, triggering release of insulin before blood glucose levels rise. Their action explains why insulin secretion increases more after an oral glucose load than after an intravenous glucose load, a phenomenon called the incretin effect.⁵⁵

There are two incretin hormones: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). They have short a half-life because they are rapidly degraded by dipeptidyl peptidase-IV (DPP-IV).⁵⁵ Available incretin-based therapies are GLP-1 receptor agonists and DPP-IV inhibitors.

When used as monotherapy, incretin-based therapies do not cause hypoglycemia because their effect is glucose-dependent.⁵⁵ GLP-1 receptor antagonists have the added benefit of inducing weight loss, but DPP-IV inhibitors are considered to be weight-neutral.

GLP-1 receptor agonists

Exenatide, the first of the GLP-1 receptor agonists, was approved in 2005. The original formulation (Byetta) is taken by injection twice daily, and timing in conjunction with food intake is important: it should be taken within 60 minutes before the morning and evening meals. Extended-release exenatide (Bydureon) is a once-weekly formulation taken without regard to timing of food intake. Exenatide (either twice-daily Byetta or once-weekly Bydureon) should not be used in those with creatinine clearance less than 30 mL/min or end-stage renal disease and should be used with caution in patients with renal transplantation.

Liraglutide (Victoza), a once-daily formulation, can be injected irrespective of food intake. The dose does not have to be adjusted for renal function, although it should be used with caution in those with renal impairment, including end-stage renal disease. Approval for a 3-mg formulation is pending with the FDA as a weight-loss drug on the basis of promising results in a randomized phase 3 trial.⁵⁶

Albiglutide (Tanzeum), a once-weekly GLP-1 receptor antagonist, was recently approved by the FDA.

DPP-IV inhibitors

Whereas GLP-1 receptor agonists are injected, the DPP-IV inhibitors have the advantage of being oral agents.

Sitagliptin (Januvia), the first DPP-IV inhibitor, became available in the United States in 2006. Since then, three more have become available: saxagliptin (Onglyza), linagliptin (Tradjenta), and alogliptin (Nesina).

Concerns about thyroid cancer with incretin drugs

Concerns of increased risk of cancer, particularly of the thyroid and pancreas, have been raised since GLP-1 receptor agonists and DPP-IV inhibitors became available.

Studies in rodents have shown C-cell hyperplasia, sometimes resulting in increased incidence of thyroid carcinoma, and dose-dependent rises in serum calcitonin, particularly with liraglutide.²⁶ This has raised concern about an increased risk of medullary thyroid carcinoma in humans. However, the density of C cells in rodents is up to 45 times greater than in humans, and C cells also express functional GLP-1 receptors.²⁶

Gier et al²⁷ assessed the expression of calcitonin and human GLP-1 receptors in normal C cells, C cell hyperplasia, and medullary cancer. In this study, calcitonin and GLP-1 receptor were co-expressed in medullary thyroid cancer (10 of 12 cases) and C-cell hyperplasia (9 of 9 cases) more commonly than in normal C cells (5 of 15 cases). Further, GLP-1 receptor was expressed in 3 of 17 cases of papillary thyroid cancer.

Calcitonin, a polypeptide hormone produced by thyroid C cells and used as a medullary thyroid cancer biomarker, was increased in a slightly higher percentage of patients treated with liraglutide than in controls, without an increase above the normal range.⁵⁷

A meta-analysis by Alves et al⁵⁸ of 25 studies found that neither exenatide (no cases reported) nor liraglutide (odds ratio 1.54, 95% CI 0.40–6.02) was associated with increased thyroid cancer risk.

MacConell et al⁵⁹ pooled the results of 19 placebo-controlled trials of twice-daily exenatide and found a thyroid cancer incidence rate of 0.3 per 100 patient-years (< 0.1%) vs 0 per 100 patient-years in pooled comparators.

Concerns about pancreatic cancer with incretin drugs

Increased risk of acute pancreatitis is a potential side effect of both DPP-IV inhibitors and GLP-1 receptor agonists and has led to speculation that this translates to an increased risk of pancreatic cancer.

In a point-counterpoint debate, Butler et al²⁸ argued that incretin-based medications have questionable safety, with increased rates of pancreatitis possibly leading to pancreatic cancer. In counterpoint, Nauck⁶⁰ argued that the risk of pancreatitis or cancer is extremely low, and clinical cases are unsubstantiated.

Bailey⁶¹ outlined the complexities and difficulties in drawing firm conclusions from individual clinical trials regarding possible adverse effects of diabetes drugs. The trials are typically designed to assess hemoglobin A_1c reduction at varying doses and are typically restricted in patient selection, patient numbers, and drug-exposure duration, which may introduce allocation and ascertainment biases. The attempt to draw firm conclusions from such trials can be problematic and can lead to increased alarm, warranted or not.

Type 2 diabetes mellitus itself is associated with an increased incidence of pancreatic cancer, and whether incretin therapy enhances this risk is still controversial. Whether more episodes of acute pancreatitis without chronic pancreatitis can be extrapolated to an increased incidence of pancreatic cancer is doubtful. A normal pancreatic duct cell may take up to 12 years to become a tumor cell from which pancreatic carcinoma develops, another 7 years to develop metastatic capacity, and another 3 years before a diagnosis is made from clinical symptoms (which are usually accompanied by metastases).⁶²

The risks and benefits of incretin therapies remain a contentious issue, and there are no clear prospective data at this time on increased pancreatic cancer incidence. Long-term prospective studies designed to analyze these specific outcomes (pancreatitis, pancreatic cancer, and medullary thyroid cancer) need to be undertaken.⁶³

OTHER DIABETES THERAPIES

Alpha glucosidase inhibitors

Oral glucosidase inhibitors ameliorate hyperglycemia by inhibiting alpha glucosidase enzymes in the brush border of the small intestines, preventing conversion of polysaccharides to monosaccharides.⁶⁴ This slows digestion of carbohydrates and glucose release into the bloodstream and blunts the postprandial hyperglycemic excursion.

