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Departments of Internal Medicine and Neurosurgery (A.L.B.), University of Michigan Medical Center, Ann Arbor, Michigan 48109-0354; Pfizer, Inc. (P.B., P.E.H.), New York, New York 10017-5755; Division of Endocrinology/Metabolism, University of North Carolina School of Medicine (D.R.C.), Chapel Hill, North Carolina 27599; Department of Endocrinology, St. Bartholomew’s Hospital (W.M.D.), London EC1A 7BE, United Kingdom; Department of Endocrinology (W.M.D., P.J.T.), Christie Hospital, Manchester M20 4BX, United Kingdom; Division of Internal Medicine, University of Texas M. D. Anderson Medical Center (R.F.G.), Houston, Texas 77030; Erasmus Medical Center Rotterdam (A.J.v.d.L.), 3000 CA Rotterdam, The Netherlands; and Department of Internal Medicine, University of Virginia Health Sciences Center (M.L.V.), Charlottesville, Virginia 22908
Address all correspondence and requests for reprints to: Dr. Ariel L. Barkan, Departments of Internal Medicine and Neurosurgery, University of Michigan Medical Center, 3920 Taubman Center, Ann Arbor, Michigan 48109-0354. E-mail: abarkan{at}med.umich.edu.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Objectives: The objectives of this study were to monitor changes in IGF-I levels, glycemic control, and safety, particularly liver function and tumor size.
Design: This was a multicenter, open-label, 32-wk trial study.
Setting: The study was performed at outpatient clinics.
Patients: Fifty-three patients with acromegaly previously treated with octreotide long-acting release (LAR) participated in this study.
Intervention: Pegvisomant (10 mg/d) was initiated 4 wk after the last dose of octreotide LAR and was adjusted based on serum IGF-I concentrations at wk 12, 20, and 28.
Main Outcome Measures: The main outcome measures were changes in IGF-I, glycosylated hemoglobin A1c (HbA1c), fasting plasma glucose, and safety during the first 12 wk after conversion.
Results: At the end of pegvisomant treatment, IGF-I was normalized in 78% of patients. At wk 32, median fasting glucose concentration and HbA1c were reduced (–1.4 mmol/liter and –0.4%, respectively; both P 
0.0001) in the study population. Improvements in glycemic control occurred in patients with normal IGF-I concentrations at wk 4 [n = 15; fasting glucose, –1.7 mmol/liter (P 0.0001); HbA1c –0.2% (P = 0.03)]. Decreases in fasting glucose and HbA1c levels were observed in patients with and without diabetes. HbA1c was reduced by more than 1.0% in patients with diabetes. Median pituitary tumor volume did not change, although tumor volume increased in two patients with macroadenomas.
Conclusions: Conversion from octreotide LAR to pegvisomant was safe and well tolerated. Improved glycemic control indicates that pegvisomant should be considered in patients with acromegaly and diabetes.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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It is well documented that lowering GH levels and normalization of IGF-I concentrations in patients with acromegaly improves glucose homeostasis. Somatostatin analogs (i.e. octreotide and somatuline) alter glucose homeostasis by inhibiting GH and insulin secretion (10, 11, 12, 13, 14). Pegvisomant is a specific GH receptor antagonist that does not directly affect insulin secretion. In two pilot studies (one in normal volunteers and one in patients with acromegaly), glucose homeostasis tended to deteriorate with octreotide treatment (12, 14), whereas treatment with pegvisomant had a neutral or positive effect (12, 15).
In clinical practice, a proportion of patients with acromegaly are switched from therapy with long-acting somatostatin analogs to pegvisomant. However, the effect of this change on glucose homeostasis has not been reported in a large series of patients. Therefore, in this study, we examined the changes in glucose homeostasis and other safety parameters that occurred in patients who were converted from octreotide long-acting release (LAR) to pegvisomant.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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This multicenter, open-label study included patients 18 yr of age or older with an established diagnosis of acromegaly. Of 53 patients enrolled in the study, 48 had been treated with pegvisomant for acromegaly in at least one of two previous clinical trials. At the conclusion of those trials and because of the lack of available pegvisomant, all patients received octreotide LAR therapy. To be eligible for enrollment in the current study, the treatment duration with octreotide LAR had to be 3 months or more.
