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Navigating the "MACE" in Cardiovascular Outcomes Trials and Decoding the Relevance of Atherosclerotic CVD Benefits versus Heart Failure Benefits

Christopher Hupfeld, Sunder Mudaliar
Diabetes, Obesity & Metabolism 2019 April 8
The publication of the recent CVOTs (Cardio Vascular Outcome Trials) has transformed the landscape of diabetes treatment. The GLP-1R agonists (GLP-1R agonists) and the SGLT2-Inhibitors have demonstrated CV benefits in large, well conducted, randomized studies. Today, empagliflozin, canagliflozin and liraglutide are FDA approved not only for glucose lowering, but also to reduce the risk of CV events/CV mortality in patients with type 2 diabetes (T2DM) and established CV Disease (CVD)/high CVD risk. Although the CVOTs were primarily powered for CV safety (non-inferiority), they also demonstrated CV efficacy (superiority). This initially surprised many in the DM community, but the replication of the CV benefits with different compounds in the same class alleviated concerns of the CV benefits being chance findings. However, many questions still remain to be answered. While the heterogeneity in the CV benefits in the various CVOTs can be attributed to the variability in CV risk in the different studies, the reason(s) for the differences in the CV benefits between the GLP-1 agonist class and the SGLT2-inhibitor class appear to be more complex. An analysis of MACE (Major Adverse Cardiovascular Events) in the CVOTs reveals that the CV benefits of the GLP-1R agonists are predominantly on atherosclerotic CV events (non-fatal myocardial infarction [MI], non-fatal stroke and CV death). On the other hand, the SGLT2-inhibitors do not have any significant effects on atherosclerotic CV events (non-fatal MI/stroke). Their benefits are predominantly on hospitalization for heart failure (HF), suggesting effects primarily on myocardial function ("the pump"), and not on the "pipes" (coronary arteries). In this article, we discuss the rationale for the conduct of CVOTs; highlight the inability of the classic 3-point MACE to capture the entire spectrum of atherosclerotic and non-atherosclerotic CVD morbidity, especially heart failure in T2DM; and finally discuss the results of the CVOTs with a focus on the clinical significance of atherosclerotic CVD (ASCVD) versus heart failure which develops in a sizeable proportion of patients with DM and without prior ASCVD. This article is protected by copyright. All rights reserved.


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