Improvement in clinical features of hypercortisolism during osilodrostat treatment: findings from the Phase III LINC 3 trial in Cushing's disease.

PURPOSE: Cushing's disease is associated with substantial morbidity and impaired quality of life (QoL) resulting from excess cortisol exposure. The current study explored improvements in clinical signs and additional specific manifestations of hypercortisolism during osilodrostat (potent oral 11ß-hydroxylase inhibitor) therapy by degree of control of mean urinary free cortisol (mUFC). METHODS: LINC 3 (NCT02180217) was a prospective, open-label, 48-week study of osilodrostat (starting dose: 2 mg bid; maximum: 30 mg bid) that enrolled 137 adults with Cushing's disease and mUFC > 1.5 times the upper limit of normal (ULN). mUFC (normal range 11‒138 nmol/24 h), cardiometabolic parameters (blood pressure, weight, waist circumference, body mass index, total cholesterol, fasting plasma glucose, glycated haemoglobin), physical manifestations of hypercortisolism (facial rubor, striae, fat distribution, bruising, hirsutism [females], muscle atrophy) and QoL were evaluated. mUFC was defined as controlled if ≤ ULN, partially controlled if > ULN but ≥ 50% reduction from baseline, and uncontrolled if > ULN and < 50% reduction from baseline. Concomitant medications were permitted throughout the study. RESULTS: At weeks 24 and 48, respectively, mUFC was controlled in 93 (67.9%) and 91 (66.4%) patients, partially controlled in 20 (14.6%) and 13 (9.5%), and uncontrolled in 24 (17.5%) and 33 (24.1%). Overall, mean improvements from baseline in cardiometabolic at week 24 were greater in patients with controlled or partially controlled versus uncontrolled mUFC; at week 48, improvements occurred irrespective of mUFC control. Generally, physical manifestations and QoL progressively improved from baseline irrespective of mUFC control. CONCLUSIONS: Improvements in clinical signs and additional specific manifestations of hypercortisolism associated with Cushing's disease occurred alongside decreases in mUFC. Trial registration NCT02180217 (first posted July 2014).

Association between biochemical control and comorbidities in patients with acromegaly: an Italian longitudinal retrospective chart review study.

PURPOSE: Achieving biochemical control (normalization of insulin-like growth factor-1 [IGF-1] and growth hormone [GH]) is a key goal in acromegaly management. However, IGF-1 and GH fluctuate over time. The true potential impact of time-varying biochemical control status on comorbidities is unclear and relies on multiple, longitudinal IGF-1 and GH measurements. This study assessed the association between time-varying biochemical control status and onset of selected comorbidities in patients with acromegaly. METHODS: Medical charts of adults with confirmed acromegaly and ≥ 6 months of follow-up at an Italian endocrinology center were reviewed. Patients were followed from the first diagnosis of acromegaly at the center until loss to follow-up, chart abstraction, or death. Biochemical control status was assessed annually and defined as IGF-1 ≤ the upper limit of normal, or GH ≤ 2.5 µg/L in the few cases where IGF-1 was unavailable. Time-varying Cox models were used to assess the association between biochemical control status and comorbidities. RESULTS: Among 150 patients, 47% were female, average age at diagnosis was 43.1, and mean length of follow-up was 10.4 years. Biochemical control was significantly associated with a lower hazard of diabetes (HR = 0.36, 95% CI 0.15; 0.83) and cardiovascular system disorders (HR = 0.54, 95% CI 0.31; 0.93), and a higher hazard of certain types of arthropathy (HR = 1.68, 95% CI 1.04; 2.71); associations for other comorbidities did not reach statistical significance. CONCLUSION: Results further support the importance of achieving biochemical control, as this may reduce the risk of high-burden conditions, including diabetes and cardiovascular system disorders. The association for arthropathy suggests irreversibility of this impairment. Due to limitations, caution is required when interpreting these results.

Occurrence and effects of octreotide antibodies during nasal, subcutaneous and slow release intramuscular treatment.

