This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sesmilo, G. Articles by Klibanski, A. Search for Related Content PubMed PubMed Citation Articles by Sesmilo, G. Articles by Klibanski, A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH

Cardiovascular Risk Factors in Acromegaly before and after Normalization of Serum IGF-I Levels with the GH Antagonist Pegvisomant

Neuroendocrine Clinical Center (W.F., L.K., K.P., D.H., A.K.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; Servicio de Endocrinologia (G.S.), Hospital Clínic de Barcelona, Barcelona, Spain; Columbia College of Physicians and Surgeons (P.F.), New York, New York; Pituitary Center (V.B.), Cedars Sinai Hospital, Los Angeles, California; Division of Endocrinology and Metabolism (E.D.), University of Michigan, Ann Arbor, Michigan 48109; Department of Internal Medicine (Endocrinology and Metabolism) (M.L.V.), University of Virginia Health System, Charlottesville, Virginia 22908; and Division of Endocrinology (S.S.), New York University Medical Center, New York, New York 10016

Address all correspondence and requests for reprints to: Anne Klibanski, M.D., Neuroendocrine Unit Massachusetts General Hospital, Fruit Street, Bulfinch 457B, Boston, Massachusetts 02114. E-mail: . aklibanski{at}partners.org

Abstract

Acromegaly is associated with premature cardiovascular mortality. GH replacement therapy decreases inflammatory markers of cardiovascular risk, but little is known about these markers in patients with acromegaly. The GH receptor antagonist, pegvisomant, reduces IGF-I levels in 98% of patients treated. We investigated the effects of GH receptor blockade on inflammatory and other cardiovascular risk markers in active acromegaly.

Forty-eight patients with acromegaly and 47 age- and body mass index-matched controls were included. The study consisted of 3 parts: a cross-sectional study, a prospective randomized 12-wk placebo-controlled study, and a longitudinal open-label study of up to 18 months of pegvisomant treatment.

After baseline evaluation, patients with acromegaly were randomized to placebo (n = 14), 10 mg (n = 12), 15 mg (n = 10), or 20 mg (n = 12) daily pegvisomant for 12 wk. Subsequently, all patients received at least 10 mg pegvisomant daily for up to 18 months, with dose adjustments to achieve a normal IGF-I level. Anthropometry, GH, IGF-I, and pegvisomant levels were measured monthly. C-reactive protein (CRP), IL-6, homocysteine, lipoprotein(a), glucose, insulin, triglycerides, total cholesterol, and high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol were determined at baseline, 4 and 12 wk in the placebo-controlled study and at 3-month intervals (during which IGF-I levels were normal) in the longitudinal study.

In the cross-sectional study, patients had lower CRP than did controls [median, 0.3 (range, 0.2–0.8) vs. 2.0 (0.6–3.7) mg/liter; P < 0.0001] and had higher insulin [78.6 (55.8–130.2) vs. 54.5 (36.6–77.5) pM, P = 0.0051]. IL-6, homocysteine, triglycerides, lipoprotein(a), LDL cholesterol and HDL cholesterol were not different between groups. In the placebo-controlled study, CRP increased in patients treated with 20 mg pegvisomant, compared with placebo (mean ± SEM, 13.7 ± 3.6 vs. 0.5 ± 3.3 mg/liter; P = 0.010). There were no significant differences in IL-6, homocysteine, glucose, insulin, triglyceride, total cholesterol, LDL cholesterol and HDL cholesterol levels. In the longitudinal open-label study (median duration, 15.6 months), CRP increased by 2.0 ± 0.5 mg/liter (P = 0.0002). Total cholesterol and triglycerides increased (0.22 ± 0.11 mM, P = 0.050; and 0.25 ± 0.09 mM, P = 0.007, respectively), whereas lipoprotein(a) decreased (-70 ± 33 mg/liter, P = 0.039). Glucose, insulin, homocysteine, HDL cholesterol, and IL-6 did not change.

