The association of exenatide and sitagliptin with pancreatitis was documented since 2006 and prompted close monitoring [14] and [15]. Later, the potential risk appeared to be increased by diabetes per se; post-approval studies have documented cases associated with incretin use, but a causal relationship between treatment and pancreatitis was neither proved nor excluded [16], [17], [18], [19] and [20]. In the registry, a few additional reports of non-severe pancreatitis or simply raised levels of pancreatic enzymes were also recorded, without differences

between drugs. When these non-adjudicated ADRs were summed up to severe pancreatitis, the total incidence Sorafenib nmr of pancreatic events was in the range reported in the general population with diabetes and should be considered in the context of the notoriety bias generated by alerts. A 2013 comprehensive review of preclinical and clinical data on pancreatic safety by the European Medicines Agency concluded that the concerns on the risk of pancreatitis

should not be minimized [21]. Later, the publication of two large cardiovascular outcome DPP-Is trials [13] and [22] and epidemiological data [23] stifled the debate; a 2014 joint Food and Drug Administration (FDA)–European Medicines Agency (EMA) assessment concluded with a low-risk [24] but suggested continuous Buparlisib solubility dmso capture of data. As expected, exenatide and DPP4-I add-ons to metformin were accompanied by low rates of hypoglycemia [25]. On the contrary, a two-to threefold increase in hypoglycemia was observed in combination with sulfonylureas, both with and without metformin, but very few cases were recorded as severe ADRs, requiring Meloxicam hospital admission. These data are in keeping with registration studies and with recent clinical trials showing that DPP4-Is are associated with very low rates of hypoglycemia when combined with metformin

[26], despite similar or only moderately inferior glucose-lowering efficacy compared to sulfonylureas. The analysis of discontinuation rates and metabolic effects may give hints for an appropriate use of these drugs in the community. This approach seems sound, as confirmed by a sensitivity analysis in a subset of selected centers with adherence to follow-up ≥80% (Supplementary Tables 1 and 2). As expected, the discontinuation rates of all drugs increased systematically with higher baseline HbA1c. They also increased with age for exenatide, not for gliptins, indicating a preferential use of oral agents in elderly subjects for whom a less strict metabolic target may be preferred [3], [4] and [27]. On the contrary, weight loss might be the reason for the lower discontinuation rates of exenatide with increasing BMI, despite injections and higher baseline HbA1c. Two subpopulations, with limited safety data in registration studies, deserve particular attention.