Randomized, Placebo-Controlled Trial to Evaluate Effects of Eplerenone on Metabolic and Inflammatory Indices in HIV

Srinivasa, Suman; Fitch, Kathleen V.; Wong, Kelly; O’Malley, Timothy K; Maehler, Patrick; Branch, Karen L.; Looby, Sara E; Burdo, Tricia H.; Martinez-Salazar, Edgar L; Torriani, Martin; Lyons, Shannon; Weiss, J. Woodrow; Feldpausch, Meghan N.; Stanley, Takara L.; Adler, Gail K.; Grinspoon, Steven

doi:10.1210/jc.2018-00330

Cited by 21 publications

(22 citation statements)

References 28 publications

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“…The observations above would suggest that mineralocorticoid receptor blockade could be beneficial for HIV-induced Mets. However, a study of eplerenone showed improvement in some inflammatory markers but not in insulin resistance in HIV subjects with MetS [57].…”

Section: The Renin-angiotensin Systemmentioning

confidence: 95%

Hypertension and Metabolic Syndrome in Persons with HIV

et al. 2020

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Purpose of Review With the advent of highly active antiretroviral therapy (ART), the life span of persons with HIV (PWH) has been nearly normalized. With aging, prevalence of the metabolic syndrome (MetS), including hypertension, has increased in the HIV population and exceeds that in the general population in some studies. This is due to a combination of traditional risk factors in addition to the effects attributable to the virus and ART. We review recent findings on the mechanisms contributing to MetS and hypertension in PWH, particularly those specific to the viral infection and to ART. Recent Findings Activation of the renin-angiotensin-aldosterone system (RAAS) and chronic immune activation contribute to the development of MetS and hypertension in PWH. HIV proteins and some ART agents alter adipocyte health contributing to dyslipidemias, weight gain, and insulin resistance. HIV infection also contributes to hypertension by direct effects on the RAAS that intertwine with inflammation by the RAAS also contributing to T cell activation. Summary Recent data suggest that in addition to current ART, therapeutic targeting of the MetS and hypertension in PWH, by interfering with the RAAS, treating insulin resistance directly or by use of immunomodulators that dampen inflammation, may be critical for preventing or treating these risk factors and to improve overall cardiovascular complications in the HIV-infected aging population.

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Section: The Renin-angiotensin Systemmentioning

confidence: 95%

Hypertension and Metabolic Syndrome in Persons with HIV

et al. 2020

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“…A small open-label study evaluating the effect of MR antagonism in HIV reported increases in liver fat [ 26 ]. We recently performed a larger placebo-controlled randomized clinical trial evaluating MR antagonism in HIV and demonstrated no treatment effect on liver fat compared with placebo [ 11 ]. Because few data are available, our primary aim in the current study was to explore the fundamental relationship of aldosterone to liver fat in HIV.…”

Section: Discussionmentioning

confidence: 99%

“…Forty-six individuals between the ages of 30 and 65 years with a known history of HIV >5 years and ART use >12 months were recruited to participate in a longitudinal study investigating a novel strategy to block the RAAS in HIV [ 11 ]. In the current study, we used baseline data from the previously completed interventional study to report relationships among key metabolic variables, specifically related to liver fat and aldosterone.…”

Section: Methodsmentioning

confidence: 99%

“…In the current study, we used baseline data from the previously completed interventional study to report relationships among key metabolic variables, specifically related to liver fat and aldosterone. These data highlighting baseline relationships were not included in the prior analyses [ 11 ]. Individuals with increased waist circumference based on National Cholesterol Education Program guidelines [>102 cm (males), >88 cm (females)] were included.…”

Section: Methodsmentioning

confidence: 99%

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Significant Association of Aldosterone and Liver Fat Among HIV-Infected Individuals With Metabolic Dysregulation

