Memorandum

Dr. Steven Kahn writes critical review of Dr. Peter Butler’s incretin study – April 18, 2013

Executive Highlights

  • In this month’s Diabetes, Dr. Steven Kahn gives a critical review of Dr. Peter Butler’s incretin study and raises five issues that cast doubt on the study’s conclusions.

This month's issue of Diabetes includes Dr. Steven Kahn's critical dissection of Dr. Peter Butler's morphological study on incretins and pancreatitis. After briefly discussing Dr. Butler's study results, Dr. Kahn raises five issues that challenge the study's conclusions: 1) he considers whether the increase in pancreas mass observed in patients on sitagliptin or exenatide could be explained by significant differences between the two diabetes groups (e.g., weight, sex, age, disease duration, perhaps even diabetes type) rather than the use of incretin therapies; 2) Dr. Kahn notes that it’s currently unclear how incretins increase beta-cell mass, as they appeared to have little effect on beta cell replication in the study; he speculates whether the differences observed for beta cell mass stem from between-group differences related to the type of diabetes (i.e., those not on incretins could have had type 1 diabetes) or the type and/or duration of life support received by the patients; 3) he noted that the high rate of glucagon-producing microadenomas observed in the study (37.5%) is inconsistent with pharmacovigilance data – given the millions of patient years of exposure to incretins, why have we not seen increased reports of such abnormalities in patient pancreas samples or a greater reporting of the symptoms caused by these abnormalities?; 4) people undergoing gastric bypass exhibit markedly elevated levels of GLP-1 post surgery (more than 3-fold), yet do not appear to exhibit the abnormalities observed in the Butler study, even eight years post surgery – perhaps this is due to confounding by weight loss; 5) Dr. Kahn highlights that preclinical evidence and the current literature consistently show no link between incretins and pancreatitis.

In closing, Dr. Kahn remarks that the most rigorous information on this topic will come from long-term studies such as the ongoing incretin cardiovascular outcomes studies (CVOT) and the GRADE study. He points out that the continuation of CVOTs (i.e., no premature trial terminations) suggests that researches have not observed a worrisome signal of excess pancreatic malignancy with incretin treatments. Dr. Kahn concludes that while the Butler study should prompt further investigation, "the current level of evidence falls short of that required to prematurely banish" incretin therapies. We greatly appreciate his thoughtful and analytical critique.

-- by Nina Ran and Kelly Close