Patients were excluded from the study if they had a pituitary adenoma within 3 mm of the optic chiasm, severe symptomatology (cranial nerve palsies or intracranial hypertension) that required surgery for tumor decompression, or another condition (severe hepatic or renal disease, malnutrition, current therapy with levodopa, or known or suspected drug or alcohol abuse) that could alter GH or IGF-I concentrations. All women of child-bearing age were required to use an acceptable form of contraception throughout the study; those who were pregnant or nursing were excluded from participation. In accordance with the Declaration of Helsinki, an institutional review board at each study site approved the protocol. All patients provided written informed consent before study participation.
Patients received their last dose of octreotide LAR at the wk 0 visit (Fig. 1
). Treatment with a dopamine receptor agonist was discontinued 8 wk before the wk 4 visit when applicable. Surgery, pituitary radiation therapy, and treatment with a somatostatin analog were prohibited after wk 0. Pegvisomant (10 mg/d, sc) was initiated at wk 4 and was adjusted in 5-mg increments at wk 12, 20, and 28 depending on the serum IGF-I concentration (Fig. 1). More rapid dose escalation (up to 40 mg) was allowed in two patients based on the effective dose observed in a previous study. Unlike previous clinical studies with pegvisomant, no loading dose was administered in this study.
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). Patients without diabetes also underwent an oral glucose tolerance test at a dose of 75 g for determination of glucose area under the concentration-time curve (AUC) at wk 4 (before the initiation of pegvisomant) and at wk 32. Plasma glucose levels were measured at 15 min before and 0, 30, 60, 90, 120, 150, and 180 min after oral glucose ingestion. Assays for serum IGF-I and GH concentrations were performed by a single independent laboratory (Endocrine Sciences, Inc., an Esoterix Co., Calabasas Hills, CA). Serum IGF-I was measured using the IGF-I Nichols Kit (Nichols Institute Diagnostics, Paris, France), a competitive binding RIA. Normal reference ranges for adult men and women were as follows: 16–24 yr, 182–780 ng/ml; 25–39 yr, 114–492 ng/ml; 40–54 yr, 90–360 ng/ml; and 55 yr or older, 71–290 ng/ml. Serum GH was measured with a standard double-antibody RIA; antiserum was saturated with B2036 (the protein component of pegvisomant) to eliminate cross-reactions with pegvisomant. The assay sensitivity was estimated at 0.5 ng/ml, and the interassay coefficient of variation was 16%. All other clinical laboratory samples were analyzed using standard commercial assays.
Vital signs and adverse effects were monitored at each study visit; clinical and laboratory assessments were conducted at screening and wk 4 visits and at 4-wk intervals during the study.
Magnetic resonance imaging (MRI) of the pituitary and ultrasound of the gallbladder were performed at wk 0 and 32. For MRI of the pituitary, coronal and sagittal T1-weighted images were obtained before and after the administration of gadolinium contrast. Films were interpreted by a single neuroradiologist after they had been scanned with a high-resolution L75 film scanner (Lumisys, Inc., Sunnyvale, CA). Tumors were measured by a neuroradiologist who used hand tracings in conjunction with National Institutes of Health image analysis software (available from Scion Corp., Frederick, MD). Total tumor volume was estimated by multiplying each slice thickness by the area inside the curve of the hand-traced image, then summing the volumes of the slices (16). Ultrasound of the gallbladder was performed at individual centers through standard procedures.