The two alpha glucosidase inhibitors currently available in the United States are acarbose and miglitol, and although data are limited, they do not appear to increase the risk of cancer.^65,66

Sodium-glucose-linked cotransporter 2 inhibitors

The newest class of oral diabetes agents to be approved are the sodium-glucose-linked cotransporter 2 (SGLT2) inhibitors canagliflozin (Invokana) and dapagliflozin (Farxiga).

SGLT2 is a protein in the S1 segment of the proximal renal tubules responsible for over 90% of renal glucose reabsorption. SGLT2 inhibitors lower serum glucose levels by promoting glycosuria and have also been shown to have favorable effects on blood pressure and weight.^67,68

Canagliflozin was the first of its class to gain FDA approval in the United States. It has not been found to be associated with increased cancer risk.⁶⁸

Dapagliflozin, originally approved in Europe, was approved in the United States on January 8, 2014. Because of a possible increased incidence of breast and bladder malignancies, the FDA advisory committee initially recommended against approval and required further data. In those who were treated, nine cases of bladder cancer and nine cases of breast cancer were reported, compared with one case of bladder cancer and no cases of breast cancer in the control group; however, the difference was not statistically significant.⁶⁸

Since SGLT2 inhibitors are still new, data on long-term outcomes are lacking. Early clinical data do not show a significant increase in cancer risk.

WHAT THIS MEANS IN PRACTICE

Many studies have found associations between diabetes, obesity, hyperinsulinemia, and cancer risk. In the last decade, concerns implicating antihyperglycemic agents in cancer development have arisen but have not been well substantiated. At this time, there are no definitive prospective data indicating that the currently available type 2 diabetes therapies increase the incidence of cancer beyond the inherent increased risk in this population. What, then, is one to do?

Educate. Lifestyle modification, including weight management, should continue to be emphasized in diabetes education, as no therapy is completely effective without adjunct modifications in diet and physical activity. Epidemiologic studies have shown the benefits of lifestyle modifications, which ameliorate many of the adverse metabolic conditions that coexist in type 2 diabetes and cancer.

Screen for cancer. Given the associations between diabetes and malignancy, cancer screening is especially important in this high-risk population.

Customize therapy to individual patients. Those with a personal history of bladder cancer should avoid pioglitazone, and those who have had pancreatic cancer should avoid sitagliptin until definitive clinical data become available.

Moreover, patients with a personal or family history of medullary thyroid cancer should not receive GLP-1 receptor agonists. These agents should also probably be avoided in patients with a personal history of differentiated thyroid carcinoma or a history of familial nonmedullary thyroid carcinoma. Until we have further elucidating data, it is not possible to say whether a family history of any of the other types of cancer should represent a contraindication to the use of any of these agents.

Discuss. The multitude of diabetes therapies warrants physician-patient discussions that carefully weigh the risks and benefits of additional agents to optimize glycemic control and metabolic factors in individual patients.

In the last quarter century, many new drugs have become available for treating type 2 diabetes mellitus. The American Association of Clinical Endocrinologists incorporated these new agents in its updated glycemic control algorithm in 2013.¹ Because diabetes affects 25.8 million Americans and can lead to blindness, renal failure, cardiovascular disease, and amputation, agents that help us treat it more effectively are valuable.²

One of the barriers to effective treatment is the side effects of the agents. Because some of these drugs have been in use for only a short time, concerns of potential adverse effects have arisen. Cancer is one such concern, especially since type 2 diabetes mellitus by itself increases the risk of cancer by 20% to 50% compared with no diabetes.³

Type 2 diabetes has been linked to risk of cancers of the pancreas,⁴ colorectum,^5,6 liver,⁷ kidney,^8,9 breast,¹⁰ bladder,¹¹ and endometri-um,¹² as well as to hematologic malignancies such as non-Hodgkin lymphoma.¹³ The risk of bladder cancer appears to depend on how long the patient has had type 2 diabetes. Newton et al,¹⁴ in a prospective cohort study, found that those who had diabetes for more than 15 years and used insulin had the highest risk of bladder cancer. On the other hand, the risk of prostate cancer is actually lower in people with diabetes,¹⁵ particularly in those who have had diabetes for longer than 4 years.¹⁶

Cancer and type 2 diabetes share many risk factors and underlying pathophysiologic mechanisms. Nonmodifiable risk factors for both diseases include advanced age, male sex, ethnicity (African American men appear to be most vulnerable to both cancer and diabetes),^17,18 and family history. Modifiable risk factors include lower socioeconomic status, obesity, and alcohol consumption. These common risk factors lead to hyperinsulinemia and insulin resistance, changes in mitochondrial function, low-grade inflammation, and oxidative stress,³ which promote both diabetes and cancer. Diabetes therapy may influence several of these processes.

Several classes of diabetes drugs, including exogenous insulin,^19–22 insulin secretagogues,^23–25 and incretin-based therapies,^26–28 have been under scrutiny because of their potential influences on cancer development in a population already at risk (Table 1).

INSULIN ANALOGUES: MIXED EVIDENCE

Insulin promotes cell division by binding to insulin receptor isoform A and insulin-like growth factor 1 receptors.²⁹ Because endogenous hyperinsulinemia has been linked to cancer risk, growth, and proliferation, some speculate that exogenous insulin may also increase cancer risk.

In 2009, a retrospective study by Hemkens et al linked the long-acting insulin analogue glargine to risk of cancer.¹⁹ This finding set off a tumult of controversy within the medical community and concern among patients. Several limitations of the study were brought to light, including a short duration of follow-up, and several other studies have refuted the study’s findings.^20,21

More recently, the Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial²² found no higher cancer risk with glargine use than with placebo. This study enrolled 12,537 participants from 573 sites in 40 countries. Specifically, risks with glargine use were as follows:

• Any cancer—hazard ratio 1.00, 95% confidence interval (CI) 0.88–1.13, P = .97
• Cancer death—hazard ratio 0.94, 95% CI 0.77–1.15, P = .52.

