Pathways to Cardiorenal Complications in Type 2 Diabetes Mellitus: A Need to Rethink.

Abstract

Occasionally, an unexpected clinical trial result makes us reevaluate what we think we know about pathogenic pathways linking 1 condition to another. The EMPA-REG OUTCOME trial ([Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) results demonstrating cardiovascular and kidney benefits with the type 2 diabetes mellitus (T2DM) drug empagliflozin,1 a sodium-glucose cotransporter 2 inhibitor (SGLT2i), did just this. It forced us to reconsider and expand our notions of the risk pathways leading to specific T2DM complications, particularly cardiovascular death, heart failure (HF), and kidney disease. For decades, the cardiac risks of T2DM had been selectively focused on incremental atherosclerotic vascular disease (ASCVD) risk. We were comfortable in the knowledge that ASCVD risk associated with T2DM stems from associated hypertension, dyslipidemia, hyperglycemia, prothrombotic tendencies, insulin resistance, endothelial dysfunction, and inflammatory stress. Thus, whenever the potential for T2DM drugs to mitigate cardiovascular risk was considered, it was most often within this narrow ASCVD and related risk framework. Likewise, cardiovascular outcomes trials in the T2DM field have focused primarily on ASCVD outcomes. Certainly lessening ASCVD risk matters, with substantial successes realized in patients with T2DM over recent decades—mostly reductions of nonfatal myocardial infarction and stroke risks—via better blood pressure and low-density lipoprotein cholesterol management, with less certainty with regard to the influence of glucose lowering on ASCVD risk. However, then came the EMPA-REG OUTCOME results, demonstrating risk reduction for cardiovascular death and hospitalization for HF with empagliflozin.1 These results were most surprising for the speed and magnitude of reduction in cardiovascular risks, as well as favorable effects on …