Ten years ago the United States Food and Drug Administration Issued a guidance for industry on assessment of cardiovascular risk (CV) in patients treated with new medications for Type 2 diabetes mellitus. Numerous cardiovascular outcome trials (CVOTs) have been conducted since then, allowing for better understanding of the pathophysiology and treatment of diabetic macrovascular disease. Most of the completed trials yielded neutral results (no harm, no benefit), however, the EMPA-Reg trial and the LEADER trial reported reduced risk of new CV events in patients treated with empagliflozin and liraglutide, respectively. The results of CVOTs trigger number of important questions, including the importance of trial design on its outcome, potential therapeutic differences between the agents from the same class and between classes, and the need to revise the current guidance to improve efficiency in clinical research. The completed CVOTs differ with respect to the population included, duration of intervention, drug compliance, potentially relevant confounding factors and operational and analytical strategy. Based on our current knowledge improvements in data quality and operational efficiency may be achieved with advanced clinical trial designs. One important question remains whether CVOTs should continue to be placebo-controlled or active comparator-controlled trials. Finally, potential studies of combination of medications that have shown to reduce cardiovascular risk is of particular relevance for progress in the field of CV disease in Type 2 diabetes.