Glycaemic control and hypoglycaemia risk with insulin glargine 300 U/mL versus glargine 100 U/mL: A patient-level meta-analysis examining older and younger adults with type 2 diabetes.

AIM: Older people with type 2 diabetes (T2DM) are at an increased risk of hypoglycaemia and its consequences. However, efficacy and safety data for basal insulin therapy are limited in these individuals. This patient-level meta-analysis assessed the treatment effects of insulin glargine 300 U/mL (Gla-300) versus glargine 100 U/mL (Gla-100) in people with T2DM ≥ 65 years old. METHODS: Data were pooled for patients randomised to receive Gla-300 or Gla-100 in the Phase 3a, treat-to-target EDITION 1, 2 and 3 trials. Glycaemic efficacy, hypoglycaemia, changes in body weight and insulin dosage and adverse events were examined over 6 months' treatment with Gla-300 versus Gla-100 for participants aged ≥ 65 and < 65 years. RESULTS: Of 2496 participants randomised, 662 were ≥ 65 years (Gla-300, n = 329; Gla-100, n = 333). Glycaemic control was comparable for Gla-300 and Gla-100 in participants ≥ 65 years (LS mean [95% CI] difference in HbA1c change from baseline to month 6: 0.00 [-0.14 to 0.15] %; 0.00 [-1.53 to 1.64] mmol/mol) and < 65 years (0.00 [-0.09 to 0.08] %; 0.00 [-0.98 to 0.87] mmol/mol). Fewer participants receiving Gla-300 versus Gla-100 experienced nocturnal confirmed (≤ 3.9 mmol/L [≤ 70 mg/dL]) or severe hypoglycaemia (relative risk: ≥ 65 years: 0.70 [0.57 to 0.85]; < 65 years: 0.77 [0.68 to 0.87]). Annualised rates of nocturnal confirmed or severe hypoglycaemia were lower with Gla-300 than Gla-100 for both age groups. CONCLUSION: Gla-300 was associated with a reduced risk of nocturnal hypoglycaemia versus Gla-100, accompanied by comparable glycaemic improvement, for people aged ≥ 65 and < 65 years with T2DM.

Horses grazing with cattle have reduced strongyle egg count due to the dilution effect and increased reliance on macrocyclic lactones in mixed farms.

Strongyle infection is an important issue in horse breeding. It impairs horse health and performance, with young horses being the most sensitive. Strongyle control has long relied on the systematic use of chemical treatments. However, expanding anthelmintic resistance among strongyles calls for alternative options. Mixed grazing is assumed to reduce strongyle load on the pasture as the result of a dilution effect. This has been shown in small ruminants grazing with cattle, but the putative benefits of co-grazing between horses and cattle have not yet been evaluated. Here, we conducted field surveys and face-to-face interviews on 44 farms from two contrasted saddle-horse production areas, Normandy and northern Massif Central, to compare equine strongyle management practices between specialized systems and mixed horse-cattle systems. Our goals were (i) to quantify breeders' awareness of the putative benefits associated with the co-grazing of horses and cattle, (ii) to establish whether mixed farming was associated with different strongyle management strategies and (iii) to test whether strongyle egg excretion was reduced in horses grazed with beef cattle. Every breeder relied on systematic calendar treatments, and only 8 out of the 23 mixed breeders were aware that co-grazing of horses with cattle could be used as part of their strongyle control strategy. Management practices were similar across both systems in Normandy. In Massif Central, mixed breeders formed a distinct cluster from their specialized counterparts: deworming was less frequent and stocking density was higher in mixed farms, while specialized breeders seemed more willing to integrate herd and plot management into control strategies. Faecal egg counts measured in horses from Massif Central were significantly reduced when horses were grazed with cattle. This was the result of an increased reliance on macrocyclic lactones in mixed farms (P < 0.01) and a significant dilution effect (P < 0.01). When considering a subsample of horses treated with macrocyclic lactones only, young horses grazed with cattle had 50% fewer strongyle eggs excreted in their faeces than horses grazed in equine-only pastures (P < 0.01). This is the first evidence of the benefits of mixed grazing with cattle as an alternative to control strongyle infection in horses, although this promising alternative remains largely unknown by horse breeders.

Efficacy and safety of alirocumab in insulin-treated patients with type 1 or type 2 diabetes and high cardiovascular risk: Rationale and design of the ODYSSEY DM-INSULIN trial.

AIMS: The coadministration of alirocumab, a PCSK9 inhibitor for treatment of hypercholesterolaemia, and insulin in diabetes mellitus (DM) requires further study. Described here is the rationale behind a phase-IIIb study designed to characterize the efficacy and safety of alirocumab in insulin-treated patients with type 1 (T1) or type 2 (T2) DM with hypercholesterolaemia and high cardiovascular (CV) risk. METHODS: ODYSSEY DM-INSULIN (NCT02585778) is a randomized, double-blind, placebo-controlled, multicentre study that planned to enrol around 400 T2 and up to 100 T1 insulin-treated DM patients. Participants had low-density lipoprotein cholesterol (LDL-C) levels at screening≥70mg/dL (1.81mmol/L) with stable maximum tolerated statin therapy or were statin-intolerant, and taking (or not) other lipid-lowering therapy; they also had established CV disease or at least one additional CV risk factor. Eligible patients were randomized 2:1 to 24weeks of alirocumab 75mg every 2weeks (Q2W) or a placebo. Alirocumab-treated patients with LDL-C≥70mg/dL at week 8 underwent a blinded dose increase to 150mg Q2W at week 12. Primary endpoints were the difference between treatment arms in percentage change of calculated LDL-C from baseline to week 24, and alirocumab safety. RESULTS: This is an ongoing clinical trial, with 76 T1 and 441 T2 DM patients enrolled; results are expected in mid-2017. CONCLUSION: The ODYSSEY DM-INSULIN study will provide information on the efficacy and safety of alirocumab in insulin-treated individuals with T1 or T2 DM who are at high CV risk and have hypercholesterolaemia not adequately controlled by the maximum tolerated statin therapy.

