Efficacy and Safety of Ertugliflozin Added to Metformin: A Pooled Population from Asia with Type 2 Diabetes and Overweight or Obesity.

INTRODUCTION: The efficacy and safety of ertugliflozin have not been well characterized in Asian populations with type 2 diabetes (T2D) and overweight or obesity as defined by the Chinese Diabetes Society [body mass index (BMI) ≥ 24 kg/m2]. METHODS: These post hoc analyses of pooled data from two randomized, double-blind, 26-week studies assessed the efficacy and safety of ertugliflozin (5 mg or 15 mg) compared with placebo in participants from Asia with T2D and baseline BMI ≥ 24 kg/m2, with inadequate glycemic control on metformin. Longitudinal analyses were used to calculate least squares (LS) mean [95% confidence interval (CI)] change from baseline in glycemic indices and body weight. The proportions of participants achieving efficacy targets and experiencing adverse events (AEs) were assessed. RESULTS: The 445 participants had a mean age of 55.5 years, T2D duration 6.6 years, glycated hemoglobin (HbA1c) 8.1%, and BMI 27.6 kg/m2. At week 26, placebo-adjusted LS mean (95% CI) changes from baseline for ertugliflozin 5 mg and 15 mg, respectively, were - 0.78% (- 0.95% to - 0.61%) and - 0.80% (- 0.98% to - 0.63%) for HbA1c, and - 1.74 kg (- 2.29 kg to - 1.19 kg) and - 2.04 kg (- 2.60 kg to - 1.48 kg) for body weight. A greater proportion of participants receiving ertugliflozin 5 mg and 15 mg versus placebo, respectively, achieved HbA1c < 7.0% (42.1% and 46.3% vs. 13.9%), body weight reduction ≥ 5% (35.5% and 38.3% vs. 11.1%), and systolic blood pressure < 130 mmHg (42.4% and 34.5% vs. 21.7%). The proportion of participants with AEs was 52.6% (ertugliflozin 5 mg), 52.3% (ertugliflozin 15 mg), and 55.6% (placebo). CONCLUSIONS: In participants from Asia with T2D inadequately controlled by metformin monotherapy, and BMI ≥24 kg/m2, ertugliflozin (5 mg or 15 mg) resulted in greater glycemic and body weight reductions compared with placebo and was generally well tolerated. TRIAL REGISTRATION: Clinicaltrials.gov identifiers NCT02033889, NCT02630706.

Individualized HbA1c Goals, and Patient Awareness and Attainment of Goals in Type 2 Diabetes Mellitus: A Real-World Multinational Survey.

AIMS: While glycemic control is key in effective type 2 diabetes mellitus management, many patients fail to reach their individualized glycemic goal. This analysis aimed to describe a real-world picture of diabetes management: individualized hemoglobin A1c (HbA1c) goals, rate of goal attainment, HbA1c at each line of therapy, and patient awareness of their glycemic goal. Secondly, we aimed to understand physician satisfaction with HbA1c amongst patients aware vs. those unaware of HbA1c goal. METHODS: Analysis of physicians and the next ten consulting patients with type 2 diabetes mellitus conducted in Europe and the USA including medical record data abstraction/assessment by physicians, a patient-reported survey and a physician survey. Patients were diagnosed for 3 months or more with a known current and target HbA1c. For the sub-analysis assessment of patient awareness of HbA1c goal, in addition to the above, these patients had to have completed a patient-reported questionnaire and answer the question on awareness of HbA1c goal. RESULTS: A total of 730 physicians provided data on 8794 patients with type 2 diabetes mellitus; 5331 patients were eligible for this analysis. Overall, mean (standard deviation, SD) individualized HbA1c goal was 6.8% (0.68%). Of eligible patients, 39.1% met their HbA1c goal; of 60.9% of patients not reaching their HbA1c goal, the mean distance from individualized HbA1c goal was 0.9% (SD 1.0%). Physicians progressed patients' antihyperglycemic therapy when HbA1c was 8% or higher. Among 2560 patients who were included in the sub-analysis assessing the effect of patient awareness of their HbA1c goal on multiple parameters, 70.5% were aware of their HbA1c goal; mean HbA1c goal was 6.8% (0.7%) and current mean HbA1c value 7.1% (1.2%). A total of 949 patients in the sub-analysis (39.2%) achieved their goal; achieving HbA1c goal was not related to knowledge of goal. Patients aware of their HbA1c goal were slightly more adherent to their antihyperglycemic medication. They also were prescribed more antihyperglycemic agents, more often on a later therapy line receiving a GLP-1 receptor agonist, SGLT2i, or insulin, and more often tested their blood glucose levels than patients who were unaware. Physicians were not satisfied with the current blood glucose level of one third of their patients, believing that more of those who were aware of their HbA1c goal could achieve better glucose control (32.4% of aware vs. 28.2% of unaware patients; p = 0.003). CONCLUSIONS: Our results showed that the proportion of patients with type 2 diabetes mellitus achieving their goals for glycemic control was suboptimal when compared to current guideline criteria, with only about 40% of patients achieving their individualized HbA1c goal. Treatment intensification was often delayed until HbA1c was 8% and higher. Patients aware of their HbA1c goal were slightly more adherent to their antihyperglycemic medication; however, awareness of HbA1c goal did not enhance goal attainment. This highlights the need for a holistic approach to diabetes management, involving patient education, and patient-physician communication and partnership.

Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice.

Accumulation of beta-amyloid (Abeta) peptides in the cerebral cortex is considered a key event in the pathogenesis of Alzheimer's disease (AD). Presenilin 1 (PS1) plays an essential role in the gamma-secretase cleavage of the amyloid precursor protein (APP) and the generation of Abeta peptides. Reduction of Abeta generation via the inhibition of gamma-secretase activity, therefore, has been proposed as a therapeutic approach for AD. In this study, we examined whether genetic inactivation of PS1 in postnatal forebrain-restricted conditional knock-out (PS1 cKO) mice can prevent the accumulation of Abeta peptides and ameliorate cognitive deficits exhibited by an amyloid mouse model that overexpresses human mutant APP. We found that conditional inactivation of PS1 in APP transgenic mice (PS1 cKO;APP Tg) effectively prevented the accumulation of Abeta peptides and formation of amyloid plaques and inflammatory responses, although it also caused an age-related accumulation of C-terminal fragments of APP. Short-term PS1 inactivation in young PS1 cKO;APP Tg mice rescued deficits in contextual fear conditioning and serial spatial reversal learning in a water maze, which were associated with APP Tg mice. Longer-term PS1 inactivation in older PS1 cKO;APP Tg mice, however, failed to rescue the contextual memory and hippocampal synaptic deficits and had a decreasing ameliorative effect on the spatial memory impairment. These results reveal that in vivo reduction of Abeta via the inactivation of PS1 effectively prevents amyloid-associated neuropathological changes and can, but only temporarily, improve cognitive impairments in APP transgenic mice.

Gene delivery of human apolipoprotein E alters brain Abeta burden in a mouse model of Alzheimer's disease.

Apolipoprotein E (apoE) alleles are important genetic risk factors for Alzheimer's disease (AD), with the epsilon4 allele increasing and the epsilon2 allele decreasing risk for developing AD. ApoE has been shown to influence brain amyloid-beta peptide (Abeta) 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 Abeta and amyloid burden in the PDAPP mouse model of AD. Expression of apoE4 in the absence of mouse apoE increases hippocampal Abeta(1-42) levels and amyloid burden. By contrast, expression of apoE2, even in the presence of mouse apoE, markedly reduces hippocampal Abeta burden. Our data demonstrate rapid apoE isoform-dependent effects on brain Abeta burden in a mouse model of AD. Gene delivery of apoE2 may prevent or reduce brain Abeta burden and the subsequent development of neuritic plaques.

An egr-1 (zif268) antisense oligodeoxynucleotide infused into the amygdala disrupts fear conditioning.

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.

Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides.

We have previously shown that apolipoprotein E (Apoe) promotes the formation of amyloid in brain and that astrocyte-specific expression of APOE markedly affects the deposition of amyloid-beta peptides (Abeta) in a mouse model of Alzheimer disease. Given the capacity of astrocytes to degrade Abeta, we investigated the potential role of Apoe in this astrocyte-mediated degradation. In contrast to cultured adult wild-type mouse astrocytes, adult Apoe(-/-) astrocytes do not degrade Abeta present in Abeta plaque-bearing brain sections in vitro. Coincubation with antibodies to either Apoe or Abeta, or with RAP, an antagonist of the low-density lipoprotein receptor family, effectively blocks Abeta degradation by astrocytes. Phase-contrast and confocal microscopy show that Apoe(-/-) astrocytes do not respond to or internalize Abeta deposits to the same extent as do wild-type astrocytes. Thus, Apoe seems to be important in the degradation and clearance of deposited Abeta species by astrocytes, a process that may be impaired in Alzheimer disease.

Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration.

Mutations in presenilins are the major cause of familial Alzheimer's disease, but the pathogenic mechanism by which presenilin mutations cause memory loss and neurodegeneration remains unclear. Here we demonstrate that conditional double knockout mice lacking both presenilins in the postnatal forebrain exhibit impairments in hippocampal memory and synaptic plasticity. These deficits are associated with specific reductions in NMDA receptor-mediated responses and synaptic levels of NMDA receptors and alphaCaMKII. Furthermore, loss of presenilins causes reduced expression of CBP and CREB/CBP target genes, such as c-fos and BDNF. With increasing age, mutant mice develop striking neurodegeneration of the cerebral cortex and worsening impairments of memory and synaptic function. Neurodegeneration is accompanied by increased levels of the Cdk5 activator p25 and hyperphosphorylated tau. These results define essential roles and molecular targets of presenilins in synaptic plasticity, learning and memory, and neuronal survival in the adult cerebral cortex.