The metabolic consequences of thyroxine replacement in adult hypopituitary patients.

The metabolic consequences of thyroxine replacement in patients with central hypothyroidism (CH) need to be evaluated. The aim was to examine the outcome of thyroxine replacement in CH. Adult hypopituitary patients (n = 1595) with and without CH from KIMS (Pfizer International Metabolic Database) were studied before and after 2 years of GH replacement. CH patients (CH, n = 1080) were compared with TSH sufficient patients (TSHsuff n = 515) as one group and divided by thyroxine dose/kg/day into tertiles (CHlow-mid-high). Anthropometry, fasting glucose, glycosylated haemoglobin (HbA1c), blood pressure, lipids, IGF-I SDS, quality of life and morbidity were studied. Analyses were standardized for gender, age, number and types of pituitary insufficiencies, stimulated GH peak, age at GH deficiency onset, aetiologies and, when appropriate, for weight and GH dose. At baseline, TSHsuff patients did not differ from CH or CHmid in any outcome. CHlow (≤ 1.18 µg thyroxine/kg/day) had increased weight, BMI and larger waist circumference (WC), CHhigh (≥ 1.58 µg thyroxine/kg/day) had lower weight, BMI, WC and IGF-I than TSHsuff and compared to their predicted weights, BMIs and WCs. For every 0.1 µg/kg/day increase of thyroxine dose, body weight decreased 1.0 kg, BMI 0.3 kg/m(2), and WC 0.65 cm. The GH sensitivity of the CH group was higher (0.76 ± 0.56 SDS/mg GH) than that of TSHsuff patients (0.58 ± 0.64 SDS/mg GH), P < 0.001. The middle thyroxine dose (1.19-1.57 µg/kg/day) seems to be the most physiological. This is equivalent to 70, 100, 125 µg thyroxine/day for hypopituitary patients of 50, 70 or 90 kg weight, respectively.

Treatment with growth hormone receptor antagonist in acromegaly: effect on cardiac structure and performance.

AIM: The aim of the current study was to evaluate the effect of short-term (6 months) and long-term (18 months) treatment with pegvisomant on cardiac structure and performance in patients with acromegaly. PATIENTS: Seventeen patients (nine women, eight men, 27-61 yr) with active acromegaly entered and 12 completed the long-term study. After a baseline evaluation, including measurement of hemodynamic, biochemical, and hormonal parameters, and a standard Doppler echocardiography, treatment with pegvisomant was started at the initial dose of 10 mg/d, increasing by 5 mg/d every 6 wk on the basis of IGF-I levels until normalization or the achievement of a maximal dose of 40 mg/d. RESULTS: After short-term treatment, IGF-I levels were normalized in 10 of the 17 (59%) patients. Left ventricular mass index (LVMi) was significantly decreased without changes in diastolic and systolic performance. After long-term treatment, IGF-I levels were normalized in 10 of the 12 (83%) patients. Blood glucose and serum insulin levels were decreased compared with baseline. LVMi was further decreased compared with short-term treatment, so that the prevalence of left ventricle hypertrophy decreased from 50% at baseline to 17% after 18 months of treatment. Moreover, ejection fraction as well as early to late (atrial) peak velocity ratio (E/A) were significantly increased, whereas isovolumic relaxation time was significantly decreased compared with baseline, demonstrating an improvement of both diastolic and systolic function. A significant correlation was found between the change in IGF-I levels and that of left ventricular ejection fraction. In general, the prevalence of cardiac insufficiency was present in 13 of the 17 (76%) patients at baseline and in one (8%) patient after 18 months of treatment. CONCLUSIONS: Long-term treatment with the GH receptor antagonist improves acromegalic cardiomyopathy by decreasing cardiac hypertrophy and enhancing diastolic and systolic function, and consequently partially or completely reverting the cardiac insufficiency.

Efficacy of 12-month treatment with the GH receptor antagonist pegvisomant in patients with acromegaly resistant to long-term, high-dose somatostatin analog treatment: effect on IGF-I levels, tumor mass, hypertension and glucose tolerance.