Statistical analysis
All patients enrolled in the study who had received at least one dose of pegvisomant were included in the analyses. All summaries were based on available data, with no imputation performed for missing values. Wilcoxon rank-sum tests were used for within-group comparisons, and P < 0.05 was considered significant. The Spearman nonparametric rank correlation was used to detect for a correlation between decreases in HbA1c levels and reduction in serum IGF-I levels.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Patients receiving previous octreotide LAR therapy had been treated for a median of 562 d (range, 107-1336 d) before they were converted to treatment with pegvisomant. Of 53 patients, 51 (96%) completed 12 wk of treatment with pegvisomant, and 49 (93%) completed the 32-wk study. Four patients discontinued the study; one became ineligible after treatment had started (wk 4) when it was confirmed that he/she had not received the full 3-month treatment with octreotide LAR before enrollment in the study, one withdrew before wk 12 because of a nonserious adverse effect (continuous headache of moderate intensity), one withdrew after wk 12 for personal reasons, and one died before wk 28 as a result of myocardial infarction. Patient demographic data at wk 4, previous treatment information, and IGF-I concentrations at wk 4 are presented in Table 1.
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In all patients, including those with diabetes and those without diabetes, indices of glycemia improved by wk 12, and improvement continued up to wk 32 of pegvisomant therapy (Table 2). Median fasting glucose concentrations decreased at wk 12 and 32 (P 0.0001 vs. wk 4 for both). Similarly, HbA1c decreased by wk 12 and continued decreasing to wk 32 (P 0.0001 vs. wk 4 for both). The decrease in HbA1c correlated with a reduction in serum IGF-I (r = 0.33; P = 0.02). Among patients without diabetes, median fasting insulin concentrations were increased at wk 12 (P = 0.003 vs. wk 4). Fasting insulin then decreased, but the values at wk 32 were still significantly greater than those at wk 4 (P = 0.044). At wk 32, the median glucose AUC decreased by 227 mmol/h·liter (P < 0.0001 vs. wk 4), and median 2-h glucose decreased by 0.8 mmol/liter (P 0.0001 vs. wk 4; Table 2). Table 3 provides data on the subset of patients with levels of IGF-I at baseline that were either normal or high; trends similar to those reported among patients with or without diabetes were observed in fasting glucose, HbA1c, fasting insulin, and glucose AUC levels. Only in the 2-h glucose levels was some variation seen from the previous comparison. The group with normal IGF-I levels showed a small increase from a median of 6.4 mmol/liter at wk 4 to 6.8 mmol/liter at wk 32, whereas the group with high IGF-I levels at baseline showed an overall decline from a median of 7.8 mmol/liter at wk 4 to 6.1 mmol/liter at wk 32.
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0.0001 vs. wk 4) after patients were converted to pegvisomant, whereas median IGF-I concentrations remained unaltered and within the normal range (Fig. 2). Median HbA1c decreased from 5.8% to 5.6% (P = 0.03). The corresponding values for median fasting insulin for nondiabetic patients were 42 and 49 pmol/liter (not significant). In patients with normal IGF-I concentrations, median glucose AUC concentrations decreased from 1509 mmol/h·liter at wk 4 to 1286 mmol/h·liter at wk 32 (P = 0.05), and median 2-h glucose concentrations decreased from 7.5 to 6.8 mmol/liter at wk 32 (not significant). Changes in fasting plasma glucose and HbA1c concentrations in this normal IGF-I group at wk 4 paralleled those in the group with high IGF-I concentrations (Fig. 3). No significant changes in median body weight occurred over the 32 wk of treatment.
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Changes in fasting glucose and HbA1c were observed at wk 32 in patients with and without diabetes. In patients without diabetes, the median change from wk 4 in HbA1c at wk 32 was –0.4% (P 0.0001). The largest differences were observed in patients with diabetes (Figs. 4 and 5), in whom HbA1c decreased by more than 1.0% by the end of the study (P = 0.007). These changes remained significant, even after exclusion of the two patients with diabetes who were converted from dietary restrictions to oral hypoglycemic agents.
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The mean final dose of pegvisomant at wk 32 was 16.0 mg/d (range, 5–40 mg/d). Overall, median IGF-I concentrations decreased from 443 ng/ml at wk 4 to 292 ng/ml at wk 32 (P < 0.001). At wk 4 (initiation of pegvisomant therapy), 15 (29%) patients had IGF-I concentrations within the normal range, whereas 37 (71%) had elevated IGF-I concentrations, and one (2%) patient had an IGF-I concentration below the age-adjusted normal range. Pegvisomant reduced IGF-I concentrations to the age-adjusted normal range in 78% (38 of 49) of patients by wk 32 (Fig. 6). IGF-I concentrations were reduced in patients with IGF-I concentrations above the age-adjusted reference range (P < 0.0001), but were not significantly changed in patients with normal IGF-I concentrations at wk 4. During the initial 12 wk of pegvisomant treatment, IGF-I concentrations decreased below the lower limit in three (6%) patients, all of whom had normal IGF-I concentrations at wk 4. Among all patients, the median level of GH at wk 4 was 3 µg/liter, rising to 13 µg/liter by wk 12 and remaining at approximately 17 µg/liter from wk 24 until the end of the study.
