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

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.

Associations between plasma insulin-like growth factor-I and the markers of inflammation interleukin 6, C-reactive protein and YKL-40 in an elderly background population

“…As an alternative hypothesis, GH-IGF-I activity could, under normal physiological conditions, have anti-inflammatory properties, but this effect might be perturbed when an inflammatory state is triggered by other factors. In support of this suggestion, studies in patients with primary growth hormone disturbances, investigated before and after normalisation of IGF-I, have indicated that levels of GH and IGF-I inversely influenced levels of inflammatory markers [25][26][27]. The GH/IGF-I excess in acromegaly, especially, seems to have dramatic anti-inflammatory effects based on measurement of subnormal levels of serum hsCRP [25,27].…”

Decreased variation of inflammatory markers in gestational diabetes

“…It downregulates IL-1-and IL-6-induced acute-phase protein gene expression in the liver through increased gene expression of the suppressor of cytokine signalling 3 [23]. The antiinflammatory effect of the growth hormone is evident also in non-pregnant subjects [24,25]. The special sensitivity of AGP to the growth hormone can be explained by an additional mechanism: the growth hormone inhibits AGP gene expression at the transcriptional level [22].…”

Distúrbios cardiovasculares na acromegalia

“…No trabalho de Sesmilo e cols. (67), após 18 meses de pegvisomanto, houve aumento do colesterol total e dos triglicerí-deos, enquanto a Lp-a diminuiu. Nesse mesmo estudo, houve aumento dos níveis de proteína C-reativa ultrasensível após o tratamento, achado este que também ocorreu no estudo de Vilar e cols.…”