Glucose-lowering therapies and cancer

Obesity, nutritional status and physical activity all influence the risk of some types of cancer as well as that of type 2 diabetes, and effective lifestyle change can reduce the risk of both outcomes. Glucose lowering medications may influence cancer risk either directly or via off-target effects, or indirectly via weight gain/loss or raising/lowering insulin levels. Individual agents are discussed in more detail in daughter pages. Metformin has useful potential anti-tumour actions, and appears protective relative to other therapies in observational trials but not in controlled trials of glucose lowering therapies. The thiazolidinediones (TZDs) may influence the risk of some cancers in either direction, but pioglitazone appears to increase the risk of bladder cancer in males. The GLP-1 based therapies are potentially linked to acute and subacute pancreatitis and carcinoma of the pancreas, although this remains controversial, and liraglutide is associated with thyroid tumours in rodents. Use of exogenous insulin is associated with a dose-related increase in cancer risk, possibly mediated by hyperinsulinemia. Insulin glargine does not increase the overall risk of cancer relative to human insulin, but a minor increase in risk of post-menopausal breast cancer has not been totally ruled out.

Background: treating diabetes

Type 2 diabetes is treated with a combination of lifestyle modification (diet, weight loss and exercise) and pharmacologic agents.[1] The number and type of glucose-lowering agents used to treat a given individual generally reflects the duration and severity of diabetes.

Treatment guidelines around the world advise that the first line pharmaceutical agent for type 2 diabetes should be metformin[1]. When metformin alone cannot control blood glucose, second and/or third-line treatments are added to maintain glycemic control. Commonly used oral agents include sulfonylureas and non-sulfonylurea insulin secretagogues [2]. Many patients with type 2 diabetes are also treated with insulin, either alone or in combination with other therapies.

Novel – and therefore less extensively-studied – agents have become options for glycemic control over the past decade: thiazolidinediones (TZDs), dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP1) analogues.

In 2010, a joint consensus report from the American Cancer Society and the American Diabetes Association reviewed evidence on the relationship between diabetes and cancer, and highlighted the potential modifying role of glucose-lowering therapies.[3]

This page summarizes updated evidence or concerns as to possible relationships between use of these agents and the risk of cancer. More detailed appraisals are provided in the daughter pages.

Why might these therapies influence cancer risk?

It is increasingly appreciated that obesity is associated with increased risk of some types of cancer in addition to the more familiar traits of hyperglycemia, hypertension, hyperlipidemia and increased cardiovascular risk. Weight loss, a spare diet or physical activity can reduce cancer risk. Any treatment affecting weight (adversely or positively) thus has the potential to influence cancer risk.

Consistent with the hyperinsulinemia hypothesis, glucose-lowering therapies that act by increasing circulating levels of insulin (e.g., sulfonylureas and exogenous insulins) are generally associated with an increased risk of cancer, whereas insulin sensitizing therapies (e.g., metformin) are generally associated with a decreased risk of cancer.[3][4][5]The magnitude and direction of association varies by pharmacologic agent and cancer site.

Over and above these wider considerations, medications used for the treatment of diabetes have the potential to influence cancer risk either because this is directly linked to their mode of action (e.g. activation of AMPK), or because of off-target effects, e.g. bladder irritation with pioglitazone or activation of GLP-1 receptors in the thyroid or exocrine pancreas (GLP-1 based therapies).

Metformin

Metformin is an insulin-sensitizing agent that lowers blood glucose by amplifying cellular responses to endogenous insulin and by suppressing glycogenolysis at the liver. It was introduced in the 1960s, but withdrawn in the USA (although not other parts of the world) following the University Group Diabetes Program (UGDP) study, only to be reintroduced in the 1990s. Many studies, including the United Kingdom Prospective Diabetes Study (UKPDS), have confirmed that metformin is safe (if used according to prescribing guidelines) and apparently beneficial in terms of cardiovascular risk.

Sulfonylureas

These are insulin secretagogues; i.e. they interact with the sulfonylurea receptor on β cells to promote the secretion of insulin. Widely used members of the class include glibenclamide (glyburide) and gliclazide. These have not been implicated as risk factors for any specific type of cancer, although observational studies indicate that overall cancer risk is greater with sulfonylureas than with metformin, most likely because of a protective effect of the latter.

Thiazolidinediones (TZDs)

TZDs are insulin-sensitizing agents that stimulate the nuclear peroxisome proliferator activated receptor gamma (PPARγ) to amplify cellular responses to endogenous insulin signals. Activation of the receptor by these agonists has far-ranging effects upon many aspects of metabolism, gene expression and cell turnover, some of which (e.g. osteopenia) only became recognised after years of use.

The first of these agents, troglitazone, was introduced in 1997 and withdrawn in 2000 because of associated acute hepatic necrosis. Rosiglitazone and pioglitazone were introduced in the same year, but rosiglitazone has since been withdrawn from many countries because of increased cardiovascular risk [6][7]; it is still used with restrictions in the USA and some other countries. Pioglitazone has been associated with an increased risk of bladder cancer in men, and is no longer on the formulary in France and Germany.

