PASIREOTIDE-INDUCED HYPERGLYCEMIA IN ACROMEGALY PATIENTS: EVALUATION OF PATHOPHISIOLOGICAL MECHANISMS AND EFFICACY OF ANTIDIABETIC TREATMENT

Pasireotide LAR (PAS) has a safety profile similar to first-generation somatostatin in analogues (SSA), except for a higher frequency of hyperglycaemia-related adverse events. However, consensus on the best management of PAS-induced hyperglycaemia in acromegalic patients has still to be defined. The current study aim at investigating the effects of long-term PAS treatment on glucose metabolism, besides GH and IGF-I control, by evaluating the clinical management of hyperglycemia adverse events in acromegalic patients followed in two Italian referral Centers, participating to the PAOLA study, a randomized, Phase III study assessing the efficacy and safety of PAS compared with patients with inadequately controlled acromegaly during first-generation SSA. Moreover, the role of metabolic parameters (weight, BMI, fasting glucose and HbA1c levels) and markers of disease activity (GH, IGF-I, duration of PAS treatment) were investigated as potential predictors of hyperglycemia development. A total of 31 patients (16 F/15 M, mean age 47.6 years) entered the present study, including 18 randomized to PAS (group 1), and 13 to continued treatment with octreotide LAR 30 mg or lanreotide Autogel 120 mg (group 2) for six months (core study). All patients in group 2 who remained uncontrolled at 6 months had the opportunity to switch to PAS in the extension phase. In all patients, fasting glucose and HbA1c were evaluated every 6 months, according to the study protocols. At baseline, pre-existing diabetes mellitus (DM) was found in five patients (27.7%) in group 1 and one (7.7%) in group 2 (p=0.34), whereas pre-existing prediabetes, defined as impaired glucose tolerance (IGT) or impaired fasting glucose (IFG), was seen in one patients (5.5%, IGT) in group 1 and in three patients (23.1%, 2 IGT, 1 IFG) in group 2 (p=0.34). Patients were treated with PAS for a mean time of 34 months (6-67 months). Hyperglycemia-related adverse events were reported in 15 patients (83.3%) in group 1, occurring after a mean time of 5 months (1-16 months). One patient required treatment discontinuation because of diabetes adverse event. Four out five patients with DM at baseline (80%) reported worsening of hyperglycemia during PAS treatment. One patient with IGT at baseline (100%) developed overt DM. Six (50%) and four (33.3%) patients with normal glucose tolerance (NGT) at baseline developed IFG and DM, respectively, during PAS treatment. In group 2, three (23%) patients reported hyperglycemia-related adverse events during the core phase (during first-generation SSA therapy), after a mean time of two months. Particularly, overt DM occurred in two patients (15.3%) with baseline NGT and in one patient (7.7%) with IGT at baseline. All cases were of mild severity, defined as grade 1. During the extension phase, nine patients (69.2%) reported hyperglycemia-related adverse events after a mean time of seven months (2-17 months) from the beginning of PAS treatment. One diabetic patient (33.3%) reported worsening hyperglycemia. Among patients with NGT at baseline, three (16.6%) developed pre-diabetes (2 IFG, 1 IGT), and two patients (15.3%) developed overt DM during PAS treatment. All cases reported in group 1 and 2 were of mild-to-moderate severity, defined as grade 2-3, and were judged to be related to PAS. The risk to develop hyperglycemia correlated neither with baseline BMI, weight, GH, IGF-I, glucose and HbA1c levels, or duration of PAS treatment (p=0.41). Similarly, glucose status did not significantly correlate with biochemical control at the last follow-up (p=0.66). At study entry, three patients (16.6%) in group 1 and one patient (7.7%) in group 2 were already treated with antidiabetic drugs. In group 1, starting of new antidiabetic treatment was required in eight patients (44.4 %) throughout the study, and metformin (MET) was the drug of choice in all these patients. Four (50%) out eight patients did not control glucose and HbA1c levels despite MET monotherapy, needing further therapies. In fact, MET was associated with DPP-4 inhibitor in one patient (25%), GLP-1 agonist in two patients (50%), and GLP-1 agonist and glargine insulin in one patient (25%) to control hyperglycemia. Two patients previously treated with antidiabetic drugs (1 patient with MET plus glargine insulin, and 1 patient with glargine insulin monotherapy) needed a dose adjustment to control hyperglycemia. In group 2, one patient (7.7%) started MET during the core phase. During the extension phase, starting of new antidiabetic treatment was required in seven patients (53.8%), and MET was the drug of choice in all these patients. Three (42.8%) out seven patients did not control glucose and HbA1c levels despite MET monotherapy, requiring further therapies. MET was associated with DPP-4 inhibitor in one patient (33.3%), GLP-1 agonist in two patients (33.3%), and GLP-1 agonist and detemir insulin in one patient (33.3%) to control hyperglycemia. The results of the present study confirm the known negative effect of PAS on glucose metabolism, however treatment intensification with DPP4 inhibitor and GLP-1 agonist resulted in good glycemic control in most patients. Further studies are needed to deeply evaluate the mechanism of PAS-induced hyperglycemia in acromegalyc patients, investigating the effect of PAS on insulin secretion and hepatic/peripheral insulin sensitivity

