Authors find that hemodynamic changes are the main contributors to jardiance-induced cardiovascular benefits. Plasma volume contraction and hematocrit rise appear to be key mediators. Reductions in glycemia and uricemia also help in the process. The SGLT-2 inhibitor saga is evolving, and will continue for many years to come.

Also see:

Diabetes Care

EMPA-REG OUTCOME

February 2018

OBJECTIVE

In the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial involving 7,020 patients with type 2 diabetes and established cardiovascular disease, empagliflozin given in addition to standard of care reduced the risk of CV death by 38% versus placebo (hazard ratio, HR 0.62).

This exploratory mediation analysis assesses the extent to which treatment group differences in covariates during the trial contributed to CV death risk reduction with empagliflozin.

METHODS

Effects of potential mediators, identified post hoc, on the HR for CV death with empagliflozin versus placebo were analyzed by Cox regression models, with treatment group adjusted for the baseline value of the variable and its change from baseline or updated mean (i.e., considering all prior values), each as a time-dependent covariate. HRs were compared with a model without adjustment for covariates. Multivariable analyses also were performed.

RESULTS

Changes in hematocrit and hemoglobin mediated 51.8% and 48.9%, respectively, of the effect of empagliflozin versus placebo on the risk of CV death on the basis of changes from baseline, with similar results in analyses on the basis of updated means. Smaller mediation effects (maximum 29.3%) were observed for uric acid, fasting plasma glucose, and HbA1c.

In multivariable models, which incorporated effects of empagliflozin on hematocrit, fasting glucose, uric acid, and urine albumin:creatinine ratio, the combined changes from baseline provided 85.2% mediation, whereas updated mean analyses provided 94.6% mediation of the effect of empagliflozin on CV death.

CONCLUSIONS

In this exploratory analysis from the EMPA-REG OUTCOME trial, changes in markers of plasma volume were the most important mediators of the reduction in risk of CV death with empagliflozin versus placebo.

More from the publication:

Empagliflozin, a highly selective sodium–glucose cotransporter 2 inhibitor, was the first glucose-lowering agent to demonstrate a reduction in cardiovascular death in patients with type 2 diabetes and high CV risk. In the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial, over a median observation time of 3.1 years, treatment with empagliflozin versus placebo in addition to standard of care led to a 14% reduction in the risk of three-point major adverse CV events (MACE [the composite of CV death, nonfatal myocardial infarction, and nonfatal stroke]).

This was driven by a 38% reduction in the risk of CV death. The finding led the U.S. Food and Drug Administration to extend the indication for empagliflozin to include reducing the risk of CV death in patients with type 2 diabetes and established CV disease. Empagliflozin also reduced the risk of hospitalization for heart failure (HR 0.65) and all-cause mortality (HR 0.68, P < 0.001) versus placebo.

As with other CV outcome trials, EMPA-REG OUTCOME was not designed to determine the mechanisms underpinning its results. 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. 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. The equally rapid reduction in the risk of hospitalization for heart failure suggests that the cardioprotective benefit of empagliflozin may be related to improved hemodynamic status. However, effects on atherogenic processes, the myocardium, ventricular remodeling, or vessel integrity cannot be ruled out because the benefits on CV death were sustained over the course of the trial, and additional mechanisms may have contributed to the reduction in the risk of CV death observed with prolonged treatment.

In the current exploratory post hoc mediation analysis of data from the EMPA-REG OUTCOME trial, we identified the extent to which treatment-induced changes in specific variables, either alone or in combination, contributed to the reduction in the risk of CV death observed with empagliflozin versus placebo and, thereby, considered potential mediators of this benefit.

We conducted this exploratory analysis to identify potential mechanisms underlying the 38% reduction in the risk of CV death observed with empagliflozin versus placebo in patients with type 2 diabetes and established CV disease in the EMPA-REG OUTCOME trial. Our approach used a traditional mediation analysis, taking the time-dynamic evolvement of the potential mediators and the outcome of CV death into account. This method has been used by others to determine or confirm the underlying mechanisms behind a treatment strategy’s effect on disease outcomes.

In the current analysis, changes in hematocrit (and hemoglobin) appeared to be the variables with the largest impact on the HR for CV death with empagliflozin versus placebo. Therefore, these variables can be considered important mediators of this benefit, mediating ∼50% of the treatment group effect. Results were consistent in analyses that were based on the current change from baseline or the updated mean.

