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Incretins and risk of neoplasia

BMJ 2013; 346 doi: https://doi.org/10.1136/bmj.f3750 (Published 10 June 2013) Cite this as: BMJ 2013;346:f3750
  1. Thorvardur R Halfdanarson, senior associate consultant 1,
  2. Rahul Pannala, senior associate consultant and assistant professor2
  1. 1Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ 85259, USA
  2. 2Division of Gastroenterology, Mayo Clinic, Scottsdale, AZ 85259, USA
  1. thorvardur.halfdanarson{at}mayo.edu

An association exists but causality has not yet been proved

Incretin based treatment for type 2 diabetes improves hyperglycaemia without causing weight gain and is increasingly being used worldwide. Concerns have been raised about long term safety, as reported by Cohen,1 especially the risk of pancreatitis and pancreatic cancers—both adenocarcinoma and neuroendocrine tumours.

Although concerns about adverse effects of incretin on the pancreas initially focused on acute pancreatitis, recent observational studies suggest an increased risk of subclinical pancreatic inflammation and pancreatic cancer.2 3 One study reported that pancreatic cancer was more common in patients with diabetes who used exenatide or sitagliptin than those who used other antihyperglycaemics.2 Similar concerns were raised by the drug commission of the German Medical Association in patients receiving exenatide.3 These concerns were reinforced by data from the Food and Drug Administration adverse event reporting system, which suggested an increased risk of pancreatic cancer in patients treated with incretins.4

Although cause for concern, these observational studies do not prove causality. Several epidemiological and mechanistic questions need to be considered when interpreting these data. Human and animal studies performed by the drug companies have uniformly reported that the risk of pancreatitis and pancreatic cancer is not increased by incretins.5 6 In addition, databases that rely on voluntarily reported information suffer from important limitations, including reporting bias. True prevalence and incidence data are difficult to ascertain given the inherent limitations of these databases. Current data also do not take into account established risk factors such as smoking, family history, obesity, use of other antidiabetic drugs (particularly metformin), and the presence of underlying chronic pancreatitis. The association between diabetes itself and pancreatic cancer is complex.7 Although longstanding diabetes is a modest risk factor for pancreatic cancer, new onset disease (<2 years) may be a manifestation of pancreatic cancer. Epidemiological studies assessing the risk of pancreatic cancer need to factor in the duration of diabetes, which current studies do not.

Chronic pancreatitis has been suggested as a potential mechanism for the development of pancreatic cancer in patients taking incretins. One study using the KrasG12D mouse model found that exendin-4, a glucagon-like peptide-1 analogue, induced disruption of pancreatic architecture and resulted in pancreatitis and increased formation of pancreatic intraepithelial neoplasia.8 Other studies have reported discordant findings, and the true histological effects of these drugs are still unclear. Asymptomatic increases in pancreatic enzymes (particularly amylase and lipase) have also been reported in patients taking incretins.9 Pancreatic acinar and ductal cell hyperplasia and possibly metaplasia related to the trophic effects of these drugs may also be a contributing factor. A recent study showed that pancreatic mass was increased and dysplastic changes were more common in pancreases from donors who had been taking incretins.10 No evidence to date suggests that incretin therapy is mutagenic. The evolution of premalignant pancreatic lesions, such as pancreatic intraepithelial neoplasia, to metastatic pancreatic cancer occurs over a decade, and most patients with such lesions will never develop pancreatic cancer. If incretins increase the risk of pancreatic cancer, they may do so by accelerating the transformation of premalignant lesions to invasive cancer.

Pancreatic neuroendocrine tumours are uncommon, but their incidence seems to be rising.11 There are concerns that incretins may increase the risk of developing these tumours, perhaps through a sustained disruption of glucagon signalling. Mice with homozygous inactivation of the glucagon receptor were found to develop islet cell hyperplasia with dysplasia and eventually pancreatic neuroendocrine tumours when compared with heterozygous or wild-type mice.12 This suggests that complete inhibition of glucagon signalling may not be a safe strategy in the treatment of diabetes.

Human data on incretin therapy and the risk of developing these tumours are limited, and it is difficult to extrapolate animal studies in knockout mouse models to humans. One study that examined explanted pancreases from organ donors found α cell hyperplasia, glucagon expressing microadenomas, and a pancreatic neuroendocrine tumour in donors with type 2 diabetes who were taking incretins.10 Such changes were not seen in patients with and without diabetes who had not received incretins. Although worrying, these observations do not confirm a causal association between pancreatic neuroendocrine tumours and incretins in humans. Although clinically apparent tumours are uncommon, postmortem studies suggest that silent pancreatic neuroendocrine tumours are common and are seen in 0.8-10% of older people.13 Diabetes seems to be more common in patients with these tumours than in controls,14 so it is not unreasonable to expect that some patients with diabetes who are taking incretins will be diagnosed with one. Much larger studies are needed to evaluate the potential effect of incretins on the risk for these tumours.

In summary, there are several worrying signals of unintended effects of incretin based treatment on the pancreas, but controlled studies are lacking. The long natural course of pancreatic tumours means that it will take many years to settle these controversies. In addition to continued pharmacovigilance, mechanistic studies assessing the trophic and inflammatory effects of these drugs are needed. In the interim, doctors should have an honest discussion with their patients about the possibility of these adverse effects before starting treatment.

Notes

Cite this as: BMJ 2013;346:f3750

Footnotes

References

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