Dissociated Agonist of Glucocorticoid Receptor or Prednisone for Active Rheumatoid Arthritis: Effects on P1NP and Osteocalcin Pharmacodynamics.

Fosdagrocorat (PF-04171327), a dissociated agonist of the glucocorticoid receptor, has potent anti-inflammatory activity in patients with rheumatoid arthritis with reduced adverse effects on bone health. To identify fosdagrocorat doses with bone formation marker changes similar to prednisone 5 mg, we characterized treatment-related changes in amino-terminal propeptide of type I collagen (P1NP) and osteocalcin (OC) with fosdagrocorat (1, 5, 10, or 15 mg) and prednisone (5 or 10 mg) in a phase II randomized trial (N = 323). The time course of markers utilized a mixed-effects longitudinal kinetic-pharmacodynamic model. Median predicted changes from baseline at week 8 with fosdagrocorat 5, 10, and 15 mg were -18, -22, and -22% (P1NP), and -7, -13, and -17% (OC), respectively. Changes with prednisone 5 and 10 mg were -15% and -18% (P1NP) and -10% and -17% (OC). The probability of fosdagrocorat doses up to 15 mg being noninferior to prednisone 5 mg for P1NP and OC changes was >90%.

A four-year, open-label, multi-center, randomized, two-arm study of Genotropin® in patients with idiopathic short stature: comparison of an individualized, target-driven treatment regimen to standard dosing of Genotropin® - analysis of two-year data.

BACKGROUND: Several models have been developed to predict growth response to growth hormone (GH) based on auxological and biochemical parameters for children with non-GH-deficient, idiopathic short stature (ISS). OBJECTIVE: To demonstrate if an individualized, formula-based, target-driven GH regimen for children with ISS would lead to a height (Ht) gain to -1.3 SDS during the first 24 months of treatment of this 4-year study, with less variability than with standard weight-based dosing. METHODS: A 4-year, open-label, multi-center, randomized, two-arm study comparing formula-based dosing of Genotropin® GH from 0.18 to 0.7 mg/kg/week versus standard FDA-approved ISS dosing of Genotropin® (0.37 mg/kg/week). Subjects (n = 316, 89 females) were prepubertal, 3-14 years of age, bone age 3-10 years (m) and 3-9 years (f), naive to GH treatment, Ht SDS -3 to -2.25, Ht velocity <25th percentile for bone age, and peak GH >10 ng/ml. RESULTS: The majority (83%) of subjects had Ht SDS within the normal range by 2 years. All subjects displayed catch-up growth consistent with other studies of GH treatment of ISS. CONCLUSION: The formula-based therapy did not meet the primary endpoint achieving targeted gain with lower variability. No new safety concerns were found.

Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe.

BACKGROUND: There is some evidence that statins may have a protective and symptomatic benefit in Alzheimer disease (AD). The LEADe study is a randomized controlled trial (RCT) evaluating the efficacy and safety of atorvastatin in patients with mild to moderate AD. METHODS: This was an international, multicenter, double-blind, randomized, parallel-group study. Subjects had mild to moderate probable AD (Mini-Mental State Examination score 13-25), were aged 50-90 years, and were taking donepezil 10 mg daily for > or 3 months prior to screening. Entry low-density lipoprotein cholesterol levels (LDL-C) were > 95 and < 195 mg/dL. Patients were randomized to atorvastatin 80 mg/day or placebo for 72 weeks followed by a double-blind, 8-week atorvastatin withdrawal phase. Coprimary endpoints were changes in cognition (Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-Cog]) and global function (Alzheimer's Disease Cooperative Study Clinical Global Impression of Change [ADCS-CGIC]) at 72 weeks. RESULTS: A total of 640 patients were randomized in the study. There were no significant differences in the coprimary endpoints of ADAS-cog or ADCS-CGIC or the secondary endpoints. Atorvastatin was generally well-tolerated. CONCLUSIONS: In this large-scale randomized controlled trial evaluating statin therapy as a treatment for mild to moderate Alzheimer disease, atorvastatin was not associated with significant clinical benefit over 72 weeks. This treatment was generally well-tolerated without unexpected adverse events. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that intensive lipid lowering with atorvastatin 80 mg/day in patients with mild to moderate probable Alzheimer disease (aged 50-90), taking donepezil, with low-density lipoprotein cholesterol levels between 95 and 195 mg/dL over 72 weeks does not benefit cognition (as measured by Alzheimer's Disease Assessment Scale-Cognitive Subscale) (p = 0.26) or global function (as measured by Alzheimer's Disease Cooperative Study Clinical Global Impression of Change) (p = 0.73) compared with placebo.

