Probing the Diabetes-Pancreatic Cancer Connection

Teasing out whether diabetes mellitus (DM) predisposes to pancreatic cancer-or if it’s the other way around-is a bit of a chicken or egg dilemma. What’s certain is that a diagnosis of pancreatic cancer usually is bad news. Global deaths resulting from pancreatic cancer are estimated at around 266,000 per year¹; the overall 5-year survival rate is about 6%.²

Pancreatic cancer is often diagnosed at such an advanced stage that resection and treatment prove ineffectual. However, earlier diagnosis could improve matters. At the onset of DM-sometimes an early sign of pancreatic cancer-the tumor often may be resectable even though CT scan can be uninformative at this stage.³

Evidence for the links between pancreatic cancer and DM includes the following:

  o About half of patients with pancreatic cancer have DM at diagnosis.⁴

  o Recent-onset DM is associated with a 4- to 7-fold increased risk of pancreatic cancer.⁴

  o Patients with chronic pancreatitis and DM may have a 30-fold increased risk of pancreatic cancer.⁴

  o Long-standing type 1 or type 2 DM could increase the risk of pancreatic cancer by 40% to 100%.⁵
 

New Study Supports Diabetes-Pancreatic Cancer Link

Patients with new-onset DM could be at highest risk for pancreatic cancer, although age and DM duration also could increase this risk, according to the largest systematic review to date, published in the March 2014 issue of Annals of Surgical Oncology.⁶ The study, conducted by researchers at the University of Melbourne in Australia, looked specifically at pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer. They analyzed a total of 88 studies published over the past 40 years, from 1973 to 2013. Newly diagnosed DM was defined as DM duration less than 1 year.

Key findings included the following⁶:

  o The overall relative risk (RR) of PDAC was 1.97 (95% CI, 1.78-2.18). 

  o Patients with new-onset DM had the greatest RR-6.69 at less than 1 year.

  o RR remained higher than 1.5 with DM duration more than 10 years.

  o In 40% to 74% of patients with PDAC, hyperglycemia developed during the 24 to 36 months preceding PDAC diagnosis.

“The results demonstrate a strong association between PDAC and recently diagnosed diabetes, which may be attributed to a paraneoplastic effect,” the authors wrote. “However, the presence of diabetes remains a modest risk factor for the development of PDAC long-term. Selective screening of patients with new-onset DM for PDAC needs to be considered.”

The authors recommended a screening cutoff for PDAC of age 50 to 55 years in cases of new-onset DM without obvious cause.

A Note About Incretins

Past studies have suggested that antidiabetic therapies may have varying effects on the risk of pancreatic cancer; some studies found a beneficial role for metformin.⁷ Perhaps the biggest question surrounds the role of incretin mimetics.

One side of the argument holds that patients with DM already are at risk for pancreatic cancer, so cases among patients receiving incretin therapy probably are related to underlying DM and not the medication. The other side holds that incretins increase the risk of pancreatic inflammation, which could predispose to preneoplastic changes and increase the risk of pancreatic cancer.

In March 2013, the FDA began investigating the association between incretin mimetics and the risk of pancreatic toxicity, including pancreatic ductal metaplasia.⁸ Joining forces with the European Medicines Agency (EMA), the FDA released its results in February 2014.⁹ In a review of hundreds of animal toxicology studies, clinical trials, and epidemiologic data, the investigators failed to find a causal link between incretin therapy and pancreatic cancer. In particular, they noted 2 recent large trials:

  o Saxagliptin Assessment of Vascular Outcomes Recorded (SAVOR) trial: a randomized, double-blind, placebo-controlled trial involving 16,492 patients in which there were 5 cases of pancreatic cancer among placebos and 12 cases in the saxagliptin group.¹⁰

  o Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial: a randomized, double-blind, placebo-controlled trial of 5380 patients in which there was no incidence of pancreatic cancer in either the placebo or the treatment groups.¹¹

“Both agencies agree that assertions concerning a causal association between incretin-based drugs and pancreatitis or pancreatic cancer, as expressed recently in the scientific literature and in the media, are inconsistent with the current data,” the authors stated. ”The FDA and the EMA have not reached a final conclusion at this time regarding such a causal relationship. 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.”

The investigators made no new recommendations regarding the Warnings and Precautions section on drug labels, which already mentions the risk of acute pancreatitis.

Where Do We Go From Here?

For the time being, these results seem reassuring. Yes, patients with DM probably are at increased risk for pancreatic cancer, and keeping that in mind during screening and diagnosis may benefit the unfortunate few affected by this deadly disease. Withholding the benefits of incretins, including weight loss and a slight reduction in blood pressure, may not be necessary.

Because pancreatic cancer is slow to develop, though, this may not be the last we’ve heard on this issue. At the very least, maintaining optimal treatment for DM and treating morbid obesity-both of which decrease the risk of pancreatic cancer⁵-is another line of attack against this silent killer.

References:

1. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69-90.

2. National Cancer Institute. SEER Stat Fact Sheets:  Pancreatic Cancer.  Accessed April 1, 2014 at http://seer.cancer.gov/statfacts/html/pancreas.html

3. Pelaez-Luna M, Takahashi N, Fletcher JG, Chari ST. Resectability of presymptomatic pancreatic cancer and its relationship to onset of diabetes:  a retrospective review of CT scans and fasting glucose values prior to diagnosis. Am J Gastroenterol. 2007;102:2157-2163.

4. National Institute of Diabetes and Kidney Diseases. NIDDK-NCI Workshop on Pancreatitis-Diabetes-Pancreatic Cancer. June 12-13, Bethesda, MD.  Accessed April 1, 2014 at http://www.niddk.nih.gov/news/events-calendar/Pages/niddknci-workshop-on-pancreatitisdiabetespancreatic-cancer.aspx

5. Magruder, JT, Elahi D, Andersen DK. Diabetes and pancreatic cancer: chicken or egg? Pancreas. 2011;40:339-351. doi: 10.1097/MPA.0b013e318209e05d.

6. Batabyal P, Vander Hoorn S, Christophi C, Nikfarjam M. Association of diabetes mellitus and pancreatic adenocarcinoma:  a meta-analysis of 88 studies. Ann Surg Oncol. 2014;21:2453-2462. Published online March 9, 2014. doi: 10.1245/s10434-04-3625-6

7. Wang Z, Lai ST, Xie L, et al. Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. Diabetes Res Clin Pract. 2014 Apr 18. doi: 10.1016/j.diabres.2014.04.007. [Epub ahead of print]

8. FDA. FDA Drug Safety Communication: FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes. Accessed March 31, 2014 at http://www.fda.gov/Drugs/DrugSafety/ucm343187.htm

9. Egan AG, Blind E, Dunder K, et al. Pancreatic safety of incretin-based drugs-FDA and EMA assessment. N Engl J Med. 2014;370:794-797.

10. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317-1326.

11. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327-1335.