OBJECTIVE: We aimed to investigate the efficacy of pegvisomant in patients with acromegaly resistant to long-term (> or = 24-month), high-dose treatment with octreotide-LAR (40 mg/month) or lanreotide (120 mg/month). DESIGN: This was an open, prospective study. SUBJECTS AND METHODS: We studied 16 patients with acromegaly (nine women; aged 28-61 years). The main outcome measures were IGF-I levels, blood pressure, glucose tolerance and safety (liver function and tumor size). Pegvisomant was given at doses of 10-40 mg s.c. daily. Dose titration was performed every month by IGF-I assay. RESULTS: Three patients spontaneously stopped pegvisomant treatment after 6-9 months because of poor compliance; from the measurement of serum pegvisomant, another patient was found not to inject herself properly. After 6 months, IGF-I levels decreased by 63 +/- 19% (767.8 +/- 152.9 vs 299.8 +/- 162.9 microg/l, P < 0.0001, t-test); serum IGF-I levels normalized in 57%. After 12 months, IGF-I levels normalized in nine (75%) patients and were reduced by over 50% in another three (25%). The mean tumor volume remained stable during the study (1198 +/- 1234 vs 1196 +/- 1351 mm(3), P = 0.37): it did not change ( +/- 25% vs basal) in nine patients, increased by 39.4% and 40.8% in two and decreased by 30.8-46.5% in four. The total/high-density lipoprotein (HDL):cholesterol ratio (from 4.4 +/- 1.0 to 3.7 +/- 0.6, P = 0.0012), glucose levels (from 5.6 +/- 1.2 to 4.4 +/- 1.4 mmol/l, P = 0.026), insulin levels (from 12.4 +/- 6.7 to 8.1 +/- 3.0 mUl/l, P = 0.0023) and homeostasis model assessment (HOMA) index (from 3.4 +/- 2.1 to 1.9 +/- 1.0, P = 0.0017) decreased. CONCLUSIONS: Treatment for 12 months with pegvisomant normalized IGF-I levels, and improved cardiovascular risk parameters and insulin sensitivity in patients with acromegaly resistant to long-term, high-dose treatment with somatostatin analogs. The tolerance of treatment was good.

Inhaled insulin provides improved glycemic control in patients with type 2 diabetes mellitus inadequately controlled with oral agents: a randomized controlled trial.

BACKGROUND: The long-term benefits of good glycemic control are well established. The aim of this proof-of-concept study was to determine whether glycemic control can be improved in patients with type 2 diabetes mellitus with suboptimal glycemic control, despite therapeutic dosages of oral antihyperglycemic agents (OHAs), by the addition of preprandial inhaled insulin (INH). METHODS: Sixty-eight patients with inadequately controlled type 2 diabetes mellitus (glycosylated hemoglobin, 8.1%-11.9%), despite therapy with a sulfonylurea and/or metformin, were randomized to receive INH in addition to their prestudy OHA therapy (INH + OHA group, n = 32) or to continue taking their prestudy OHA alone for 12 weeks (OHA group, n = 36). Premeal INH doses were delivered in 1 to 2 inhalations of 1-mg or 3-mg doses (equivalent to 3 IU and 9 IU, respectively, of subcutaneously injected regular insulin). RESULTS: At week 12, there was a significantly greater reduction in glycosylated hemoglobin for the INH + OHA cohort (mean reduction, -2.3%) compared with the OHA-only cohort (mean reduction, -0.1%, P<.001). Eleven patients (34%) receiving INH + OHA achieved glycosylated hemoglobin values of less than 7%, compared with none taking OHAs only. Fasting plasma glucose improved significantly more in the INH + OHA group compared with the OHA-only group (-60.69 mg/dL (-3.37 mmol/L] greater reduction, P<.001), and the postprandial increase in glucose was significantly lower in those patients receiving INH + OHA (P =.02). There was 1 report of severe hypoglycemia in the INH + OHA group (home blood glucose, 54 mg/dL [3.0 mmol/L]) and a greater increase in body weight. Pulmonary function was unchanged in both groups. CONCLUSION: The addition of preprandial INH to existing OHAs improves glycemic control without the need for injections in patients with type 2 diabetes mellitus failing to achieve satisfactory control with OHAs alone.

Pharmacokinetics and pharmacodynamics of extended-release glipizide GITS compared with immediate-release glipizide in patients with type II diabetes mellitus.

This study was designed to compare the pharmacokinetic and short-term pharmacodynamic profile of extended-release glipizide GITS (Glucotrol XL) given in a dosage of 20 mg once daily with that of immediate-release glipizide (Glucotrol) 10mg twice daily in patients with type II diabetes mellitus. In an open-label, randomized, two-way crossover study, each glipizide formulation was administered for 5 days. Serial blood samples were drawn at baseline and on the 5th day of each treatment phase for measurement of glipizide, glucose, insulin, and C-peptide concentrations. At steady state, the mean Cmax after immediate-release glipizide was significantly greater than after glipizide GITS, and the tmax was considerably shorter. Although the mean Cmin with glipizide GITS was about 80% higher than with immediate-release glipizide, the mean AUC0-24 was significantly lower. Despite the lower plasma concentrations with glipizide GITS in this short-term study, the two formulations had similar effects on serum concentrations of glucose, insulin, and C-peptide. The absence of a pronounced peak plasma concentration with the GITS formulation might confer advantages in terms of maintaining clinical effectiveness and reducing the potential to cause adverse effects.

Treatment satisfaction in type 2 diabetes: a comparison between an inhaled insulin regimen and a subcutaneous insulin regimen.

BACKGROUND: In patients with type 2 diabetes, published data suggest that glycemic control can be achieved as effectively with an inhaled insulin regimen (preprandial inhaled intrapulmonary insulin plus a single bedtime Ultralente injection) as with a conventional subcutaneous insulin regimen involving 2 to 3 injections per day. It is unknown whether inhalation delivery of insulin improves patient satisfaction. OBJECTIVE: Our objective was to compare patient satisfaction between an inhaled insulin regimen and a subcutaneous insulin regimen. METHODS: This was a 12-week randomized, open-label, parallel-group, controlled trial in patients with type 2 diabetes. They were randomized to receive either a subcutaneous insulin regimen (split/mixed insulin with 2 to 3 injections daily) or an inhaled insulin regimen (inhaled insulin before meals and a single Ultralente insulin injection at bedtime). Change in glycosylated hemoglobin (HbA1c) from baseline to week 12 was the study's primary end point. At baseline and week 12, patients completed a questionnaire (Patient Satisfaction with Insulin Therapy Questionnaire) covering attributes of patient satisfaction. Treatment regimens were compared on each item with the Wilcoxon rank sum test and on the overall score with a t test. RESULTS: Fifty-one patients (age range, 35-65 years) participated in the study, 26 receiving inhaled insulin and 25 receiving subcutaneous insulin. Forty-seven patients (22 inhaled insulin, 25 subcutaneous insulin) completed the satisfaction questionnaire. The mean percent improvement in overall satisfaction with an inhaled insulin regimen (31%; 95% CI, 14-50) was significantly greater (P < 0.05) than that with a subcutaneous insulin regimen (13%; 95% CI, 7-19). Increases in overall satisfaction correlated with improvements in glycemic control (r = 0.30; P < 0.05). Both treatment regimens experienced a mean HbA1c reduction of approximately 0.7%. Although patient satisfaction was the chief focus of this article, these results should be considered exploratory, as the trial was powered prospectively for HbA1c values (the primary end point) and not for patient satisfaction. CONCLUSIONS: Administration of an inhaled insulin regimen may offer the first practical, noninvasive alternative to insulin injections. In the patients with type 2 diabetes studied, an inhaled insulin regimen with the need for only 1 subcutaneous injection at bedtime appeared to offer more ease of use, comfort, and convenience, as well as greater overall satisfaction, than a subcutaneous insulin regimen of 2 to 3 injections daily.

Lipoatrophy in GH deficient patients treated with a long-acting pegylated GH.

