Esaxerenone, a non-steroidal mineralocorticoid receptor blocker, has shown promise as a second-line antihypertensive agent, particularly when used in combination with angiotensin receptor blockers (ARBs). A recent subgroup analysis of the EXCITE-HT study, published in Nature, investigated the comparative efficacy of esaxerenone and trichlormethiazide, a thiazide diuretic, when added to either ARBs or calcium channel blockers (CCBs) in patients with uncontrolled hypertension. The study highlights esaxerenone's potential to provide a stronger antihypertensive effect compared to diuretics, with fewer safety concerns such as uric acid elevation and hypokalemia risk.
The EXCITE-HT study enrolled patients already taking either an ARB (approximately 40%) or a CCB (approximately 60%) as their basal antihypertensive medication. The primary outcome was the change in morning home blood pressure. The subgroup analysis revealed that esaxerenone was non-inferior to trichlormethiazide in lowering morning home blood pressure, irrespective of the basal antihypertensive agent used. Specifically, in the CCB subgroup, esaxerenone demonstrated superiority in lowering systolic blood pressure (SBP) and non-inferiority in lowering diastolic blood pressure (DBP) compared to trichlormethiazide.
Antihypertensive Effects and Basal Therapy
Interestingly, the antihypertensive effect of trichlormethiazide appeared less potent in the CCB subgroup compared to the ARB subgroup, even after accounting for baseline differences. This may be attributed to the synergistic effect of combining an ARB and a thiazide diuretic, as ARB efficacy can be attenuated by excessive salt intake, while diuretics inhibit sodium reabsorption. The study authors suggest that aldosterone breakthrough, a phenomenon where aldosterone production increases despite RAS inhibition, may be more prevalent in patients taking ARBs, potentially influencing the observed differences.
Esaxerenone, however, maintained a consistent antihypertensive effect regardless of the basal antihypertensive agent. A pooled analysis of five clinical studies further supports the finding that esaxerenone exhibits a stronger antihypertensive effect when combined with a RAS inhibitor compared to a CCB.
Potential Mechanisms and Patient Characteristics
The mechanism behind the stronger antihypertensive effect of esaxerenone when co-administered with an ARB is not fully understood. Factors such as obesity, type 2 diabetes mellitus (T2DM), chronic kidney disease, excessive salt intake, and aldosterone breakthrough may play a role. In the EXCITE-HT study, the ARB subgroup had a higher percentage of patients with T2DM (44.5% vs. 37.5% in the CCB subgroup), higher mean UACR (159.7 mg/g Cr vs. 86.9 mg/g Cr), and higher mean NT-proBNP (161.5 pg/mL vs. 74.1 pg/mL), suggesting a greater prevalence of diabetic kidney disease in this subgroup.
Safety Considerations: Potassium and Uric Acid
Regarding safety, the study found no instances of serum potassium levels ≥6.0 mEq/L in either group. However, the percentage of patients with serum potassium levels ≥5.5 mEq/L was higher in the esaxerenone group, particularly in the ARB subgroup (4.2% vs. 0.6% in the CCB subgroup). This highlights the importance of monitoring serum potassium levels, especially when combining esaxerenone with ARBs. The study also noted that elevations in uric acid were less frequent with esaxerenone compared to trichlormethiazide.
Clinical Implications and Future Directions
The findings from this subgroup analysis of the EXCITE-HT study provide valuable insights into the use of esaxerenone as a second-line antihypertensive agent. The results suggest that adding esaxerenone to CCB monotherapy may have a stronger antihypertensive effect compared to diuretics, with fewer safety concerns. Furthermore, introducing esaxerenone in patients on ARB monotherapy can be expected to provide a more potent antihypertensive effect than when added to a CCB, but with closer monitoring of serum potassium levels.
The authors emphasize the importance of adhering to package insert guidelines, starting with low doses and titrating carefully with regular monitoring, to ensure safe use. They also call for further research into combination therapies with different drug classes to optimize hypertension management and reduce the number of patients with inadequately controlled blood pressure.
