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Recently, great attention is paid to cardiovascular impact of non-insulin glucose-lowering drugs, particularly in terms of major cardiovascular events and risk of heart failure. In this regard, a surprising diversity among different molecules within the same pharmacological class has been noticed, yielding to an intra-class discrepancy which has no analogous in other cardiovascular fields. The aim of this paper is to review the literature, giving an insight of the heterogeneous effects among groups and within group shown by oral antidiabetic drugs, with a special concern to fragile patients, such as those with or at risk of heart failure.