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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.
ACROMEGALY IS ASSOCIATED with increased morbidity and premature mortality from cardiovascular disease (1, 2, 3, 4, 5). Patients with acromegaly have an increased prevalence of hypertension (6) and disturbances of intermediary metabolism, including insulin resistance and increased metabolic rate (7, 8). Increased levels of triglycerides (9, 10) and lipoprotein(a) (11) have been reported in acromegaly, whereas hypercholesterolemia has been inconsistently found (11, 12, 13). Therefore, GH hypersecretion may influence risk factors contributing to the increased cardiovascular morbidity associated with acromegaly.
Inflammatory markers, including C-reactive protein (CRP), have emerged as important cardiovascular risk markers (14, 15, 16, 17, 18, 19, 20). We have previously reported that CRP levels are elevated in men with GH deficiency and that GH replacement therapy decreased CRP, suggesting an inverse relationship between GH and CRP levels (21). Little is known regarding levels of inflammatory cardiovascular risk markers in patients with acromegaly. Hyperhomocysteinemia has also been proposed as an independent risk factor for atherosclerosis and thrombosis. Several prospective studies support the association between elevated homocysteine levels and increased cardiovascular risk and mortality (22, 23), but some studies do not (24, 25). Although genetic and dietary factors are the main determinants of homocysteine levels, hormonal influences have been described (26). GH replacement decreases homocysteine levels in men with GH deficiency, suggesting a relationship between GH and homocysteine (27). Homocysteine levels in acromegaly have not been investigated previously.
A genetically engineered GH receptor antagonist, pegvisomant, was developed for the treatment of acromegaly. Pegvisomant binds the GH receptor with high affinity, blocking GH action at the tissue level. In a placebo-controlled trial of 112 acromegalic subjects, pegvisomant administration decreased IGF-I levels in a dose-dependent fashion, and IGF-I levels were reduced to normal in 89% of patients treated with 20 mg/d (28). Results from the ongoing phases II and III studies indicate that continued pegvisomant administration normalizes IGF-I in 98% of patients (29). Therefore, pegvisomant administration produces a model to investigate the impact of selective lowering of IGF-I levels on cardiovascular risk markers in subjects with acromegaly.
Subjects and Methods
Patients
Forty-eight patients with acromegaly (23 females and 25 males) and 47 age- and body mass index-matched healthy controls (29 females, 18 males) were included. Patients were recruited as part of a multicenter trial evaluating the safety and efficacy of pegvisomant (28). Acromegaly was diagnosed according to standard clinical and biochemical criteria (confirmed pituitary adenoma by imaging techniques and elevated IGF-I levels). Inclusion criteria included an elevated IGF-I level of 30% or greater above the age-adjusted upper limit of the normal range. Patients had received primary surgical therapy (n = 24), surgery plus radiation therapy (n = 21), radiation alone (n = 2), or primary medical treatment (n = 1). All patients had active acromegaly at study enrollment, and the majority of patients required medical treatment, mostly with somatostatin analogs (n = 34). After the initial screening visit, medical therapy was withdrawn (
2 wk for short-acting somatostatin analog therapy, 5 wk for dopamine agonist therapy, and 12 wk for long-acting somatostatin analog therapy) before serum IGF-I assessment. Conventional hormone replacement therapy was administered for pituitary hormone deficiencies. Diabetes was diagnosed according to American Diabetes Association criteria (30). Control subjects were recruited through local advertisements. All controls were in good health and had IGF-I levels within the age- and gender-specific normal range.
Study design
The study protocol was approved by the human-research committee at each study site, and all patients provided written informed consent. The study was composed of three parts: 1) a cross-sectional study in which patients at baseline were compared with healthy controls; 2) a prospective 12-wk placebo-controlled study of the effects of the GH antagonist pegvisomant; and 3) a follow-up longitudinal open-label study of pegvisomant therapy for up to 18 months. Parts 2 and 3 are a post hoc analysis of cardiovascular risk factors from the ongoing phase III trial designed to study efficacy and safety of pegvisomant. Only United States centers where sufficient serum was available participated in this substudy.
Cross-sectional study
After an overnight fast, a medical history, blood samples, blood pressure, and anthropometric measures were obtained from all subjects. The cross-sectional visit for patients with acromegaly coincided with the baseline visit of the placebo-controlled study and was performed at six different medical centers. The controls were recruited only at Massachusetts General Hospital after acromegalic subjects had completed the placebo-controlled and the longitudinal open-label studies.