TZDs may influence cancer risk via their receptor, PPARγ, a known activator of potent tumor suppression pathways such as mTOR and LKB1.[8], and TZDs also have PPARγ¬-independent effects on suppression of cancer cell growth and division[9]. TZDs have the potential to influence cancer risk both positively and negatively. Some studies have suggested a reduced all-round cancer risk [10], but pioglitazone has more recently been implicated as a risk factor for bladder cancer in men[11]. Ironically, clinical trials are currently investigating both pioglitazone and rosiglitazone as potential cancer treatments.[12][13][14]

GLP-1 analogues and DPP-4 inhibitors

The more recently available glucose-lowering therapies for clinical use are the GLP-1 mimetic therapies, including the dipeptidyl peptidase-4 inhibitors (DPP-4), which stimulate glucose-dependent pancreatic insulin secretion.1 This line of therapy has been considered an attractive clinical option because there is a lower risk for hypoglycemia and weight gain, than is seen with other glucose-lowering therapies.[15] However, despite the suggested benefits of GLP-1 therapies, there has been some safety concerns associated with these drugs.[16] In particular, there have been reports of potentially negative effects on the thyroid, antibody formation, and a possible association with pancreatitis, which has also sparked concerns about pancreatic cancer risk.[17]

Exogenous insulin

In addition to oral glucose-lowering agents, exogenous insulin is often added on to oral therapy regimens in individuals with type 2 diabetes. Exogenous insulin therapy directly increases circulating insulin levels in the body, and as such, it is thought to accelerate tumour growth.

A number of epidemiologic studies have reported an increased risk of cancer outcomes associated with exogenous insulin use.[18][19][20][21][22][23][24] There has been great interest surrounding recent epidemiologic evidence on the different types of insulins, and in particular, the long-acting analog, insulin glargine. Given its structural similarity to insulin-like growth factor, insulin glargine has been thought to have potential for increased mitogenicity relative to human insulin.[25]There was considerable controversy surrounding the publication of an initial observational study that suggested an increased risk of overall cancer with insulin glargine therapy.[26], but many subsequent analyses have confirmed that this is not the case. Some reports have suggested a minor increase in risk of post-menopausal breats cancer, whereas others have been negative; this issue is discussed further in the page on Breast Cancer.

References

  1. ^ Canadian Diabetes Association. Clinical practice guidelines for the prevention and management of diabetes in Canada. Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2008;32(suppl 1):S1-S201

  2. ^ Krentz AJ. Comparative safety of newer oral antidiabetic drugs. Expert Opin Drug Saf. 2006;5(6):827–834

  3. ^ Giovannucci E et al. Diabetes and a consensus report. Diabetes Care. 2010;33(7):1674–1785

  4. ^ Johnson JA et al. Diabetes and cancer (1): evaluating the temporal relationship between type 2 diabetes and cancer incidence. Diabetologia. 2012;55(6):1607–1618

  5. ^ Renehan AG et al. Diabetes and cancer (2): evaluating the impact of diabetes on mortality in patients with cancer. Diabetologia. 2012;55(6):1619-1632

  6. ^ Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457–2471.

  7. ^ Morrow RL et al. Impact of rosiglitazone meta-analysis on use of glucose-lowering medications. Open Med. 2010;4(1):e50–59.

  8. ^ Belfiore A et al. PPAR-gamma agonists and their effects on IGF-I receptor implications for cancer. PPAR Res. 2009;1–18.

  9. ^ Wei S et al. PPARgamma-independent antitumor effects of thiazolidinediones. Cancer Lett. 2009;276(2):119–124.

  10. ^ Govindarajan R et al. Thiazolidinediones and risk of lung, prostate, and colon cancer in patients with diabetes. J Clin Oncol 2007;1476–1481.

  11. ^ Lewis JD et al. Risk of bladder cancer among diabetic patients treated with interim report of a longitudinal cohort study. Diabetes Care 2011;916–922.

  12. ^ Pioglitazone hydrochloride in treating patients with stage I, stage II, or stage III non-small cell lung cancer In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2012 Jun. 4]. Available from: http://clinicaltrials.gov/ct2/show/NCT01342770

  13. ^ Pioglitzaone for lung cancer chemoprevention. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2012 Aug 17] Available: http://clinicaltrials.gov/ct2/show/NCT00780234

  14. ^ Rosiglitazone (Avandia) vs. Placebo for Androgen Dependent Prostate Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2012 Aug 17] Available: http://clinicaltrials.gov/ct2/show/NCT00182052

  15. ^ Lewis JD 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.

  16. ^ Tseng CH. Pioglitazone and bladder cancer: a population-based study of Taiwanese. Diabetes Care 2012;35:278-80.

  17. ^ Tseng CH. Diabetes and risk of bladder cancer: a study using the National Health Insurance database in Taiwan. Diabetologia 2011;54:2009–15.

  18. ^ Bodmer M et al. Use of antidiabetic agents and the risk of pancreatic cancer: a case-control analysis. Am J Gastroenterol 2012;107:620-6.

  19. ^ Currie CJ et al. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009;52:1766-77

  20. ^ Bowker S et al. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 2006;29:254-8.

  21. ^ Bowker SL et al. Glucose-lowering agents and cancer mortality rates in type 2 diabetes: assessing effects of time-varying exposure. Diabetologia 2010;53:1631-7.

  22. ^ Li D et al. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology 2009;137:482-8.

  23. ^ Yang YX et al. Insulin therapy and risk of colorectal cancer risk among type 2 diabetes mellitus patients. Gastroenterology 2004;127:1044-50.

  24. ^ Chung YW et al. Insulin therapy and colorectal adenoma risk among patients with type 2 diabetes mellitus: a case-control study in Korea. Dis Colon Rectum 2008;51:593-7.

  25. ^ Kurtzahls P et al. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 2000;49:999-1005

  26. ^ Hemkens LG et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia. 2009;52:1732-44.

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