Danish Study: No Excess Pancreatitis Risk in Incretin Users

Miriam E Tucker

February 09, 2015

A new study from Denmark is the latest to find no connection between incretin-based drugs used to treat type 2 diabetes and acute pancreatitis.

Incretin-based agents include the injectable glucagonlike peptide-1 (GLP-1) agonists and oral dipeptidyl-peptidase (DPP-4) inhibitors; in 2013, controversy arose as to whether these agents were associated with a higher risk for pancreatitis and even pancreatic cancer in diabetic patients who are taking them long term.

In fact, this new study of 12,868 pancreatitis patients and 128,680 matched controls found similarly elevated risks for pancreatitis among patients taking all classes of glucose-lowering drugs, and those risks disappeared after adjustment for well-known pancreatitis risk factors.

"These results argue against any specific incretin effect and for the possibility that diabetes and related conditions such as obesity and gallstones cause an increase in pancreatitis risk, rather than the specific treatment chosen for diabetes," lead author Reimar Wernich Thomsen, MD, PhD, associate professor, department of clinical epidemiology, Aarhus University Hospital Denmark, told Medscape Medical News.

He added, "The potential risks of pancreatitis and pancreatic cancer with GLP-1–based therapies are far outweighed by the proven [benefits] and potential cardiovascular benefits."

Results from the large population-based, case-control study of medical databases were published online January 29, 2015 in Diabetes Care by Dr Thomsen and colleagues.

Asked to comment, David C Whitcomb, MD, PhD, chief, division of gastroenterology, hepatology, and nutrition, University of Pittsburgh, Pennsylvania, told Medscape Medical News, "This is not novel, but it is a well-done paper that will likely be cited as…strong evidence that incretins do not increase the risk of pancreatitis. It also shows that diabetes is associated with pancreatitis directly, which is known. "

Dr Whitcomb cochaired a 2-day meeting held in June 2013 at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), in which experts concluded that there was little evidence for an increased risk for pancreatic cancer and pancreatitis associated with use of GLP-1 agonists and DPP-4 inhibitors. That meeting had been prompted by an in-depth investigation by the BMJ concluding that such a link had been downplayed by the pharmaceutical industry.

Soon after the NIDDK meeting, both the European Medicines Agency and the US Food and Drug Administration concluded that available data did not support the concerns, but they said that more research was needed.

Since then, at least one other large, population-based observational study has shown no increased risk of acute pancreatitis.

Pancreatitis Risk Elevated in Users of All Diabetes Drugs

In the current study, Dr Thomsen and colleagues aimed to account for all the confounders that raise the risk for pancreatitis among people with diabetes, something they say has not previously been achieved in other trials.

To do that, they individually matched each of the 12,868 acute-pancreatitis patients with 10 controls (total 128,680) for birth year, sex, index date, and Danish region of residence. As expected, well-known risk factors for acute pancreatitis were more common among the pancreatitis cases, including history of gallstone disease (17% vs 4%) and alcoholism-related disease (15% vs 4%).

A medium or high Charlson Comorbidity Index score was found in 33% of cases vs 21% of controls, and more patients than controls had filled prescriptions for medications that have been linked with pancreatitis, including nonsteroidal anti-inflammatory drugs and antiepileptics.

A total of 89 pancreatitis patients (0.69%) and 684 controls (0.53%) had ever used incretins, and 0.42% and 0.37%, respectively, were current users. The patients with pancreatitis were more likely to be users of both incretins (crude odds ratio 1.36) and of nonincretin glucose-lowering drugs, including metformin, sulfonylureas, thiazolidinediones, and alpha-glucosidase inhibitors (crude OR, 1.44).

After adjustment for potential confounders, the risk of acute pancreatitis was not increased among incretin users (odds ratio for ever-use of incretins was a nonsignificant 0.95), including DPP-4–inhibitor users (OR, 1.04) and GLP-1-receptor–agonist users (OR, 0.82), or among nonincretin antihyperglycemic drug users (OR, 1.05), compared with nonusers of any glucose-lowering medications.

The findings were similar among current vs ever-users. The relationship between pancreatitis and former use of most incretins and nonincretin diabetes drugs was actually stronger than current use, suggesting a possible "reverse causality" due to pancreatogenic diabetes, the authors speculate.

Results were also similar in a separate analysis comparing pancreatitis risk just among the diabetes-drug users, with an OR of 0.97 for incretin-based therapy vs others.

More Study Needed

Dr Thomsen told Medscape Medical News, "By now, most — yet not all — observational evidence suggests that risk with incretins is not increased compared with other glucose-lowering agents."

Some of the prior studies that did show an elevated risk "included selected populations of insured individuals or specific age groups, incomplete prescription data, or limited confounder control," he pointed out.

In contrast, "I believe our study adds to the literature by providing a rather robust and statistically precise null-result for an association between incretins and pancreatitis, in a nationwide comprehensive tax-supported healthcare system with universal population coverage."

But he also cautioned that further large studies are needed, including those looking at pancreatic cancer, which was not investigated in this study.

"Happily, there are more incretin trial results to be expected in the coming years. Very large and carefully designed multinational observational studies may be appropriate to provide further safety evidence."

In all, Dr Whitcomb told Medscape Medical News, "The data are becoming stronger and stronger that these medications do not increase the risk for pancreatitis."

The study was supported by the Clinical Epidemiological Research Foundation, Denmark. Dr Thomsen has reported no relevant financial relationships; disclosures for the coauthors are listed in the article. The department of clinical epidemiology is a member of the Danish Center for Strategic Research in Type 2 Diabetes (DD2), supported by the Danish Agency for Science, the Danish Health and Medicines Authority, the Danish Diabetes Association, and an unrestricted donation from Novo Nordisk. Dr Whitcomb has reported no relevant financial relationships.

Diabetes Care. Published online January 29, 2015. Abstract

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