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

Abstract

ccasionally, 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 kidney outcomes-findings broadly confirmed with the SGLT2i canagliflozin in the CANVAS trial program (Canagliflozin Cardiovascular Assessment Study). 2 As a result, researchers and providers alike began asking how the SGLT2is could lead to such benefits.HF is a common complication of T2DM, now occurring more frequently than incident myocardial infarction, thus hinting at non-ASCVD pathways to HF.Although several hypotheses have emerged with regard to the mechanism of HF and cardiovascular death benefit of the SGLT2is, indirect evidence suggests a potential role of modest and sustained plasma volume reduction via effects that likely include reduction of cardiac pre-and afterload, thereby favorably affecting cardiac workload and myocardial energetics.Because of hyperglycemia-associated glomerular hyperfiltration and increased reclamation of filtered glucose, and with it sodium by SGTL2 in patients with T2DM, these patients tend to have persistent mild intravascular volume expansion. 3The HF benefits observed with SGLT2is added to the existing knowledge regarding HF risk in T2DM have helped reshape our understanding of the patho-