However, the study was designed to assess cardiovascular outcomes, not cancer risk. Furthermore, the participants were not typical of patients seen in clinical practice: their insulin doses were lower (the median insulin dose was 0.4 units/kg/day by year 6, whereas in clinical practice, those with type 2 diabetes mellitus often use more than 1 unit/kg/day, depending on duration of diabetes, diet, and exercise regimen), and their baseline median hemoglobin A_1c level was only 6.4%. And one may argue that the median follow-up of 6.2 years was too short for cancer to develop.²²

In vitro studies indicate that long-acting analogue insulin therapy may promote cancer cell growth more than endogenous insulin,³⁰ but epidemiologic data have not unequivocally substantiated this.^20–22 There is no clear evidence that analogue insulin therapy raises cancer risk above that of human recombinant insulin, and starting insulin therapy should not be delayed because of concerns about cancer risk, particularly in uncontrolled diabetes.

INSULIN SECRETAGOGUES

Sulfonylureas: Higher risk

Before 1995, only two classes of diabetes drugs were approved by the US Food and Drug Administration (FDA)—insulin and sulfonylureas.

Sulfonylureas lower blood sugar levels by binding to sulfonylurea receptors and inhibiting adenosine triphosphate-dependent potassium channels. The resulting change in resting potential causes an influx of calcium, ultimately leading to insulin secretion.

Sulfonylureas are effective, and because of their low cost, physicians often pick them as a second-line agent after metformin.

The main disadvantage of sulfonylureas is the risk of hypoglycemia, particularly in patients with renal failure, the elderly, and diabetic patients who are unaware of when they are hypoglycemic. Other potential drawbacks are that they impair cardiac ischemic preconditioning³¹ and possibly increase cancer risk.^21,32 (Ischemic preconditioning is the process in which transient episodes of ischemia “condition” the myocardium so that it better withstands future episodes with minimal anginal pain and tissue injury.³³) Of the sulfonylureas, glyburide has been most implicated in cardiovascular risk.³²

In a retrospective cohort study of 62,809 patients from a general-practice database in the United Kingdom, Currie et al²¹ found that sulfonylurea monotherapy was associated with a 36% higher risk of cancer (95% CI 1.19–1.54, P < .001) than metformin monotherapy. Prescribing bias may have influenced the results: practitioners are more likely to prescribe sulfonylureas to leaner patients, who have a greater likelihood of occult cancer. However, other studies also found that the cancer death rate is higher in those who take a sulfonylurea alone than in those who use metformin alone.^23,24

Some evidence indicates that long-acting sulfonylurea formulations (eg, glyburide) likely hold the most danger, certainly in regard to hypoglycemia, but it is less clear if this translates to cancer concerns.³¹

Meglitinides: Limited evidence

Meglitinides, the other class of insulin secretagogues, are less commonly used but are similar to sulfonylureas in the way they increase endogenous insulin levels. The data are limited regarding cancer risk and meglitinide therapy, but the magnitude of the association is similar to that with sulfonylurea therapy.²⁵

INSULIN SENSITIZERS

There are currently two classes of insulin sensitizers: biguanides and thiazolidinediones (TZDs, also known as glitazones). These drugs show less risk of both cancer incidence and cancer death than insulin secretagogues such as sulfonylureas.^21,23,24 In fact, they may decrease cancer potential by alteration of signaling via the AKT/mTOR (v-akt murine thymoma viral oncogene homolog 1/mammalian target of rapamycin) pathway.³⁴

Metformin, a biguanide, is the oral drug of choice

Metformin is the only biguanide currently available in the United States. It was approved by the FDA in 1995, although it had been in clinical use since the 1950s. Inexpensive and familiar, it is the oral antihyperglycemic of choice if there are no contraindications to it, such as renal dysfunction (creatinine ≥ 1.4 mg/dL in women and ≥ 1.5 mg/dL in men), acute decompensated heart failure, or pulmonary or hepatic insufficiency, all of which may lead to an increased risk of lactic acidosis.¹

Metformin lowers blood sugar levels primarily by inhibiting hepatic glucose production (gluconeogenesis) and by improving peripheral insulin sensitivity. It directly activates AMP-activated protein kinase (AMPK), which affects insulin signaling and glucose and fat metabolism.³⁵ It may exert further beneficial effects by acutely increasing glucagon-like peptide-1 (GLP-1) levels and inducing islet incretin-receptor gene expression.³⁶ Although the exact mechanisms have not been fully elucidated, metformin’s insulin-sensitizing properties are likely from favorable effects on insulin receptor expression, tyrosine kinase activity, and influences on the incretin pathway.^36,37 These effects also mitigate carcinogenesis, both directly (via AMPK and liver kinase B1, a tumor-suppressor gene) and indirectly (via reduction of hyperinsulinemia).³⁵

Overall, biguanide therapy is associated with a lower cancer incidence or, at worst, no effect on cancer incidence. In vitro studies demonstrate that metformin both suppresses cancer cell growth and induces apoptosis, resulting in fewer live cancer cells.³⁴ Several retrospective studies found lower cancer risk in metformin users than in patients receiving antidiabetes drugs other than insulin-sensitizing agents,^{21,23,25,38–40} while others have shown no effect.⁴¹ Use of metformin was specifically associated with lower risk of cancers of the liver, colon and rectum, and lung.⁴² Further, metformin users have a lower cancer mortality rate than nonusers.^24,43

Thiazolidinediones

TZDs, such as pioglitazone, work by binding to peroxisome proliferator-activated gamma receptors in the cell nucleus, altering gene transcription.⁴⁴ They reduce insulin resistance and levels of endogenous insulin levels and free fatty acids.⁴⁴

Concern over bladder cancer risk with TZD use, particularly with pioglitazone, has increased in the last few years, as various cohort studies found a statistically significant increased risk with this agent.⁴⁴ The risk appears to rise with cumulative dose.^45,46

Randomized controlled trials also found an increased risk of bladder cancer with TZD therapy, although the difference was not statistically significant.^47–49 In a mean follow-up of 8.7 years, the Prospective Pioglitazone Clinical Trial in Macrovascular Events reported 23 cases of bladder cancer in the pioglitazone group vs 22 cases in the placebo group, for rates of 0.9% vs 0.8% (relative risk [RR] 1.06, 95% CI 0.59–1.89).⁴⁹

On the other hand, the risk of cancer of the breast, colon, and lung has been found to be lower with TZD use.⁴⁷ In vitro studies support the clinical data, showing that TZDs inhibit growth of human cancer cells derived from cancers of the lung, colon, breast, stomach, ovary, and prostate.^50–53

Home et al⁵⁴ compared rosiglitazone against a sulfonylurea in patients already taking metformin in the Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes (RECORD) trial. Malignancies developed in 6.7% of the sulfonylurea group compared with 5.1% of the rosiglitazone group, for a hazard ratio of 1.33 (95% CI 0.94–1.88).

