CLINICAL STUDIES
Atorvastatin but not L-arginine improves endothelial function in type I diabetes mellitus: a double-blind study
Michael J. Mullen, MRCP*,
David Wright, PhD ,
Ann E. Donald, AVT*,
Sara Thorne, MD, MRCP*,
Hyeyoung Thomson, BSc* and
John E. Deanfield, FRCP*
* Vascular Physiology Unit, Great Ormond Street Hospital for Children, London, UK
Department of Statistical Science, University College London, Gower Street, London, UK
Manuscript received October 26, 1999;
revised manuscript received January 28, 2000,
accepted March 30, 2000.
Reprint requests and correspondence: Dr. Michael J. Mullen, Vascular Physiology Unit, Gt. Ormond Street, Hospital for Children, London, WC1N 3JH, United Kingdom
MichaelJMullen{at}cs.com
OBJECTIVES
We sought to determine the effects of oral L-arginine and the hexamethylglutaryl coenzyme A reductase inhibitor atorvastatin on endothelial function in young patients with type I diabetes mellitus (DM).
BACKGROUND
Endothelial dysfunction, a key early event in atherosclerosis, occurs in young patients with type I DM, and its reversal may benefit the progression of vascular disease. Cholesterol reduction in L-arginine improve endothelial function in nondiabetic subjects, but their effect in patients with type I DM is unknown.
METHODS
In a double-blind, 2 x 2 factorial study, we investigated the effect of L-arginine (7 g twice daily) and atorvastatin (40 mg/day) on conduit artery vascular function in 84 normocholesterolemic young adults (mean ± SD: age 34 years [range 18 to 46], low density lipoprotein [LDL] cholesterol 2.96 ± 0.89 mmol/liter) with type I DM. Brachial artery dilation to flow (flow-mediated dilation [FMD]) and to the direct smooth muscle dilator glyceryl trinitrate (GTN) were assessed noninvasively using high resolution ultrasound at baseline and after six weeks of treatment.
RESULTS
Atorvastatin resulted in a 48 ± 10% decrease in serum LDL cholesterol levels, whereas L-arginine levels increased by 247 ± 141% after L-arginine therapy. By analysis of covariance, treatment with atorvastatin resulted in a significant increase in FMD (p = 0.018. L-Arginine therapy had no significant effect on endothelial function, and there was no significant change in dilation to GTN after either intervention.
CONCLUSIONS
In young patients with type I DM, improvement in endothelial dysfunction can be demonstrated after just six weeks of treatment with atorvastatin. In contrast to studies of hypercholesterolemia, however, L-arginine had no benefit. Treatment with atorvastatin at an early stage may have an impact on the progression of atherosclerosis in these high risk patients.
|
Abbreviations and Acronyms
| | CI | = confidence interval | | DM | = diabetes mellitus | | FMD | = flow-mediated dilation | | GTN | = glyceryl trinitrate | | GTN-MD | = glyceryl trinitrate–mediated dilation | | HDL | = high density lipoprotein | | HMG-CoA | = hexamethylglutaryl coenzyme A | | LDL | = low density lipoprotein | | NO | = nitric oxide |
|
This article has been cited by other articles:
|
|
|
|
 
V. Martina, A. Masha, V. R. Gigliardi, L. Brocato, E. Manzato, A. Berchio, P. Massarenti, F. Settanni, L. Della Casa, S. Bergamini, et al.
Long-Term N-Acetylcysteine and L-Arginine Administration Reduces Endothelial Activation and Systolic Blood Pressure in Hypertensive Patients With Type 2 Diabetes
Diabetes Care,
May 1, 2008;
31(5):
940 - 944.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Sugita, H. Sugita, and M. Kaneki
Farnesyltransferase Inhibitor, Manumycin A, Prevents Atherosclerosis Development and Reduces Oxidative Stress in Apolipoprotein E-Deficient Mice
Arterioscler. Thromb. Vasc. Biol.,
June 1, 2007;
27(6):
1390 - 1395.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Gkaliagkousi, A. Shah, and A. Ferro
Review: Pharmacological and non-pharmacological treatment of endothelial dysfunction: relevance to diabetes
The British Journal of Diabetes & Vascular Disease,
January 1, 2007;
7(1):
5 - 10.
[Abstract]
[PDF]
|
|
|
|
|
|
|
A Ozkiris, K Erkilic, A Koc, and S Mistik
Effect of atorvastatin on ocular blood flow velocities in patients with diabetic retinopathy
Br. J. Ophthalmol.,
January 1, 2007;
91(1):
69 - 73.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B.-K. Son, K. Kozaki, K. Iijima, M. Eto, T. Kojima, H. Ota, Y. Senda, K. Maemura, T. Nakano, M. Akishita, et al.
Statins Protect Human Aortic Smooth Muscle Cells From Inorganic Phosphate-Induced Calcification by Restoring Gas6-Axl Survival Pathway
Circ. Res.,
April 28, 2006;
98(8):
1024 - 1031.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Charakida, A. E. Donald, M. Terese, S. Leary, J. P. Halcox, A. Ness, G. D. Smith, J. Golding, P. Friberg, N. J. Klein, et al.
