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Acute Effect of Pegvisomant on Cardiovascular Risk Markers in Healthy Men: Implications for the Pathogenesis of Atherosclerosis in GH Deficiency

Departments of Internal Medicine (A.F.M., J.A.M.J.L.J., S.W.J.L., L.H., A.J.V.D.L.) and Hematology (F.W.G.L.), Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: A. F. Muller, M.D., Department of Internal Medicine, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. E-mail: muller{at}inw3.azr.nl

Abstract

Cardiovascular risk is increased in GH deficiency (GHD). GHD adults are frequently abdominally obese and display features of the metabolic syndrome. Otherwise healthy abdominally obese subjects have low GH levels and show features of the metabolic syndrome as well. We investigated in healthy nonobese males the effect of the GH receptor antagonist pegvisomant in different metabolic conditions. This is a model for acute GHD without the alterations in body composition associated with GHD. We compared the effect of pegvisomant with that of placebo before and after 3 d of fasting. In addition, we investigated the effect of pegvisomant under normal, i.e. fed, conditions.

Three days of fasting as well as pegvisomant alone decreased serum free IGF-I levels (1.0 ± 0.15 vs. 0.31 ± 0.05 ng/ml and 0.86 ± 0.23 vs. 0.46 ± 0.23 ng/ml, respectively). Fasting in combination with pegvisomant also decreased serum free IGF-I levels (1.0 ± 0.15 vs. 0.31 ± 0.07 ng/ml). Treatment with pegvisomant had no additional influence on the decline of free IGF-I induced by fasting. Pegvisomant alone had no influence on insulin sensitivity. The increase in insulin sensitivity induced by fasting was comparable to the increase in insulin sensitivity induced by fasting combined with pegvisomant. Among serum lipid concentrations, only serum triglycerides increased significantly as a result of pegvisomant alone (1.0 ± 0.2 vs. 1.6 ± 0.4 mmol/liter). The changes in lipid concentrations induced by fasting alone or pegvisomant were not different from those induced by pegvisomant alone. von Willebrand factor antigen levels declined significantly under the influence of pegvisomant alone (1.1 ± 0.07 vs. 0.8 ± 0.06 U/ml).

In conclusion, in different metabolic conditions the GH receptor antagonist pegvisomant induces no significant acute changes in the major risk markers for cardiovascular disease. These data suggest that the secondary metabolic changes, e.g. abdominal obesity or inflammatory factors, that develop as a result of long-standing GHD are of primary importance in the pathogenesis of atherosclerosis in patients with GHD.

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