Randomized placebo controlled trial to evaluate effects of mineralocorticoid blockade on insulin sensitivity and inflammation in HIV

Metabolic dysfunction is prevalent among the HIV population. HIV‐infected individuals demonstrate unique renin‐angiotensin‐aldosterone system (RAAS) physiology characterized by increased RAAS activation in association with visceral adiposity, insulin resistance, and inflammation. We hypothesized that a physiologically‐based treatment approach targeting mineralocorticoid receptor (MR) blockade may have beneficial effects on improving insulin sensitivity and other inflammatory and metabolic indices in HIV. We conducted the first double‐blinded, placebo‐controlled, randomized trial using eplerenone in HIV. 46 well‐treated HIV‐infected individuals with increased waist circumference (WC) and abnormal glucose homeostasis by oral glucose tolerance testing were randomized to eplerenone 50mg (n=25) or placebo (n=21) daily for 6 months supplemented with lifestyle counseling. The primary endpoint was change in insulin stimulated glucose uptake normalized to insulin and lean body mass (M/I/LBM) measured by the euglycemic hyperinsulinemic clamp technique. Secondary endpoints included change in body composition and markers of inflammation. Metabolic and inflammatory parameters, including RAAS components, were evaluated under controlled sodium and posture conditions. Absolute change was determined by Student's T‐test or Wilcoxon Rank Sums Test depending on normality of distribution. Treatment groups (eplerenone vs. placebo) did not differ by age (49±1 vs. 52±1 years), male sex (60 vs. 71%), Caucasian race (60 vs. 43%), WC (111±2 vs. 112±2 cm) or HOMA‐IR (2.0[1.5,3.3] vs. 1.6[0.9,2.5]) (all P>.05). Eplerenone did not improve insulin sensitivity compared to placebo (M/I/LBM 0.48 [‐1.28,1.48] vs. 0.43 [‐1.95,2.55] mg/min per μ/mL, P=.71). There was a modest decrease in MCP‐1 (‐9±10 vs. 26±13 pg/mL, P=.04) and intramyocellular lipid (‐0.1[‐0.3,0.1] vs. 0.0[‐0.1,0.2]%, P=.04), and a trend towards decreases in IL‐6 (‐1.2[‐7.6,1.4] vs. 3.1[‐2.5,4.8] pg/mL, P=.10) and hsCRP (‐0.3[‐2.0,0.9] vs. 0.9[‐0.1,1.9] mg/L, P=.10) on eplerenone vs. placebo. A trend towards an increase in HDL (2±2 vs. ‐2±1 mg/dL, P=.06) on eplerenone vs. placebo was seen, and after controlling for statin use, the increase in HDL became significantly different (P=.04). Changes in plasma renin activity (0.20[0.00,1.55] vs. 0.00[‐0.08,0.01) ng/mL/hr, P=.002) and serum aldosterone (2.50[‐0.32,12.81] vs. 0.29[‐0.94,1.98] ng/dL, P=.07) were greater in the eplerenone vs. placebo group demonstrating expected physiology. MR antagonism with eplerenone was well‐tolerated among the HIV population with no significant changes in blood pressure (BP) or potassium. While MR blockade did not improve insulin sensitivity, it may have other novel properties to dampen inflammation in HIV and improve selected metabolic indices, aside from its well‐known mechanism of action related to BP and sodium regulation.