Acute Pancreatitis with Liraglutide – Discussion

An analysis of MedWatch adverse event reports submitted to the Food and Drug Administration in the first two years following approval

June 5, 2014

• Cover Letter to the FDA (pdf)
• Full Report (pdf)
• View the Press Release
• June 17, 2014 – FDA Response
• Executive Summary
• Part 1: Background
• Part 2: Methods
• Part 3: Results
• Part 4: Discussion
• Part 5: Conclusion
• Acknowledgements
• Appendix: Charts & Graphs

PART IV: DISCUSSION

This is the first study to assess the likelihood of causality of acute pancreatitis with an incretin mimetic drug using the clinical information present in the original MedWatch case report forms submitted to the FDA. In the first two years following its approval, liraglutide was listed as the primary suspect drug in 278 unique cases of acute pancreatitis reported to the FDA. The majority of cases occurred within the first three months after the initiation of liraglutide and resolved promptly after discontinuation of the drug. Using the Naranjo scale, we identified 51 “probable” cases with enough information reported to suggest a causal link to liraglutide use, including a subgroup of 12 cases in which we deemed a link to be highly probable.

There was, in addition, one “definite” case that, to our knowledge, is the first documented case of recurrent acute pancreatitis following rechallenge with liraglutide. This patient had no prior history of, or risk factors for, pancreatitis, and alternative causes for pancreatitis were excluded at the time of presentation. The recurrence of a rare adverse event, such as acute pancreatitis, after reintroduction of a drug, without other confounding factors in the interim, is considered one of the strongest indicators of causality.[19]

That incretin mimetics have been associated with acute pancreatitis is widely accepted and is included in the drugs’ labels.[20] However, there is an ongoing debate as to whether acute pancreatitis cases are due to an inherent property of the drugs or merely to the underlying increased risk from diabetes itself.[21],[22] Liraglutide’s manufacturer recently claimed that “no cause and effect association has been established…” between liraglutide and pancreatitis.[23]

Acute pancreatitis was identified in randomized clinical trials of liraglutide, before FDA approval, as a potential adverse effect. Summed across all trials, the adjusted rate of acute pancreatitis was 2.2 cases per 1,000 patient years in liraglutide-treated subjects versus 0.6 cases per 1,000 patient years in diabetic control subjects, a 3.7-fold increase.[24] Following approval, there have been, to our knowledge, five published individual case reports of liraglutide-associated acute pancreatitis.[25],[26],[27],[28],[29] In four of the five cases, the patients had no prior history of pancreatitis, and in all cases, there was prompt resolution of symptoms following discontinuation of liraglutide.

Two recent randomized controlled trials of two other incretin mimetics, saxagliptin and alogliptin, reported numerically (though not statistically significantly) higher rates of acute pancreatitis in incretin mimetic-treated subjects. This included a near-doubling of “definite” cases of acute pancreatitis in those given saxagliptin.[30],[31] A recently completed randomized controlled trial of weight loss in more than 3,700 non-diabetic obese and overweight subjects found that a daily dose of 3.0 mg of liraglutide tripled the risk of acute pancreatitis over 56 weeks of use (0.3 vs. 0.1 events per 100 patient-years of exposure in liraglutide- and placebo-treated subjects, respectively).[32] Notably, this trial excluded subjects with diabetes or a prior history of acute or chronic pancreatitis.

Several observational, administrative claims-based studies examining the relationship between acute pancreatitis and use of incretin mimetic drugs have reported mixed results.[33],[34],[35],[36],[37] However, the studies used different sample sizes, selection criteria, and analytic approaches, which impede the ability to draw definitive conclusions regarding the association between acute pancreatitis and incretin mimetic drugs.

If cases of acute pancreatitis with incretin mimetic drugs such as liraglutide were caused merely by the patients’ underlying diabetes, one would expect a similar rate of reported cases for all diabetes drugs, incretin mimetics and non-incretin mimetics alike. However, three separate analyses of the FDA’s AERS database have demonstrated that reports of acute and chronic pancreatitis were far more likely to be reported in association with incretin mimetic drugs (reporting odds ratios [RORs] of 27-56 with liraglutide) when compared with a control group of non-incretin diabetes drugs and insulin.[38],[39],[40] A more recent study based on reports to the French Pharmacovigilance Database found a ROR of acute and chronic pancreatitis with incretin mimetics of 14.86 (95 % CI: 9.24–23.92) after adjusting for multiple potential confounders, with no significantly increased signal for pancreatitis seen with any non-incretin diabetes drugs.[41]

We conducted a similar analysis using the same methodology as for our liraglutide search. We retrieved a total of 1,019 cases of “pancreatitis acute” with the five incretin mimetics reported to the FDA from 2005 to 2011, as opposed to only 202 cases for 10, collectively much more widely prescribed[42] non-incretin mimetic oral diabetes drugs reported between 1997 and 2011 (Figure 2).

