DIABETES AND

Do GLP-1–Based Therapies Increase Cancer Risk?

1 MICHAEL A. NAUCK, MD and a reduction in acinar cells (10–12). 2 NELE FRIEDRICH, PHD The histological hallmarks of developing pancreatic after chronic pan- creatitis are pancreatic intraepithelial neoplasia, intraductal papillary mucinous ases of pancreatitis have been de- , , and others or neoplasms, and so-called pancreatic duct – scribed in connection with the use dipeptidyl peptidase-4 (DPP-4) inhibitors glands (10 12). These phenomena are C characteristic lesions that occur during of exenatide (1), liraglutide (2) and such as sitagliptin, vildagliptin, saxagliptin, other glucagon-like peptide (GLP)-1 re- alogliptin, and linagliptin (8). However, al- the transition from chronic pancreatitis ceptor agonists. From these findings, the most all available data and quoted studies to . Recent estimations, following hypothesis has been generated: have specifically examined exenatide and based on known mutation rates and the stimulating the GLP-1 receptor with re- sitagliptin, which have been available for accumulation of somatic mutations at dif- spective agonists has a potential to cause the longest time. ferent stages of the development of pan- pancreatitis, perhaps chronic pancreati- The questions of whether certain creatic cancer, indicate that it is a chronic tis, and in the long term, potentially drugs can cause pancreatitis and whether process. It takes ~12 years for a normal even pancreatic cancer (3–5). Further- certain drugs can cause pancreatic carci- duct to get initiated as a tumor cell more, in rodents like mice and rats, stim- noma are interrelated, since chronic pan- and to give life to a parental clone, from ulating the GLP-1 receptor raises cAMP in creatitis increases the risk for pancreatic which a pancreatic carcinoma can grow. It C cells, initiates the release of cal- carcinoma approximately 26-fold com- takes another 7 years (approximately) for citonin, and upon longer-term exposure, pared with subjects not suffering from such cells to develop subclones with met- is accompanied by C-cell proliferation chronic pancreatitis (9). There is an etio- astatic capacity and another 3 years (ap- and the formation of C-cell logical sequence leading from a healthy proximately) before the disease will be and (medullary thyroid) (6). to chronic pancreatitis, with diagnosed due to clinical symptoms Based on these findings, it was hypothe- the main drivers being genetic suscepti- and a clinically apparent primary tumor sized that GLP-1–derived medications bility, alcohol abuse, and certain drugs accompanied by metastases (13). This have a potential to cause medullary thy- (10–12). Once chronic pancreatitis has time frame is important relative to the du- roid carcinoma in humans as well (3,7). It been established, chronic inflammation ration of exposure to antidiabetes drugs is the purpose of the current review to and enhanced intraductal pressure due that might have a potential to accelerate discuss the evidence in favor and against to stenosis of the pancreatic duct(s) may the progression of malignant disease. the hypothesis that GLP-1–based thera- lead to the development of pancreatic car- Thus, any database that does not cover – pies increase cancer risk, specifically the cinoma (10–12). While this sequence is at least 5 6yearsofobservationwith risk for pancreatic and thyroid carcino- established in the case of chronic pancre- any drug cannot contribute reliable infor- mas in patients with type 2 diabetes trea- atitis, it is not as certain whether an epi- mation on the risks for malignant disease, ted with exenatide and sitagliptin. sode of acute pancreatitis will have the since the development of cancer can most fl In principle, there could be weak or same consequences. This is of importance likely only be in uenced over long periods strong evidence, either in favor of or because most of the episodes of pancrea- of time. against, the hypothesis that incretin- titis associated with GLP-1 receptor ago- – based medications can increase the nist treatment seem to be episodes of GLP-1 based therapies and risk for pancreatic, (medullary) thyroid, acute pancreatitis (1). In the course of de- pancreatitis or other carcinomas. For the purpose of velopment of chronic pancreatitis, there is In the year 2008, a report of 30 cases of this