Both ADOPT (A Diabetes Outcome Progression Trial) and the RECORD trial found rosiglitazone comparable to metformin in terms of cancer risk.⁵⁴

Colmers et al⁴⁷ pooled data from four randomized controlled trials, seven cohort studies, and nine case-control studies to assess the risk of cancer with TZD use in type 2 diabetes. Both the randomized and observational data showed neutral overall cancer risk with TZDs. However, pooled data from observational studies showed significantly lower risk with TZD use in terms of:

• Colorectal cancer RR 0.93, 95% CI 0.87–1.00
• Lung cancer RR 0.91, 95% CI 0.84–0.98
• Breast cancer RR 0.89, 95% CI 0.81–0.98.

INCRETIN-BASED THERAPIES

Incretins are hormones released from the gut in response to food ingestion, triggering release of insulin before blood glucose levels rise. Their action explains why insulin secretion increases more after an oral glucose load than after an intravenous glucose load, a phenomenon called the incretin effect.⁵⁵

There are two incretin hormones: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). They have short a half-life because they are rapidly degraded by dipeptidyl peptidase-IV (DPP-IV).⁵⁵ Available incretin-based therapies are GLP-1 receptor agonists and DPP-IV inhibitors.

When used as monotherapy, incretin-based therapies do not cause hypoglycemia because their effect is glucose-dependent.⁵⁵ GLP-1 receptor antagonists have the added benefit of inducing weight loss, but DPP-IV inhibitors are considered to be weight-neutral.

GLP-1 receptor agonists

Exenatide, the first of the GLP-1 receptor agonists, was approved in 2005. The original formulation (Byetta) is taken by injection twice daily, and timing in conjunction with food intake is important: it should be taken within 60 minutes before the morning and evening meals. Extended-release exenatide (Bydureon) is a once-weekly formulation taken without regard to timing of food intake. Exenatide (either twice-daily Byetta or once-weekly Bydureon) should not be used in those with creatinine clearance less than 30 mL/min or end-stage renal disease and should be used with caution in patients with renal transplantation.

Liraglutide (Victoza), a once-daily formulation, can be injected irrespective of food intake. The dose does not have to be adjusted for renal function, although it should be used with caution in those with renal impairment, including end-stage renal disease. Approval for a 3-mg formulation is pending with the FDA as a weight-loss drug on the basis of promising results in a randomized phase 3 trial.⁵⁶

Albiglutide (Tanzeum), a once-weekly GLP-1 receptor antagonist, was recently approved by the FDA.

DPP-IV inhibitors

Whereas GLP-1 receptor agonists are injected, the DPP-IV inhibitors have the advantage of being oral agents.

Sitagliptin (Januvia), the first DPP-IV inhibitor, became available in the United States in 2006. Since then, three more have become available: saxagliptin (Onglyza), linagliptin (Tradjenta), and alogliptin (Nesina).

Concerns about thyroid cancer with incretin drugs

Concerns of increased risk of cancer, particularly of the thyroid and pancreas, have been raised since GLP-1 receptor agonists and DPP-IV inhibitors became available.

Studies in rodents have shown C-cell hyperplasia, sometimes resulting in increased incidence of thyroid carcinoma, and dose-dependent rises in serum calcitonin, particularly with liraglutide.²⁶ This has raised concern about an increased risk of medullary thyroid carcinoma in humans. However, the density of C cells in rodents is up to 45 times greater than in humans, and C cells also express functional GLP-1 receptors.²⁶

Gier et al²⁷ assessed the expression of calcitonin and human GLP-1 receptors in normal C cells, C cell hyperplasia, and medullary cancer. In this study, calcitonin and GLP-1 receptor were co-expressed in medullary thyroid cancer (10 of 12 cases) and C-cell hyperplasia (9 of 9 cases) more commonly than in normal C cells (5 of 15 cases). Further, GLP-1 receptor was expressed in 3 of 17 cases of papillary thyroid cancer.

Calcitonin, a polypeptide hormone produced by thyroid C cells and used as a medullary thyroid cancer biomarker, was increased in a slightly higher percentage of patients treated with liraglutide than in controls, without an increase above the normal range.⁵⁷

A meta-analysis by Alves et al⁵⁸ of 25 studies found that neither exenatide (no cases reported) nor liraglutide (odds ratio 1.54, 95% CI 0.40–6.02) was associated with increased thyroid cancer risk.

MacConell et al⁵⁹ pooled the results of 19 placebo-controlled trials of twice-daily exenatide and found a thyroid cancer incidence rate of 0.3 per 100 patient-years (< 0.1%) vs 0 per 100 patient-years in pooled comparators.

Concerns about pancreatic cancer with incretin drugs

Increased risk of acute pancreatitis is a potential side effect of both DPP-IV inhibitors and GLP-1 receptor agonists and has led to speculation that this translates to an increased risk of pancreatic cancer.

In a point-counterpoint debate, Butler et al²⁸ argued that incretin-based medications have questionable safety, with increased rates of pancreatitis possibly leading to pancreatic cancer. In counterpoint, Nauck⁶⁰ argued that the risk of pancreatitis or cancer is extremely low, and clinical cases are unsubstantiated.