The precise mechanism by which incretin mimetics may cause pancreatitis is unknown. However, a plausible hypothesis has been suggested based on the proliferative action of GLP-1 on pancreatic ductal epithelium in humans and animal models. Proliferation of ductal epithelium could lead to duct occlusion and an increase in back pressure within the pancreatic acini.[43],[44] Such obstruction could cause low-grade, chronic inflammation, which, in the case of predisposed patients, may potentially develop into acute pancreatitis.[45]

A recent study in deceased human organ donors compared pancreata of diabetic patients treated for a year or more with sitagliptin or exenatide to those of diabetic patients not treated with incretin mimetics as well as non-diabetics. The pancreata of those taking incretin mimetics were 40% larger than those of diabetic patients not on incretin mimetic therapy, as a result of increased exocrine cell proliferation.[46] Pancreatic exocrine cell proliferation and/or inflammation in response to incretin mimetic therapy have also been seen in mouse,[47] rat,[48] and monkey[49] pancreata.

There are several limitations to note in this study. The FDA’s AERS database depends on voluntary reporting of adverse events. As a result, it is estimated that as few as 2-20% of medication-related adverse events are reported to the agency.[50] This suggests that our study underestimates the number of cases of acute pancreatitis associated with liraglutide therapy.

In addition, the data provided in MedWatch reports are often insufficient to determine whether the adverse event was drug-induced or due to some alternative cause. We made an effort to be conservative in our assessment of potential confounders. We considered as plausible alternative causes significant alcohol use, gallstones (including likely incidental findings on imaging), concomitant medications previously associated with pancreatitis (including those that the patient had been taking longer than liraglutide with no untoward effects), and a prior history of chronic pancreatitis or idiopathic acute pancreatitis.

Nevertheless, diabetes and obesity (mean weight of 104 kg in our sample), both identified as possible risk factors for pancreatitis,[51],[52] are examples of potential confounders not accounted for in our analysis. Another possible confounder is the Weber effect, whereby more adverse events are reported with recently-approved drugs, such as liraglutide, than with older diabetes medications.[53] However, neither of these factors is likely to account for the large number of reports with liraglutide, as no signal for acute pancreatitis has appeared with any non-incretin mimetic diabetes drug, at any time following approval (Figure 2).

It is also possible that physicians have been more likely to report cases of pancreatitis with liraglutide and other incretin mimetics than cases with drugs not previously implicated in pancreatitis, a so-called notoriety bias. However, reports to the FDA of acute pancreatitis with the first approved incretin mimetic, exenatide, occurred before concerns of pancreatitis with incretin mimetic drugs became known, and despite the fact that no pre-approval safety signal for acute pancreatitis had been identified (and therefore no label warnings required).[54],[55]

Next Page » Part V: Conclusion

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[19] FDA. Reviewer guidance: Conducting a clinical safety review of a new product application and preparing a report on the review. FDA/CDER, Silver Spring; February 2005. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072974.pdf. Accessed April 17, 2014.

[20] FDA. FDA-approved drug products. FDA/CDER, Silver Spring. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed April 7, 2014.

[21] Butler PC, Elashoff M, Elashoff R, Gale EA. A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe? Diabetes Care 2013, 36: 2118-25.

[22] Nauck MA. A critical analysis of the clinical use of incretin-based therapies: The benefits by far outweigh the potential risks. Diabetes Care 2013, 36: 2126-32.

[23] Moses A. Novo Nordisk replies to BMJ investigation on incretins and pancreatic damage. BMJ 2013, 347: f4386.

[24] FDA. Liraglutide clinical safety review. FDA/CDER, Silver Spring; July 2009. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022341s000medr_P2.pdf. Accessed April 8, 2014.

[25] Lee PH, Stockton MD, Franks AS. Acute pancreatitis associated with liraglutide. Ann Pharmacother 2011, 45: e22.

[26] Knezevich E, Crnic T, Kershaw S, Drincic A. Liraglutide-associated acute pancreatitis. Am J Health Syst Pharm 2012, 69: 386-389.

[27] Famularo G, Gasbarrone L, Minisola G. Pancreatitis during treatment with liraglutide. JOP 2012, 13: 540-1.

[28] Bourezane H, Kastler B, Kantelip JP. Late and severe acute necrotizing pancreatitis in a patient with liraglutide. Therapie 2012, 67: 539-43.

[29] Nakata H, Sugitani S, Yamaji S, et al. Pancreatitis with pancreatic tail swelling associated with incretin-based therapies detected radiologically in two cases of diabetic patients with end-stage renal disease. Intern Med 2012, 51: 3045-9.

[30] White WB, Cannon CP, Heller SR, et al; EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013, 369: 1327-35.

[31] Scirica BM, Bhatt DL, Braunwald E, et al; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013, 369: 1317-26.

