In 2008, the US Food and Drug Administration (FDA) released a Guidance for industry on evaluation of cardiovascular safety of new drugs for type 2 diabetes . This promoted large-scale global cardiovascular outcome trials (CVOT’s), where the addition of the investigational drug to existing treatment was compared to placebo. So far, three trials on dipeptidyl peptidase 4 (DPP-4) inhibitors and four trials on glucagon-like peptide 1 (GLP-1) receptor agonists have been reported, all in the New England Journal of Medicine [2,3,4,5,6,7,8]. In total, the staggering number of exactly 70,000 patients were randomized in these trials. Overall, the results range from reassuring to positive, but also give rise to new uncertainties. These uncertainties stem from the much larger datasets on efficacy and safety now available for these new drugs, thus providing us with much more granular knowledge than we used to have for drugs on the market. In other words, with these datasets also the frequency of more infrequent side effects can be assessed with some detail. However, even these large-scale trials are of course not powered for really rare side effects, adding a new level of uncertainty if a non-significant signal is seen.