Bailey⁶¹ outlined the complexities and difficulties in drawing firm conclusions from individual clinical trials regarding possible adverse effects of diabetes drugs. The trials are typically designed to assess hemoglobin A_1c reduction at varying doses and are typically restricted in patient selection, patient numbers, and drug-exposure duration, which may introduce allocation and ascertainment biases. The attempt to draw firm conclusions from such trials can be problematic and can lead to increased alarm, warranted or not.

Type 2 diabetes mellitus itself is associated with an increased incidence of pancreatic cancer, and whether incretin therapy enhances this risk is still controversial. Whether more episodes of acute pancreatitis without chronic pancreatitis can be extrapolated to an increased incidence of pancreatic cancer is doubtful. A normal pancreatic duct cell may take up to 12 years to become a tumor cell from which pancreatic carcinoma develops, another 7 years to develop metastatic capacity, and another 3 years before a diagnosis is made from clinical symptoms (which are usually accompanied by metastases).⁶²

The risks and benefits of incretin therapies remain a contentious issue, and there are no clear prospective data at this time on increased pancreatic cancer incidence. Long-term prospective studies designed to analyze these specific outcomes (pancreatitis, pancreatic cancer, and medullary thyroid cancer) need to be undertaken.⁶³

OTHER DIABETES THERAPIES

Alpha glucosidase inhibitors

Oral glucosidase inhibitors ameliorate hyperglycemia by inhibiting alpha glucosidase enzymes in the brush border of the small intestines, preventing conversion of polysaccharides to monosaccharides.⁶⁴ This slows digestion of carbohydrates and glucose release into the bloodstream and blunts the postprandial hyperglycemic excursion.

The two alpha glucosidase inhibitors currently available in the United States are acarbose and miglitol, and although data are limited, they do not appear to increase the risk of cancer.^65,66

Sodium-glucose-linked cotransporter 2 inhibitors

The newest class of oral diabetes agents to be approved are the sodium-glucose-linked cotransporter 2 (SGLT2) inhibitors canagliflozin (Invokana) and dapagliflozin (Farxiga).

SGLT2 is a protein in the S1 segment of the proximal renal tubules responsible for over 90% of renal glucose reabsorption. SGLT2 inhibitors lower serum glucose levels by promoting glycosuria and have also been shown to have favorable effects on blood pressure and weight.^67,68

Canagliflozin was the first of its class to gain FDA approval in the United States. It has not been found to be associated with increased cancer risk.⁶⁸

Dapagliflozin, originally approved in Europe, was approved in the United States on January 8, 2014. Because of a possible increased incidence of breast and bladder malignancies, the FDA advisory committee initially recommended against approval and required further data. In those who were treated, nine cases of bladder cancer and nine cases of breast cancer were reported, compared with one case of bladder cancer and no cases of breast cancer in the control group; however, the difference was not statistically significant.⁶⁸

Since SGLT2 inhibitors are still new, data on long-term outcomes are lacking. Early clinical data do not show a significant increase in cancer risk.

WHAT THIS MEANS IN PRACTICE

Many studies have found associations between diabetes, obesity, hyperinsulinemia, and cancer risk. In the last decade, concerns implicating antihyperglycemic agents in cancer development have arisen but have not been well substantiated. At this time, there are no definitive prospective data indicating that the currently available type 2 diabetes therapies increase the incidence of cancer beyond the inherent increased risk in this population. What, then, is one to do?

Educate. Lifestyle modification, including weight management, should continue to be emphasized in diabetes education, as no therapy is completely effective without adjunct modifications in diet and physical activity. Epidemiologic studies have shown the benefits of lifestyle modifications, which ameliorate many of the adverse metabolic conditions that coexist in type 2 diabetes and cancer.

Screen for cancer. Given the associations between diabetes and malignancy, cancer screening is especially important in this high-risk population.

Customize therapy to individual patients. Those with a personal history of bladder cancer should avoid pioglitazone, and those who have had pancreatic cancer should avoid sitagliptin until definitive clinical data become available.

Moreover, patients with a personal or family history of medullary thyroid cancer should not receive GLP-1 receptor agonists. These agents should also probably be avoided in patients with a personal history of differentiated thyroid carcinoma or a history of familial nonmedullary thyroid carcinoma. Until we have further elucidating data, it is not possible to say whether a family history of any of the other types of cancer should represent a contraindication to the use of any of these agents.

Discuss. The multitude of diabetes therapies warrants physician-patient discussions that carefully weigh the risks and benefits of additional agents to optimize glycemic control and metabolic factors in individual patients.

In the last quarter century, many new drugs have become available for treating type 2 diabetes mellitus. The American Association of Clinical Endocrinologists incorporated these new agents in its updated glycemic control algorithm in 2013.¹ Because diabetes affects 25.8 million Americans and can lead to blindness, renal failure, cardiovascular disease, and amputation, agents that help us treat it more effectively are valuable.²

One of the barriers to effective treatment is the side effects of the agents. Because some of these drugs have been in use for only a short time, concerns of potential adverse effects have arisen. Cancer is one such concern, especially since type 2 diabetes mellitus by itself increases the risk of cancer by 20% to 50% compared with no diabetes.³

Type 2 diabetes has been linked to risk of cancers of the pancreas,⁴ colorectum,^5,6 liver,⁷ kidney,^8,9 breast,¹⁰ bladder,¹¹ and endometri-um,¹² as well as to hematologic malignancies such as non-Hodgkin lymphoma.¹³ The risk of bladder cancer appears to depend on how long the patient has had type 2 diabetes. Newton et al,¹⁴ in a prospective cohort study, found that those who had diabetes for more than 15 years and used insulin had the highest risk of bladder cancer. On the other hand, the risk of prostate cancer is actually lower in people with diabetes,¹⁵ particularly in those who have had diabetes for longer than 4 years.¹⁶

Cancer and type 2 diabetes share many risk factors and underlying pathophysiologic mechanisms. Nonmodifiable risk factors for both diseases include advanced age, male sex, ethnicity (African American men appear to be most vulnerable to both cancer and diabetes),^17,18 and family history. Modifiable risk factors include lower socioeconomic status, obesity, and alcohol consumption. These common risk factors lead to hyperinsulinemia and insulin resistance, changes in mitochondrial function, low-grade inflammation, and oxidative stress,³ which promote both diabetes and cancer. Diabetes therapy may influence several of these processes.