Growth hormone nadir during oral glucose load depends on waist circumference, gender and age: normative data in 231 healthy subjects.

Objective  (i) To analyse the predictors of GH suppression after standard glucose load (oGTT) in the healthy population and (ii) to establish the 97th percentile of GH nadir post-oGTT according to these variables. Design  Analytical, retrospective. Measurements  GH nadir after oGTT. Subjects  Two hundred and thirty-one healthy subjects (113 women, 118 men 15-80 years) were studied. Results  The GH nadir after glucose load ranged from 0·01 (<assay detection limit) to 0·65 μg/l was higher in women and was inversely correlated with age, BMI, waist circumference, waist/hip, total cholesterol, triglycerides, basal and maximal glucose and basal insulin levels and directly correlated with basal GH levels, IGF-I SDS and HDL-cholesterol (P values ranging 0·004-<0·0001). On multistep regression analysis, the best predictors of nadir GH levels were waist circumference (t = -9·64, P < 0·0001), gender (t = -3·86, P = 0·0001) and age (t = -3·63, P = 0·0003). The results of comparative analysis among subjects grouped according to these variable showed different results in GH nadir in premenopausal women with waist circumference ≤88 cm (97th percentile 0·65 μg/l), in premenopausal women with waist circumference ≤88 cm and in men of any age with waist circumference ≤102 cm (97th percentile 0·33 μg/l) and in subjects of either gender and any age with waist circumference >88 cm in women and 102 cm in men (97th percentile 0·16 μg/l). Conclusions  The results of this study show that GH nadir after oGTT should be analysed according to gender, menopausal status and waist circumference. The GH cut-off should be limited to the assay used

Comparison of the effects of primary somatostatin analogue therapy and pituitary adenomectomy on survival in patients with acromegaly: a retrospective cohort study

Objective: Acromegalic patients have an increased risk of mortality. The objective of this study was to compare the effect of different therapies for acromegaly on mortality. Design and methods: The mortality rate of 438 consecutive acromegalic patients was compared with that of the general population using the standardized mortality ratio (SMR); the effect of different therapies on survival was evaluated using Cox regression analysis. Results: Twenty patients (4.5%) died between 1999 and 2009. Age- and sex-adjusted SMR was 0.70 (95% CI 0.43–1.08). The Cox regression analysis revealed that, in the whole population, both general risk factors (age and physical status) and specific factors for acromegaly (macroadenoma, hypopituitarism and uncontrolled disease) were associated with death. The most compromised patients at diagnosis had a higher mortality rate (PZ0.001), which also occurred in patients with controlled acromegaly. Death occurred in 2.4% (adenomectomy), 2.6% (adenomectomy followed by somatostatin analogue (SSA) therapy) and 11.4% (SSA therapy as the primary therapy) of the patients. The risk of death was higher in patients receiving SSA therapy as the primary therapy (hazard ratio (HR) 5.52, 95% CI 1.06–28.77, PZ0.043) than in all patients submitted to adenomectomy; however, a higher risk of death occurred only in diabetic patients treated with SSAs alone (HR 21.94, 95% CI 1.56–309.04, PZ0.022). Radiotherapy was associated with an increased risk of mortality, which occurred in patients with the more locally advanced disease. Conclusions: Therapies for acromegaly and comorbidities have lowered the risk of mortality to the level of the general population; the effect of SSA therapy alone or that following pituitary adenomectomy was comparable to that of curative neurosurgery on survival in non-diabetic patients; on the contrary, SSA therapy as the primary therapy may be less effective than adenomectomy in reducing mortality rate in diabetic patients

