Most important mediator due to changes in markers of plasma volume.
Sodium-glucose cotransporter 2 inhibitor, Empagliflozin, demonstrates the ability to reduce cardiovascular death in patients with high cardiovascular risk and type 2 diabetes. The EMPA-REG OUTCOME trial showed that treatment with empagliflozin led to a 14% reduction in the risk of major cardiovascular events, such as cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Empagliflozin was able to show a 38% reduction in risk from cardiovascular death and also reduce hospitalization from heart failure and overall mortality. The mechanism by which empagliflozin works to reduce cardiovascular outcomes is still controversial, but it has been proposed to reduce plasma volume and improved hemodynamic status. In this post hoc analysis of data from the EMPA-REG OUTCOME trial, they examined variables that might have contributed to the reduction in cardiovascular events from the use of empagliflozin vs placebo.
The inclusion criteria for EMPA-REG OUTCOME included adults with type 2 diabetes who were either drug naïve with HbA1c of 7.0 – 10.0%, or who were taking glucose-lowering medication with HbA1c of 7.0 – 9.0% and had established cardiovascular disease. In this trial, patients were randomized in 1:1:1 fashion to receive either empagliflozin 10mg, empagliflozin 25mg, or placebo.
Results found that empagliflozin was able to show reduction in HbA1c, weight, waist circumference, uric acid, systolic and diastolic blood pressure. Also, empagliflozin did not alter the heart rate, and a small increase in LDL and HDL cholesterol was also observed. Empagliflozin, furthermore, led to significant reductions in urine albumin: creatinine ratio [UACR] compared to placebo treatment. Data shows that an increase in fasting plasma glucose, heart rate, and uric acid leads to an increased risk of cardiovascular death.
Changes in hematocrit, hemoglobin levels, uric acid, and albumin from baseline mediated a 51.8%, 48.9%, 25.5%, and 24.6% reduction in cardiovascular death from empagliflozin, respectively. Other studied mediators such as HbA1c, weight, BMI, LDL and HDL cholesterol, triglycerides, and free fatty acids had no effect on mortality rates. As seen from the results, hematocrit was the strongest variable that had the largest impact on heart rate and cardiovascular death with empagliflozin. Therefore, this is an important variable to be considered with empagliflozin treatment.
Empagliflozin selectively inhibits sodium-glucose cotransporter 2 in the proximal tubule of the kidney. This inhibition by empagliflozin leads to reduced renal glucose reabsorption and thus more glucose is excreted in the urine. Moreover, empagliflozin is able to reduce volume and sodium load through its properties such as glucuretic, diuretic, and natriuretic. The increase in hematocrit due to treatment with empagliflozin reflects hemodynamic changes related to a decrease in plasma volume. Also, an increase in eGFR with empagliflozin treatment is also believed to reflect hemodynamic alterations that involves renal blood flow. It is believed that one of the important mechanism to which empagliflozin reduces mortality is due to a decrease in circulatory load, especially reduced ventricular filling pressure and cardiac workload. Most cardiovascular deaths are seen in patients with heart failure. In this EMPA-REG OUTCOME trial, patients were a mean age of 63 years of which about 76% had coronary artery disease. Even though only about 10% of the participants had heart failure at baseline, many participants had diastolic dysfunction, which can eventually lead to heart failure with preserved ejection fraction. Thus, results of this study conclude that the key factor that reduces cardiovascular death with use of empagliflozin is its ability to change renal sodium and glucose handing and contributing to reduction in fluid burden, ventricular stress, sudden cardiac decompensation.
Another mechanism that can contribute to empagliflozin’s ability to reduce cardiac death is an increase in erythropoiesis leading to hemodynamic changes. The increase in hematocrit and hemoglobin levels leads to changes in blood flow between the renal cortex and the medulla. The extent to which an increase in erythropoiesis contributes to cardiovascular benefit is unknown. In conclusion, it was determined that the mortality benefits of empagliflozin are multifactored. Blood pressure, lipids, renal function, weight, and BMI did not have any contribution to reduction in cardiovascular events.
- One of the most important mediators contributing to empagliflozin’s ability to reduce cardiovascular death is an increase in hematocrit and hemoglobin, which reduces plasma volume.
- Factors such as blood pressure, lipids, renal function, and cardiovascular risk factors did not make any contributions to the overall cardiovascular mortality reduction following the use of empagliflozin.
- Small effects were observed from uric acid, albumin, and HbA1c for reduction in cardiovascular death.
Inzucchi S, Zinman B, Fitchett D. How Does Empagliflozin Reduce Cardiovascular Mortality? Insights From a Mediation Analysis of the EMPA-REG OUTCOME Trial. Diabetes Care 2018; 41: 356-363.
Vidhi Patel, Pharm. D. Candidate 2018, LECOM School of Pharmacy