Atazanavir improves cardiometabolic measures but not vascular function in patients with long-standing type 1 diabetes mellitus

Abstract

Aims Vascular disease is the leading cause of morbidity and mortality in type 1 diabetes mellitus (T1DM). We previously demonstrated that patients with T1DM have impaired endothelial function, a forme fruste of atherosclerosis, as a result of increased oxidative stress. Bilirubin has emerged as a potent endogenous antioxidant with higher concentrations associated with lower rates of myocardial infarction and stroke. Methods We tested the hypothesis that increasing endogenous bilirubin using atazanavir would improve cardiometabolic risk factors and vascular function in patients with T1DM to determine whether targeting bilirubin may be a novel therapeutic approach to reduce cardiovascular disease risk in this population. In this single-arm, open-label study, we evaluated blood pressure, lipid profile, and conduit artery function in fifteen subjects (mean age 45 ± 9 years) with T1DM following a 4-day treatment with atazanavir. Results As anticipated, atazanavir significantly increased both serum total bilirubin levels (p < 0.0001) and plasma total antioxidant capacity (p < 0.0001). Reductions in total cholesterol (p = 0.04), LDL cholesterol (p = 0.04), and mean arterial pressure (p = 0.04) were also observed following atazanavir treatment. No changes were seen in either flow-mediated endothelium-dependent (p = 0.92) or nitroglycerine-mediated endothelium-independent (p = 0.68) vasodilation, measured by high-resolution B-mode ultrasonography at baseline and post-treatment. Conclusion Increasing serum bilirubin levels with atazanavir in subjects with T1DM over 4 days favorably reduces LDL and blood pressure but is not associated with improvements in endothelial function of conduit arteries.

Conflicting effects of atazanavir therapy on atherosclerotic risk factors in stable HIV patients: A randomized trial of regimen switch to atazanavir

“…Moreover, our data verify a lack of benefit on endothelial function associated with long-term therapy in older subjects [50]. The results confirm our prior experience with atazanavir in patients with type 1 diabetes [28]. The lack of change in endothelial function is surprising given that increases in bilirubin decreased oxidative stress.…”

“…However, the increase in bilirubin could also have beneficial effects, as bilirubin is a well-described potent endogenous antioxidant [26, 27]. Atazanavir, presumably through its increase in bilirubin, could improve the systemic atherosclerotic environment through improvements in lipid profile, inflammation, and oxidative stress[25, 28–30]. In support of this hypothesis, treatment with atazanavir slowed-progression in carotid intima media thickness compared to treatments with darunavir (another protease inhibitor] and raltegravir (an integrase inhibitor)[31, 32].…”

“…Both curcumin and peroxisome proliferator-activated receptor (PPAR)-alpha agonists induce HO-1 and have been shown in animals models to improve endothelial function [52–55] and improve vascular function in patients with diabetes [56, 57]. In contrast, a strategy of increasing bilirubin by blocking its conjugation in the liver has failed multiple times to improve endothelial function in subjects with HIV [30, 42, 49, 58] and type 1 diabetes [28], but had its single success in a 4-day study of subjects with type 2 diabetes [59]. It is possible that the success of the last study occurred because of factors particular to type 2 diabetes (its microvessel rather than conduit artery focus), the duration of the study (which was shorter than the length of time necessary to increase mitochondrial superoxide production), or because of random chance.…”

Bilirubin Is Inversely Associated With Cardiovascular Disease Among HIV‐Positive and HIV‐Negative Individuals in VACS (Veterans Aging Cohort Study)

“…For example, the antiretroviral drug atazanavir can competitively inhibit uridine diphosphate glucuronosyltransferase 1A1, leading to an increase in unconjugated bilirubinemia 15. Several studies have shown atazanavir use can improve endothelial function and reduce lipid levels and blood pressure in HIV‐uninfected diabetic patients 16, 17. Among HIV‐positive individuals, atazanavir decreased markers of inflammation and slowed progression of carotid intimal‐medial thickness when compared with other antiretroviral treatment (ART), an effect that appears to be partially mediated by bilirubin 18, 19…”

Atazanavir and Cardiovascular Risk Among Human Immunodeficiency Virus-Infected Patients: A Systematic Review

“…In patients with type 1 diabetes, the initiation of ATV decreased lipid parameters and increased total plasma antioxidant capacity from baseline; however, similar to the studies of HIV-infected patients analyzed in this review, it did not result in an improvement in endothelial function [12]. In an experimental double-blind, placebo-controlled crossover study of HIV-negative patients with type 2 diabetes, ATV was associated with a significant improvement in both plasma antioxidant capacity and endothelial function [13].…”