IL (Interleukin)-1 Receptor Antagonist Increases Ang (Angiotensin [1–7]) and Decreases Blood Pressure in Obese Individuals

Abstract

IL (Interleukin)-1 antagonism decreases blood pressure in obese individuals. The underlying mechanisms are unknown. Based on experimental data, we hypothesized an effect of IL-1 antagonism via modulation of the renin-angiotensin-aldosterone system. In this explorative study, we examined shorter- (2 days) and longer-term effects (4 weeks) of IL-1 antagonism (anakinra/Kineret) on renin-angiotensin system peptide profiles and on hemodynamic parameters assessed by noninvasive measurement in obese (body mass index ≥30 kg/m²) individuals from 2 interventional trials (a prospective interventional trial [n=73] and a placebo controlled-double blinded interventional trial [n=67]). A total of 140 patients were included. Systolic blood pressure decreased after short-term (absolute difference -5.2 mm Hg [95% CI, -8.5 to -1.8]; <i>P</i>=0.0006) and after longer-term treatment with anakinra (absolute difference -3.9 mm Hg [95% CI, -7.59 to -0.21]; <i>P</i>=0.04), with no change in blood pressure in the placebo group. Upon IL-1 antagonism, equilibrium levels of Ang II (angiotensin II), Ang I, aldosterone, and renin remained unchanged. In contrast, Ang (1-7) peptide levels increased after 4 weeks (between-group difference 16.35 pmol/L [95% CI, 1.22-30.17], <i>P</i>=0.03), as well as the Ang (1-7)/Ang II ratio (between-group difference 0.42 [95% CI, 0.17-0.67], <i>P</i>=0.02) in comparison to placebo. Consistently, the stroke systemic vascular resistance index significantly decreased in the anakinra group (between-group difference of -62.65 dyn/sec per cm^-5 per m² [95% CI, -116.94 to -18.36], <i>P</i>=0.008, consistent with a 25% decrease). IL-1 antagonism increased the vasodilatory Ang (1-7) peptide after 4 weeks of treatment in obese individuals, paralleled by a decrease in peripheral vascular resistance. These findings point to an IL-1 mediated blood pressure-lowering mechanism via modulation of Ang (1-7). Registration- URL: https://www.clinicaltrials.gov. Unique identifiers: NCT02227420 and NCT02672592.