The first decade of the 21st century was marked by the end of the “glucocentric paradigm” in relation to cardiovascular outcomes in cardiovascular diabetes.
Three importants researchs ( ACCORD trial [1] , ADVANCE trial[2] and the VADT trial [3]) despite that showed a significant reduction in the levels of HbA1c in patients with type 2 diabetes treated with an intensified strategy in relation to a “standard” care ( with differences in the levels of HbA1c between the two branches of 1,1 %, 0,8% and 1,5% respectively),however ,they didn´t obtain a similar reducción in the mayor adverse cardiovascular events (MACE: myocardial infarction, stroke and cardiovascular mortality.
Moreover, the ACCORD trial had to be interrupted due to an increase in the total mortality in the arm of patients with type 2 diabetes treated with intensified strategy.
Due to the uncertainty of the cardiovascular safety of some antihyperglycemic drugs,in 2008 the United States Food and Drug Administration issued a guideline adressing the pharmaceutical industry in wich they established that the main requirement for the approval of a new drug was that it does not demonstrate an inacceptable rise in the cardiovascular risk[4]
After that the European Medical Agency and other regulatories entities published similar guidelines[5] that focused on the next points:

– In researchs in phase 2-3 ,the adjudication of adverse cardiovascular events must be prospective and independent in order to facilitate a metaanálysis of these events in all the controled studies of drugs versus placebo, drug plus standard therapy ( add on ) or with active comparators.

-The mayor cardiovascular end points defined as cardiovascular mortality, acute myocardial infarction and stroke(MACE),can be also evaluated with other criteria such as hospitalization due to unstable angina,revascularization procedures or heart failure (extended MACE of 4 points)