OBJECTIVE: Previous studies have indicated that antibody formation against octreotide is extremely rare. We examined the occurrence of octreotide antibody formation after treatment with three administration forms in large populations of patients with acromegaly or carcinoid syndrome. DESIGN: (i) Nasally administered octreotide: 70 previously untreated patients and 81 previously s.c. octreotide-treated patients participated. (ii) Subcutaneously administered octreotide: 172 acromegalic patients and 59 patients with carcinoid syndrome treated for up to 12 years participated. (iii) Intramuscularly administered depot octreotide (Sandostatin LAR): 62 acromegalic patients participated. METHODS: Presence of antibodies is defined as increased precipitation by polyethylene glycol of (125)I-octreotide after incubation with serum; this was also used for screening of cross-reaction with somatostatin and lanreotide (Somatuline). RESULTS: In patients who received nasal octreotide for at least 9 and up to 12 months (n=42), the occurrence of octreotide antibodies was 77% and 81% for previously untreated and treated patients respectively. In subcutaneously treated patients it was 63/231 (27%) after a mean exposure of 3 years. In patients treated for more than 5 years (n=53) it was 57% and after 8 years (n=18) 72%. In contrast, no patient could with certainty be identified to be antibody-positive after a mean of 2.5 years intramuscular Sandostatin LAR treatment (n=47). In all populations, the antibody-positive patients were as well controlled as the antibody-negative patients. Octreotide antibodies did not cross-react with native somatostatin (n=141), while about 25% of the antibody-positive sera did cross-react with the somatostatin analogue, lanreotide (Somatuline, Ipstyl, Angiopeptin). CONCLUSIONS: Antibody formation against octreotide is much more frequent than previously believed. It depends primarily on drug exposure time and route of administration. It does not alter the GH/IGF-I status in treated acromegalic patients and induces only mild local reactions in some patients.

Slow-release lanreotide in the treatment of acromegaly: a study in 66 patients.

OBJECTIVE: Slow-release (SR) lanreotide is a long-acting somatostatin analog that has been developed in order to overcome the inconvenience of multiple daily subcutaneous injections of octreotide, required for metabolic control in acromegaly. Lanreotide SR has been found to be well tolerated and effective in reducing GH and IGF-I levels but clinical data are still limited compared with those with subcutaneous octreotide treatment. DESIGN: Sixty-six unselected patients with active acromegaly were therefore evaluated in a multi-center, prospective, open label study. Lanreotide SR was given at a dose of 30mg intramuscular every 7-14 days. METHODS: At baseline and after 2, 4, 8, 12, 24, 36 and 48 weeks patients underwent a clinical examination with assessment of acromegaly related symptoms, and blood was sampled for serum GH, IGF-I, prolactin, glycosylated hemoglobin, fasting glucose, hematology, kidney function and liver function tests. Biliary ultrasonography and pituitary magnetic resonance imaging were performed at baseline and after one year. RESULTS: Treatment resulted in a significant improvement in the symptom score from 2.69+/-0.27 to 1.06+/-0.17 (P<0.0001). Serum IGF-I levels fell from 699+/-38microg/l at baseline to 399+/-26microg/l (P<0.0001, n=60) after one month, after which levels remained stable: 480+/-37microg/l after 6 months (n=54) and 363+/-32microg/l after one year (n=46). GH levels dropped from 13.8+/-3.2microg/l to 4.3+/-0.7microg/l after one month (P<0.0001, n=60) and remained stable thereafter: 3.9+/-0.4microg/l (n=54) after 6 months and 3.5+/-1.1microg/l after one year (n=46). Twenty-nine out of 66 patients (44%) attained a normal age-corrected IGF-I level and 30 patients (45%) attained a GH level below 2.5microg/l. Pituitary adenoma shrinkage of at least 25% was found in 5 of 14 patients (36%) after one year. Side effects were mainly transient gastrointestinal symptoms and pain at the injection site, resulting in drug discontinuation in only 6 patients (9%). Two patients developed new gall stones. No difference was found between subcutaneous octreotide and lanreotide SR in efficacy and almost all patients preferred the easier dose administration of lanreotide SR. CONCLUSIONS: Long-term treatment of acromegaly with SR-lanreotide is effective in controlling GH and IGF-I levels and symptoms and is well tolerated in the majority of patients. Compared with subcutaneous octreotide, lanreotide SR considerably improves patient's acceptance of therapy while having the same overall efficacy.

