Search

Evidence from clinical trials suggest that newer antihyperglycemic agents (AHAs) have a better clinical profile at a higher dose. However, the utilization of the different doses in the real world is not well known. This study aimed to assess the dose utilization of the 2 newer classes of AHAs using the 2018 Adelphi T2DM Disease Specific Programme, a survey involving 730 physicians and 8794 patients in the U.S. and Europe. The analysis included 1612 patients on sodium glucose cotransporter 2 inhibitors (SGLT2i) and 1073 patients on glucagon like peptide-1 receptor agonist (GLP-1RA), either monotherapy or combined therapy. Dose cut points for SGLT2i drugs were based on doses utilized in cardiovascular outcomes trials (at a compound level, Table 1). There is no standard cut point on dosing in GLP-1RA, therefore a conservative approach was applied (see Table for details). Analyses were performed at class level. SGLT2i drugs were more likely to be prescribed at a high dose (85.7%) to patients who were slightly younger than those receiving a lower dose (57.1 vs. 58.9 years). GLP-1RA were prescribed at high dose in 63.2% of the patients. Mean BMI was higher in patients receiving high dose of a GLP-1 receptor agonist. Disclosure D. Lautsch: Employee; Self; Merck & Co., Inc. E. McLeod: Employee; Self; Pfizer Inc. Stock/Shareholder; Self; Pfizer Inc. T. Wang: Employee; Spouse/Partner; Janssen Pharmaceuticals, Inc. Employee; Self; Merck & Co., Inc. C.D. Gonzalez: Employee; Self; Merck & Co., Inc. S. Rajpathak: Employee; Self; Menarini Group. S. Malkani: None. J. Jackson: None. G. Milligan: None. V. Higgins: None. Funding Merck Sharp & Dohme Corp; Pfizer Inc.

Apolipoprotein E (apoE) alleles are important genetic risk factors for Alzheimer's disease (AD), with the ε4 allele increasing and the ε2 allele decreasing risk for developing AD. ApoE has been shown to influence brain amyloid-β peptide (Aβ) and amyloid burden, both in humans and in transgenic mice. Here we show that direct intracerebral administration of lentiviral vectors expressing the three common human apoE isoforms differentially alters hippocampal Aβ and amyloid burden in the PDAPP mouse model of AD. Expression of apoE4 in the absence of mouse apoE increases hippocampal Aβ 1–42 levels and amyloid burden. By contrast, expression of apoE2, even in the presence of mouse apoE, markedly reduces hippocampal Aβ burden. Our data demonstrate rapid apoE isoform-dependent effects on brain Aβ burden in a mouse model of AD. Gene delivery of apoE2 may prevent or reduce brain Aβ burden and the subsequent development of neuritic plaques.

Studies of gene expression following fear conditioning have demonstrated that the inducible transcription factor, egr-1, is increased in the lateral nucleus of the amygdala shortly following fear conditioning. These studies suggest that egr-1 and its protein product Egr-1 in the amygdala are important for learning and memory of fear. To directly test this hypothesis, an egr-1 antisense oligodeoxynucleotide (antisense-ODN) was injected bilaterally into the amygdala prior to contextual fear conditioning. The antisense-ODN reduced Egr-1 protein in the amygdala and interfered with fear conditioning. A 250-pmole dose produced an 11% decrease in Egr-1 protein and reduced long-term memory of fear as measured by freezing in a retention test 24 h after conditioning, but left shock-induced freezing intact. A larger 500-pmole dose produced a 25% reduction in Egr-1 protein and significantly decreased both freezing immediately following conditioning and freezing in the retention test. A nonsense-ODN had no effect on postshock or retention test freezing. In addition, 500 pmole of antisense-ODN infused prior to the retention test in previously trained rats did not reduce freezing, indicating that antisense-ODN did not suppress conditioned fear behavior. Finally, rats infused with 500 pmole of antisense-ODN displayed unconditioned fear to a predator odor, demonstrating that unconditioned freezing was unaffected by the antisense-ODN. The data indicate that the egr-1 antisense-ODN interferes with learning and memory processes of fear without affecting freezing behavior and suggests that the inducible transcription factor Egr-1 within the amygdala plays important functions in long-term learning and memory of fear.

Expression of the immediate-early gene, NGFI-B (nerve growth factor inducible gene B), was examined in the amygdala, hippocampus, and neocortex following contextual fear conditioning. Rats were either handled, placed within the testing context without receiving the footshock, received a footshock immediately upon placement within the context, or received a footshock after a 3-min delay (delayed-shock). Only the delayed-shock group displayed a fear response (freezing) in the post-shock period and in a retention test 24 h after fear conditioning. Expression of NGFI-B mRNA was increased in the dorsolateral part of the lateral nucleus of the amygdala (LaDL) and the neocortex 30 min following conditioning in the delayed-shock group compared to the other three groups. In addition, following a retention test conducted 24 h after fear conditioning, NGFI-B mRNA expression was increased in the neocortex of the delayed-shock group compared to the handled group. In a subsequent experiment, the effects of pretreatment with the anxiolytic drug, diazepam, on fear conditioning and the concomitant increases in NGFI-B mRNA were investigated. Rats administered a 2.5 mg/kg, i.p. dose of diazepam before fear conditioning did not acquire contextual fear as demonstrated by a lack of freezing in a retention test. Although diazepam blocked fear conditioning while the 40% propylene glycol, 10% ethanol vehicle solution did not, both diazepam and the vehicle reduced the conditioning-induced increase in NGFI-B expression in the LaDL. In contrast, the fear-conditioning-induced NGFI-B increase in the neocortex was blocked by diazepam, but not by the vehicle. The data suggest that the transcriptional factor NGFI-B in the LaDL and neocortex may play a functional role in learning and memory of contextual fear, but blocking the increase in NGFI-B expression in the LaDL is not essential for diazepam to interfere with fear conditioning.