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Invited Commentary
April 8, 2013

Glucagonlike Peptide 1–Based Drugs and Pancreatitis: Clarity at Last, but What About Pancreatic Cancer?Comment on “Glucagonlike Peptide 1–Based Therapies and Risk of Hospitalization for Acute Pancreatitis in Type 2 Diabetes Mellitus”

Author Affiliations

Author Affiliations: Larry L. Hillblom Islet Research Center (Drs Gier and Butler) and Jonsson Comprehensive Cancer Center (Dr Butler), University of California, Los Angeles, David Geffen School of Medicine.

JAMA Intern Med. 2013;173(7):539-541. doi:10.1001/jamainternmed.2013.3374

The worldwide prevalence of type 2 diabetes mellitus (T2DM) is approaching 100 million.1 Most affected individuals are treated for decades. Not surprisingly, the market for drug treatment of T2DM is worth more than $20 billion per year. The most lucrative drugs are those still protected by patent and deemed worthy of selection despite high expense because of clear advantages over cheaper drugs no longer covered by patent protection.

The glucagonlike peptide 1 (GLP-1)–based drugs are the most recently launched drug class for treatment of T2DM. Proponents of these drugs claim they are safe and offer advantages over existing drugs.2 Glucagonlike peptide 1 is a hormone released by endocrine cells in the gut after meal ingestion, and one of its best characterized actions is amplification of glucose-mediated insulin secretion, a property that is of course desirable in T2DM. The first drug in this class approved in the United States was a peptide agonist of the GLP-1 receptor, exenatide (Byetta), followed by sitagliptin (Januvia), an inhibitor of the enzyme that degrades endogenously secreted GLP-1, dipeptidyl peptidase 4. Singh and colleagues3 report that treatment with either of these GLP-1 mimetic drugs is associated with an increased risk of hospital admission for acute pancreatitis compared with other diabetes medications. The many strengths of this study include the large size of the sample, the ability to adjust for confounders, and the independence of the authors from the companies marketing the drugs. Because both drugs already carry US Food and Drug Administration (FDA) warnings for the risk of pancreatitis, why is this study important?

Pancreatitis associated with exenatide treatment was first described in case reports,4 followed by adverse event reports by the FDA for sitagliptin and other drugs in this class. Vendors and supporters of GLP-1 treatment refuted the reported association of pancreatitis as being an artifact of the increased risk of pancreatitis in T2DM and pointed to a myriad of negative findings of animal and clinical studies, most performed by and/or sponsored by the marketing companies.2 We appreciate why an increased risk of pancreatitis associated with drug treatment, even if rare, would be unwelcome. Antecedent pancreatitis is the commonest risk factor for subsequent pancreatic cancer. Analysis of the FDA adverse event reporting system already showed a possible signal for pancreatic cancer with exenatide and sitagliptin by 2009.5 Questions that arise include, how would a signal for a cancer emerge so soon after launch of these drugs? Also, because GLP-1 mimetic drugs cause clinically detectable pancreatitis in a few individuals, do they induce more frequent subclinical effects on the exocrine pancreas in a higher proportion of individuals?

These questions constitute the real crux of the controversy with regard to the safety of GLP-1–based treatment.6 Now that Singh and colleagues3 have brought clarity to the increased risk of pancreatitis with GLP-1–based therapy, the time has come to move forward and address the wider implications of this finding. Pancreatic cancer develops after progressive accumulation of somatic mutations leads to the formation of pancreatic intraepithelial neoplasia (PanIN) of increasing grade that, in a subset of individuals, transforms to malignant neoplasms (Figure). The PanIN lesions are relatively common in middle-aged adults and express the GLP-1 receptor.8 Glucagonlike peptide 1 induces growth of lesions similar to intraductal papillary mucinous neoplasia in rats and accelerates dysplasia of PanIN lesions and pancreatitis in mice prone to pancreatic cancer.8

Figure. Human expression of glucagonlike peptide 1 (GLP-1) receptor in healthy tissue and malignant disease. A, Morphological stages in the transition from normal healthy ducts through intermediate premalignant pancreatic intraepithelial neoplasia (PanIN) lesions and invasive pancreatic cancer. Modified from Hruban et al. B, Corresponding immunohistochemical labeling of human tissue for GLP-1 receptor (brown) in normal pancreatic ducts, premalignant PanIN lesions, and pancreatic cancer.

Figure. Human expression of glucagonlike peptide 1 (GLP-1) receptor in healthy tissue and malignant disease. A, Morphological stages in the transition from normal healthy ducts through intermediate premalignant pancreatic intraepithelial neoplasia (PanIN) lesions and invasive pancreatic cancer. Modified from Hruban et al.7 B, Corresponding immunohistochemical labeling8,9 of human tissue for GLP-1 receptor (brown) in normal pancreatic ducts, premalignant PanIN lesions, and pancreatic cancer.

Therefore, in those individuals with preexisting PanIN lesions or intraductal papillary mucinous neoplasia, GLP-1–based therapy may promote growth of these lesions, causing partial ductal obstruction and pancreatitis in some individuals. Of even greater concern, GLP-1–based therapy might accelerate the progression and transformation of premalignant PanIN lesions, much like the effect of estrogen therapy in women with estrogen receptor–expressing breast neoplasia. Similar concerns arise in relation to GLP-1–based treatment and the risk for thyroid cancer. The GLP-1 receptors are expressed in most medullary thyroid cancer, its precursor C-cell hyperplasia, and approximately 20% of papillary thyroid cancer.9 Increased thyroid tumors were detected in preclinical rodent studies and in association with exenatide in the FDA adverse event reporting system.5

Where forward from here? Access to human pancreas is a challenge. Therefore, perhaps in light of these concerns, a careful open independent reevaluation of the exocrine pancreas in the nonhuman primate toxicology studies performed with these drugs should occur.

What of the potential for more widespread subclinical pancreatic exocrine pancreatitis? A cross-sectional study in a small number of individuals showed an increase in pancreatic enzyme levels.10 A common approach taken in studies by the marketing companies is to require a substantial increase in pancreatic enzyme levels and imaging proof of pancreatitis. That approach clearly misses the potential subclinical long-term moderate increase in pancreatic inflammation that would be of particular concern in relation to the risk for pancreatic cancer. Prospective independent studies to evaluate even small increases in pancreatic enzyme levels in relation to GLP-1 treatment, rather than just very high levels, are required.

At present, the GLP-1 class of drugs is heavily promoted (and prescribed) as having purported advantages that outweigh its risks.2 Singh and colleagues3 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. Unfortunate recent history documents unacceptable delays by regulatory authorities to act on serious adverse effects detected in postmarketing surveillance of drugs for T2DM, deemed 2 times a farce by Gale.11 We hope history will not repeat itself with the GLP-1–based drugs, because in this case, 3 times would not be a charm.

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Article Information

Correspondence: Dr Butler, Larry L. Hillblom Islet Research Center, University of California, Los Angeles, David Geffen School of Medicine, 900 Veteran Ave, 24-130 Warren Hall, Los Angeles, CA 90095 (pbutler@mednet.ucla.edu).

Dr Gier reports that, as of February 1, 2013, she is employed by Bristol-Myers Squibb, Munich, Germany.

Published Online: March 5, 2013. doi:10.1001/jamainternmed.2013.3374

Conflict of Interest Disclosures: None reported.

Editor's Note: At the time this commentary was solicited, submitted, reviewed, and accepted for publication, the editors were unaware that Dr Gier had any pending affiliation with Bristol-Myers Squibb.

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