ALT and viral load decline during PEG-IFN alpha-2b treatment for HBeAg-positive chronic hepatitis B.

BACKGROUND: Alanine aminotransferase (ALT) is one of the main indicators for inflammatory activity in chronic hepatitis B. During interferon-based therapy, approximately 25%-40% of patients exhibit an ALT flare. OBJECTIVES AND STUDY DESIGN: To analyze the relation between ALT and HBV-DNA during pegylated interferon alpha-2b (PEG-IFN) treatment and compare different patterns of on-treatment viral load decline with the occurrence of ALT flares. RESULTS: Of the 123 patients included in this study 31 (25%) exhibited an ALT flare during treatment or follow-up. Six out of 8 (75%) host-induced flares, i.e. ALT flares which were followed by a HBV-DNA decrease associated with a favorable treatment outcome, occurred in patients with a delayed HBV-DNA decline pattern (delayed vs. non-delayed decline, p=.022); 5 of these 8 patients exhibited HBeAg loss and 4 even HBsAg loss at the end of follow-up. The prediction of ALT normalization was possible using on-treatment viral load. Based on the difference from baseline, the evolution of viral load and ALT level were strongly interrelated during treatment and follow-up. With a joint model we estimated a correlation coefficient of 0.38 (p<0.001) during the first 4 weeks of the treatment and of 0.72 (p<0.0001) thereafter. CONCLUSION: There was a strong relation between ALT and viral load in HBeAg-positive chronic hepatitis B patients treated with PEG-IFN alpha-2b, especially after 4 weeks of treatment. Patients with a delayed decline in viral load often exhibited a host-induced flare associated with a favorable outcome.

Evolution during growth of the mechanical properties of the cortical bone in equine cannon-bones.

Two specimens (70.0 x 4.5 x 1.8 mm) (proximal and distal) of cortical bone were taken from each of the cranial, caudal, lateral and medial quadrants at mid-diaphysis of the third metacarpus and metatarsus of French saddle horses (12 males and seven females) aged from 1 day to 4 years. The mechanical properties (bending strength, Young's modulus, yield stress and ultimate specific deflection) were determined by a 4-point bending test, loading at a rate of 166 x 10(-6) ms-1. During growth, the mechanical properties of the cortical bone were not significantly different (p > 0.05) between metacarpus and metatarsus, but they were slightly higher in the proximal than in the distal diaphysis. The variations in these properties were significant (p < 0.0001) between quadrants. From birth to adult age, the lateral and medial quadrants had greater average bending strength (Sb = 226 +/- 27 MPa), average Young's modulus (E = 16 +/- 2 GPa) and average yield stress (Sy = 110 +/- 23 MPa) than the cranial quadrant (Sb = 209 +/- 23 MPa, E = 15 +/- 2 GPa, Sy = 99 +/- 18 MPa) while the caudal quadrant gave the lowest values (Sb = 195 +/- 30 MPa, E = 14 +/- 2 GPa, Sy = 92 +/- 21 MPa). During the growing period, the bending strength, the Young's modulus and the yield stress were positively correlated with age (p < 0.01) and the total body weight (p < 0.001) of the horses. Conversely, the ultimate specific deflection decreased slightly during the same period. The mechanical properties of the cortex were also related (p < 0.005) to the mineral content (ash or calcium). The Young's modulus was particularly correlated to calcium content (p < 0.0001). It is also linearly related to the bending strength (r = 0.8), and its in vivo determination by the ultrasound method should provide an easy and non-invasive investigation means of the mechanical properties of the cortical bone in equine cannon-bones.

Stimulation of phosphoenolpyruvate carboxykinase gene expression by fatty acids.

We used the 3T3-F442A adipocytes and the FAO hepatoma cells to analyze the effect of oleate on phosphoenolpyruvate carboxykinase (PEPCK) gene expression. In serum-deprived, glucose-free medium, 1 mM oleate, bound to albumin in a 6:1 ratio, specifically stimulated PEPCK mRNA. In 3T3-F442A adipocytes, the maximum 5-fold increase occurred in 4 hours then rapidly declined to reach the basal level 20 hours later. This increase was cycloheximide-independent and actinomycin D-dependent, suggesting a direct, transcriptional effect of oleate. FAO cells also responded to oleate with a transient induction of PEPCK mRNA, although the extent of stimulation was lower. Thus, the PEPCK gene provides a useful molecular tool for studying the mechanisms by which fatty acids stimulate gene expression.