review, GLP-1–based therapies an exocrine pancreatic infiltrate of T cells acute pancreatitis associated with the use are GLP-1 receptor agonists such as and macrophages, a fibrotic reaction, of exenatide as an antidiabetes treatment for type 2 diabetes was published (1). ccccccccccccccccccccccccccccccccccccccccccccccccc There was a wide range of time until the From 1Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany; and the 2Department of Clinical onset of symptoms: on average 34 days Chemistry and Laboratory Medicine, Ernst-Moritz-Arndt-Universität Greifswald, Greifswald, Germany. but ranging from 4 to 300 days. Usually, amy- Corresponding author: Michael A. Nauck, [email protected]. lase and lipase were elevateddsometimes This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10 substantiallydand in the majority of .2337/dcS13-2004/-/DC1. cases, the patients recovered from the This publication is based on the presentations from the 4th World Congress on Controversies to Consensus in Diabetes, and Hypertension (CODHy). The Congress and the publication of this supplement were apparent episode of acute pancreatitis (1). made possible in part by unrestricted educational grants from Abbott, AstraZeneca, Boehringer Ingelheim, With this background, animal experi- Bristol-Myers Squibb, Eli Lilly, Ethicon Endo-Surgery, Janssen, Medtronic, Novo Nordisk, Sanofi, and ments were performed exposing trans- Takeda. genic rats who overexpressed human islet DOI: 10.2337/dcS13-2004 © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly polypeptide in the endocrine cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/ pancreas (HIP rats) to treatment with licenses/by-nc-nd/3.0/ for details. sitagliptin, metformin, the combination care.diabetesjournals.org DIABETES CARE, VOLUME 36, SUPPLEMENT 2, AUGUST 2013 S245 Incretin-based drugs and cancer of sitagliptin and metformin, or placebo. (18) described a change toward a less in- clinical trial with ~89,000 patient-years Matveyenko et al. (14) described an area flammatory state in animals treated with of observation would be necessary per of pancreatitis in one of the HIP rats trea- GLP-1 receptor agonists. This certainly group (GLP-1 receptor agonist, DPP-4 in- ted with sitagliptin and in none of the does not support GLP-1 receptor stimu- hibitor, or control medication). It is quite other groups. Statistical analysis of these lation as a mechanism to induce acute obvious that such a large and costly study numbers does not indicate a significantly pancreatitis. Furthermore, the same au- will never be performed; other methods of increased risk for pancreatitis under sita- thors studied the effects of GLP-1 recep- surveillance of increased pancreatitis risk gliptin treatment. Another remarkable tor stimulation on the proliferation of need to be developed. The cardiovascular fact was that in the group treated with human pancreatic adenomcarcinoma outcome studies under way for incretin- both sitagliptin and metformin, no pan- cell lines and found no growth-promoting based medications (Liraglutide Effect and creatitis was observed. The observation of effects (19). These findings do not sup- Action in Diabetes: Evaluation of Cardio- pancreatitis with sitagliptin treatment in port the potential of GLP-1 recpetor stim- vascular Outcome Results - A Long Term the HIP rats was the reason for a more ulation to promote pancreatic tumor Evaluation [LEADER] with liraglutide elaborate analysis of the effects of sitaglip- proliferation. [clinicaltrials.gov, NCT01179048] [27], tin treatment on the exocrine pancreas. Other studies have examined lipase Exenatide Study of Cardiovascular Event Among other aspects, a significantly en- and amylase activities in serum (20) and Lowering [EXCSEL] with exenatide once hanced ductal cell proliferation rate based the incidence of acute pancreatitis in pa- weekly [NCT01144338], Trial Evaluating on Ki67 expression (a proliferation tients with type 2 diabetes while receiving Cardiovascular Outcomes with Sitagliptin marker) was found and again reversed different forms of antidiabetes treatment [TECOS] with sitagliptin [NCT00790205], when sitagliptin and metformin were (21–26). Small but consistent elevations Saxagliptin Assessment of Vascular Out- combined (14). Based on these findings, mostly within the normal range in lipase comes Recorded in Patients