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 A1c 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.
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