Glycemic control with preprandial versus basal insulin in patients with type 2 diabetes mellitus poorly controlled by oral antidiabetes agents.

OBJECTIVE: This study was designed to compare glycemic control (glycated hemoglobin [A1C] level) with either once-daily basal insulin (BI) (insulin glargine) or preprandial insulin (PPI) (Exubera) [insulin human (recombinant DNA origin)] inhalation powder, Pfizer Inc., New York, NY) in patients with type 2 diabetes mellitus (T2DM) poorly controlled on at least two oral antidiabetes agents (OADs). METHODS: This was a 26-week, open-label, parallel-group, randomized study where 257 patients (mean A1C 8.6%) on OAD treatment for > or = 3 months were treated with either BI (n = 122) or PPI (n = 135). Based on self-monitored blood glucose levels, PPI dose was adjusted before each major meal, whereas BI dose was titrated in the morning or before bedtime. Prestudy OADs were continued, but doses could be modified. RESULTS: At 26 weeks, change from baseline in A1C was greater with PPI (-1.7 vs. -1.4%, P = 0.0389). Numerically, more patients achieved A1C <6.5% (28% vs. 19%) and A1C <7.0% (63% vs. 55%) with PPI compared with BI. PPI had lower postmeal glucose increments, but higher prebreakfast glucose and weight gain (1.1kg), than BI. Mild or moderate hypoglycemic events were more frequent with PPI (6.2 vs. 2.9 events/months), but nocturnal hypoglycemic events were less frequent (22% vs. 30%). CONCLUSIONS: PPI improved postprandial glucose and A1C levels significantly more than BI. More patients achieved A1C targets with PPI, at the expense of more hypoglycemia and body weight gain. These results illustrate the potential benefits and detriments of prandial insulin supplementation in patients with T2DM poorly controlled on OADs alone.

Plasma levels of tumour necrosis factor-alpha in patients with chronic periodontitis and type 2 diabetes.

OBJECTIVES: Studies suggest that elevated circulating tumour necrosis factor-alpha (TNF-alpha) may contribute to insulin resistance in patients with type 2 diabetes. The source of plasma TNF has been thought to be adipocytes associated with obesity, but inflammation and infection result in TNF-alpha production as well. METHODS: We studied 46 patients with type 2 diabetes and chronic periodontitis to determine the relationship between plasma TNF-alpha levels and clinical measures of periodontitis, gingival crevicular fluid (GCF) interleukin-1beta (IL-1beta), plasma endotoxin, serum glucose, and glycated haemoglobin (HbA1c). TNF-alpha levels were measured using a high sensitivity enzyme-linked immunosorbent assay. RESULTS: TNF-alpha showed a significant positive correlation with attachment loss (r=0.40, p=0.009), plasma endotoxin (r=0.33, p=0.03), and GCF IL-1beta (r=0.33, p=0.035), but not probing depth (r=0.28, p=0.07), bleeding on probing (r=0.30, p=0.053), plaque index (r=0.22, p=0.17), serum glucose, HbA1c (r=0.10, p=0.50), or body mass index (r=0.077, p=0.62). A dose-response relationship was observed between periodontitis severity and TNF-alpha (p=0.012). CONCLUSION: The finding that chronic periodontitis is associated with plasma TNF-alpha levels in subjects with type 2 diabetes supports the hypothesis that periodontal infection and inflammation may contribute to insulin resistance.