with Diabetes it was reasoned that sitagliptin might and amylase, not accompanied by other Mellitus [SAVOR-TIMI 53] with saxaglip- cause ductal cell proliferation in these signs or symptoms of pancreatitis, were tin [NCT01107886] [28], and Cardiovas- HIP rats, thereby leading to pancreatitis observed over time with liraglutide treat- cular Outcome Study of Linagliptin versus and perhaps, in the long run, to pancre- ment in obese and type 2 diabetic popu- Glimepiride in Patients with Type 2 Di- atic carcinoma. In similar experiments in lations. Whether this indicates the abetes (CAROLINA) with linagliptin another transgenic animal model, overex- induction of low-grade pancreatic inflam- [NCT01243424]) will help in that respect, pressing human islet amyloid polypeptide mation or of membrane leakage leading to although the number of events from a sin- did not reveal any ductal abnormalities more spillover of intracellular (pro)en- gle trial will probably be too low for definite (histology) or a change in ductal cell pro- zymes into the extracellular space or an answers. Meta-analyses might help to draw liferation rates with sitagliptin, metformin, altered level of expression of digestive en- firmer conclusions. Other helpful initia- sitagliptin with metformin, or placebo zymes in pancreatic acinar cells will need tives are the Sentinel and Mini-Sentinal treatment (15). to be clarified in future studies. Results programs initiated by the U.S. Food and Additional animal studies have also from pharmacoepidmiological analyses, Drug Administration (FDA), which will al- described histological alterations within which have typically been based on claims low better postmarketing surveillance re- the exocrine pancreatic tissuedthis time databases, indicate that the population of garding rare adverse events of novel drugs with exendin-4 treatment. Exendin-4 is a obese type 2 diabetic patients is at higher (29,30). peptide used for the treatment of type 2 risk of developing acute pancreatitis and diabetes; the synthetic form is known as that the relative risk is approximately two- GLP-1–based therapies and exenatide. Nachnani et al. (16) found to threefold higher than in nonobese con- thyroid C-cell carcinomas higher degrees of exocrine pancreatic in- trol populations (21). However, the rate of , generally speaking, is a flammation after treatment with exendin- diagnosed acute pancreatitis was not dif- rare disease (31). Of all cases of thyroid 4, with a significantly increased number ferent between patients who were treated cancer, is diag- of pyknotic nuclei, but just a trend toward with exenatide (as an example of a GLP-1 nosed in ~2% of the female patients and more fibrosis. receptor agonist) or with sitagliptin (as an ,4% of the male patients with an inci- Other animal studies tested the hy- example of a DPP-4 inhibitor) and diabetic dence that increases with older age (31). pothesis that the presence of exenatide patients receiving other forms of antidia- While C-cell abnormalities and especially treatment will affect the outcome of ex- betes treatments (21). The results of this medullary thyroid carcinoma are a rare perimentally induced acute pancreatitis and similar studies, most of which have disease entity in humans, they occur in ob/ob and high-fat diet streptozocin only been reported as abstracts, are sum- spontaneously in certain rodent species diabetic mice. In these studies, the admin- marized in Fig. 1. Uniformly, such studies including mice and rats. C-cell disease istration of exenatide before the induction described an odds ratio near 1, with, how- ranges from C-cell hyperplasia to C-cell of experimental acute pancreatitis using ever, 95% CIs that were too wide to and (6). cerulein reduced the increments in amylase exclude a slightly elevated risk (Fig. 1). In mice and rats, a once-daily injection or lipase activity (17). Based on these find- On the other hand, there was no hint to- of liraglutide, a GLP-1 receptor agonist ings, even a protective effect of GLP-1 re- ward such an elevated risk. Based on these that has an approximate half-life of 13 h, ceptor stimulation could be hypothesized. findings, a sample size calculation could leads to permanently elevated circulating In another important study, the ex- be performed (nQuery Advisor, version drug concentrations (32,33) and in- pression of cytokines and other molecular 6.02; Statistical Solutions, Cork, Ireland): creased rate of C-cell abnormalities in markers of the inflammatory state were this calculation indicates that to rule out a both mice and rats, with some animals measured with and without GLP-1 re- risk for acute pancreatitis elevated by at developing C-cell carcinomas, especially ceptor agonist treatment. Koehler et al. least 25%, a prospective randomized among male rats (6). Experiments with