Determinants of cardiac disease in newly diagnosed patients with acromegaly: results of a 10 year survey study

CONTEXT: The most frequent cause of death in acromegaly is cardiomyopathy. OBJECTIVE: To evaluate determinants of acromegalic cardiomyopathy. DESIGN: Observational, open, controlled, retrospective study. SUBJECTS: Two hundred and five patients with newly diagnosed active acromegaly (108 women and 97 men; median age 44 years) and 410 non-acromegalic subjects sex- and age-matched with the patients. MAIN OUTCOME MEASURES: Left ventricular (LV) mass index (LVMi), transmitral inflow early-to-atrial (E/A) peak velocity ratio, and LV ejection fraction (LVEF) were measured by Doppler echocardiography to determine the prevalence of LV hypertrophy (LVH), diastolic and systolic dysfunction. The role of age, estimated disease duration, body mass index, GH and IGF1 levels, systolic and diastolic blood pressure, lipid profile and glucose tolerance in determining different features of the acromegalic cardiomyopathy was investigated. RESULTS: Compared with controls, the patients had lower E/A, LVEF, high-density lipoprotein (HDL)-cholesterol levels and higher LVMi, total- and low-density lipoprotein (LDL)-cholesterol, triglycerides, glucose and insulin levels, homeostatic model assessment of insulin resistance (HOMA-R) and HOMA-β. The relative risk to develop mild (odds ratio (OR)=1.67 (1.05-2.66); P=0.027) or severe hypertension (OR=1.58 (1.04-2.32); P=0.027), arrhythmias (OR=4.93 (1.74-15.9); P=0.001), impaired fasting glucose/impaired glucose tolerance (OR=2.65 (1.70-4.13); P10 years had a relative risk to present cardiac complications three times higher than patients with estimated disease duration ≤5 years. CONCLUSIONS: The prevalence of different features of cardiomyopathy is 3.3-14.2 times higher in the acromegalic than in the non-acromegalic population. The major determinant of cardiomyopathy is disease duration

Clinical and metabolic effects of first-line treatment with somatostatin analogues or surgery in acromegaly: a retrospective and comparative study

To evaluate the metabolic effects of first-line somatostatin analogues or surgery in acromegaly. Retrospective, comparative, 12-month follow-up. Two hundred and thirty one patients (123 men, age 47.32 ± 14.63 years) with active acromegaly, first line treatments were somatostatin analogues in 151 (65.4%) and surgery in 80 (34.6%). Metabolic syndrome (MS) parameters, glucose, insulin and GH during oral glucose tolerance test, stimulated insulin sensitivity by insulin sensitivity index (ISI Matsuda), early and total insulin-secretion rate by insulinogenic index and AUC(INS), visceral adiposity function, expressed by visceral adipose index (VAI). Somatostatin analogues treatment improved all MS parameters and significantly reduced fasting glucose (P &lt; 0.001), HbA1c (P = 0.014) and the prevalence of DM (P = 0.003) when disease control was achieved. Both somatostatin analogues and surgery improved ISI Matsuda (P &lt; 0.001) and reduced AUC(INS) (P &lt; 0.001) and VAI (P &lt; 0.001 and P = 0.003, respectively). Only in controlled somatostatin analogues-treated patients a significant reduction in insulinogenic index (P = 0.010) was observed. ISI Matsuda showed a significant independent correlation with IGF-1 levels (β = -0.258; P = 0.001) and VAI score (β = -0.430; P &lt; 0.001). VAI was independently correlated with IGF-1 (β = 0.183; P = 0.004). Both somatostatin analogues and surgery can safely be used as first-line therapy in acromegaly, without any untoward effects on glucose tolerance. The control of acromegaly is the main determinant of beneficial effects on general features of insulin sensitivity. VAI could represent an additional link between disease control and insulin sensitivity

Pregnancy in acromegaly: experience from two referral centers and systematic review of the literature.

