Reduced Risk of MASLD and Cardiometabolic Disease Following Renal Denervation Therapy in Patients With Resistant Hypertension

Introduction Autonomic dysfunction increases the risk of cardio‐kidney‐metabolic (CKM) syndrome including metabolic dysfunction‐associated steatotic liver disease (MASLD), type 2 diabetes (T2D), cardiovascular disease (CVD) and chronic kidney disease (CKD). Renal denervation reduces renal sympathetic nerve activity and lowers blood pressure independent of long‐term pharmacotherapy, with potential downstream effects on metabolic and hepatic pathways. We aimed to evaluate the impact of renal denervation, compared with intensive antihypertensive therapy, on cardiometabolic disease risk. Methods We conducted a target trial emulation using the TriNetX global federated health research network. Eligible participants were adults with hypertension (ICD‐10 code I10) who were treated with either renal denervation therapy and pharmacological treatment (identified via ICD‐10 or Current Procedural Terminology codes), acting as the treatment group, or an intensive pharmacological antihypertensive regime (four of a beta blocker, calcium channel blocker, angiotensin‐converting enzyme inhibitor, angiotensin II receptor blocker, alpha blocker or diuretic), acting as the control group. Propensity score matching (1:1) balanced the treatment and control groups, accounting for confounding variables. The primary outcome was of MASLD/metabolic dysfunction‐associated steatohepatitis (MASH), while secondary outcomes included T2D, CKD and a composite of major adverse cardiovascular events (MACE): sudden cardiac death, ischaemic heart disease (IHD), cerebrovascular accident (CVA), peripheral vascular disease (PVD) and heart failure (HF). Cox regression generated hazard ratios (HRs) and 95% confidence intervals (CIs). Results After matching, 1735 patients remained in each group, with well‐balanced baseline characteristics (mean age 42 vs. 41 years; standardised mean difference [SMD] 0.05; 52.6% vs. 54.3% male; SMD 0.03). After PSM, renal denervation was associated with a lower risk of MASLD (HR 0.38 [0.29, 0.51]), T2D (HR 0.21 [0.13, 0.33]), CKD (HR 0.26 [0.20, 0.35]), MACE (HR 0.46 [0.34, 0.62]), IHD (HR 0.56 [0.39, 0.80]), CVA (HR 0.33 [0.20, 0.52]) and HF (HR 0.39 [0.25, 0.62]). Conclusion Control of the sympathetic nervous system with renal denervation therapy in patients with resistant hypertension is associated with a lower risk of incident CKM syndrome including MASLD, T2D, CVD and CKD, supporting the role of autonomic dysfunction in the progression of cardiometabolic disease.