Reanalysis of study of pancreatic effects of incretin therapy: methodological deficiencies

Abstract

A recently published study by Butler et al. concluded that incretin treatment had adverse effects on the human type 2 diabetic pancreas including ‘a marked expansion of the exocrine and endocrine pancreatic compartments, the former being accompanied by increased proliferation and dysplasia and the latter by α‐cell hyperplasia with the potential for evolution into neuroendocrine tumours’. Incretin therapy has become widely used for type 2 diabetes, so these conclusions have instigated major concerns with regard to patient safety. We reassessed both the clinical case information and virtual microscopy images of the same 34 cases that were used in the Butler study as well as Network for Pancreatic Organ Donation (nPOD) cases that were not included. Whereas we would like to stress that it is important to investigate in depth any indication that incretin treatment may lead to inflammation or dysplasia in the pancreas, we find that the data presented in the Butler paper have serious methodological deficiencies that preclude any meaningful conclusions.

Is There a Link Between Liraglutide and Pancreatitis? A Post Hoc Review of Pooled and Patient-Level Data From Completed Liraglutide Type 2 Diabetes Clinical Trials

“…Based on a report showing pancreatic pathology in human tissue (15) and a claims database study indicating increased hospitalization for acute pancreatitis with sitagliptin or exenatide treatment (19), which were subsequently re-evaluated and criticized (25)(26)(27), both the European Medicines Agency (EMA) and the FDA initiated investigations regarding the pancreatic safety of incretin-based therapies. In February 2014, the EMA and FDA concluded that based on available data, the "assertions concerning a causal association between incretin-based drugs and pancreatitis or pancreatic cancer, as expressed recently in the scientific literature and in the media, are inconsistent with the current data" (28).…”

Adverse Effects of GLP-1 Receptor Agonists

“…-The increase in pancreatic mass was due to an outlier in the GLP-1 receptor agonists group. -The increase in pancreatic mass may also be due to the possible inclusion of type 1 diabetic patients (who have decreased pancreatic mass) in the type 2 diabetic control group [163]. -The distinction between alpha-and betacells was not clear due to variability in staining intensity [163].…”

Inkretintengelyen ható antidiabetikumok és a pancreas betegségei (pancreatitis, pancreascarcinoma)

“…Bonner-Weir és mtsai, a Joslin Diabetes Center (Harvard University, Boston) kutatói, a szigetsejt-morfológia kivá-ló szakemberei 2014-ben áttekintették a Butler-tanulmányban szereplő 34 beteg klinikai adatait és hisztológi-ai mintáit. Arra a következtetésre jutottak, hogy a tanulmány olyan súlyos metodikai bizonytalanságokkal terhelt, hogy azok kizárják az érdemi következtetések levonását [19].…”

“…Nem véletlen, hogy a Diabetes Care hasábjain a szerkesztőség -átérezve azt, hogy a kibontakozó szakmai vita kapcsán a szakmai folyóiratoknak is felelősségük van -helyt adott az ellentétes szakmai vélemények egyidejű kifejté-sének, szerkesztőségi kommentár kíséretében [18]. Ér-dekes körülmény, hogy a nagy vihart kavart Butler-köz-lemény metodikai megbízhatóságát később erős kritikával illették [19]. A szakmai vitában megszólaltak a hatóságok (FDA, EMA), illetve a tudományos társasá-gok (ADA, EASD, IDF) is [20,21].…”