S246 DIABETES CARE, VOLUME 36, SUPPLEMENT 2, AUGUST 2013 care.diabetesjournals.org Nauck and Friedrich

Figure 1dOdds ratio and 95% CIs for chronic pancreatitis in studies examining the risk of pancreatitis in patients with type 2 diabetes receiving treatment with the GLP-1 receptor agonist exenatide (A) or the DPP-4 inhibitor sitagliptin (B) relative to other glucose-lowering medications. Analysis of claims databases capturing both prescriptions of specific medications and (hospitalization due to) acute pancreatitis. Data depicted in this figure have been taken from refs. 21–26. cell lines originating from rodent C cells receptor agonists does not lead to ele- papillary thyroid carcinomas, indicating a showed that exposure to GLP-1, exena- vated concentrations. From potential of GLP-1 receptor stimulation to tide, or liraglutide (GLP-1 receptor ago- these findings, one can depict the follow- have an influence on the growth rate of nists) will lead to an elevated production ingview(Fig.2):Inrodents,thereare other thyroid cancer types as well (7). An- of cAMP and to the immediate stimula- sufficient GLP-1 receptors on thyroid C other recent study using an even more spe- tion of calcitonin secretion (6). However, cells to increase cAMP production upon cific method to detect (and rule out) GLP-1 similar cell lines originating from human exposure to GLP-1 or other GLP-1 recep- receptors in tissues (a radioligand assay) 2 C cells can be exposed to up to a 10 6 tor agonists. This will be accompanied by did not confirm GLP-1 receptors in human molar concentration of GLP-1, exenatide, calcitonin release and, in the long term, by thyroid tissue outside C cells (35). There- or liraglutide and not increase in level C-cell proliferation and the formation of fore, more information is needed to reach a of cAMP or the secretion of calcitonin C-cell adenomas or even medullary thy- consensus in this respect. The one conse- (6). Only very high concentrations of roid carcinomas. In humans, thyroid C quence to be drawn from these considera- forskolin-raised cAMP elicited a calcito- cells are equipped with GLP-1 receptors tions is not to treat subjects at high risk for nin response, but this occurred indepen- at a much lower degree of expression, developing medullary thyroid carcinoma dent from the stimulation of GLP-1 and exposure to GLP-1 receptor stimula- based on multiple endocrine neoplasia or receptors. The behavior of human C cells tion does not elevate cAMP or trigger cal- familial medullary thyroid carcinoma with has also been tested in long-term clinical citonin release. Since C-cell proliferation liraglutide (according the label), and it is trials, in which liraglutide and other anti- in rodents occurs concomitantly with in- advisable to practice caution with other diabetes medications were used. In some crements in cAMP and the release of cal- incretin-based medications as well. of these clinical studies, liraglutide treat- citonin as immediate markers of GLP-1 ment had been used for up to 52 weeks at receptor stimulation, it is a reasonable as- Analyses of data reported to the FDA doses ranging up to 3 mg daily (only in sumption that in human C cells, incretin- Adverse Event Reporting System nondiabetic obese populations) or up to based medications would not lead to In 2011, Elashoff et al. (3) compared re- 1.8 mg daily (patients with type 2 diabe- C-cell proliferation, potentially leading to ports of pancreatitis, pancreatic carci- tes) with no systematic change in calcitonin C-cell adenomas or medullary thyroid noma, and thyroid carcinoma in patients concentrations indicating any mea- carcinomas. However, a recent study us- with type 2 diabetes treated with either surable response to GLP-1 receptor stim- ing immunocytochemistry to detect GLP- exenatide or sitagliptin relative to other ulation (34). Thus, the conclusion seems 1 receptors described such receptors not antidiabetes treatments (rosiglitazone, to be justified that chronic exposure to only on human C cells but also in some, repaglinide, nateglinide, and glipizide), clinically effective doses of GLP-1 but not all, follicular cells and in some also controlling for the reports of “control

