Incretins and pancreatitis — is there a problem?

Published in Health News and Evidence

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Practice points | Regulators investigate pancreatic risks | Incretin-based medicines | More reports of acute pancreatitis | Conflicting evidence and conflicts of interest — what to believe? | Reports of abnormal pancreatic growth | The burden and business of diabetes | References

Summary

  • Regulatory bodies in the US and Europe are investigating the risk of pancreatitis and precancerous findings in the pancreas with incretin-based medicines for type-2 diabetes.
  • Observational studies suggest an increase in the rate of pancreatitis in patients taking exenatide and sitagliptin.
  • Incretin-based drugs may also be associated with an increase in pancreatic mass and dysplasia.
  • This evidence suggests patient risk factors for pancreatitis may need to be considered when selecting glucose-lowering therapy from the incretin class.

Practice points

  • Consider risk factors for pancreatitis when selecting glucose-lowering medicines from the incretin class. These include a past history of pancreatitis, gallstones, alcoholism or severe hypertriglyceridaemia.1,2
  • Inform your patients of the characteristic symptoms of acute pancreatitis and advise them to see a doctor immediately if they experience persistent, severe abdominal pain that may radiate to the back, particularly if coupled with vomiting or diarrhoea.3,4
  • If a patient is tolerating the regimen, advise them to continue taking their incretin-based medicines, as there is generally no need to discontinue use at this time.
  • If pancreatitis is suspected, discontinue incretin-based drugs, initiate supportive medical care and monitor with appropriate investigation (e.g. a serum amylase test).3,4
  • Report all adverse events associated with incretin medicines to the TGA. For information about reporting adverse events, see the TGA website.

Regulators investigate pancreatic risks

The US FDA first drew attention to the potential risk of pancreatitis associated with exenatide and sitagliptin after spontaneous reports of postmarketing adverse events,3,4 and the product information was updated.

For more details on postmarketing reports of pancreatitis with sitagliptin see the NPS RADAR article Postmarketing reports of pancreatitis with sitagliptin products (Janumet, Januvia).

The TGA also published a safety update about drug-induced pancreatitis in relation to exenatide in 2010.5

Prompted by recent findings of abnormal pancreatic growth in tissue specimens from organ donors who had been taking incretin-based medicines for type 2 diabetes,6 in March the FDA and European Medicines Agency (EMA) announced further investigation into the possible increased risk of pancreatitis and precancerous pancreatic changes in people with type 2 diabetes who are treated with medicines in the incretin class.7,8

Incretin-based medicines

These are the latest class of diabetes medicines to become available in Australia. Incretin-based medicines rely on the glucose-lowering properties of the incretin hormone glucagon-like peptide (GLP-1), which stimulates insulin and suppresses glucagon secretion, inhibits gastric emptying and reduces appetite and food intake.9 Therapeutic approaches for enhancing incretin action include use of GLP-1 agonists and inhibitors of dipeptidyl peptidase-4 (DPP-4), which metabolises incretin hormones.

Medicines in the incretin class, approved for use in Australia, include:


* Subsidised on the PBS.

More reports of acute pancreatitis

Adding to earlier case reports10 and postmarketing reviews3,4,11 there is also new observational evidence suggesting people taking either exenatide or sitagliptin have double the risk of developing acute pancreatitis after adjusting for metformin exposure and other variables (e.g. alcohol use, gallstones and obesity).12

The data come from a retrospective case–control study of 1269 hospitalisations for acute pancreatitis in patients using exenatide or sitagliptin, from database records on more than a million adults with type 2 diabetes.12

A recent study of the FDA adverse events database also found either exenatide or sitagliptin were associated with:

  • a 6-fold higher rate of pancreatitis adverse events compared with controls,13 adjusted to a 2.5-fold increase after excluding adverse events reported after the FDA warning for exenatide in 200711
  • a 2.5-fold higher rate of pancreatic cancers.13

These studies acknowledged several limitations and called for further prospective trials to address long-term effects of incretin-based drugs on the pancreas.

Overall, these studies suggest patients treated with incretin-based medicines have a higher rate of pancreatitis. The findings also raise caution about the potential long-term actions of these medicines in promoting pancreatic cancer;13 however, more research is needed to established a causal link.

Conflicting evidence and conflicts of interest — what to believe?

