Dapagliflozin and Endothelin Receptor Antagonism in Large Vessel Vasculitis (DERAIL-LVV)

Large vessel vasculitis (LVV) is an autoimmune disease characterised by inflammatory damage to the blood vessels. Although symptoms initially are non-specific, complications such as vessel stenosis can lead to heart failure and stroke. While current immunosuppressive treatments have improved short-term outcomes, they have not led to improvements in long-term outcomes. Patients with LVV remain at an increased risk of developing cardiovascular disease, the underlying mechanisms of which are not yet fully understood.

The inflammatory damage to blood vessels in LVV can result in endothelial dysfunction. Endothelin-1 (ET-1) is a potent vasoconstrictor produced by the endothelium. In endothelial dysfunction, excess ET-1 production causes raised blood pressure, increased arterial stiffness and reduced fibrinolytic capacity. Previous research has demonstrated that short-term blockade of endothelin receptors improves arterial stiffness and fibrinolytic capacity.

Inhibitors of the sodium-glucose co-transporter 2 (SGLT2i) target the renal proximal tubule to promote glycosuria. Recent large studies have demonstrated their impressive cardiovascular benefits across a range of conditions. Previous work has also demonstrated their ability to improve endothelial function and arterial stiffness in patients with diabetes.

Recently, the randomised, active-controlled Zenith-CKD trial demonstrated that the combination of zibotentan (an endothelin receptor antagonist) and the SGLT2 inhibitor dapagliflozin was effective in reducing albuminuria in patients with chronic kidney disease. Part of the rationale for combining these therapies was to offset the potential for fluid retention with zibotentan alone by harnessing the diuretic effect of dapagliflozin. The safety profile of an endothelin receptor antagonist and an SGLT2 inhibitor was excellent.

Bosentan is a dual endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension. Combining it with dapagliflozin will minimise the potential for fluid retention. Additionally, the potential for improved endothelial function and enhanced CVD protection with both of these agents used in combination is significant. To date, dual endothelin receptor antagonism and SGLT2 inhibition have not been trialled in patients with LVV.

The investigators will conduct a cross-sectional, case-control study comparing blood vessel function in patients with LVV with sex-, age-, and cardiovascular disease risk factor-matched control participants. This will be followed by an open-label trial in patients with LVV. Patients with LVV will be given 6 weeks of treatment with Bosentan and dapagliflozin, followed by 4 weeks of dapagliflozin to assess whether these drugs can improve blood vessel function and stiffness. Assessment of blood vessel function will be measured by venous occlusion plethysmography, a gold standard measure.