Placebo-controlled study
Patients with acromegaly entered a 12-wk multicenter longitudinal study. Methods and main results regarding IGF-I, GH, and clinical responses of the placebo-controlled part of the trial were previously reported (28). In brief, patients were randomized to receive either placebo (n = 14), 10 mg (n = 12), 15 mg (n = 10), or 20 mg (n = 12) pegvisomant, administered by daily sc injections after a loading dose. Follow-up visits occurred every 4 wk.
Longitudinal open-label study
After the first 12-wk placebo-controlled phase, all patients entered an open-label phase. During this part of the study, pegvisomant was administered at an initial dose of 10 mg/d and individually adjusted, in 5-mg increments at 8-wk intervals, to a maximum daily dose of 35 mg or until IGF-I levels were within the age- and gender-specific normal range. Subjects returned monthly for drug dispensing and safety assessment. Because of a drug shortage, some patients were randomly withdrawn from the study.
Procedures
Blood pressure, anthropometric measures, and fasting blood specimens for GH, IGF-I, and pegvisomant levels were obtained at each visit. Cardiovascular risk markers [including CRP, lipoprotein(a), IL-6, glucose, insulin, homocysteine, triglycerides, total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol] were measured in serum obtained at the baseline and at the 4-wk and 12-wk visits in the placebo-controlled study. In the longitudinal open-label study, the first and all subsequent samples at 3-month intervals in which IGF-I levels were normal were selected to measure cardiovascular risk markers. Only patients who achieved normal IGF-I levels were considered for analysis in the present study (n = 34). In both the placebo- controlled and longitudinal open-label studies, the ratio of total cholesterol to HDL cholesterol was calculated, and the insulin resistance index by the homeostasis model assessment (IRHOMA) (glucose in mM x insulin, in mIU/liter·22.5), was computed as described previously (31).
Biochemical analysis
Total cholesterol and HDL cholesterol concentrations were simultaneously measured on the 911 analyzer (Hitachi Scientific Instruments, Inc., San Jose, CA), using reagents and calibrators from Roche Diagnostics (Indianapolis, IN). The interassay coefficients of variation were 1.65% for total cholesterol and 1.7–3.3% for HDL cholesterol. LDL cholesterol was determined by a homogenous direct method from Genzyme Transgenics Corp., Cambridge, MA. The interassay coefficient of variation, over a wide range of concentrations, was below 3.1%. Insulin was measured by a microparticle enzyme immunoassay, on the IMx analyzer (Abbott Laboratories, Abbott Park, IL), with an interassay coefficient of variation of 3.4–4.5%. Glucose was assessed, using a hexokinase reaction, on Hitachi Scientific Instruments, Inc. instrumentation using Roche Diagnostics reagents with an interassay coefficient of variation of 3.4% at a level of 89 and 3.0% at a level of 230. Triglyceride levels were measured using enzymatic reaction with lipase, glycerol kinase, and glycerol oxidase also using Hitachi instrumentation and Roche Diagnostics reagents, with a coefficient of variation of 2.5% at a level of 121, and 2.2% at a level of 191. Serum insulin-like growth factor-I levels were measured by RIA after acid-alcohol extraction (Nichols Institute Diagnostics, San Juan Capistrano, California), with an intraassay coefficient of variation of 2.4–3.0%. Serum GH was measured by RIA (Endocrine Sciences, Inc., Calabasas Hills, CA) that was modified to avoid cross-reactivity with pegvisomant. Lipoprotein(a) and CRP levels were measured simultaneously on the Behring BNII analyzer (Dade Behring, Newark, DE) by ultrasensitive and latex-enhanced immunotechniques. The interassay coefficients of variation were less than 6%, 7%, and 5.6%, respectively, over a wide range of concentrations. Serum IL-6 concentrations were measured by ultrasensitive ELISA assay from R&D Systems (Minneapolis, MN), with an interassay coefficient of variation of 5.8%. Homocysteine concentration was measured using HPLC with fluorometric detection. The interassay coefficient of variation, at concentrations of 7 and 12 µM, was 3.3% and 2.9%, respectively.