[32] Pi-Sunyer X, Astrup A, Fujioka K, et al. Efficacy and safety of liraglutide 3.0 mg for weight management in overweight and obese adults: the SCALE obesity and prediabetes, a randomized, double-blind and placebo-controlled trial. Abstract #700. American Association of Clinical Endocrinologists 23rd Annual Scientific and Clinical Congress. https://www.citizen.org/sites/default/files/abstract-book.pdf. Accessed May 20, 2014.

[33] Singh S, Chang HY, Richards TM, et al. Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: A population-based matched case-control study. JAMA Intern Med 2013, 173: 534-9.

[34] Garg R, Chen W, Pendergrass M. Acute pancreatitis in type 2 diabetes treated with exenatide or sitagliptin: A retrospective observational pharmacy claims analysis. Diabetes Care 2010, 33: 2349-54.

[35] Dore DD, Hussein M, Hoffman C, et al. A pooled analysis of exenatide use and risk of acute pancreatitis. Curr Med Res Opin 2013, 29: 1577-86.

[36] Wenten M, Gaebler JA, Hussein M, et al. Relative risk of acute pancreatitis in initiators of exenatide twice daily compared with other anti-diabetic medication: a follow-up study. Diabet Med 2012, 29: 1412-8.

[37] Romley JA, Goldman DP, Solomon M, McFadden D, Peters AL. Exenatide therapy and the risk of pancreatitis and pancreatic cancer in a privately insured population. Diabetes Technol Ther 2012, 14: 904-11.

[38] Butler PC, Elashoff M, Elashoff R, Gale EA. A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe? Diabetes Care 2013, 36: 2118-25.

[39] Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterol 2011, 141: 150-156.

[40] Institute for Safe Medication Practices. Perspectives on GLP-1 Agents for Diabetes. QuarterWatch. April 18, 2013 ? Partial Data from 2012 Quarter 3. http://www.ismp.org/quarterwatch/pdfs/2012Q3.pdf. Accessed April 8, 2014.

[41] Faillie JL, Babai S, Crépin S, et al. The French Pharmacovigilance Centers Network: The French Pharmacovigilance Centers Network. Pancreatitis associated with the use of GLP-1 analogs and DPP-4 inhibitors: A case/non-case study from the French Pharmacovigilance Database. Acta Diabetol 2013 Dec 19. [Epub ahead of print]

[42] In 2011, there were more than five times as many prescriptions for the non-incretin mimetic metformin than all five incretin mimetics on the market at the time. Source: IMS Health.

[43] Butler PC, Elashoff M, Elashoff R, Gale EA. A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe? Diabetes Care 2013, 36: 2118-25.

[44] Gale EA. GLP-1-based therapies and the exocrine pancreas: more light, or just more heat? Diabetes 2012, 61: 986-8.

[45] Gale EA. GLP-1-based therapies and the exocrine pancreas: more light, or just more heat? Diabetes 2012, 61: 986-8.

[46] Butler AE, Campbell-Thompson M, Gurlo T, et al. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes 2013, 62: 2595-604.

[47] Gier B, Matveyenko AV, Kirakossian D, et al. Chronic GLP-1 receptor activation by exendin-4 induces expansion of pancreatic duct glands in rats and accelerates formation of dysplastic lesions and chronic pancreatitis in the Kras(G12D) mouse model. Diabetes 2012, 61: 1250-62.

[48] Nachnani JS, Bulchandani DG, Nookala A, et al. Biochemical and histological effects of exendin-4 (exenatide) on the rat pancreas. Diabetologia 2010, 53: 153-9.

[49] FDA. Liraglutide Pharmacology Review. FDA/CDER, Silver Spring; July 2009. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022341s000pharmr_P1.pdf; and http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022341s000pharmr_P2.pdf. Accessed April 9, 2014.

[50] Hazell L, Shakir SA. Under-reporting of adverse drug reactions: a systematic review. Drug Saf 2006, 29: 385-96.

[51] Solanki NS, Barreto SG, Saccone GT. Acute pancreatitis due to diabetes: the role of hyperglycaemia and insulin resistance. Pancreatology 2012, 12: 234-9.

[52] Hong S, Qiwen B, Ying J, Wei A, Chaoyang T. Body mass index and the risk and prognosis of acute pancreatitis: A meta-analysis. Eur J Gastroenterol Hepatol 2011, 23: 1136-43.

[53] FDA. The clinical impact of adverse event reporting. FDA/CDER, Silver Spring; October 1996. http://www.fda.gov/downloads/Safety/MedWatch/UCM168505.pdf. Accessed April 8, 2014.

[54] FDA. Safety alert: Byetta (exenatide). FDA/CDER, Silver Spring; October 2007. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124712.htm. Accessed April 10, 2014.

[55] FDA. Exenatide medical review. FDA/CDER, Silver Spring; March 2005. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021773_Byetta_medr.PDF. Accessed April 9, 2014.