Antihypertensive Efficacy and Safety of Angiotensin Receptor Blockers (ARBs) with and without Inverse Agonism: A Systematic Review and Network Meta-analysis.

INTRODUCTION: While not all angiotensin receptor blockers (ARBs) exhibit inverse agonistic activity, certain ARBs with this property may offer greater potential for blood pressure (BP) reduction compared with ARBs without inverse agonism. This study aimed to evaluate the antihypertensive efficacy and safety of ARBs with or without inverse agonism. METHODS: A systematic literature review and network meta-analysis identified randomized clinical trials (RCTs) of first-line monotherapy for mild-to-moderate hypertension: azilsartan medoxomil (AZL-M), candesartan, olmesartan, losartan, valsartan, telmisartan, irbesartan, allisartan isoproxil, sacubitril/valsartan, sacubitril/allisartan, or placebo. Treatments were grouped as ARBs with or without inverse agonism, angiotensin receptor neprilysin inhibitors (ARNIs), and placebo. AZL-M was separately analyzed as part of ARBs with inverse agonism. BP changes and adverse events (AEs) were assessed. RESULTS: Of 2659 RCTs screened, 23 studies were analyzed. ARBs with inverse agonism demonstrated superior systolic BP and diastolic BP reductions compared with ARBs without inverse agonism, ARNIs, and placebo. When analyzed separately, AZL-M significantly outperformed ARBs without inverse agonism in systolic BP and diastolic BP reduction and was superior to other ARBs with inverse agonism in systolic BP reduction. Surface under the cumulative ranking curves (SUCRA) indicated AZL-M had the highest probability of being the best treatment for systolic BP (98%) and diastolic BP (95%) reduction. CONCLUSIONS: This study supports that ARBs with inverse agonism, especially AZL-M, have a better BP-lowering efficacy compared with ARBs without inverse agonism and ARNIs, while maintaining favorable safety profiles. Future research is encouraged to explore the effects on long-term outcomes, combination therapies, and safety in diverse populations.