Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Acta Diabetologica
Published in: Acta Diabetologica 4/2015

01-08-2015 | Original Article

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

Authors: Jessica Milian, Allison B. Goldfine, Jonah P. Zuflacht, Caitlin Parmer, Joshua A. Beckman

Published in: Acta Diabetologica | Issue 4/2015

Login to get access

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.
Literature
1.
Beckman JA et al (2013) Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part II. Eur Heart J 34(31):2444–2452PubMedCrossRef
2.
3.
Stamler JS et al (1994) Nitric oxide regulates basal systemic and pulmonary vascular resistance in healthy humans. Circulation 89(5):2035–2040PubMedCrossRef
4.
Forstermann U, Munzel T (2006) Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation 113(13):1708–1714PubMedCrossRef
5.
Nishikawa T et al (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404(6779):787–790PubMedCrossRef
6.
Beckman JA et al (2001) Ascorbate restores endothelium-dependent vasodilation impaired by acute hyperglycemia in humans. Circulation 103(12):1618–1623PubMedCrossRef
7.
Gokce N et al (2002) Risk stratification for postoperative cardiovascular events via noninvasive assessment of endothelial function: a prospective study. Circulation 105(13):1567–1572PubMedCrossRef
8.
Heitzer T et al (2001) Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 104(22):2673–2678PubMedCrossRef
9.
Johnstone MT et al (1993) Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 88(6):2510–2516PubMedCrossRef
10.
Beckman JA et al (2003) Oral antioxidant therapy improves endothelial function in Type 1 but not Type 2 diabetes mellitus. Am J Physiol Heart Circ Physiol 285(6):H2392–H2398PubMedCrossRef
11.
Timimi FK et al (1998) Vitamin C improves endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. J Am Coll Cardiol 31(3):552–557PubMedCrossRef
12.
Heart Protection Study Collaborative Group (2002) MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360(9326):23–33CrossRef
13.
Stocker R et al (1987) Bilirubin is an antioxidant of possible physiological importance. Science 235(4792):1043–1046PubMedCrossRef
14.
Perlstein TS et al (2008) Serum total bilirubin level and prevalent lower-extremity peripheral arterial disease: National Health and Nutrition Examination Survey (NHANES) 1999–2004. Arterioscler Thromb Vasc Biol 28(1):166–172PubMedCrossRef
15.
Perlstein TS et al (2008) Serum total bilirubin level, prevalent stroke, and stroke outcomes: NHANES 1999–2004. Am J Med 121(9):781e1–788e1CrossRef
16.
Vitek L et al (2002) Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels. Atherosclerosis 160(2):449–456PubMedCrossRef
17.
Dekker D et al (2011) The bilirubin-increasing drug atazanavir improves endothelial function in patients with type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol 31(2):458–463PubMedCrossRef
18.
Ollinger R et al (2005) Bilirubin: a natural inhibitor of vascular smooth muscle cell proliferation. Circulation 112(7):1030–1039PubMedCrossRef
19.
Forstermann U (2008) Oxidative stress in vascular disease: causes, defense mechanisms and potential therapies. Nat Clin Pract Cardiovasc Med 5(6):338–349PubMedCrossRef
20.
21.
American Diabetes, A. (2010) Standards of medical care in diabetes–2010. Diabetes Care 33(Suppl 1):S11–S61CrossRef
22.
Beckman JA et al (2004) Atorvastatin restores endothelial function in normocholesterolemic smokers independent of changes in low-density lipoprotein. Circ Res 95(2):217–223PubMedCentralPubMedCrossRef
23.
Beckman JA et al (2007) Endothelial function varies according to insulin resistance disease type. Diabetes Care 30(5):1226–1232PubMedCrossRef
24.
25.
Corretti MC et al (2002) Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 39(2):257–265PubMedCrossRef
26.
Lieberman EH et al (1996) Flow-induced vasodilation of the human brachial artery is impaired in patients <40 years of age with coronary artery disease. Am J Cardiol 78(11):1210–1214PubMedCrossRef
27.
28.
Benzie IF, Strain JJ (1996) The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Anal Biochem 239(1):70–76PubMedCrossRef
29.
Paneni F et al (2013) Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Eur Heart J 34(31):2436–2443PubMedCentralPubMedCrossRef
30.
Inoguchi T et al (2007) Relationship between Gilbert syndrome and prevalence of vascular complications in patients with diabetes. JAMA 298(12):1398–1400PubMedCrossRef
31.
Murphy RL et al (2010) Change to atazanavir/ritonavir treatment improves lipids but not endothelial function in patients on stable antiretroviral therapy. AIDS 24(6):885–890PubMedCrossRef
32.
Flammer AJ et al (2009) Effect of atazanavir versus other protease inhibitor-containing antiretroviral therapy on endothelial function in HIV-infected persons: randomised controlled trial. Heart 95(5):385–390PubMedCrossRef
33.