Statistical analysis
Cross-sectional study. Descriptive statistics were used to summarize the subject characteristics. In the cross-sectional phase, groups were compared by ANOVA (normally distributed variables), Wilcoxon rank-sum test (abnormally distributed variables), or chi-square test (nominal variables). Results are presented as the mean ± SD for normally distributed, and median (interquartile range) for nonnormally distributed, variables. Two-sided P values 0.05 or less were considered significant.
Placebo-controlled study. In the prospective placebo-controlled study, ANOVA was used to test whether there was a difference in the change from baseline, at 3 months, between the 20-mg group and the placebo group. We chose to compare the 20-mg group with the placebo group, because this contrast was most likely to show an effect, assuming a monotonic effect of pegvisomant dose.
Longitudinal open-label study.
We, a priori, decided to base the analysis of the longitudinal open treatment study only on those patients who achieved normal IGF-I levels (n = 34). This decision was based on the fact that each patient had an individually adjusted dose regimen and required different times to normalize IGF-I levels. Moreover, some patients were withdrawn from the study before they could attain a normal IGF-I level (because of a drug shortage), and almost all patients treated with an adequate dose and duration of pegvisomant achieved normal IGF-I levels (29). Change from baseline was analyzed using repeated-measures ANOVA at all time points when IGF-I was normal. Results are presented as the estimated change ± SE. Two-sided P values 
0.05 were considered significant.
Patients with diabetes were excluded from analysis of glucose and insulin levels, as well as the IRHOMA index, in all three studies.
Results
Cross-sectional study
Subjects with acromegaly had a mean duration of disease of 4.56 ± 8.2 yr. Of the 48 patients, 21 (44%) had a history of hypertension, 8 (17%) had hypercholesterolemia, 8 (17%) had diabetes mellitus and were treated with insulin or oral hypoglycemic agents, 1 (2%) had impaired fasting glucose, 2 (4%) had congestive heart failure, and 2 (4%) had a history of an acute ischemic event (1 had had a myocardial infarction; and the other, a stroke). Eighteen patients with acromegaly had 1 (n = 12), 2 (n = 4), or 3 (n = 2) pituitary hormone deficiencies. Clinical characteristics of patients and controls included in the cross-sectional study are shown in Table 1
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Longitudinal study (placebo-controlled phase)
Fourteen patients were randomized to placebo, and 12 were randomized to 20 mg pegvisomant. One of the patients randomized to placebo was not considered in the analysis because he received pegvisomant by mistake at the 3-month visit. Four patients (2 in the placebo group and 2 in the 20-mg group) had diabetes and were not considered in the analysis of glucose and insulin levels. Eighty-three percent of patients in the 20-mg group achieved normal IGF-I levels. CRP increased significantly in subjects treated with 20 mg pegvisomant, as compared with placebo (13.7 ± 3.6 vs. 0.5 ± 3.3 mg/liter, P = 0.010) (Fig. 1). No differences, compared with placebo, were found in homocysteine; IL-6; lipoprotein(a); insulin; glucose; triglyceride; total, LDL, and HDL cholesterol levels; or in the insulin resistance index IRHOMA. IGF-I decreased and GH levels increased with pegvisomant treatment, as previously reported (28). Results from the placebo-controlled part of the trial are shown in Table 2.
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Of the 48 patients who entered the open-label follow-up study, 34 (71%) achieved normal IGF-I levels and were considered in the analysis. Eight patients had diabetes and were not considered in the analysis of glucose and insulin levels. CRP levels increased by 2.0 ± 0.5 mg/liter after IGF-I normalization with pegvisomant (P = 0.0002) (Fig. 2). Total cholesterol levels modestly increased by 0.22 ± 0.11 mM (P = 0.050). LDL levels and the ratio of total cholesterol to HDL cholesterol showed a trend toward increasing by 0.13 ± 0.07 mM (P = 0.074) and 0.21 ± 0.11 (P = 0.051), respectively. Serum triglyceride concentrations increased by 0.25 ± 0.09 mM (P = 0.007) (Fig. 3). Lipoprotein(a) levels decreased by 70 ± 33 mg/liter (P = 0.039) (Fig. 4). Glucose, insulin, IRHOMA, homocysteine, HDL cholesterol, and IL-6 did not change significantly with IGF-I normalization. GH levels increased by 13.4 ± 2.4 µg/liter (P < 0.0001), and IGF-I levels decreased by 53 ± 4 nM (P < 0.0001) after pegvisomant administration. Results are shown in Table 3.