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MRI data at wk 0 and 32 were available for 41 patients. Overall, no significant change in pituitary tumor volume was noted over the study period (median change, 0.02 cm3; range, –0.73 to 1.1; P = 0.3). Two patients had increased tumor volume of approximately 1 cm3. One patient had a large (18.6 cm3) aggressive tumor at the start of the study that continued to grow despite multiple treatments with surgery (twice), radiotherapy (twice), dopamine agonist therapy, somatostatin analog therapy, and chemotherapy (two cycles of 5-fluorouracil plus lomustine and pegvisomant). The second patient had undergone surgery for a macroadenoma in 1987, at which time acromegaly was not confirmed. Seven years later, the patient was referred because of signs and symptoms and was diagnosed with acromegaly. MRI illustrated a tumor with intrasellar and parasellar locations. The patient was treated with a dopamine agonist and octreotide LAR for approximately 4 yr. Treatment with pegvisomant was then given for a total period of 21 months, during which tumor volume remained unchanged. Because of the lack of pegvisomant availability, the patient was switched to octreotide LAR for approximately 18 months before he was enrolled in the current study. During this period, tumor size was not significantly changed. The tumor was 1.33 cm3 at the beginning of the study; after octreotide LAR had been stopped and pegvisomant had been initiated, an increase in tumor size to 2.24 cm3 was observed at the 32 wk visit. Additional treatment with pegvisomant for another 12 months resulted in a stable tumor size.
Other safety parameters
Conversion from octreotide LAR to pegvisomant was generally well tolerated. Overall, from wk 4 to 32, 14 of 53 (26%) patients reported at least one adverse event that was considered possibly related to treatment. Treatment-related adverse events most frequently reported during the study were constipation (n = 2) and injection site reaction (n = 2); both were reported to be mild. Serious adverse effects, which were not judged to be treatment related, were single cases of spinal stenosis (before wk 20) and fatal myocardial infarction (before wk 28). In addition, no abnormalities in clinical or laboratory assessments were noted. Transiently abnormal hepatic function test results were reported in three patients at some point in the study. Single elevations in alanine aminotransferase occurred at wk 20 (
7 times the upper limit of normal) in one patient and at wk 24 (4.5 times the upper limit of normal) in another patient. The third patient had fluctuations in alanine aminotransferase throughout the study, but the value was never greater than 3.5 times the upper limit of normal. In all patients, elevations returned to normal with continued treatment and without dose reduction of pegvisomant. Ultrasound of the gallbladder was performed at wk 0 and 32 in 48 patients. At wk 0, 40% (19 of 48) of patients had signs of gallbladder disease, 15 had gallstones, and four had gallbladder sludge. Five patients had previously undergone cholecystectomy. Ultrasound results at wk 32 (after 28 wk of treatment with pegvisomant) showed gallstones in 13 patients and gallbladder sludge in three patients.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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GH increases glucose production, primarily through its ability to stimulate lipolysis, providing free fatty acids and glycerol as metabolic substrates. Additionally, GH inhibits insulin-induced suppression of hepatic gluconeogenesis (4). In patients with GH deficiency, the combined administration of GH and acipimox, a compound that inhibits lipolysis, is accompanied by enhanced insulin sensitivity (17, 18). In acromegaly, excessive GH secretion is compensated by hyperinsulinemia. Abnormal glucose tolerance develops in patients with acromegaly and concomitant ß-cell insufficiency (19), and a proportion of patients (19–38%) develop overt diabetes mellitus (19), with a higher incidence (49%) reported in Japanese patients (9, 10, 11, 12, 20). The effects on glucose balance reflect the relative influence of insulin secretion and GH antagonism of insulin action as well as other variables that alter individual susceptibility to the development of type 2 diabetes.
