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In addition to weight loss, triple agonists are being studied for their effects on: Liver fat and NASH/MASLD (metabolic dysfunctionassociated steatotic liver disease)

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ETA Selective vs Dual ETA/ETB Blockade Feature ETA Selective (e.g., zibotentan, ambrisentan) Dual ETA/ETB (e.g., macitentan, bosentan) Pulmonary vasodilation Strong Strong Antifibrotic effect Preserved Preserved ET1 clearance via ETB Preserved Blocked Nitric oxide signaling Preserved Reduced Fluid retention risk Lower Higher HFpEF tolerability Better Worse PHLHD trial outcomes Neutral Negative / harmful Clinical Trial Signals (HighLevel) * Dual ERAs in PH due to left heart disease showed no benefit and more edema * ETA selective agents demonstrated: * Better hemodynamic tolerability * Less sodium and water retention * More favorable pulmonary vascular resistance effects without excessive PCWP rise No ERA has shown outcome benefit in HFpEF, but harm signals are stronger with dual blockade

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Withdraw the needle using the same 90-degree angle, then release the skin fold and apply gentle pressure with a dry cotton ball for 10 seconds if any bleeding occurs

Therapies with improved efficacy would ideally not come at the cost of compromised tolerability, especially considering that patient discontinuation due to AEs is an important factor in physician decision making in this space