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We measured levels of inflammatory and other cardiovascular risk markers in subjects with active acromegaly before and after IGF-I normalization with the GH receptor antagonist, pegvisomant. Our results show that patients with active acromegaly have low CRP levels and that CRP levels increase in association with IGF-I normalization during pegvisomant administration. Based on these results and our previous studies in GH-deficient patients (21, 33), we propose that the GH/IGF-I axis is an important determinant of CRP levels. There is an inverse relationship between GH action and CRP levels, consistent with a negative regulation of the acute-phase response by GH.
CRP is an acute-phase reactant synthesized mainly by hepatocytes in the acute-phase response after stimulation by proinflammatory cytokines (34). The mechanisms underlying the negative association between CRP and GH are unclear, but there is strong evidence of a complex cross-talk between GH and acute-phase cytokine signaling at the molecular level (35, 36). GH acts through cytokine-superfamily receptors and uses molecular pathways involved in cytokine signaling (37). It has been shown that GH and acute-phase response signaling pathways compete for different intracellular proteins, including STAT-5, which could be involved in the inhibition of the acute-phase response (and therefore, CRP synthesis) by GH (38). In addition, several GH-responsive genes are among the negative acute-phase reactants (38). There are different clinical models that support the negative regulation of the acute-phase response by GH. Experimental studies in murine models of stress, including sepsis and burn trauma, have shown that GH administration attenuates the acute-phase response and reduces cytokine hyperproduction (39, 40). Cytokine and CRP production have been studied also in adults with GH deficiency (21, 41). Serri et al. (41) demonstrated an increase in plasma levels of TNF-
and IL-6 in patients with GH deficiency, compared with healthy control subjects. In addition, elevated cytokine production by monocytes in patients with GH deficiency was demonstrated, and GH treatment decreased plasma cytokine levels and monocyte-macrophage cytokine production in vitro (41). We recently demonstrated high CRP levels both in men and women with hypopituitarism and GH deficiency (21, 33). CRP levels in GH-deficient patients were in the highest quintile, compared with normative data for the general population. Moreover, both CRP and IL-6 levels were lowered by GH therapy, compared with placebo, suggesting an effect of GH in lowering CRP levels (21).
Another potential hypothesis to explain GH effects on CRP is the effect of GH on visceral and central fat. Because adipose tissue is a source of IL-6 synthesis (42, 43) and IL-6 is an important regulator of CRP production (34), low CRP levels in active acromegaly may reflect the low proportion of fat in such patients (44). However, we could not detect significant changes in IL-6 levels in the present study, suggesting that the increases in CRP were attributable to other mechanisms.
Pegvisomant blocks GH receptor activation, preventing intracellular signaling and decreasing IGF-I levels (28). The effects observed on CRP could be mediated by the decrease in IGF-I production or a direct effect of GH receptor blockade.
The significance of our findings is not clear. Rising levels of CRP during acute inflammation and chronic elevations, as determined by high-sensitivity assay, are thought to represent silent chronic inflammation, including processes such as atherosclerosis and other chronic inflammatory diseases (45). CRP levels have been shown to predict risk of future cardiovascular events (14, 17, 46). Moreover, CRP adds to the total to HDL cholesterol ratio in cardiovascular risk prediction, and algorithms for cardiovascular risk assessment based on these 2 parameters have recently been proposed (32). In this study, we show that active acromegaly is associated with very low levels of CRP. Compared with published normative data, patients with active acromegaly have levels in the lowest quintile of the distribution for the United States population (32). After administration of pegvisomant, CRP levels increased both in the 12-wk placebo and in the open-label phase. However, acromegaly is known to be associated with high cardiovascular risk and atherosclerosis. Our data suggests that CRP in patients with acromegaly is not a marker of cardiovascular risk, as it is in the general population. Recently, Otsuki et al. (47) have studied the intimal media thickness in a cohort of 21 patients with active acromegaly and have compared it with 2 control groups. The authors concluded that, intimal-media thickness in patients with acromegaly is lower than in matched controls and lower than that predicted by classic cardiovascular risk factors (age, sex, dyslipoproteinemia, smoking history, hypertension, and diabetes), based on a cohort of 282 controls. It could be speculated that low CRP levels in acromegaly counteract the risk given by other cardiovascular risk factors, including hypertension and diabetes. There are no systematic prospective studies that assess cardiovascular risk markers and cardiovascular morbidity or mortality in acromegaly. Additional studies are needed to determine the significance of our findings and the pathogenesis underlying cardiovascular mortality in patients with acromegaly.
