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DPP-4 can also have signaling functions via interactions with the extracellular matrix (90), and it was therefore speculated that the DPP-4 inhibitor might have improved insulin sensitivity by interfering with this process in some way rather than by blocking the enzymatic activity per se (79, 89)

Indeed, these studies were originally designed primarily as safety studies, and the accumulation of a large number of CV events in high-risk patients was a strategy to limit the sample size and duration of these trials [37]

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