Cardiovascular Effects of New Oral Glucose-Lowering Agents: DPP-4 and SGLT-2 Inhibitors.

In CANVAS, the interaction test between the 2 subgroups of T2DM patients with and without previous CV complications did not reach statistical significance ( P =0.18). 121 However, the reduction in CV mortality among the subgroup of patients in secondary prevention in CANVAS was much lower than the corresponding reduction noticed in EMPA-REG OUTCOME.

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31 CV Outcomes in Meta-Analyses of Phase 2 to 3 Trials With DPP-4 Inhibitors Several meta-analyses of RCTs with each of the DPP-4 inhibitor commercialized in the United States (vildagliptin is not available in the United States) and in Europe generally reported a nonsignificant trend toward a lower incidence of MACE compared with placebo or other active glucose-lowering compounds: alogliptin, 38 saxagliptin, 39 sitagliptin, 40 linagliptin, 41 and vildagliptin 42 (Table 1 ).

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In CANVAS (Canagliflozin Cardiovascular Assessment Study), the reduction in CV mortality with canagliflozin failed to reach statistical significance despite a similar reduction in major cardiovascular events.

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The results showed a trend for reduction in the incidence of primary CV outcomes in metformin-treated patients contrasting with a trend for an increase in MACE in patients not receiving metformin. 73 As the between-group was statistically significant, it was considered that metformin may act as a CV moderator of DPP-4 inhibitors, but obviously these hypothesis-generating findings require further confirmation. 74 Indeed, possible bias could not be excluded, especially because a major reason for not prescribing metformin may have been CKD, a condition known to be associated with higher CV risk as already mentioned.

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