Srinivasa

Fitch

Quadri

et al. 2018

Journal of the Endocrine Society

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ObjectiveFatty liver disease is increased among individuals with HIV. We sought to explore how aldosterone, a key hormone linked to insulin resistance and inflammation, relates to liver fat in the large population of individuals with HIV and metabolic abnormalities.MethodsForty-six individuals with HIV and increased waist circumference and dysglycemia were assessed for liver fat using proton magnetic resonance spectroscopy. Serum aldosterone level was obtained following strictly controlled posture conditions and a standardized sodium diet and was related to liver fat.ResultsAmong the entire group [median (interquartile range) liver fat: 5% (3%, 12%) and homeostatic model assessment of insulin resistance: 1.74 (1.21, 2.83)], serum aldosterone significantly correlated with liver fat (r = 0.31; P = 0.049). Liver fat level was significantly higher in those with aldosterone above vs below the median [8% (3%, 20%) vs 4% (2%, 10%); P = 0.02]. In the presence of metabolic syndrome, individuals with aldosterone levels above vs below the median had markedly elevated liver fat values [14% (9%, 23%) vs 5% (3%, 12%); P = 0.005] and increased presence of fatty liver disease (FLD; 92% vs 50%; P = 0.02). Controlling for metabolic syndrome, hepatitis C virus, and alcohol use, aldosterone was a significant and independent predictor of liver fat (β estimate: 0.6038, P = 0.01; overall model r2 = 0.41, P = 0.0005) and FLD (OR: 1.38, P = 0.02; overall model r2 = 0.28, P = 0.002).ConclusionThese data highlight a robust association between aldosterone and liver fat among individuals with HIV and metabolic dysregulation. Increased aldosterone may be a risk factor for liver fat accumulation among the population with HIV.

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“…Increased aldosterone signaling has been implicated in heart failure, diabetic cardiovascular injury including diabetic cardiomyopathy and may also play a role in the pathophysiology of insulin resistance 119 . Inhibition of aldosterone receptor signaling with eplerenone may reduce indices of inflammation and markers of insulin resistance in HIV infected subjects 120 . Thus, it would be of interest to determine metabolic and cardiovascular outcomes (including heart failure incidence) in high-risk subjects with diabetes treated with aldosterone receptor antagonists.…”

Section: Heart Failure Therapies and Their Effect On Glycemic Controlmentioning

confidence: 99%

Heart Failure in Type 2 Diabetes Mellitus

Kenny

Abel

2019

Circulation Research

490

361

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Patients with diabetes have greater than two-times the risk for developing heart failure (HFrEF and HFpEF). Cardiovascular outcomes, hospitalization and prognosis are worse for patients with diabetes relative to those without. Beyond the structural and functional changes that characterize diabetic cardiomyopathy, a complex underlying, and interrelated pathophysiology exists. Despite the success of many commonly used antihyperglycemic therapies to lower hyperglycemia in type 2 diabetes the high prevalence of heart failure persists. This, therefore, raises the possibility that additional factors beyond glycemia might contribute to the increased HF risk in diabetes. This review summarizes the state of knowledge regarding the impact of existing anti-hyperglycemic therapies on heart failure and discusses potential mechanisms for beneficial or deleterious effects. Second, we review currently approved pharmacological therapies for heart failure and review evidence that addresses their efficacy in the context of diabetes. Dysregulation of many cellular mechanisms in multiple models of diabetic cardiomyopathy and in human hearts have been described. These include oxidative stress, inflammation, endoplasmic reticulum (ER) stress, aberrant insulin signaling, accumulation of advanced glycated end-products, altered autophagy, changes in myocardial substrate metabolism and mitochondrial bioenergetics, lipotoxicity and altered signal transduction such as g-protein receptor kinase (GRK) signaling, renin angiotensin aldosterone signaling and beta2 adrenergic receptor signaling. These pathophysiological pathways might be amenable to pharmacological therapy to reduce the risk of heart failure in the context of type 2 diabetes. Successful targeting of these pathways could alter the prognosis and risk of heart failure beyond what is currently achieved using existing antihyperglycemic and heart failure therapeutics.

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Randomized, Placebo-Controlled Trial to Evaluate Effects of Eplerenone on Metabolic and Inflammatory Indices in HIV

Abstract: MR blockade may improve selected metabolic and inflammatory indices in HIV-infected individuals. Further studies are necessary to understand the clinical potential of MR antagonism in HIV.

Cited by 21 publications

References 28 publications

Hypertension and Metabolic Syndrome in Persons with HIV

Hypertension and Metabolic Syndrome in Persons with HIV

Significant Association of Aldosterone and Liver Fat Among HIV-Infected Individuals With Metabolic Dysregulation

Heart Failure in Type 2 Diabetes Mellitus

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