Dube MP et al (2008) No impairment of endothelial function or insulin sensitivity with 4 weeks of the HIV protease inhibitors atazanavir or lopinavir-ritonavir in healthy subjects without HIV infection: a placebo-controlled trial. Clin Infect Dis 47(4):567–574PubMedCentralPubMedCrossRef
34.
Hileman C et al (2012) Relationship between total bilirubin and endothelial function, inflammation and oxidative stress in HIV-infected adults on stable antiretroviral therapy. HIV Med 13(10):609–616PubMedCentralPubMedCrossRef
35.
Ingram DG et al (2007) Chronic nitric oxide synthase inhibition blunts endothelium-dependent function of conduit coronary arteries, not arterioles. Am J Physiol Heart Circ Physiol 292(6):H2798–H2808PubMedCentralPubMedCrossRef
36.
37.
Guzik TJ et al (2000) Vascular superoxide production by NAD(P)H oxidase: association with endothelial dysfunction and clinical risk factors. Circ Res 86(9):E85–E90PubMedCrossRef
38.
Fukui T et al (1997) p22phox mRNA expression and NADPH oxidase activity are increased in aortas from hypertensive rats. Circ Res 80(1):45–51PubMedCrossRef
39.
Mehta JL et al (1994) Alterations in nitric oxide synthase activity, superoxide anion generation, and platelet aggregation in systemic hypertension, and effects of celiprolol. Am J Cardiol 74(9):901–905PubMedCrossRef
40.
Yusuf S et al (2000) Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The heart outcomes prevention evaluation study investigators. N Engl J Med 342(3):145–153PubMedCrossRef
41.
Curb JD et al (1996) Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. Systolic hypertension in the elderly program cooperative research group. JAMA 276(23):1886–1892PubMedCrossRef
42.
Tuomilehto J et al (1999) Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. Systolic hypertension in Europe trial investigators. N Engl J Med 340(9):677–684PubMedCrossRef
43.
Goldberg RB et al (1998) Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial. The care investigators. Circulation 98(23):2513–2519PubMedCrossRef
44.
Cholesterol Treatment Trialists (2008) Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 371(9607):117–125CrossRef
45.
Collins R et al (2003) MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 361(9374):2005–2016PubMedCrossRef
46.
Madhavan M et al (1997) Serum bilirubin distribution and its relation to cardiovascular risk in children and young adults. Atherosclerosis 131(1):107–113PubMedCrossRef
47.
Tapan S et al (2011) Decreased small dense LDL levels in Gilbert’s syndrome. Clin Biochem 44(4):300–303PubMedCrossRef
48.
Kodama S et al (2014) Meta-analysis of the quantitative relation between pulse pressure and mean arterial pressure and cardiovascular risk in patients with diabetes mellitus. Am J Cardiol 113(6):1058–1065PubMedCrossRef
49.
Oda E, Aizawa Y (2013) Total bilirubin is inversely associated with metabolic syndrome but not a risk factor for metabolic syndrome in Japanese men and women. Acta Diabetol 50(3):417–422PubMedCrossRef
50.
Di Filippo C et al (2006) Oxidative stress as the leading cause of acute myocardial infarction in diabetics. Cardiovasc Drug Rev 24(2):77–87PubMedCrossRef
51.
Aksoy S et al (2012) Oxidative stress and severity of coronary artery disease in young smokers with acute myocardial infarction. Cardiol J 19(4):381–386PubMedCrossRef
52.
McMurray J et al (1993) Evidence of oxidative stress in chronic heart failure in humans. Eur Heart J 14(11):1493–1498PubMedCrossRef
53.
Keshavan P et al (2005) Unconjugated bilirubin inhibits VCAM-1-mediated transendothelial leukocyte migration. J Immunol 174(6):3709–3718PubMedCrossRef
54.
World Medical Association (2009) I., Declaration of Helsinki. Ethical principles for medical research involving human subjects. J Indian Med Assoc 107(6):403–405
Metadata
Title
Atazanavir improves cardiometabolic measures but not vascular function in patients with long-standing type 1 diabetes mellitus
Authors
Jessica Milian
Allison B. Goldfine
Jonah P. Zuflacht
Caitlin Parmer
Joshua A. Beckman
Publication date
01-08-2015
Publisher
Springer Milan
Published in
Acta Diabetologica / Issue 4/2015
Print ISSN: 0940-5429
Electronic ISSN: 1432-5233
DOI
https://doi.org/10.1007/s00592-014-0708-6

Other articles of this Issue 4/2015

Acta Diabetologica 4/2015 Go to the issue

Original Article

l-Valine appended PLGA nanoparticles for oral insulin delivery

Case Report

Bilateral lower limbs edema with “wooden” character induced by insulin glargine treatment

Original Article

Ethnic/racial determinants of glycemic markers in a UK sample

Original Article

Systematic review and meta-analysis of randomized clinical trials comparing efficacy and safety outcomes of insulin glargine with NPH insulin, premixed insulin preparations or with insulin detemir in type 2 diabetes mellitus

Review Article

Screening of glucose metabolism derangements in pediatric cystic fibrosis patients: how, when, why

Original Article

Excess mortality in Type 1 diabetes diagnosed in childhood and adolescence: a systematic review of population-based cohorts
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits