Pasireotide monotherapy in Cushing's disease: a single-centre experience with 5-year extension of phase III Trial.

PURPOSE: A recent phase III randomized controlled trial (NCT00434148) showed efficacy of pasireotide in the treatment of patients with Cushing's disease (CD). Patients were invited to participate in an extension phase of the protocol and a subgroup had a sustained response. We report the experience with 4 patients in our center of which 2 full responders have completed 5.5 and 4.25 years of treatment with disease control. METHODS: The trial protocol was described previously. The extension phase consisted of 3-monthly visits with clinical, biochemical, and imaging evaluation and investigator-driven pasireotide titration. Research charts were retrospectively analyzed. RESULTS: Four patients with persistent CD following pituitary surgery completed the first 6 months of the trial and 3 continued in the next 6 month open-label phase. Two patients with baseline urinary free cortisol (UFC) 5.3-6.7 times the upper limit of normal had a rapid sustained response to pasireotide and entered the extension phase after 12 months. They remain in clinical and biochemical disease remission and 1 patient now only requires 300 µg daily of pasireotide. All 4 patients developed glucose intolerance; however, the two patients in the extension phase were eventually able to discontinue all diabetes pharmacotherapy. Adverse events included second degree atrioventicular block type 1 without QT prolongation in a patient with pre-existing sinus bradycardia, and symptomatic cholelithiasis requiring cholecystectomy in a second patient. CONCLUSIONS: Pasireotide therapy can provide normalization of UFC and of clinical symptoms and signs of CD during up to 5 years of follow-up. This study demonstrates the possible recuperation of normoglycemia after continued use of pasireotide and control of underlying hypercortisolemia. Longer-term monitoring for potential adverse events related to continued use of pasireotide is indicated.

Long-term cabergoline therapy is not associated with valvular heart disease in patients with prolactinomas.

Ergot-derived dopamine receptor agonists, especially pergolide and cabergoline, have been associated with an increased risk of valvular heart disease in patients treated for Parkinson's disease. Cabergoline at lower doses than those employed in Parkinson's disease is widely used in patients with prolactinomas, because of its high efficacy and tolerability; however, its safety with regard to cardiac valve disease is unknown. In order to assess the prevalence of cardiac valve regurgitation in patients with prolactinomas treated with long-term cabergoline, we performed a prospective and multicentric study including four university centers in the province of Quebec. A transthoracic echocardiogram was performed in 70 patients with prolactinomas treated with cabergoline for at least 1 year (duration of treatment, 55 +/- 22 months; cumulative dose 282 +/- 271 mg, mean +/- SD) and 70 control subjects matched for age and sex. Valvular regurgitation was graded according to the American Society of Echocardiography recommendations as mild, moderate, or severe. Moderate valvular regurgitation was found in four patients (5.7%) and five control subjects (7.1%) (P = 0.73). No patient had severe valvular regurgitation. There was no correlation between the presence of significant heart-valve regurgitation and cabergoline cumulative dose, duration of cabergoline treatment, prior use of bromocriptine, age, adenoma size, or prolactin levels. Our results show that low doses of cabergoline seem to be a safe treatment of hyperprolactinemic patients. However, in patients with prolonged cabergoline treatment, we suggest that echocardiographic surveillance may be warranted.

Impact of a high-monounsaturated-fat diet on lipid profile in subjects with type 1 diabetes.

OBJECTIVE: Controversy persists regarding the use of a high-monounsaturated-fat diet in people with type 1 diabetes. The purpose of this study was to compare the effects of a high-monounsaturated-fat diet containing 43% to 46% carbohydrates and 37% to 40% fat (17% to 20% monounsaturated fat) with those of a high-carbohydrate diet containing 54% to 57% carbohydrates and 27% to 30% fat (10% to 13% monounsaturated fat) on the quantitative and qualitative lipoprotein profile in type 1 diabetes. DESIGN: A randomized crossover study was conducted. Two months before the dietary trial, subjects were monitored on their intensive insulin regimen to normalize glycemic and lipid levels. SUBJECTS: Twenty-six individuals followed each diet for 2 months. Eight subjects lost or gained >2 kg, and three had the same dietary intakes during the two diets. For the remaining 15, seven adhered to the two diet prescriptions and eight followed one of the two diets. STATISTICAL ANALYSIS: Analysis of variance for crossover design (intent-to-treat group of 26) and Wilcoxon signed rank test (group of seven) were used to assess differences between the two diets. RESULTS: For the intent-to-treat group (n=26), low-density lipoprotein cholesterol, although within normal range, was lower by 7% (P=.034) at the end of the high-monounsaturated-fat diet. The other 17 lipid parameters tested were not statistically significant. For those who adhered to the two diets (n= 7), lower plasma total triglycerides by 18% (P=.027), lower very low-density lipoprotein triglycerides by 26% (P=.043), lower very low-density lipoprotein cholesterol by 48% (P=.043), higher apolipoprotein A1 by 7% (P=.018), smaller low-density lipoprotein particle size by 1% (P=.043), and longer low-density lipoprotein oxidation lag time by 25% (P=.043) were found after the high-monounsaturated-fat diet. APPLICATIONS/CONCLUSIONS: A high-monounsaturated-fat diet seemed to have a favorable effect on fasting lipoprotein profile in people with type 1 diabetes. Further research is needed with a larger sample to recommend a high-monounsaturated-fat diet as an alternative diet therapy in type 1 diabetes.

Iatrogenic Cushing syndrome in patients receiving inhaled budesonide and itraconazole or ritonavir: two cases and literature review.

OBJECTIVE: To present two cases of iatrogenic Cushing syndrome caused by the interaction of budesonide, an inhaled glucocorticoid, with ritonavir and itraconazole. METHODS: We present the clinical and biochemical data of two patients in whom diagnosis of Cushing syndrome was caused by this interaction. We also reviewed the pertinent literature and management options. RESULTS: A 71-year-old man was treated with inhaled budesonide for a chronic obstructive pulmonary disease and itraconazole for a pulmonary aspergillosis. The patient rapidly developed a typical Cushing syndrome complicated by bilateral avascular necrosis of the femoral heads. Serum 8:00 AM cortisol concentrations were suppressed at 0.76 and 0.83 µg/dL on two occasions. The patient died 4 days later of a massive myocardial infarction. The second case is a 46-year-old woman who was treated for several years with inhaled budesonide for asthma. She was put on ritonavir, a retroviral protease inhibitor, for the treatment of human immunodeficiency virus (HIV). In the following months, she developed typical signs of Cushing syndrome. Her morning serum cortisol concentration was 1.92 µg/dL. A cosyntropin stimulation test showed values of serum cortisol of <1.10, 2.65, and 5.36 µg/dL at 0, 30, and 60 minutes, respectively, confirming an adrenal insufficiency. Because the patient was unable to stop budesonide, she was advised to reduce the frequency of its administration and eventually taper the dose until cessation. CONCLUSION: Clinicians should be aware of the potential occurrence of iatrogenic Cushing syndrome and secondary adrenal insufficiency due to the association of inhaled corticosteroids with itraconazole or ritonavir.

Cabergoline monotherapy in the long-term treatment of Cushing's disease.

BACKGROUND: Cabergoline is a long-acting dopamine receptor agonist used to treat prolactinomas. Identification of D(2) receptors in corticotroph tumors led to clinical trials of cabergoline therapy in limited cases of Nelson's syndrome, ectopic ACTH-secreting tumors, and recently Cushing's disease (CD). OBJECTIVE: To evaluate the long-term efficacy of cabergoline monotherapy in patients with CD. METHODS: Retrospective analysis of non-randomized clinical therapy with cabergoline in 30 patients with CD treated in academic centers of Buenos Aires and Montreal. Cabergoline was initiated at 0.5-1.0 mg/week and adjusted up to a maximal dose of 6 mg/week based on urinary free cortisol (UFC) levels. Complete response to cabergoline was defined as a sustained normalization of UFC with at least two normal values measured at 1-3 months interval; partial response was defined as a decrease of UFC to <125% of the upper limit of normal, and treatment failure as UFC ≥ 125% of it. RESULTS: Within 3-6 months, complete response was achieved in 11 patients (36.6%) and partial response in 4 patients (13.3%). After long-term therapy, nine patients (30%) remain with a complete response after a mean of 37 months (range from 12 to 60 months) with a mean dose of 2.1 mg/week of cabergoline. Two patients escaped after 2 and 5 years of complete response, but one patient transiently renormalized UFC after an increase in cabergoline dosage. No long-term response was maintained in four initial partial responders. CONCLUSIONS: Cabergoline monotherapy can provide an effective long-term medical therapy for selected patients with CD, but requires close follow-up for dose adjustments.

Effects of a diet higher in carbohydrate/lower in fat versus lower in carbohydrate/higher in monounsaturated fat on postmeal triglyceride concentrations and other cardiovascular risk factors in type 1 diabetes.

OBJECTIVE: To compare the effects of a eucaloric diet higher in carbohydrate/lower in fat versus lower in carbohydrate/higher in monounsaturated fat on postmeal triglyceride (TG) concentrations and other cardiovascular disease risk factors in nonobese subjects with type 1 diabetes and in good glycemic control. RESEARCH DESIGN AND METHODS: In a parallel group design study, 30 subjects were randomly assigned and completed one of the two eucaloric diets. Assessments included: BMI, blood pressure, A1C, plasma lipids, and markers of oxidation, thrombosis, and inflammation. At 6 months, subjects were hospitalized for 24 h to measure plasma TG excursions. RESULTS: There were no significant differences between groups other than decreased plasminogen activator inhibitor 1 (PAI-1) levels and weight gain in the lower-carbohydrate/higher-monounsaturated fat group. During the 24-h testing, the lower-carbohydrate/higher-monounsaturated fat group had a lower plasma TG profile. CONCLUSIONS: A diet lower in carbohydrate/higher in monounsaturated fat could offer an appropriate choice for nonobese type 1 diabetic individuals with good metabolic and weight control.

Canadian consensus guidelines for the diagnosis and management of acromegaly.

Acromegaly is a chronic condition associated with considerably increased morbidity and mortality if left unchecked. In December 2004, a national meeting was held to discuss the diversity in clinical practice across the country in diagnosing and treating patients with acromegaly, as well as to seek consensus on a number of management principles. The group reviewed recent guidelines and discussed issues of diagnosis, treatment, monitoring and treating comorbidities to seek a Canadian consensus on the management of this rare disorder. Consensus was that diagnosis should include clinical and biochemical findings, but is hinged on establishing GH hypersecretion with IGF-I and OGTT testing. Treatment has traditionally included surgical resection or debulking, along with adjunctive medical therapy (primarily somatostatin analogues), if necessary, to normalize GH levels. The option of primary medical therapy in managing this condition has recently emerged and can be justified for non-surgical candidates or for those in whom surgery is not expected to be curative. Overall, improved screening practices and superior epidemiological data are required, since timely diagnosis and appropriate treatment are crucial for reducing the potentially debilitating effects of this chronic, progressive disease. The current evidence also supports the need for long-term follow-up of disease activity and comorbidities in diagnosed patients. A national meeting was held to discuss the diversity in clinical practice across the country in diagnosing and treating patients with acromegaly, as well as to seek consensus on a number of management principles. After brief reviews of the most recent Canadian guidelines and the 2004 guidelines published by the American Association of Clinical Endocrinologists, the group was asked to specifically examine the issues of diagnosis, treatment, monitoring and treating comorbidities and seek a Canadian consensus on practice. This paper summarizes the working group's findings and the points of consensus that were achieved.

Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state.

Diabetic ketoacidosis and the hyperglycemic hyperosmolar state are the most serious complications of diabetic decompensation and remain associated with excess mortality. Insulin deficiency is the main underlying abnormality. Associated with elevated levels of counterregulatory hormones, insulin deficiency can trigger hepatic glucose production and reduced glucose uptake, resulting in hyperglycemia, and can also stimulate lipolysis and ketogenesis, resulting in ketoacidosis. Both hyperglycemia and hyperketonemia will induce osmotic diuresis, which leads to dehydration. Clinical diagnosis is based on the finding of dehydration along with high capillary glucose levels with or without ketones in the urine or plasma. The diagnosis is confirmed by the blood pH, serum bicarbonate level and serum osmolality. Treatment consists of adequate correction of the dehydration, hyperglycemia, ketoacidosis and electrolyte deficits.