Background: GLP-1 has anti-apoptotic and pro-proliferative actions. In beta cells, this could be beneficial; however such an effect has not yet been demonstrated in vivo in humans. In the exocrine pancreas, this could potentially be harmful.
Clinical question: What is the effect of incretin treatments (GLP-1 mimetics and DPP-4 inhibitors) on the endocrine and exocrine human pancreas?
Study design: Histological examination of pancreata from organ donors. Three groups were compared: people with diabetes treated with an incretin for more than 1 year, people with diabetes not treated with an incretin, and people without diabetes (Diabetes. 2013 Mar 22. [Epub ahead of print])
Findings: There was an expansion of both endocrine and exocrine tissue in patients treated with an incretin compared to the other 2 groups. This included 1) increased beta cell mass, 2) marked alpha cell hyperplasia, including one glucagonoma, and alpha cells growing into the pancreatic ducts; the authors suggest these could block ducts and lead to pancreatitis. 3) increased premalignant pancreatic intraepithelial neoplasia lesions.
Imperial Centre for Endocrinology (ICE) views: This study has several limitations: 1) The groups were poorly matched: patients with diabetes who were not receiving an incretin were younger, more likely to be female, and some patients may have had type 1 diabetes. 2) Seven out of eight patients treated with an incretin were on DPP-4 inhibitors. It is unclear if any findings apply to both DPP-4 inhibitors and GLP-1 mimetics. 3) Duration of incretin therapy was not provided; a causative link between incretin treatment and tumorogenesis seems less likely if treatment was short term. 4) Critical illness and prolonged life support leads to changes in pancreatic histology which could confound findings.
Nevertheless, this paper raises important questions, some of which will hopefully be answered by large long-term studies. In the meantime, incretin therapy should continue to be considered on a case-by-case basis, as is currently our practice.
Background: Previous studies have raised the possibility that GLP-1–based therapies may increase the risk of acute pancreatitis.
Clinical question: Are exenatide (GLP-1 mimetic) and sitagliptin (dipeptidyl peptidase 4 inhibitor) associated with an increased risk of acute pancreatitis?
Study design: A population-based case-control study using a large administrative database of adults with type 2 diabetes (JAMA Intern Med. 2013 Feb 25:1-6).
Findings: Treatment with sitagliptin and exenatide was associated with an approximately two-fold increase in the odds of hospitalisation for acute pancreatitis.
Imperial Centre for Endocrinology (ICE) Views: This study adjusted for confounding factors e.g. obesity, gallstones and hypertriglyceridaemia. However, alcohol, tobacco abuse and obesity are undercoded in claims. Misclassification of cases may have occurred due to lack of access to the clinical records. Approximately 3 cases of acute pancreatitis were detected per 1000 patients with type 2 diabetes. Therefore, the absolute risk of pancreatitis is still very low even if the suggested increase in the odds of pancreatitis with GLP-1-based therapies is true. This paper is unlikely to change our clinical practice. The risk/benefit of GLP-1-based therapy in patients with other risk factors for pancreatitis should be considered on a case-by-case basis.
Background: The 3rd International Workshop on management of primary hyperparathyroidism (PHP) sets out clear criteria for parathyroidectomy (PTx) in patients with asymptomatic PHP: age < 50 years; osteoporosis or fracture; nephrolithiasis; corrected calcium >0.25mmol/l above reference range; creatinine clearance <60ml/min.
Clinical question: To determine the rate of PTx in patients with PHP in Southern California, USA fulfilling the criteria for PTx.
Study design: A retrospective analysis of an electronic database containing 3 million people was performed (Ann Surg. 2012; 255(6): 1179-83). Multivariate logistic regression was used to examine predictors of PTx. PHP was defined as raised serum calcium and PTH without evidence of renal disease. The study therefore could not conclusively exclude rare disorders such as familial hypocalciuric hypercalcaemia.
Findings: Approximately 3000 patients were assigned a diagnosis of PHP. 40% of patients with PHP fulfilled at least one criterion for PTx, and this proportion increased after 2002 to 50% with relaxation of guideline on bone mineral density. Only 40% of patients fulfilling at least 1 criterion for PTx, actually received PTx. Comorbidity and increased serum creatinine were two factors associated with lower likelihood of PTx.
Imperial Centre for Endocrinology (ICE) Views: Asymptomatic patients diagnosed with PHP should be referred for PTx if they fulfill the criteria for PTx. Guidance on criteria for PTx need to be disseminated to other hospital physicians and primary healthcare providers. In particular, renal impairment is a reason to proceed with PTX, rather than hold off PTx in patients with PHP.
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