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

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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.

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Acknowledgments

Dr. Beckman is supported by National Institutes of Health, National Institute of Diabetes, Digestive and Kidney Disease Grant 1R03 DK094510-01. Dr. Goldfine is supported by NIDDK Diabetes Research Center Grant P30DK036836. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

Conflict of interest

Dr. Goldfine, Mr. Zuflacht, Ms. Parmer, and Ms. Milian have no conflicts of interest. Dr. Beckman has received honoraria for consulting and support for investigator-initiated research from Bristol Myers Squibb.

Ethical standard

The protocol was approved by the Partners Human Research Committee of Brigham and Women’s Hospital and all subjects provided informed consent.

Human and animal rights disclosure

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 [54].

Informed consent disclosure

Informed consent was obtained from all patients for being included in the study.

Author information

Authors and Affiliations

  1. Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA, 02115, USA

    Jessica Milian, Jonah P. Zuflacht, Caitlin Parmer & Joshua A. Beckman

  2. Clinical Research, Joslin Diabetes Center, Boston, MA, USA

    Allison B. Goldfine

Authors
  1. Jessica Milian
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  2. Allison B. Goldfine
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  3. Jonah P. Zuflacht
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  4. Caitlin Parmer
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  5. Joshua A. Beckman
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Correspondence to Joshua A. Beckman.

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Milian, J., Goldfine, A.B., Zuflacht, J.P. et al. Atazanavir improves cardiometabolic measures but not vascular function in patients with long-standing type 1 diabetes mellitus. Acta Diabetol 52, 709–715 (2015). https://doi.org/10.1007/s00592-014-0708-6

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  • DOI: https://doi.org/10.1007/s00592-014-0708-6

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