For uric acid and measures of glycemia, modest mediation effects were found, with those of HbA1c and FPG appearing to be stronger in analyses that were based on the updated mean, which assessed the more chronic effects of these measures. In contrast, the mediation effects of other variables, including changes in classical CV risk factors, such as BMI, blood pressure, lipids, and other parameters of renal function, were absent or negligible.

In the multivariable models, a much higher percentage mediation was demonstrated (up to 85.2% in the change from baseline analysis and up to 94.6% in the updated mean analysis). These models incorporated widely disparate effects of empagliflozin, including those on hematocrit, FPG, uric acid, and UACR. These data suggest that although the major influence governing the reduction in CV death may have been plasma volume reduction (as reflected in the increased hematocrit), other variables may have played more modest, yet complementary roles, and multiple mechanisms may be responsible for the reduction in CV death with empagliflozin in patients with type 2 diabetes and established CV disease.

Mechanism of benefit:

Empagliflozin is a selective inhibitor of SGLT2 in the proximal tubule of the kidney. Inhibition of SGLT2 by empagliflozin leads to reduced renal glucose reabsorption and increased urinary glucose excretion. Treatment with empagliflozin reduces volume and sodium load through its glucuretic, diuretic, and natriuretic properties. The initial increase in hematocrit with empagliflozin followed by stabilization during the rest of the trial likely reflect hemodynamic changes related to plasma volume contraction. The same pattern was observed for changes in eGFR with empagliflozin, which also are believed to reflect hemodynamic alterations involving renal blood flow. 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. 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).

Although only 10% of patients in the EMPA-REG OUTCOME trial had heart failure at baseline, the trial population comprised individuals with a mean age of 63 years, of whom 76% had coronary artery disease and 52% were obese. Therefore, many participants in this trial likely had unrecognized left ventricular dysfunction, particularly diastolic dysfunction, which may eventually lead to clinical heart failure with preserved ejection fraction. Thus, a tenable conclusion is that a key contributor to the reduction in CV death with empagliflozin is the change in renal sodium and glucose handling with resultant reductions in fluid burden, ventricular stress, and risk of sudden cardiac decompensation.

An increase in erythropoiesis could be a complementary mechanism to the hemodynamic changes reflected by an increase in hematocrit and hemoglobin in patients treated with empagliflozin. Increased erythropoietin and a median 7% increase in red blood cell mass, measured with 51Cr-labeled erythrocytes, were observed in a small study (n = 30) of the SGLT2 inhibitor dapagliflozin in patients with type 2 diabetes. In a larger study, a mean increase in erythropoietin of 30–40% was observed 4 weeks after initiating empagliflozin, which may be related to changes in blood flow between the renal cortex and the medulla. The extent to which this mechanism contributes to the CV benefits observed with empagliflozin is unclear, however. Although an improvement in tissue oxygenation in a compromised cellular milieu may be hypothesized to be beneficial, such a robust effect on mortality would be unexpected on the basis of current understanding of oxygen delivery dynamics at hemoglobin concentrations within the normal range.

Uric Acid:

Change in uric acid had a modest mediation effect (24.6% in the analysis adjusting for the change from baseline). Empagliflozin reduces uric acid, possibly as a result of the effect of increased glucose concentration on glucose transporter 9 in the basolateral membrane of the proximal tubule and resulting increased uricosuria. Serum uric acid has been associated with an increased risk of CV death, but evidence is limited regarding the CV benefits of reducing uric acid, especially within the normal range and/or to the small degree observed in the EMPA-REG OUTCOME trial.

In conclusion, this exploratory investigation into potential mediators of the reduction in risk of CV death with empagliflozin versus placebo in the EMPA-REG OUTCOME trial found that changes in hematocrit and hemoglobin—ostensibly markers of the effects of the drug on volume—appeared to be important mediators of the reduction in mortality risk in univariable and multivariable models. Changes in variables related to glycemia and uric acid metabolism had smaller mediating effects. These, in addition to changes in UACR, contributed in the multivariable models, suggesting that the underpinnings of empagliflozin’s CV mortality benefit are likely multifaceted.

In contrast, changes in some traditional CV risk factors, including obesity, blood pressure, lipids, and renal function, made negligible contributions. Ongoing studies, including mechanistic trials, the EMPEROR outcome trials that are evaluating empagliflozin in patients with heart failure with and without diabetes and studies in patients with chronic kidney disease, will provide additional physiological insights into the cardioprotective effects of this selective SGLT2 inhibitor.