Several classes of diabetes drugs, including exogenous insulin,^19–22 insulin secretagogues,^23–25 and incretin-based therapies,^26–28 have been under scrutiny because of their potential influences on cancer development in a population already at risk (Table 1).

INSULIN ANALOGUES: MIXED EVIDENCE

Insulin promotes cell division by binding to insulin receptor isoform A and insulin-like growth factor 1 receptors.²⁹ Because endogenous hyperinsulinemia has been linked to cancer risk, growth, and proliferation, some speculate that exogenous insulin may also increase cancer risk.

In 2009, a retrospective study by Hemkens et al linked the long-acting insulin analogue glargine to risk of cancer.¹⁹ This finding set off a tumult of controversy within the medical community and concern among patients. Several limitations of the study were brought to light, including a short duration of follow-up, and several other studies have refuted the study’s findings.^20,21

More recently, the Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial²² found no higher cancer risk with glargine use than with placebo. This study enrolled 12,537 participants from 573 sites in 40 countries. Specifically, risks with glargine use were as follows:

• Any cancer—hazard ratio 1.00, 95% confidence interval (CI) 0.88–1.13, P = .97
• Cancer death—hazard ratio 0.94, 95% CI 0.77–1.15, P = .52.

However, the study was designed to assess cardiovascular outcomes, not cancer risk. Furthermore, the participants were not typical of patients seen in clinical practice: their insulin doses were lower (the median insulin dose was 0.4 units/kg/day by year 6, whereas in clinical practice, those with type 2 diabetes mellitus often use more than 1 unit/kg/day, depending on duration of diabetes, diet, and exercise regimen), and their baseline median hemoglobin A_1c level was only 6.4%. And one may argue that the median follow-up of 6.2 years was too short for cancer to develop.²²

In vitro studies indicate that long-acting analogue insulin therapy may promote cancer cell growth more than endogenous insulin,³⁰ but epidemiologic data have not unequivocally substantiated this.^20–22 There is no clear evidence that analogue insulin therapy raises cancer risk above that of human recombinant insulin, and starting insulin therapy should not be delayed because of concerns about cancer risk, particularly in uncontrolled diabetes.

INSULIN SECRETAGOGUES

Sulfonylureas: Higher risk

Before 1995, only two classes of diabetes drugs were approved by the US Food and Drug Administration (FDA)—insulin and sulfonylureas.

Sulfonylureas lower blood sugar levels by binding to sulfonylurea receptors and inhibiting adenosine triphosphate-dependent potassium channels. The resulting change in resting potential causes an influx of calcium, ultimately leading to insulin secretion.

Sulfonylureas are effective, and because of their low cost, physicians often pick them as a second-line agent after metformin.

The main disadvantage of sulfonylureas is the risk of hypoglycemia, particularly in patients with renal failure, the elderly, and diabetic patients who are unaware of when they are hypoglycemic. Other potential drawbacks are that they impair cardiac ischemic preconditioning³¹ and possibly increase cancer risk.^21,32 (Ischemic preconditioning is the process in which transient episodes of ischemia “condition” the myocardium so that it better withstands future episodes with minimal anginal pain and tissue injury.³³) Of the sulfonylureas, glyburide has been most implicated in cardiovascular risk.³²

In a retrospective cohort study of 62,809 patients from a general-practice database in the United Kingdom, Currie et al²¹ found that sulfonylurea monotherapy was associated with a 36% higher risk of cancer (95% CI 1.19–1.54, P < .001) than metformin monotherapy. Prescribing bias may have influenced the results: practitioners are more likely to prescribe sulfonylureas to leaner patients, who have a greater likelihood of occult cancer. However, other studies also found that the cancer death rate is higher in those who take a sulfonylurea alone than in those who use metformin alone.^23,24

Some evidence indicates that long-acting sulfonylurea formulations (eg, glyburide) likely hold the most danger, certainly in regard to hypoglycemia, but it is less clear if this translates to cancer concerns.³¹

Meglitinides: Limited evidence

Meglitinides, the other class of insulin secretagogues, are less commonly used but are similar to sulfonylureas in the way they increase endogenous insulin levels. The data are limited regarding cancer risk and meglitinide therapy, but the magnitude of the association is similar to that with sulfonylurea therapy.²⁵

INSULIN SENSITIZERS

There are currently two classes of insulin sensitizers: biguanides and thiazolidinediones (TZDs, also known as glitazones). These drugs show less risk of both cancer incidence and cancer death than insulin secretagogues such as sulfonylureas.^21,23,24 In fact, they may decrease cancer potential by alteration of signaling via the AKT/mTOR (v-akt murine thymoma viral oncogene homolog 1/mammalian target of rapamycin) pathway.³⁴

Metformin, a biguanide, is the oral drug of choice

Metformin is the only biguanide currently available in the United States. It was approved by the FDA in 1995, although it had been in clinical use since the 1950s. Inexpensive and familiar, it is the oral antihyperglycemic of choice if there are no contraindications to it, such as renal dysfunction (creatinine ≥ 1.4 mg/dL in women and ≥ 1.5 mg/dL in men), acute decompensated heart failure, or pulmonary or hepatic insufficiency, all of which may lead to an increased risk of lactic acidosis.¹

Metformin lowers blood sugar levels primarily by inhibiting hepatic glucose production (gluconeogenesis) and by improving peripheral insulin sensitivity. It directly activates AMP-activated protein kinase (AMPK), which affects insulin signaling and glucose and fat metabolism.³⁵ It may exert further beneficial effects by acutely increasing glucagon-like peptide-1 (GLP-1) levels and inducing islet incretin-receptor gene expression.³⁶ Although the exact mechanisms have not been fully elucidated, metformin’s insulin-sensitizing properties are likely from favorable effects on insulin receptor expression, tyrosine kinase activity, and influences on the incretin pathway.^36,37 These effects also mitigate carcinogenesis, both directly (via AMPK and liver kinase B1, a tumor-suppressor gene) and indirectly (via reduction of hyperinsulinemia).³⁵

