Acute effect of pegvisomant on cardiovascular risk markers in healthy men:Implications for the pathogenesis of atherosclerosis in GH deficiency

Cardiovascular risk is increased in GH deficiency (GHD). GHD adults are fre quently abdominally obese and display features of the metabolic syndrome. O therwise healthy abdominally obese subjects have low GH levels and show fea tures of the metabolic syndrome as well. We investigated in healthy nonobes e males the effect of the GH receptor antagonist pegvisomant in different m etabolic conditions. This is a model for acute GHD without the alterations in body composition associated with GHD. We compared the effect of pegvisom ant with that of placebo before and after 3 d of fasting. In addition, we i nvestigated 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 fr ee IGF-I induced by fasting. Pegvisomant alone had no influence on insulin sensitivity. The increase in insulin sensitivity induced by fasting was com parable to the increase in insulin sensitivity induced by fasting combined with pegvisomant. Among serum lipid concentrations, only serum triglyceride s 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 fa sting alone or pegvisomant were not different from those induced by pegviso mant alone. von Willebrand factor antigen levels declined significantly und er 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 metaboli c 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.