Treatment of acromegaly with SS analogues: should GH and IGF-I target levels be lowered to assert a tight control of the disease?

BACKGROUND: in acromegaly, the criteria for the cure of the disease after neurosurgery have become tighter and tighter. In contrast, the evaluation of control of disease activity during medical treatment is based upon the normalisation of IGF-I levels and epidemiological criteria, i.e. lessening GH (assessed by RIA) to levels reported to normalise increased mortality. The aim of this study was to evaluate GH and IGF-I suppression during prolonged SS analogues (SA) treatment. The concordance between "safe" GH and normalised IGF-I levels during SA was also assessed, according to gender and gonadal status. DESIGN: multicentre, retrospective. Patients. GH/IGF-I levels were evaluated in 207 acromegalic patients (132 females, aged 20-85 yr) during a prolonged treatment (longer than 12 months) with individually tailored doses of depot SA( lanreotide or octreotide-LAR in 97 and 110 patients, respectively). Final IGF-I levels were transformed in z-scores using data collected in a large cohort of normal subjects of 3 different age groups (20-40 yr old, 41-60 yr old, 61-80 yr old, n=160, 148, 115, respectively), that allowed to set up quartiles of normality (I = 3rd-25th percentile, II = 26th-50th, III = 51th-75th, IV = 76th-97th). RESULTS: fifty-nine and 19.3% of patients achieved GH levels <2.5 and <1 microg/l, respectively. IGF-I were normalised (z-score between 2 and -2) in 58.4% of patients. The distribution of normal IGF-I values among quartiles was uneven: 7%, 19%, 25%, and 49% of values were distributed in the I, II, III, and IV quartile, respectively. The concordance between GH and IGF-I values was poor: 28.4% of patients attaining GH values <2.5 microg/l had still pathological IGF-I (even 12.5% of those with GH <1 microg/l), and 39.3% of those with GH levels still above the "safe" limit had "nor IGF-I. Although proportions of IGF-I normalisation were not different between males and females, the regression line obtained between GH and IGF-I z-score showed the same slope but with a significantly lower intercept in regularly cycling women than in males and in postmenopausal females. Thus for any GH value, cycling females had lower IGF-I than menopausal women and males, and their IGF-I normalisation could be achieved by higher GH values. By ROC analysis, the achievement of normal IGF-I was predicted by the GH value of 1.8 microg/l in males and 2.4 microg/l in females. CONCLUSIONS: in acromegalic patients on SA treatment, GH and IGF-I levels are often not concordant. In addition to age, sex is to be taken into account in the evaluation of hormonal targets. A better refinement of GH and IGF-I targets to be reached while on treatment with SA is warranted.

Gender- and age-related differences in the endocrine parameters of acromegaly.

Acromegaly is a severe slow-developing disease associated with a poor prognosis for cardiovascular disease. To evaluate the impact of age and gender on the severity of the disease, 151 de novo patients with acromegaly (79 women, 72 men, age range 19-77 yr) were included in this open retrospective multi-center cohort study. Basal GH and IGF-I levels, GH response after glucose load and maximal tumor diameter at MRI were measured in all patients at diagnosis. Fasting GH levels and maximal tumor diameter were similar in women and men, while serum IGF-I levels were lower (664.9+/-24.9 vs 755.9+/-32 microg/l; p=0.02) and GH nadir after glucose load was higher (27.5+/-3.7 vs 18.5+/-2.2 microg/l; p=0.04) in women than in men. In both sexes, patients' age was negatively correlated with basal and nadir GH, IGF-I levels and tumor size; fasting GH levels were positively correlated with IGF-I levels and nadir GH after glucose. No interaction between age and gender was found on biochemical and morphological parameters. At diagnosis, elderly patients with acromegaly have lower GH and IGF-I levels, lower GH nadir after glucose load and smaller adenomas than young patients. Women have lower IGF-I levels but higher GH nadir after glucose load than men. These age and gender differences should be considered to appropriately evaluate the activity of acromegaly throughout a life-span.