Overall, biguanide therapy is associated with a lower cancer incidence or, at worst, no effect on cancer incidence. In vitro studies demonstrate that metformin both suppresses cancer cell growth and induces apoptosis, resulting in fewer live cancer cells.³⁴ Several retrospective studies found lower cancer risk in metformin users than in patients receiving antidiabetes drugs other than insulin-sensitizing agents,^{21,23,25,38–40} while others have shown no effect.⁴¹ Use of metformin was specifically associated with lower risk of cancers of the liver, colon and rectum, and lung.⁴² Further, metformin users have a lower cancer mortality rate than nonusers.^24,43

Thiazolidinediones

TZDs, such as pioglitazone, work by binding to peroxisome proliferator-activated gamma receptors in the cell nucleus, altering gene transcription.⁴⁴ They reduce insulin resistance and levels of endogenous insulin levels and free fatty acids.⁴⁴

Concern over bladder cancer risk with TZD use, particularly with pioglitazone, has increased in the last few years, as various cohort studies found a statistically significant increased risk with this agent.⁴⁴ The risk appears to rise with cumulative dose.^45,46

Randomized controlled trials also found an increased risk of bladder cancer with TZD therapy, although the difference was not statistically significant.^47–49 In a mean follow-up of 8.7 years, the Prospective Pioglitazone Clinical Trial in Macrovascular Events reported 23 cases of bladder cancer in the pioglitazone group vs 22 cases in the placebo group, for rates of 0.9% vs 0.8% (relative risk [RR] 1.06, 95% CI 0.59–1.89).⁴⁹

On the other hand, the risk of cancer of the breast, colon, and lung has been found to be lower with TZD use.⁴⁷ In vitro studies support the clinical data, showing that TZDs inhibit growth of human cancer cells derived from cancers of the lung, colon, breast, stomach, ovary, and prostate.^50–53

Home et al⁵⁴ compared rosiglitazone against a sulfonylurea in patients already taking metformin in the Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes (RECORD) trial. Malignancies developed in 6.7% of the sulfonylurea group compared with 5.1% of the rosiglitazone group, for a hazard ratio of 1.33 (95% CI 0.94–1.88).

Both ADOPT (A Diabetes Outcome Progression Trial) and the RECORD trial found rosiglitazone comparable to metformin in terms of cancer risk.⁵⁴

Colmers et al⁴⁷ pooled data from four randomized controlled trials, seven cohort studies, and nine case-control studies to assess the risk of cancer with TZD use in type 2 diabetes. Both the randomized and observational data showed neutral overall cancer risk with TZDs. However, pooled data from observational studies showed significantly lower risk with TZD use in terms of:

• Colorectal cancer RR 0.93, 95% CI 0.87–1.00
• Lung cancer RR 0.91, 95% CI 0.84–0.98
• Breast cancer RR 0.89, 95% CI 0.81–0.98.

INCRETIN-BASED THERAPIES

Incretins are hormones released from the gut in response to food ingestion, triggering release of insulin before blood glucose levels rise. Their action explains why insulin secretion increases more after an oral glucose load than after an intravenous glucose load, a phenomenon called the incretin effect.⁵⁵

There are two incretin hormones: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). They have short a half-life because they are rapidly degraded by dipeptidyl peptidase-IV (DPP-IV).⁵⁵ Available incretin-based therapies are GLP-1 receptor agonists and DPP-IV inhibitors.

When used as monotherapy, incretin-based therapies do not cause hypoglycemia because their effect is glucose-dependent.⁵⁵ GLP-1 receptor antagonists have the added benefit of inducing weight loss, but DPP-IV inhibitors are considered to be weight-neutral.

GLP-1 receptor agonists

Exenatide, the first of the GLP-1 receptor agonists, was approved in 2005. The original formulation (Byetta) is taken by injection twice daily, and timing in conjunction with food intake is important: it should be taken within 60 minutes before the morning and evening meals. Extended-release exenatide (Bydureon) is a once-weekly formulation taken without regard to timing of food intake. Exenatide (either twice-daily Byetta or once-weekly Bydureon) should not be used in those with creatinine clearance less than 30 mL/min or end-stage renal disease and should be used with caution in patients with renal transplantation.

Liraglutide (Victoza), a once-daily formulation, can be injected irrespective of food intake. The dose does not have to be adjusted for renal function, although it should be used with caution in those with renal impairment, including end-stage renal disease. Approval for a 3-mg formulation is pending with the FDA as a weight-loss drug on the basis of promising results in a randomized phase 3 trial.⁵⁶

Albiglutide (Tanzeum), a once-weekly GLP-1 receptor antagonist, was recently approved by the FDA.

DPP-IV inhibitors

Whereas GLP-1 receptor agonists are injected, the DPP-IV inhibitors have the advantage of being oral agents.

Sitagliptin (Januvia), the first DPP-IV inhibitor, became available in the United States in 2006. Since then, three more have become available: saxagliptin (Onglyza), linagliptin (Tradjenta), and alogliptin (Nesina).

Concerns about thyroid cancer with incretin drugs

Concerns of increased risk of cancer, particularly of the thyroid and pancreas, have been raised since GLP-1 receptor agonists and DPP-IV inhibitors became available.

Studies in rodents have shown C-cell hyperplasia, sometimes resulting in increased incidence of thyroid carcinoma, and dose-dependent rises in serum calcitonin, particularly with liraglutide.²⁶ This has raised concern about an increased risk of medullary thyroid carcinoma in humans. However, the density of C cells in rodents is up to 45 times greater than in humans, and C cells also express functional GLP-1 receptors.²⁶

Gier et al²⁷ assessed the expression of calcitonin and human GLP-1 receptors in normal C cells, C cell hyperplasia, and medullary cancer. In this study, calcitonin and GLP-1 receptor were co-expressed in medullary thyroid cancer (10 of 12 cases) and C-cell hyperplasia (9 of 9 cases) more commonly than in normal C cells (5 of 15 cases). Further, GLP-1 receptor was expressed in 3 of 17 cases of papillary thyroid cancer.