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Figure 2dSchematic representation of thyroid C cells, their equipment with GLP-1 receptors, and physiological responses to stimulation with GLP- 1 or GLP-1 receptor agonists like exenatide and liraglutide comparing rodent (A) and human (B) C cells. While rodent C cells respond to GLP-1 receptor stimulation with cAMP production, calcitonin release, and proliferative responses (giving rise to hyperplasia, adenomas, or even medullary carcinomas), human C cells express GLP-1 receptors at much lower levels, do not increase cAMP levels, and do not secrete calcitonin in response to GLP-1 receptors even upon long-term stimulation (exposure to GLP-1 receptor agonists in clinical trials lasting up to 1 year). events” (back pain, chest pain, cough, uri- whether the FDA Adverse Event Report- (metformin is known not to cause hypo- nary tract infection, and syncope). Based ing System is a suitable database for glycemia [37]). Analyzing the FDA Ad- on this analysis, a significant excess of reaching solid conclusions regarding the verse Event Reporting System showed pancreatitis (11-fold and 7-fold, respec- incidence of certain adverse events related sitagliptin to be the drug reported to cause tively) was found for exenatide and to drug treatment (36). Obviously, re- the most hypoglycemia, whereas the hy- sitagliptin treatment. Similarly, an ap- porting bias is an important phenomenon poglycemic potential of the meglitinides proximately threefold, significant excess to be considered in this respect (Table 1). (short-acting sulfonylurea analogs) was of pancreatic carcinomas was reported Onewaytocapturethevalueof not picked up as significant and the hypo- for both treatment groups. Finally, a sig- conclusions derived from analyzing the glycemic potential of sulfonylureas and nificant 4.7-fold excess of thyroid carci- FDA Adverse Event Reporting System is even of insulin was greatly underestimated nomas (histology not specified) was to pose a question, the answer to which when these results are compared with reported for exenatide treatment, but no is well-known. As an example, we have well-known epidemiological data (Sup- significantly elevated risk was found with looked for reported hypoglycemia in plementary Fig. 1) (37,38). The explana- sitagliptin treatment. This report (Fig. 3A) patients treated with different anti- tion most likely is that the high odds ratio impressed with numbers indicating ro- diabetes drug classes. The odds ratio for sitagliptin allegedly causing hypogly- bust effect sizes but was extremely con- was expressed relative to hypoglycemia cemia is due to concomitant medications, troversial. It raised the question of occurring with metformin treatment which have not been adequately

Figure 3dOdds ratios (95% CI) for reporting pancreatitis, pancreatic carcinoma, thyroid carcinoma, and other/all malignancies in patients with type 2 diabetes prescribed exenatide (green bars) or sitagliptin (blue bars) relative to those taking control diabetes medications, taking into account the frequency of reporting control events (back pain, chest pain, cough, syncope, and urinary tract infection) based on data retrieved from the FDA Adverse Event Reporting System (A), as described by Elashoff et al. (3), for the period from the first quarter, 2004, to the third quarter, 2009. In our confirmatory analysis (B), we used broader search terms for pancreatitis (acute and chronic pancreatitis, pancreatic insufficiency, pancreatic pseudocysts, pancreatic duct stenosis, pancreatic calcifications, pancreatolithisasis, and elevated or abnormal lipase and/or amylase) and used all sulfonylureas as control medications. In the elaborate analysis (C), we included data from the second quarter of 2005 to the fourth quarter of 2010, used broader search terms regarding control events, and included pioglitazone, all sulfonylureas, metformin, and any insulin treatment in the control medications. Numbers indicate case subjects with this diagnosis retrieved from the dataset.

