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.