Cardiovascular Effects of Depot Long-Acting Somatostatin Analog Sandostatin LAR in Acromegaly*

Abstract

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.

Cardiovascular Disease and Sleep-Disordered Breathing in Acromegaly

“…A lower diastolic blood pressure has also been reported after surgery [47]. Similarly, SSA therapy has been shown to have a beneficial effect on blood pressure [48,49,50] and to bring about significant improvements in left ventricular mass, systolic and diastolic function and exercise tolerance [50,51,52,53]. Rhythm disturbances may improve following commencement of SSA therapy [49,54,55], but asymptomatic bradycardia is a potential side effect.…”

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“…Subcutaneous octreotide increased left ventricular ejection fraction and exercise workload, and improved exercise duration while decreasing heart rate and blood pressure in 30 acromegalic patients investigated by Colao et al over a period of one year [84]. In a similar study of 15 octreotide-naïve patients treated with octreotide LAR for 6 months, left ventricular mass index (LVMi), interventricular septum thickness, and LV posterior wall thickness were improved in all patients after 3 and 6 months of treatment [85]. Six of eleven patients with left ventricular hypertrophy at study entry normalized their LVMi while on treatment.…”

Medical Consequences of Long-term Treatment of Acromegaly

“…21 Only limited data are available about the impact of surgery on acromegalic cardiomyopathy, but it has been recognised to improve diastolic and systolic performance. 22,23 Somatostatin analogues have been reported to dramatically improve cardiovascular parameters, inducing reduction of cardiac mass and enhancement of diastolic filling, [24][25][26][27][28][29] particularly in patients achieving disease control. 30 Systolic function seems to improve to a greater extent in patients treated with somatostatin analogues than in those treated by surgery.…”