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Table 1dTypes of reporting bias and examples of how they may have altered reporting rates for adverse events potentially associated with incretin-based medications in analysis based on data from the FDA Adverse Event Reporting System

Type of bias Description of bias Examples Literature/evidence Channelling bias • Prescribing patterns • Exenatide, due to its weight-lowering 44,45 depend on patient capacity, may preferentially be used characteristics, medical history, in obese patients, who are at greater risk and product profiles for gallstones or pancreatitis • Differences in drug costs can introduce bias due to socioeconomic factors Underreporting • More serious adverse events • Back pain or cough (control events) 46,47 are typically reported more will be reported less frequently frequently than minor or more than pancreatitis common adverse events • Common illnesses, which can occur independent from drug use, will be reported less frequently Weber effect • The number of reported adverse • More adverse events were reported events for a drug are higher for exenatide and sitagliptin immediately Fig. 4; 48,49 immediately after launch after their respective launches (April 2005 and October 2006, respectively) • Acaseismorelikelytobereported if the patient is exposed to a drug known (or suspected) to cause this event Detection bias • The number of reported adverse • Because of suspected pancreatitis, 52 events rise because tests are performed lipase and amylase are measured in to confirm or rule out a suspected patients receiving incretin-based drugs, adverse event which detect more cases with suspected pancreatitis

considered, and that sulfonylurea- or associated with chronic pancreatitis and 2 diabetic patients treated with exenatide insulin-induced hypoglycemic episodes its complications (Fig. 3), and to allow all or sitagliptin compared with other anti- are such a well-known phenomenon that sulfonylurea compounds to be analyzed as diabetes medications. events falling into this category will be control medications (not just glipizide as To further test the robustness of the greatly underreported. Overall, such described by Elashoff et al. [3]). Per- conclusions, we performed a more elabo- “fake analyses” demonstrate the kind of forming this confirmatory, Elashoff-like rate analysis, using as control medica- bias potentially associated with analyzing analysis (Fig. 3B), we also describe a sig- tions, in addition to rosiglitazone, the FDA Adverse Event Reporting System nificantly elevated odds ratio for pancrea- repaglinide, nateglinide, and glipizide, and shed doubt on simple conclusions de- titis with exenatide and sitagliptin as originally described: piogitazone, all rived from such an analysis. Some typical treatmentdat, however, a somewhat other sulfonylurea compounds, metfor- forms of reporting bias are defined and lower effect size. Likewise, we confirm min, and all insulin preparations. This is described with their potential impact on the significantly elevated odds ratio for the least restrictive approach that can be the interpretation of data retrieved from pancreatic cancer with exenatide and si- taken, although including all insulin the FDA Adverse Event Reporting System tagliptin treatment and the significantly treatment might allow results from type in Table 1. elevated risk for thyroid cancer with exe- 1 diabetic patients into this analysis, who Therefore, it appeared appropriate to natide but not sitagliptin treatment. The will always be a minority within the dia- reproduce the findings reported by odds ratios were somewhat lower than in betic population. Furthermore, we ex- Elashoff et al. (3) and to add some analy- the original publication by Elashoff et al. panded the search for specificadditions ses testing the robustness of such an ap- (3), and the number of captured cases was to the terms “back pain, chest pain, proach. First, we wanted to reproduce the higher based on the more comprehensive cough, syncope, and urinary tract infec- analysis as reported (3). To this end, we search terms regarding pancreatitis, pan- tion” by also including urinary tract infec- analyzed the same period of time (from creatic cancer, and thyroid cancer. Basi- tions with specific bacterial etiology, the 1st quarter, 2004, to the 3rd quarter, cally, however, we confirm that analyzing noncardiac chest pain, productive cough, 2009), although exenatide and sitagliptin the FDA Adverse Event Reporting System and unconsciousness in addition to the were not approved before 2005 and 2007, with a strategy described in detail by narrower search terms used by Elashoff respectively. We decided to use a broader Elashoff et al. (3), a greater number of re- et al. (3). In addition, we extended the set of search terms capturing more ports of pancreatitis, pancreatic cancer, period of analysis to the second quarter pancreatitis-related events, especially those and thyroid carcinoma is found for type of 2005 (when exenatide was first