Endothelial Dysfunction in Childhood Infection
Circulation,
April 5, 2005;
111(13):
1660 - 1665.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. L. Bots, J. Westerink, T. J. Rabelink, and E. J.P. de Koning
Assessment of flow-mediated vasodilatation (FMD) of the brachial artery: effects of technical aspects of the FMD measurement on the FMD response
Eur. Heart J.,
February 2, 2005;
26(4):
363 - 368.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. R. Morgan, L. J. Dixon, C. G. Hanratty, S. M.T. Hughes, W. J. Leahey, K. P. Rooney, G. D. Johnston, and G. E. McVeigh
Impaired endothelium-dependent and -independent vasodilation in elderly patients with chronic heart failure
Eur J Heart Fail,
December 1, 2004;
6(7):
901 - 908.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Haller, M. Samyn, W. W. Nichols, T. Brusko, C. Wasserfall, R. F. Schwartz, M. Atkinson, J. J. Shuster, G. L. Pierce, and J. H. Silverstein
Radial Artery Tonometry Demonstrates Arterial Stiffness in Children With Type 1 Diabetes
Diabetes Care,
December 1, 2004;
27(12):
2911 - 2917.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Janatuinen, J. Knuuti, J. O. Toikka, M. Ahotupa, P. Nuutila, T. Ronnemaa, and O. T. Raitakari
Effect of Pravastatin on Low-Density Lipoprotein Oxidation and Myocardial Perfusion in Young Adults With Type 1 Diabetes
Arterioscler. Thromb. Vasc. Biol.,
July 1, 2004;
24(7):
1303 - 1308.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Davignon
Beneficial Cardiovascular Pleiotropic Effects of Statins
Circulation,
June 15, 2004;
109(23_suppl_1):
III-39 - III-43.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
P. A. Economides, A. Caselli, E. Tiani, L. Khaodhiar, E. S. Horton, and A. Veves
The Effects of Atorvastatin on Endothelial Function in Diabetic Patients and Subjects at Risk for Type 2 Diabetes
J. Clin. Endocrinol. Metab.,
February 1, 2004;
89(2):
740 - 747.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Wassmann, A. Faul, B. Hennen, B. Scheller, M. Bohm, and G. Nickenig
Rapid Effect of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibition on Coronary Endothelial Function
Circ. Res.,
October 31, 2003;
93
(9):
e98 - e103.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. G Regensteiner, S. Popylisen, T. A Bauer, J. Lindenfeld, E. Gill, S. Smith, C. K Oliver-Pickett, J. E. Reusch, and J. V Weil
Oral L-arginine and vitamins E and C improve endothelial function in women with type 2 diabetes
Vascular Medicine,
August 1, 2003;
8(3):
169 - 175.
[Abstract]
[PDF]
|
|
|
|
|
|
|
T. P. Singh, H. Groehn, and A. Kazmers
Vascular function and carotid intimal-medial thickness in children with insulin-dependent diabetes mellitus
J. Am. Coll. Cardiol.,
February 19, 2003;
41(4):
661 - 665.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Schwartz
Amelioration of Microvascular Angina with Arginine Supplementation
Ann Intern Med,
January 21, 2003;
138(2):
160 - 160.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Mcdougall and M. Fisher
Prevention of diabetes in cardiovascular studies: implications for the aetiology of type 2 diabetes
The British Journal of Diabetes & Vascular Disease,
September 1, 2002;
2(5):
384 - 389.
[Abstract]
[PDF]
|
|
|
|
|
|
|
D. Tousoulis, C. Antoniades, C. Tentolouris, G. Goumas, C. Stefanadis, and P. Toutouzas
L-Arginine in cardiovascular disease: dream or reality?
Vascular Medicine,
August 1, 2002;
7(3):
203 - 211.
[Abstract]
[PDF]
|
|
|
|
|
|
|
K. C. B. Tan, W. S. Chow, S. C. F. Tam, V. H. G. Ai, C. H. L. Lam, and K. S. L. Lam
Atorvastatin Lowers C-Reactive Protein and Improves Endothelium-Dependent Vasodilation in Type 2 Diabetes Mellitus
J. Clin. Endocrinol. Metab.,
February 1, 2002;
87(2):
563 - 568.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. H. Stein, C. M. Carlsson, T. Hayashi, T. Tsunekawa, H. Kano, D. Sumi, H. Matsui-Hirai, N. K. Thakur, A. Iguchi, and K. Egashira
Cerivastatin and Endothelial Function in Elderly Patients With Diabetes Mellitus Response
Circulation,
January 29, 2002;
105
(4):
e32 - e33.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Asberg, A. Hartmann, E. Fjeldsa, and H. Holdaas
Atorvastatin improves endothelial function in renal-transplant recipients
Nephrol. Dial. Transplant.,
September 1, 2001;
16(9):
1920 - 1924.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. A Brown and F. B Hu
Dietary modulation of endothelial function: implications for cardiovascular disease
Am. J. Clinical Nutrition,
April 1, 2001;
73(4):
673 - 686.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Calles-Escandon and M. Cipolla
Diabetes and Endothelial Dysfunction: A Clinical Perspective
Endocr. Rev.,
February 1, 2001;
22(1):
36 - 52.
[Abstract]
[Full Text]
|
|
|
|