The study of the FDA database (outlined above) has been challenged by the manufacturers of sitagliptin and exenatide.14 The manufacturers have published studies of their own describing no associated risk of acute pancreatitis.15,16 However, the duration of these studies is typically short, with limited follow-up.17 Moreover, an increase in the incidence of pancreatitis in recent and past users of exenatide was discounted because those affected were no longer taking the drug.15

Several studies conducted with and without the involvement of manufacturers have questioned the link between incretin-based medicines and effects on the pancreas. One study, sponsored and conducted by the manufacturers, showed people with type 2 diabetes have nearly a 3-fold greater risk of pancreatitis regardless of the medicine used in their treatment.18

Another large independent study (more than 700,000 people) also found an increase in the incidence of acute pancreatitis in people with type 2 diabetes with no reported association with exenatide or sitagliptin, although only 154 cases of pancreatitis were identified.19

These data establish, as has been shown in pooled analyses,20 that people with type 2 diabetes are at increased risk of pancreatitis. The underlying mechanisms remain unclear21 and the available data do little to clarify the contribution of incretin-based medicines to the development of pancreatitis.

Reports of abnormal pancreatic growth

The latest safety issue has been raised because a study published in March 2013 showed that, compared with other treatments, incretin-based medicines contribute to abnormal pancreatic growth, including a 40% increase in pancreatic mass, with more pancreatic dysplastic lesions that have the potential to become cancerous.6 However, the findings of this study need to be confirmed to clarify the action of incretin therapy on the pancreas.

Investigation in humans is difficult because of limited access to human pancreatic tissue. Both exenatide and sitagliptin have been linked to acute pancreatitis in an animal model of type 2 diabetes,22,23 in which changes characteristic of human pancreatitis and pancreatic cancer (e.g. increased duct cell replication and metaplasia), were seen.22 People with type 2 diabetes also show increased cell replication in the pancreatic duct.24

The burden and business of diabetes

Diabetes represents a major health burden

  • In 2011–12 more than 850,000 Australians reported having diabetes (excluding gestational diabetes) with type 2 diabetes accounting for 85% of cases.25
  • Diabetes accounted for 2.7% of all problems managed by GPs in 2011–2012, making it the third most frequently managed chronic condition in general practice and the most frequent problem referred to specialist.26

The business of treating diabetes

The debate on whether incretin-based medicines contribute to elevated risk of acute pancreatitis in people with type 2 diabetes highlights some important limitations in the approval and postmarketing surveillance of new medicines:

  • the current paradigm in which drug manufacturers are largely responsible for surveillance of safety issues for their own medicines has been questioned17,27,28
  • how diabetes medicines reach the market without published data from long-term clinical trials has also been questioned.29

The FDA and EMA are independently evaluating the potential for pancreatic toxicity associated with exenatide and sitagliptin by reviewing the latest published findings.7,8 The EMA is also pursuing independing pharmacovigilance data for its investigation.8 In Australia the TGA is also conducting a review of the problem.

In the absence of any conclusions on this potential safety issue, watchful waiting may be the best approach.

References
  1. Eli Lilly Australia Pty. Limited. Product Information Byetta (exenatide). 2012. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-04381-3 (accessed 26 March 2013).
  2. Merck Sharp & Dohme Pty Ltd. Product Information Januvia (sitagliptin phosphate monohydrate). 2013. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-03937-3  (accessed 26 March 2013).
  3. US Food and Drug Administration. Information for Healthcare Professionals: Exenatide (marketed as Byetta) – 8/2008 Update. 2008. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124713.htm (accessed 22 March 2013).
  4. U.S. Food and Drug Administration. Information for Healthcare Professionals – Acute pancreatitis and sitagliptin (marketed as Januvia and Janumet). 2009. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm183764.htm (accessed 22 March 2013).
  5. Therapeutic Goods Administration. Medicines Safety Update: Drug-induced pancreatitis and exenatide (Byetta). Australian Prescriber 2010; 33: 82–3 (accessed 26 March 2013).
  6. 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. [PubMed]
  7. U.S. Food and Drug Administration. FDA investigating reports of possible increased risk of pancreatisis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes. FDA Drug Safety Communication: 2013. http://www.fda.gov/Drugs/DrugSafety/ucm343187.htm (accessed 22 March 2013).
  8. European Medicines Agency. European Medicines Agency investigates findings on pancreatic risks with GLP-1-based therapies for type-2 diabetes. European Medicines Agency, 2013. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/03/news_detail_001753.jsp&mid=WC0b01ac058004d5c1 (accessed 3 April 2013).
  9. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006;368:1696-705. [PubMed]
  10. Cure P, Pileggi A, Alejandro R. Exenatide and rare adverse events. N Engl J Med 2008;358:1969–70; discussion 71–2. [PubMed]
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