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and stromal tumors and tumors of the female genital tract was apparently significantly elevated, and with sitagliptin treatment leukemias appeared to be re- ported significantly more often. This anal- ysis was not based on any specific hypothesis, and the results are based on relatively small numbers of tumors and likely are subject to the same reporting bias as those originally reported by Elashoff et al. (3). Summing up the odds ratios for “all other malignant disease” (except for pan- creatic carcinoma and thyroid cancer) re- sulted in significantly reduced odds ratios regardless of whether insulin-treated patients were used as control subjects. This additional sensitivity analysis was performed because of the well-known tumor-promoting potential of insulin (42,43). When taking into consideration all malignant disease categories together (in- cluding pancreatic carcinoma and thyroid cancer), the analysis demonstrated not an overall increase in the odds ratio for “all malignant disease” but, rather, a trend toward a reduction, especially with sita- Figure 4dNumber of subjects with reports (A) and number of adverse events (B) reported to the gliptin treatment (P = 0.068; not signifi- FDA Adverse Event Reporting System between 2004 and 2010 for different glucose-lowering cant [details not shown]). Thus, even if medications including exenatide (green lines) and sitagliptin (blue lines). Obviously, in the case of there were an increased risk for the devel- exenatide there was an initial peak, probably related to the fact that this was the first drug in the opment of pancreatic cancer and thyroid new class of GLP-1 receptor agonists, and after a nadir in the last quarter of 2007 there was carcinomas with exenatide and sitagliptin renewed interest, probably as the consequence of initial reports linking exenatide to cases of treatment or perhaps with incretin-based pancreatitis (1). With sitagliptin, a similar pattern was observed at a lower level. medications in general, this would not in- dicate any tumor-promoting potential in more general terms. If there might be an approved and used) and to the last quar- more frequently with exenatide but not apparently increased risk for specificma- ter of 2010 (the last period available, with sitagliptin treatment (details not lignant disease entities, this seems to be when the present analysis was per- shown). More complications related to counterbalanced by a potentially protec- formed). This analysis again confirmed a gallbladder disease, especially gallbladder tive effect for other specific malignant tu- significantly elevated odds ratio for pan- stones and bile duct stones, could poten- mors.However,thesamereservations creatitis and pancreatic cancer with both tially provide clues to a mechanism caus- regarding conclusions to be drawn from exenatide and sitagliptin and for thyroid ing pancreatitis, perhaps related to such an analysis of the FDA Adverse Event carcinoma with exenatide but not motility effects of exenatide in the upper Reporting System apply as discussed sitagliptin (Fig. 3C). This analysis in- gastrointestinal tract (39–41). above regarding the findings of an in- cluded a much greater number of re- In addition to the analysis more or creased reporting rate for pancreatitis, trieved cases with the index diseases less reproducing the findings by Elashoff pancreatic carcinoma, and thyroid cancer (Fig. 3). In principle, this did not change et al. (3), we looked at subcategories of with exenatide and sitagliptin. the overall pattern, attesting to the robust- malignant disease entities. To our sur- ness of findings based on this general prise, for several of these subcategories Conclusions strategy. Obviously, the suggested con- exenatide and sitagliptin apparently sig- Regarding the controversy of whether clusions were not sensitive to minor or nificantly reduced the odds ratios, in the GLP-1–based therapy can increase the even major changes in the methodology. case of exenatide, for example, regarding risk for specific malignant disease like Similar analyses show that with exenatide lung cancer, prostate cancer, / pancreatic carcinoma and thyroid cancer, treatment, not only cases with acute pan- multiple myeloma, metastasising tumors our conclusion is that apparently there is creatitis (or all pancreatitis) were reported of unknown origin, and “other tumours neither firm evidence in favor of this hy- more frequently but also cases suggestive not specified.” Sitagliptin significantly re- pothesis nor evidence strong enough to of chronic pancreatitis (details not duced the odds ratios for colon cancer, rule out any such increased risk based shown). This, however, was not the case prostate cancer, and “other tumours not on results available at present. We may with sitagliptin treatment. Along the same specified.” On the other hand, with learn answers to some of the questions lines, gallbladder disease was reported exenatide treatment the rate of reporting from ongoing randomized controlled

