GLP-1 Mimetics Double Pancreatitis Risk in Diabetics

February 25, 2013

(Updated) A new study has found that people with type 2 diabetes using the glucagonlike peptide-1 (GLP-1)–based therapies exenatide (Byetta, Amylin Pharmaceuticals) and sitagliptin (Januvia, Merck) have a 2-fold increased risk of being hospitalized for acute pancreatitis.

The findings — from a large population-based case-control study — consolidate concerns about GLP-1–based therapies and the potential risk for pancreatitis that have emerged following case reports to the Food and Drug Administration (FDA), as well as from data in animals, resulting in warnings about the risk with these drugs in the United States, Sonal Singh, MD, from Johns Hopkins University School of Medicine, Baltimore, Maryland, told Medscape Medical News. Dr. Singh and colleagues report their study results online February 25 in JAMA Internal Medicine.

Dr. Singh stressed, however, that although the new findings indicate the link between these agents and pancreatitis may be causal, "this doesn’t mean people should stop using these drugs." Rather, he said, people should follow the FDA advice and watch for signs and symptoms of pancreatitis, which include severe nausea, vomiting, and abdominal pain, and if these occur they need to have pancreatic enzyme levels checked and stop the medications, at least temporarily, he noted.

But most important, said Dr. Singh, the study should raise a red flag because "pancreatitis is on the pathway toward pancreatic cancer." Writing in an accompanying commentary, Belinda Gier, PhD, and Peter Butler, MD, from the Larry L. Hillblom Islet Research Center, University of California, Los Angeles, agree, calling the issue of pancreatic cancer "the real crux of the controversy with regard to the safety of GLP-1–based treatment."

"At present, the GLP-1 class of drugs is heavily promoted (and prescribed) as having purported advantages that outweigh its risks. Singh and colleagues provide a timely reminder that, despite large numbers of underpowered studies claiming the contrary from marketing companies, little is yet known about long-term adverse effects of the GLP-1 class of drugs on the exocrine pancreas," they observe.

But in a joint statement, the American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association come to the defense of GLP-1–based therapies, calling into question the strength of this new study, which they stress "does not provide the basis for changing treatment in people with diabetes."

"While there are risks and benefits associated with any therapy, the retrospective analysis indicates GLP-1–based therapies are associated with a relatively small excess risk of hospitalization for acute pancreatitis, with only 2 additional cases per 100 patients over a 3-year period. This same population of adults, between the ages of 18 and 64 with type 2 diabetes, had a greater risk of hospitalization for acute pancreatitis if they used tobacco, consumed alcohol, or were obese," they note.

Fortunately, there will be new data available relatively soon that will allow physicians to definitively assess risks and benefits of this class of medicines, they add, noting that there are currently 9 ongoing, prospective, controlled trials of GLP-1–based therapy with more than 65,000 subjects, "which should provide answers to these important safety questions."

Large, Independent Study Adjusted for Confounders

Singh and colleagues provide a timely reminder that…little is yet known about long-term adverse effects of the GLP-1 class of drugs on the exocrine pancreas. Drs. Belinda Gier and Peter Butler

GLP-1 is a hormone released by endocrine cells in the gut after a meal, which amplifies glucose-mediated insulin secretion, a property that is desirable in type 2 diabetes. The GLP-1 mimetic drugs — which include GLP-1 agonists such as exenatide and DPP-4 inhibitors such as sitagliptin — are the most recently launched drug classes for the treatment of type 2 diabetes. (DPP-4 is an enzyme that prevents the breakdown of endogenous GLP-1.)

Exenatide and sitagliptin were the first drugs in their respective classes to be approved in the United States, following which reports of pancreatitis began to emerge, resulting in the  warnings. However, "vendors and supporters of GLP-1 treatment refuted the reported association of pancreatitis as being an artifact of the increased risk for pancreatitis in type 2 diabetes mellitus," note Drs. Gier and Butler in their editorial.

They therefore applaud the "many strengths" of this new study by Dr. Singh and colleagues, including the "large size of the sample, the ability to adjust for confounders, and the independence of the authors from the companies marketing the drugs."

Using a large claims database from 7 Blue Cross Blue Shield Association plans, Dr. Singh and colleagues assessed a population of type 2 diabetes patients aged 18 to 64 years who filled at least 1 prescription for any drug to treat diabetes between February 2005 and December 2008.

The main outcome measure was hospitalization for acute pancreatitis. They identified 1269 hospitalized cases with acute pancreatitis using a validated algorithm and 1269 control subjects matched for age category, sex, enrollment pattern, and diabetes complications.

After adjustment for confounders and metformin use, current use of GLP-1–based therapies within 30 days (adjusted odds ratio, 2.24; 95% confidence interval [CI], 1.36 – 3.68]) and recent use past 30 days and less than two years (adjusted odds ratio, 2.01; 95% CI, 1.37 – 3.18]) were associated with significantly increased odds of acute pancreatitis relative to the odds in nonusers.

Pancreatic Cancer Should Be Evaluated in the Long Term

"These drugs are associated with a 2-fold increased risk for hospitalization for pancreatitis, so in patients having symptoms [physicians] should carefully evaluate them and consider temporarily stopping them," Dr. Singh reiterated.

He told Medscape Medical News that he believes the association with pancreatitis is likely a "mechanistic" class effect of all GLP-1 agonists and DPP-4 inhibitors: "This is 1 more link in the chain; there is some pancreatic inflammation going on with GLP-1," he noted.

Future studies should determine whether monitoring of serum enzyme levels can be used to predict the occurrence of acute pancreatitis among patients using GLP-1–based therapies, he and his colleagues add. And long-term prospective studies "should examine other outcomes such as chronic pancreatitis and pancreatic cancer."

Drs. Gier and Butler concur. "Now Singh and colleagues have brought clarity to the increased risk for pancreatitis with GLP-1–based therapy, the time has come to move forward and address the wider implications of this finding: pancreatic cancer."

Because access to the human pancreas "is a challenge," they suggest going back to reexamine exocrine pancreas from primate toxicology studies performed with these drugs. And prospective independent studies should evaluate even small increases in pancreatic enzyme levels in relation to GLP-1 treatment, they add.

"Unfortunate recent history documents unacceptable delays by regulatory authorities to act on serious adverse effects detected in postmarketing surveillance of drugs for type 2 diabetes mellitus… We hope history will not repeat itself with the GLP-1–based drugs," they conclude.

The authors and editorialists have disclosed no relevant financial relationships.

JAMA Intern Med. Published online February 25, 2013. Abstract