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Departments of Molecular and Clinical Endocrinology and Oncology (A.Co., P.M., D.F., G.L.), Internal Medicine I (L.S., D.B.), Biomorphological and Functional Sciences, National Council for Research, Nuclear Medicine (A.Cu., M.S.), "Federico II" University of Naples, 80131 Naples, Italy; Scientific Institute for Research and Care Neuromed (A.Cu.), Pozzilli, Italy; and Novartis Pharma A.G. (V.B., I.L.), 4002 Basel, Switzerland
Address correspondence and requests for reprints to: Annamaria Colao, Department of Molecular and Clinical Endocrinology and Oncology, "Federico II" University of Naples, via S. Pansini 5, 80131 Naples, Italy. E-mail: colao{at}unina.it
Cardiovascular disease is the most severe complication of acromegaly accounting for the increased mortality of these patients. Recently, the slow-release form of octreotide (OCT; Sandostatin LAR, OCT-LAR), for im injection every 28 days, was reported to induce suppression of GH levels below 7.5 mU/L (2.5 µg/L) in 39–75% of patients, and normalization of insulin-like growth factor (IGF)-I levels for age in 64–88% of patients, with an excellent patients’ compliance.
The aim of the present study was to investigate the early effect of OCT-LAR treatment on the left ventricular (LV) structure and performance in 15 somatostatin analog-naive patients with acromegaly (GH, 94.8 ± 24.9 mU/L; IGF-I, 757.9 ± 66.6 µg/L), focusing on the early effect of GH and IGF-I suppression on the heart. Cardiac structure was investigated by echocardiography, whereas LV performance was investigated by gated-blood-pool scintigraphy, before and after 3 and 6 months of treatment with OCT-LAR.
OCT-LAR was initially administered im, at a dose of 20 mg every 28 days, for 3 months. In six patients, the dose was then increased to 30 mg every 28 days to achieve disease control, which was considered when fasting and/or glucose-suppressed GH values were below 7.5 and 3.0 mU/L, respectively, together with IGF-I values within the normal range for age.
The treatment with OCT-LAR for 6 months induced a significant decrease of GH (to 12.9 ± 3.0 mU/L) and IGF-I levels (to 340.3 ± 40.2 µg/L) in all 15 patients. After 6 months of treatment, the percent IGF-I suppression was 52.8 ± 4.4%, and serum GH/IGF-I levels were normalized in 9 patients. A significant decrease of LV mass index (LVMi), interventricular septum thickness, and LV posterior wall thickness was observed in all 15 patients after 3 and 6 months of OCT-LAR treatment: LVMi was decreased by 19.1 ± 2.0% without any difference in patients with (19.9 ± 2.7%) or without disease control (17.8 ± 3.3%). Among the 11 patients with LV hypertrophy, 6 normalized their LVMi after treatment.
At study entry, an inadequate LV ejection fraction (LVEF) at rest (<50%) was found in 5 patients (33.3%), whereas an impaired response of LVEF at peak exercise (<5% increase of basal value) was found in 9 patients (60%). A significant increase in LVEF, both at rest (from 51.6 ± 2.6 to 58.1 ± 1.7%, P < 0.01) and at peak exercise (from 51.6 ± 2.3 to 60.2 ± 2.4%, P < 0.001) was found in patients with (as compared with those without) disease control (from 55.2 ± 3.8 to 58.0 ± 4% and from 61.8 ± 4.6 to 61.8 ± 3.4%, respectively). Among the 5 patients with inadequate LVEF at rest, all but 1 regained a normal LVEF after 6 months of treatment; whereas, among the 9 patients with an impaired response of the LVEF at peak exercise, 3 patients normalized, 4 improved, and 2 impaired their responses after treatment. The percent of IGF-I suppression was significantly correlated with the percent increase of resting LVEF (r = 0.644, P < 0.01). Exercise duration (from 6.0 ± 0.7 to 7.3 ± 0.7 min) and capacity (from 69.0 ± 8.2 to 80 ± 7.8 watts) were increased in the 15 patients considered as a whole, but the improvement in the exercise response was significant only in patients with disease control (P < 0.01 and P < 0.05, respectively) who also had an increase in the peak ejection rate (P = 0.03). No change in hemodynamic parameters, either at rest or at peak exercise, was found after treatment with OCT-LAR in the 15 patients.
In conclusion, the results of the present study demonstrate that OCT-LAR im injections every 28 days induces a sustained suppression of GH levels and IGF-I levels in all acromegalic patients, allowing achievement of disease control in 60% of patients after 6 months of treatment. The sustained suppression of IGF-I levels was followed by a significant reduction of LVMi in all patients already after 3 months of treatment, with recovery of LV hypertrophy in 6 of 11 patients. In contrast, LV performance was significantly improved only in patients achieving normalization of their hormone levels. These data suggest that the treatment with OCT-LAR, by inducing a rapid suppression of circulating GH and IGF-I levels, could produce an early improvement of the cardiac abnormalities of acromegaly, thus contributing to reversal of the poor prognosis for cardiovascular diseases of these patients.
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