S250 DIABETES CARE, VOLUME 36, SUPPLEMENT 2, AUGUST 2013 care.diabetesjournals.org Nauck and Friedrich trials (e.g., cardiovascular safety trials un- 4. Butler PC, Matveyenko AV, Dry S, attenuates chemically induced pancreati- derway for most approved compounds Bhushan A, Elashoff R. Glucagon-like tis in normal and diabetic rodents. Am within the classes of GLP-1 receptor ago- peptide-1 therapy and the exocrine pan- J Physiol Endocrinol Metab 2010;299: creas: innocent bystander or friendly fire? E1076–E1086 nists or DPP-4 inhibitors) by analyzing – databases or registries better suited for Diabetologia 2010;53:1 6 18. Koehler JA, Baggio LL, Lamont BJ, Ali S, 5. Gier B, Matveyenko AV, Kirakossian D, Drucker DJ. Glucagon-like peptide-1 re- an unbiased postmarketing surveillance Dawson D, Dry SM, Butler PC. Chronic ceptor activation modulates pancreatitis- of adverse events associated with novel GLP-1 receptor activation by exendin-4 associated gene expression but does not antidiabetes drugs. However, as of today induces expansion of pancreatic duct modify the susceptibility to experimental the evidence in favor of the hypothesis glands in rats and accelerates formation of pancreatitis in mice. Diabetes 2009;58: that incretin-based medications cause dysplastic lesions and chronic pancreatitis 2148–2161 specific types of malignant disease (e.g., in the Kras(G12D) mouse model. Diabetes 19. Koehler JA, Drucker DJ. Activation of pancreatic or [medullary] thyroid cancer) 2012;61:1250–1262 glucagon-like peptide-1 receptor signal- or increase the risk for cancer in a more 6. Bjerre Knudsen L, Madsen LW, Andersen S, ing does not modify the growth or apo- et al. Glucagon-like Peptide-1 receptor ago- ptosis of human pancreatic cancer cells. general sense is not convincing enough to – be seriously considered when making nists activate rodent thyroid C-cells causing Diabetes 2006;55:1369 1379 treatment decisions regarding the choice calcitonin release and C-cell proliferation. 20. Steinberg W, DeVries JH, Wadden T, et al. 2010;151:1473–1486 Longitudinal monitoring of lipase and of antidiabetes medications. 7. Gier B, Butler PC, Lai CK, Kirakossian D, amylase in adults with type 2 diabetes and DeNicola MM, Yeh MW. Glucagon like obesity: evidence from two phase 3 ran- peptide-1 receptor expression in the hu- domized clinical trials with the once-daily AcknowledgmentsdM.A.N. has received re- man thyroid gland. J Clin Endocrinol GLP-1 analog lirgalutide (Abstract). Gas- search grants (to his institution, Diabeteszentrum Metab 2012;97:121–131 troenterol 2012;142(Suppl. 1):S850– Bad Lauterberg) from AstraZeneca, Boehringer 8. Drucker DJ, Nauck MA. The incretin S851 Ingelheim, Eli Lilly & Co., Merck Sharp & system: glucagon-like peptide-1 receptor 21. Dore DD, Seeger JD, Arnold Chan K. Use Dohme, Novartis Pharma, GlaxoSmithKline, agonists and dipeptidyl peptidase-4 in- of a claims-based active drug safety sur- Novo Nordisk, Roche, and Tolerx. He has re- hibitors in type 2 diabetes. Lancet 2006; veillance system to assess the risk of acute ceived consulting fees or honoraria for speaking 368:1696–1705 pancreatitis with exenatide or sitagliptin from AstraZeneca, Berlin Chemie, Boehringer 9. Lowenfels AB, Maisonneuve P, Cavallini compared to metformin or glyburide. Ingelheim, Bristol-Myers Squibb, Diartis, Eli Lilly G, et al.; International Pancreatitis Study Curr Med Res Opin 2009;25:1019–1027 & Co., F. Hoffmann-La Roche, Intarcia Thera- Group. Pancreatitis and the risk of pan- 22. Garg R, Chen W, Pendergrass M. Acute peutics, Merck Sharp & Dohme, Novo Nordisk, creatic cancer. N Engl J Med 1993;328: pancreatitis in type 2 diabetes treated with fi Sano , and Versartis, including reimbursement 1433–1437 exenatide or sitagliptin: a retrospective for travel expenses in connection with the above- 10. Bhanot UK, Möller P. Mechanisms of pa- observational pharmacy claims analysis. fl mentioned activities. No other potential con icts renchymal injury and signaling pathways Diabetes Care 2010;33:2349–2354 of interest relevant to this article were reported. in ectatic ducts of chronic pancreatitis: 23. Pendergrass M, Chen W. Association be- M.A.N. designed the analysis, researched implications for pancreatic carcinogene- tween diabetes, exenatide, sitagliptin and data, and wrote the manuscript. N.F. retrieved sis. Lab Invest 2009;89:489–497 acute pancreatitis (Abstract). Diabetes data from the FDA Adverse Event Reporting 11. Vincent A, Herman J, Schulick R, Hruban 2010;59(Suppl. 1):A160 System, helped with analyses, and reviewed RH, Goggins M. Pancreatic cancer. 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