SGLT2 Inhibition and cardiovascular events: why did EMPA-REG Outcomes surprise and what were the likely mechanisms?

Abstract

While the modest reduction in the primary composite outcome of myocardial infarction, stroke or cardiovascular death in the EMPA-REG Outcomes trial was welcome, the 30–40% reductions in heart failure hospitalisation (HFH) and cardiovascular and all-cause deaths in patients treated with empagliflozin were highly impressive and unexpected. In this review, we discuss briefly why cardiovascular endpoint trials for new diabetes agents are required and describe the results of the first four such trials to have reported, as a precursor to understanding why the EMPA-REG Outcomes results came as a surprise. Thereafter, we discuss potential mechanisms that could explain the EMPA-REG Outcomes results, concentrating on non-atherothrombotic effects. We suggest that the main driver of benefit may derive from the specific effects of sodium-glucose linked transporter-2 (SGLT2) inhibition on renal sodium and glucose handling, leading to both diuresis and improvements in diabetes-related maladaptive renal arteriolar responses. These haemodynamic and renal effects are likely to be beneficial in patients with clinical or subclinical cardiac dysfunction. The net result of these processes, we argue, is an improvement in cardiac systolic and diastolic function and, thereby, a lower risk of HFH and sudden cardiac death. We also discuss whether other drugs in this class are likely to show similar cardiovascular benefits. Finally, areas for future research are suggested to better understand the relevant mechanisms and to identify other groups who may benefit from SGLT2 inhibitor therapy.

How Does Empagliflozin Reduce Cardiovascular Mortality? Insights From a Mediation Analysis of the EMPA-REG OUTCOME Trial

“…The same pattern was observed for changes in eGFR with empagliflozin, which also are believed to reflect hemodynamic alterations involving renal blood flow (13). The resulting decrease in circulatory load, especially reduced ventricular filling pressures and cardiac workload, could be an important mechanism behind the mortality benefits seen with empagliflozin (5,9). This finding is supported by the observation that the most frequent modes of CV death are those typically seen in patients with heart failure (sudden death, death as a result of heart failure, and presumed CV death, the latter designated when insufficient data exist for the adjudication committees to attribute a cause of death) (24).…”

“…Several explanations for the reduction in CV death with empagliflozin have been proposed, including hemodynamic changes related to plasma volume reduction, a switch in use of fuel, and direct cardiac effects (3)(4)(5)(6)(7)(8)(9). The very early reduction in CV death observed in this trial and the heterogeneity of the HRs for the components of three-point MACE suggest that the predominant mechanism, at least in the early part of the trial, was not primarily an attenuation of atherosclerosis, the traditional consideration in CV outcome trials in patients with diabetes.…”

Effects of reducing blood pressure on cardiovascular outcomes and mortality in patients with type 2 diabetes: Focus on SGLT2 inhibitors and EMPA-REG OUTCOME

“…The mode of action of empagliflozin targeting the kidney may mimic that of a diuretic and a "diuretic hypothesis" has been put forward to explain the early and marked CV protection in EMPA-REG OUTCOME [33][34][35][36][37]. Therefore, the comparison of the CV effects of empagliflozin in EMPA-REG OUTCOME with those of different diuretics deserves further attention.…”

“…Because of the reduction in CV mortality occurred already within the first few months, concomitant with a significant reduction in hospitalization for heart failure [30], an haemodynamic rather than an antiatherogenic effect has been suspected [31,32]. This may be attributed to the diuretic (natriuretic/osmotic) activity of the SGLT2 inhibitor, which accompanied the glucuretic effect [33][34][35][36][37], although the so-called "diuretic hypothesis" has also been challenged [38,39].…”

Is It Time to Change the Type 2 Diabetes Treatment Paradigm? No! Metformin Should Remain the Foundation Therapy for Type 2 Diabetes

“…It is impossible to know whether empagliflozin might have benefits in those without overt macrovascular complications. Given the prominent effects of empagliflozin in this trial on heart failure hospitalization rates (HR 0.65 [95% CI 0.50, 0.85]) and its recognized diuretic actions, some have proposed that the drug exerts its benefits on cardiovascular mortality by simply offloading the left ventricle in those with known and even perhaps yet unrecognized ventricular dysfunction (25). In LEADER (21) and SUSTAIN-6 (22), eligibility criteria included those over age 50 years with overt CVD but also a smaller cohort (about 1 in 5 to 6 participants) over age 60 years with cardiovascular risk factors only.…”