We conclude that patients with active acromegaly have lower CRP and higher insulin levels than healthy controls. Administration of pegvisomant increases CRP levels. We propose that GH secretory status is an important determinant of serum CRP levels, although additional studies are needed to determine the mechanism and significance of this finding.

This article has been cited by other articles:

				M. P. Brugts, A. W. van den Beld, L. J. Hofland, K. van der Wansem, P. M. van Koetsveld, J. Frystyk, S. W. J. Lamberts, and J. A. M. J. L. Janssen Low Circulating Insulin-Like Growth Factor I Bioactivity in Elderly Men Is Associated with Increased Mortality J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2515 - 2522. [Abstract] [Full Text] [PDF]

				E. A. Lawson, K. K. Miller, V. A. Mathur, M. Misra, E. Meenaghan, D. B. Herzog, and A. Klibanski Hormonal and Nutritional Effects on Cardiovascular Risk Markers in Young Women J. Clin. Endocrinol. Metab., August 1, 2007; 92(8): 3089 - 3094. [Abstract] [Full Text] [PDF]

				A. N. Paisley, C. J. O'Callaghan, K. C. Lewandowski, C. Parkinson, M. E. Roberts, W. M. Drake, J. P. Monson, P. J. Trainer, and H. S. Randeva Reductions of Circulating Matrix Metalloproteinase 2 and Vascular Endothelial Growth Factor Levels after Treatment with Pegvisomant in Subjects with Acromegaly J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4635 - 4640. [Abstract] [Full Text] [PDF]

				H Biering, B Saller, J Bauditz, M Pirlich, B Rudolph, A Johne, M Buchfelder, K Mann, M Droste, I Schreiber, et al. Elevated transaminases during medical treatment of acromegaly: a review of the German pegvisomant surveillance experience and a report of a patient with histologically proven chronic mild active hepatitis Eur. J. Endocrinol., February 1, 2006; 154(2): 213 - 220. [Abstract] [Full Text] [PDF]

				C. A. Hurty and B. Flatland Feline Acromegaly: A Review of the Syndrome J. Am. Anim. Hosp. Assoc., September 1, 2005; 41(5): 292 - 297. [Abstract] [Full Text] [PDF]

				K.-C. Leung, G. Johannsson, G. M. Leong, and K. K. Y. Ho Estrogen Regulation of Growth Hormone Action Endocr. Rev., October 1, 2004; 25(5): 693 - 721. [Abstract] [Full Text] [PDF]

				A. Colao, D. Ferone, P. Marzullo, and G. Lombardi Systemic Complications of Acromegaly: Epidemiology, Pathogenesis, and Management Endocr. Rev., February 1, 2004; 25(1): 102 - 152. [Abstract] [Full Text] [PDF]

				D. R. Clemmons, K. Chihara, P. U. Freda, K. K. Y. Ho, A. Klibanski, S. Melmed, S. M. Shalet, C. J. Strasburger, P. J. Trainer, and M. O. Thorner Optimizing Control of Acromegaly: Integrating a Growth Hormone Receptor Antagonist into the Treatment Algorithm J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4759 - 4767. [Abstract] [Full Text] [PDF]

				W. Vongpatanasin, M. Tuncel, Z. Wang, D. Arbique, B. Mehrad, and I. Jialal Differential effects of oral versus transdermal estrogen replacement therapy on C-reactive protein in postmenopausal women J. Am. Coll. Cardiol., April 16, 2003; 41(8): 1358 - 1363. [Abstract] [Full Text] [PDF]

				X. Zhang, T. Zhu, Y. Chen, H. C. Mertani, K.-O. Lee, and P. E. Lobie Human Growth Hormone-regulated HOXA1 Is a Human Mammary Epithelial Oncogene J. Biol. Chem., February 21, 2003; 278(9): 7580 - 7590. [Abstract] [Full Text] [PDF]