The magnitude of the increase in CRP levels in the placebo-controlled study was considerable (13.7 ± 3.6 mg/liter). Levels of CRP over 15 mg/liter in the general population (
99th percentile of the general population) are considered to represent acute inflammation (48). In the placebo-controlled study, 42% of patients who took 20 mg/d pegvisomant had CRP levels over 15 mg/liter in the first 3 months of therapy (whereas none on placebo did), and 12% of patients in the longitudinal study had at least one value of CRP over 15 mg/liter. The pathophysiological significance of elevated CRP levels with pegvisomant treatment is unknown. One must consider the possibility that pegvisomant therapy may directly result in inflammation.
We did not find differences in total, LDL, and HDL cholesterol or triglyceride levels between patients and controls at baseline. In addition, no significant changes in these levels were found during pegvisomant administration in the placebo-controlled part of the study. In the longitudinal open-label treatment phase, there were small increases in total cholesterol, the ratio of total to HDL cholesterol, and triglyceride levels and a decrease in lipoprotein(a) levels. Total cholesterol levels in patients with acromegaly were previously reported to be either increased (12) or comparable (49) with levels in control subjects. Somatostatin analog therapy in acromegaly decreases triglyceride levels, but its impact upon cholesterol levels has been contradictory (9, 13, 50). Because a number of patients who participated in the present study had previously been treated with somatostatin analog therapies, it is impossible to rule out an effect of somatostatin analog withdrawal. Moreover, the changes seen only in the longitudinal open-label study could be attributable to factors other than the drug intervention. Additional studies are needed to confirm an effect of IGF-I normalization with pegvisomant on cholesterol and triglyceride levels.
Lipoprotein(a) levels decreased after IGF-I normalization with pegvisomant. Other treatment modalities of acromegaly have been reported to decrease lipoprotein(a) levels (11). Conversely, lipoprotein(a) levels increase after GH replacement in adults with GH deficiency, supporting a role for GH in the regulation of lipoprotein(a) levels. This influence may be a direct effect of GH not mediated by IGF-I, because IGF-I administration alone lowered lipoprotein(a) in one study (51).
No significant changes in glucose, insulin, or IRHOMA were observed in the placebo-controlled and the longitudinal open-label studies. Although the present study does not carefully evaluate insulin resistance, long-term treatment with pegvisomant did not change fasting insulin levels or insulin resistance parameters. In a recent abstract, administration of pegvisomant to 16 acromegalic subjects in an open-label study resulted in a reduction in fasting plasma insulin and an improvement in insulin sensitivity, calculated by the homeostasis model assessment (52). The reasons for our different results are unclear.
Limitations of this study have to be considered. The placebo-controlled and longitudinal open-label studies were not designed to assess the effects of pegvisomant on cardiovascular risk factors; therefore, it was not powered to detect changes in the parameters studied in the present work. This study is based on the phase III efficacy and safety trial of a new drug, and our findings are preliminary.
In conclusion, our study shows that patients with active acromegaly have low levels of CRP and that CRP levels increase after IGF-I normalization with administration of the GH receptor antagonist pegvisomant. We propose that GH status is an important determinant of CRP levels. Additional studies are needed to clarify the mechanism and the pathophysiologic significance of these findings.
Acknowledgments
Footnotes
This work was supported by Sensus Drug Development Corporation, Austin, Texas.
Abbreviations: CRP, C-reactive protein; HDL, high-density lipoprotein; IRHOMA, insulin resistance index by the homeostasis model assessment; LDL, low-density lipoprotein.
Received October 19, 2001.
Accepted December 19, 2001.
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), 10 mg (•), 15 mg (
), and 20-mg (
) groups. The P value for comparison of changes from baseline, between the 20-mg and placebo groups, at 3 months, is 0.010. Error bars, SEM.