In the current study, the peak increase in insulin concentrations observed at wk 12 is consistent with an escape from the inhibitory effects of octreotide LAR. At wk 32, a higher percentage of patients had normal IGF-I levels, an effect of antagonizing the excessive effects of GH. This was accompanied by an expected reduction in insulin levels compared with those at wk 12. Pegvisomant, which is a specific GH receptor antagonist, does not in itself suppress insulin secretion but lowers insulin secretion indirectly by blocking the effects of excess GH on insulin action. Consistent with previous studies (21, 22), indices of glucose homeostasis improved during treatment with pegvisomant. Additionally, a subgroup of patients who had normal IGF-I concentrations while receiving octreotide LAR experienced additional reductions in glucose and HbA1c while receiving pegvisomant, illustrating the different effects of the two compounds on insulin homeostasis. Diabetic patients were excluded from analyses of the effects of therapy on insulin homeostasis because they received insulin or oral hypoglycemic agents, which affects insulin secretion.
In patients with type 2 diabetes, a decrease in HbA1c of the magnitude observed in this study has been found to significantly reduce the risk for microvascular complications (23). Moreover, in a large cohort of 4743 patients with diabetes, fasting plasma glucose was a predictor of cardiovascular disease-related death in type 2 diabetes, independent of other traditional risk factors (24). In patients with acromegaly, the presence of diabetes has been observed to contribute to premature mortality (25), and impaired glucose tolerance has been found to correlate with the severity of acromegalic cardiomyopathy (26). These observations deserve consideration in the selection among therapeutic choices for patients with acromegaly and diabetes mellitus.
In the present study, the percentage of patients who achieved age-adjusted normal IGF-I concentrations reached 78% at wk 32. In two previous clinical trials with pegvisomant (21, 27), IGF-I normalization rates as high as 89% and 97% were reported. The lower rate of normalization in this study may be attributable to a limitation inherent in the study design [i.e. fixed dose escalation regimen allowing for a maximum dose of pegvisomant of 20 mg/d in most patients; exception in two patients (40 mg/d)].
The conversion of octreotide LAR to pegvisomant was safe and well tolerated. In contrast to the situation in which somatostatin analogs have been washed out before pegvisomant therapy commences, the dose of pegvisomant that first normalizes IGF-I will not reliably predict the final dose requirement with the present procedure. Overlapping pharmacological effects on IGF-I concentrations must be taken into consideration when the dose of pegvisomant is titrated within the first 3–4 months of octreotide LAR therapy discontinuation.
Overall, tumor volumes were not changed. However, in one patient with an aggressive and large tumor that required multiple treatments, the tumor continued to grow. In the second patient, an increase in tumor size was noted during the study, after which tumor size remained stable during another 12 months of treatment with pegvisomant. Increases in tumor volume after discontinuation of a somatostatin analog could be the result of rebound growth. Ezzat et al. (28) observed an increase in tumor size in 20% of patients after a 1-month washout from short-acting octreotide. Given that the effects of long-acting octreotide may remain in the body for 3–4 months (29), volume changes would be expected to occur after a longer period compared with short-acting octreotide. As with all treatments for acromegaly, patients treated with pegvisomant should undergo periodic imaging for monitoring of tumor size. Long-term follow-up with MRI is important in confirming the lack of tumor growth during treatment with pegvisomant.
In summary, even with the limitations inherent in this open study design, these longitudinal data add to the growing body of evidence that pegvisomant may be a particularly suitable therapy for patients with acromegaly and diabetes. To what extent an improvement in glucose tolerance in patients without diabetes translates into a clinical benefit remains to be established.
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Acknowledgments |
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Footnotes |
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Abbreviations: AUC, Area under the concentration-time curve; HbA1c, glycosylated hemoglobin A1c; LAR, long-acting release; MRI, magnetic resonance imaging.
Received February 15, 2005.
Accepted July 22, 2005.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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