Background  Acromegaly results from increased growth hormone and its target insulin-like growth factor-1, most commonly due to a pituitary tumour. As it is frequently accompanied by infertility, little is known about the course of this disease in pregnancy. Objective  We describe 13 new pregnancies in acromegalic women and compare their outcomes in a systematic review of the literature. Methods  We collected clinical, biochemical, imaging, and outcomes data during and following pregnancy and performed a systematic review for a total of 47 pregnancies. An extended analysis of 106 pregnancies was also performed. Results  In 13 newly described cases, pregnancy was un-complicated without need for additional surgical intervention. In these pregnancies, adjunctive medical therapy was required in three patients. This was in the form of somatostatin analogs (SA) (3/13) as well as pegvisomant in 1/13 to control symptomatic and biochemical progression. One 37-year-old female succeeded in having two separate pregnancies 2 years apart both without need for any form of medical therapy. Review of an additional 34 published reports allowed for an analysis of outcomes in 47 pregnancies. Adjunctive medical therapy during pregnancy was required in 15 of these cases where 12 received SA and an additional three received dopamine agonists. None of these patients developed endocrine or neurologic complications during pregnancy. In an extended analysis of 106 pregnancies, treatment during pregnancy appears to be associated with good disease control but increased risk of microsomic or macrosomic newborns depending on the medical agent used. Conclusions  In 13 newly described pregnancies along with systematic review of an additional 34 cases indicate that pregnancy in treated acromegalic women can proceed without significant complications or teratogenicity. Medical treatment during pregnancy with DA or SA appears to be associated with altered neonatal weight. Nevertheless, gestation may have a beneficial impact on acromegaly control both during and following pregnancy

Complete disappearance of a GH-secreting pituitary macroadenoma in a patient with acromegaly: effect of treatment with lanreotide Autogel and consequence of treatment withdrawal.

BACKGROUND: Somatostatin analogs (SA) are the cornerstone in the medical treatment of acromegaly, used as either primary or adjunctive therapy. In particular, SA are effective in inducing the biochemical remission of the disease and tumor shrinkage, although only few cases of complete disappearance of the pituitary tumor in patients treated with SA as long-acting formulations have been reported. SA withdrawal has been demonstrated to keep safe levels of GH and IGF1 at least in a small subset of patients well responsive to SA, although it is generally followed by disease recurrence after several months. CASE REPORT: A 61-year-old female patient bearing a very large GH-secreting pituitary macroadenoma was treated with 12-month lanreotide Autogel (ATG), at the initial dose of 120 mg/28 days. After 3 months, GH and IGF1 levels were fully normalized, to prolong the administration interval from 28 to 56 days. After 6 months of treatment, a significant tumor shrinkage (90% of baseline size) was observed, whereas GH and IGF1 excess was still well controlled. After 12-month therapy, a complete disappearance of the pituitary tumor was observed, and the hormonal evaluation confirmed the complete biochemical remission of acromegaly. Lanreotide ATG treatment was withdrawn. The clinical, biochemical, and radiological remission of acromegaly was maintained 24 months after lanreotide ATG treatment discontinuation, without evidence of disease recurrence. CONCLUSIONS: This report represents an exemplary case of the potentiality of treatment with lanreotide ATG in inducing a complete remission of acromegalic disease, persistent after a long period of time from treatment withdrawal

Treatment with GH receptor antagonist in acromegaly:effect on cardiac arrhythmias.

Objective: To evaluate the effects of short- and long-term treatment with pegvisomant (PEG) on arrhythmias in acromegalic patients resistant to long-term, high-dose therapy with somatostatin analogs (SA). Materials and methods: Thirteen patients entered the study. All patients started PEGat initial dose of 10 mg daily and then titrated to 5 mg every 6 weeks on the basis of IGF1. A standard 24-h electrocardiography registration was performed in all patients at baseline and after 6 and 18 months of PEG to evaluate: mean (HR), maximum (MHR), and minimum (mHR) heart rate; pauses number (P) and duration (PD); supraventricular episodes (SEs) number and duration (SED); and ventricular ectopic beats (EB) number and duration (EBD). Left ventricular mass (LVM) was also evaluated by standard echocardiography. Results: A slight but not significant decrease in HR, MHR, and mHR was observed after 6-month PEG, whereas a significant decrease in HR (P=0.03), MHR (P=0.05), and mHR (P=0.05) was found after 18-month PEG compared with baseline. LVM significantly (P=0.05) correlated with MRH (r=-0.50) after short-term treatment, and with HR (r=-0.54) and mHR (r=-0.55) after long-term treatment. Long-term PEG induced the complete recovery of arrhythmias recorded at baseline in one patient and the improvement of rhythm disorders developed after 6-month therapy in another patient. The prevalence of conduction disturbances passed from 15 to 7.7% after long-term PEG. Conclusions: Long-term treatment with PEG reduces HR, MHR, and mHR and improves rhythm abnormalities in acromegaly