Calcitonin, a polypeptide hormone produced by thyroid C cells and used as a medullary thyroid cancer biomarker, was increased in a slightly higher percentage of patients treated with liraglutide than in controls, without an increase above the normal range.⁵⁷

A meta-analysis by Alves et al⁵⁸ of 25 studies found that neither exenatide (no cases reported) nor liraglutide (odds ratio 1.54, 95% CI 0.40–6.02) was associated with increased thyroid cancer risk.

MacConell et al⁵⁹ pooled the results of 19 placebo-controlled trials of twice-daily exenatide and found a thyroid cancer incidence rate of 0.3 per 100 patient-years (< 0.1%) vs 0 per 100 patient-years in pooled comparators.

Concerns about pancreatic cancer with incretin drugs

Increased risk of acute pancreatitis is a potential side effect of both DPP-IV inhibitors and GLP-1 receptor agonists and has led to speculation that this translates to an increased risk of pancreatic cancer.

In a point-counterpoint debate, Butler et al²⁸ argued that incretin-based medications have questionable safety, with increased rates of pancreatitis possibly leading to pancreatic cancer. In counterpoint, Nauck⁶⁰ argued that the risk of pancreatitis or cancer is extremely low, and clinical cases are unsubstantiated.

Bailey⁶¹ outlined the complexities and difficulties in drawing firm conclusions from individual clinical trials regarding possible adverse effects of diabetes drugs. The trials are typically designed to assess hemoglobin A_1c reduction at varying doses and are typically restricted in patient selection, patient numbers, and drug-exposure duration, which may introduce allocation and ascertainment biases. The attempt to draw firm conclusions from such trials can be problematic and can lead to increased alarm, warranted or not.

Type 2 diabetes mellitus itself is associated with an increased incidence of pancreatic cancer, and whether incretin therapy enhances this risk is still controversial. Whether more episodes of acute pancreatitis without chronic pancreatitis can be extrapolated to an increased incidence of pancreatic cancer is doubtful. A normal pancreatic duct cell may take up to 12 years to become a tumor cell from which pancreatic carcinoma develops, another 7 years to develop metastatic capacity, and another 3 years before a diagnosis is made from clinical symptoms (which are usually accompanied by metastases).⁶²

The risks and benefits of incretin therapies remain a contentious issue, and there are no clear prospective data at this time on increased pancreatic cancer incidence. Long-term prospective studies designed to analyze these specific outcomes (pancreatitis, pancreatic cancer, and medullary thyroid cancer) need to be undertaken.⁶³

OTHER DIABETES THERAPIES

Alpha glucosidase inhibitors

Oral glucosidase inhibitors ameliorate hyperglycemia by inhibiting alpha glucosidase enzymes in the brush border of the small intestines, preventing conversion of polysaccharides to monosaccharides.⁶⁴ This slows digestion of carbohydrates and glucose release into the bloodstream and blunts the postprandial hyperglycemic excursion.

The two alpha glucosidase inhibitors currently available in the United States are acarbose and miglitol, and although data are limited, they do not appear to increase the risk of cancer.^65,66

Sodium-glucose-linked cotransporter 2 inhibitors

The newest class of oral diabetes agents to be approved are the sodium-glucose-linked cotransporter 2 (SGLT2) inhibitors canagliflozin (Invokana) and dapagliflozin (Farxiga).

SGLT2 is a protein in the S1 segment of the proximal renal tubules responsible for over 90% of renal glucose reabsorption. SGLT2 inhibitors lower serum glucose levels by promoting glycosuria and have also been shown to have favorable effects on blood pressure and weight.^67,68

Canagliflozin was the first of its class to gain FDA approval in the United States. It has not been found to be associated with increased cancer risk.⁶⁸

Dapagliflozin, originally approved in Europe, was approved in the United States on January 8, 2014. Because of a possible increased incidence of breast and bladder malignancies, the FDA advisory committee initially recommended against approval and required further data. In those who were treated, nine cases of bladder cancer and nine cases of breast cancer were reported, compared with one case of bladder cancer and no cases of breast cancer in the control group; however, the difference was not statistically significant.⁶⁸

Since SGLT2 inhibitors are still new, data on long-term outcomes are lacking. Early clinical data do not show a significant increase in cancer risk.

WHAT THIS MEANS IN PRACTICE

Many studies have found associations between diabetes, obesity, hyperinsulinemia, and cancer risk. In the last decade, concerns implicating antihyperglycemic agents in cancer development have arisen but have not been well substantiated. At this time, there are no definitive prospective data indicating that the currently available type 2 diabetes therapies increase the incidence of cancer beyond the inherent increased risk in this population. What, then, is one to do?

Educate. Lifestyle modification, including weight management, should continue to be emphasized in diabetes education, as no therapy is completely effective without adjunct modifications in diet and physical activity. Epidemiologic studies have shown the benefits of lifestyle modifications, which ameliorate many of the adverse metabolic conditions that coexist in type 2 diabetes and cancer.

Screen for cancer. Given the associations between diabetes and malignancy, cancer screening is especially important in this high-risk population.

Customize therapy to individual patients. Those with a personal history of bladder cancer should avoid pioglitazone, and those who have had pancreatic cancer should avoid sitagliptin until definitive clinical data become available.

Moreover, patients with a personal or family history of medullary thyroid cancer should not receive GLP-1 receptor agonists. These agents should also probably be avoided in patients with a personal history of differentiated thyroid carcinoma or a history of familial nonmedullary thyroid carcinoma. Until we have further elucidating data, it is not possible to say whether a family history of any of the other types of cancer should represent a contraindication to the use of any of these agents.

Discuss. The multitude of diabetes therapies warrants physician-patient discussions that carefully weigh the risks and benefits of additional agents to optimize glycemic control and metabolic factors in individual patients.