OBJECTIVE: Changes observed during adult GH deficiency (GHD) are most often reversed with the administration of recombinant human GH (rhGH). To avoid daily injections, a long-acting GH molecule has been obtained by covalent binding of polyethylene glycol (PEG) with rhGH (PEG-GH), allowing weekly s.c. injections. This study was designed to assess its efficacy and safety, in adult GHD subjects. DESIGN AND METHODS: This was a randomized, double-blind, placebo-controlled, multiple-dose, parallel group study. Subjects were recruited from 34 centers. A total of 105 subjects with GHD were assigned a treatment. They received 6 weekly injections of either PEG-GH or placebo. Subjects were randomized into one out of four treatment groups (Groups A-D) or placebo (Group E). Groups A, B, and C received 1, 3, and 4 mg PEG-GH respectively, for the first 3 weeks followed by 2, 6, and 8 mg PEG-GH respectively, for the remaining 3 weeks. Group D received 4 mg PEG-GH for 6 weeks. Group E received placebo. The study was suspended because of the development of lipoatrophy in certain subjects and restarted with an injection rotation plan, before being terminated due to further subjects developing lipoatrophy. RESULTS: A total of 13 cases of injection-site lipoatrophy were reported, of which ten were in females and three occurred after the first injection; all cases were independent of PEG-GH dose or IGF1 levels, either basal or under treatment. CONCLUSION: The unpredictable occurrence of injection-site lipoatrophy with weekly long-acting pegylated GH molecules may be a limiting factor for their development.

Growth hormone (GH) replacement decreases serum total and LDL-cholesterol in hypopituitary patients on maintenance HMG CoA reductase inhibitor (statin) therapy.

OBJECTIVE: Adult onset GH deficiency (GHD) is characterized by abnormalities of serum lipoprotein profiles and GH replacement results in favourable alterations in serum total and low density lipoprotein (LDL)-cholesterol. Preliminary evidence has indicated that the effect of GH replacement in this respect may be additive to that of HMG CoA reductase inhibitor (statin) therapy. We have examined this possibility during prospective follow-up of adult onset hypopituitary patients enrolled in KIMS (Pfizer International Metabolic Database), a pharmacoepidemiological study of GH replacement in adult hypopituitary patients. DESIGN: Lipoprotein profiles were measured centrally at baseline and after 12 months GH replacement therapy. PATIENTS: Sixty-one hypopituitary patients (30 male, 31 female) on maintenance statin therapy (mean 2.5 +/- 2.7 SD years before GH) (statin group - SG) and 1247 (608 male, 639 female) patients not on hypolipidaemic therapy (nonstatin group - NSG) were studied. All patients were naïve or had not received GH replacement during the 6 months prior to study. Patients who developed diabetes mellitus during the first year of GH therapy or in the subsequent year and those with childhood onset GHD were excluded from this analysis. An established diagnosis of diabetes mellitus was present in 18% SG and 4.4% NSG at baseline. MEASUREMENTS: Serum concentrations of total, high density lipoprotein (HDL)-cholesterol, triglycerides and IGF-I were measured centrally in all patients and LDL-cholesterol was estimated using Friedewald's formula. RESULTS: The relative frequency of various statin use was simvastatin 52% (15.8 +/- 8.1 mg, mean +/- SD), atorvastatin 30% (14.4 +/- 7.8 mg), pravastatin 9.8% (31.6 mg +/- 13.9 mg), lovastatin 6.6% (17.5 +/- 5 mg) and fluvastatin 1.6% (40 mg). Baseline serum total and LDL-cholesterol (mean +/- SD) were 5.2 +/- 1.4 and 3.1 +/- 1.3 mmol/l in SG and 5.8 +/- 1.2 and 3.7 +/- 1.0 mmol/l in NSG, respectively (P < 0.0001, SG vs. NSG). After 12 months GH replacement (SG: 0.32 +/- 0.17 mg/day; NSG: 0.38 +/- 0.1 mg/day) serum total and LDL-cholesterol decreased by a mean (+/-SD) of 0.48 (+/- 1.25) mmol/l (P < 0.0004) and 0.53 (+/- 1.08) mmol/l (P < 0.0001) in SG and by 0.30 (+/- 0.89) mmol/l (P < 0.0001) and 0.28 (+/- 0.80) mmol/l (P < 0.0001) in NSG, respectively. There were no significant changes in HDL-cholesterol or triglycerides in either group (SG vs. NSG: NS). A relationship between LDL-cholesterol at baseline and the decrease in LDL-cholesterol after 12 months GH was evident in both groups (SG: R = -0.54, P < 0.001; NSG: R = -0.4, P < 0.001) and a similar relationship for cholesterol was observed. CONCLUSIONS: These data indicate that GH replacement exerts additional beneficial effects on lipoprotein profiles in patients on maintenance statin therapy, confirming that the effects of these interventions are complementary rather than exclusive.