The TOMM40 poly-T rs10524523 variant is associated with cognitive performance among non-demented elderly with type 2 diabetes

The variable length poly-T, rs10524523 (‘523’) located within the TOMM40 gene, was recently associated with several phenotypes of cognitive function. The short (S) allele is associated with later AD onset age and better cognitive performance, compared to the longer alleles (long and very-long (VL)). There is strong linkage disequilibrium between variants in the TOMM40 and APOE genes. In this study, we investigated the effect of ‘523’ on cognitive performance in a sample of cognitively normal Jewish elderly with type 2 diabetes, a group at particularly high risk for cognitive impairment. Using a MANCOVA procedure, we compared homozygous carriers of the S/S allele (N=179) to carriers of the VL/VL allele (N=152), controlling for demographic and cardiovascular covariates. The S/S group performed better than the VL/VL group (p=0.048), specifically in the executive function (p=0.04) and episodic memory (p=0.050) domains. These results suggest that previous findings of an association of the TOMM40 short allele with better cognitive performance, independently from the APOE variant status, are pertinent to elderly with diabetes.     

Real-world evaluation of glycemic control among patients with type 2 diabetes mellitus treated with canagliflozin versus dipeptidyl peptidase-4 inhibitors

Objective To evaluate glycemic control among patients with type 2 diabetes mellitus (T2DM) treated with canagliflozin (CANA) vs. dipeptidyl peptidase-4 (DPP-4) inhibitors.

Methods Using integrated claims and lab data from a US health plan of commercial and Medicare Advantage enrollees, this matched-control cohort study assessed adult T2DM patients receiving treatment with CANA or DPP-4 inhibitors (1 April 2013–31 December 2013). Cohorts were chosen hierarchically; the first pharmacy claim for CANA was identified as the index date; then the first pharmacy claim for a DPP-4 inhibitor was identified and index date set. Eligible patients had 6 months of continuous health plan enrollment before the index date (baseline) and 9 months after (follow-up) and no evidence of index drug in baseline. Patients were matched 1:1 using propensity score matching. Changes in glycated hemoglobin (HbA1c) and percentages of patients with HbA1c <8% and <7% during the follow-up were evaluated.

Results The matched CANA and DPP-4 inhibitor cohorts (53.2% treated with sitagliptin) included 2766 patients each (mean age: 55.7 years). Among patients with baseline and follow-up HbA1c results, mean baseline HbA1c values were similar, 8.62% and 8.57% (p?=?0.615) for the CANA (n?=?729) and DPP-4 inhibitor (n?=?710) cohorts, respectively. Change in HbA1c was greater among patients in the CANA cohort than for those in the DPP-4 inhibitor cohort (?0.92% vs. ?0.63%, p?<?0.001), and also among the subset of patients with baseline HbA1c ≥7% (-1.07% [n?=?624] vs. ?0.79% [n?=?603], p?=?0.004). During follow-up, greater percentages of the CANA cohort relative to the DPP-4 inhibitor cohort achieved HbA1c of <8% (66.0% vs. 58.6%, p?=?0.004) and <7% (35.4% vs. 29.9%, p?=?0.022).

Limitations This study was observational and residual confounding remains a possibility.

Conclusions In this real-world study of patients with T2DM, CANA use was associated with greater HbA1c reduction and higher percentages of patients attaining HbA1c goals than those treated with DPP-4 inhibitors.     

A randomized clinical trial of the safety and efficacy of sitagliptin in patients with type 2 diabetes mellitus inadequately controlled by acarbose alone

Objective: To evaluate the safety and efficacy of sitagliptin when added to the treatment of patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control on acarbose monotherapy.

Research design and methods: This was a multicenter, randomized, placebo-controlled, double-blind clinical trial. Patients (N?=?381) with T2DM and inadequate glycemic control (glycated hemoglobin [HbA1c] ≥?7.0% and ≤10.0%) on acarbose monotherapy (at least 50?mg three times daily) were randomized in a 1:1 ratio to receive the addition of sitagliptin 100?mg or matching placebo once daily for 24 weeks.

Main outcome measures: Changes from baseline in HbA1c and fasting plasma glucose (FPG) at Week 24.

Results: The mean baseline HbA1c in randomized patients was 8.1%. At Week 24, the placebo-controlled, least squares mean changes from baseline (95% confidence interval) in HbA1c and FPG in the sitagliptin group were ?0.62% and ?0.8?mmol/L (p?p?Conclusions: Sitagliptin was generally well tolerated and provided statistically superior and clinically meaningful improvements in glycemic control after 24 weeks of treatment compared to placebo when added to treatment of patients with inadequate glycemic control on acarbose monotherapy.

Clinicaltrials.gov: NCT01177384.     

Impact of Common KIBRA Allele on Human Cognitive Functions

The rs17070145 polymorphism (C → T substitution, intron 9) of the KIBRA gene has recently been associated with episodic memory and cognitive flexibility. These findings were inconsistent across reports though, and largely lacked gene–gene or gene–environment interactions. The aim of the present study was to determine the impact of the rs17070145 polymorphism on clinically relevant cognitive domains and its interaction with the modifiers ‘lifestyle'' and ‘cardiovascular risk factors''. Five-hundred forty-five elderly volunteers (mean age 64 years, ±7 years, 56% women) accomplished a comprehensive cognitive testing. Principal component analysis was used to reveal the internal structure of the data, rendering four composite scores: verbal memory, word fluency, executive function/psychomotor speed, and working memory. Lifestyle was assessed with a detailed questionnaire, age-associated risk factors by clinical interview and examination. There was no main effect of the rs17070145 genotype on any cognitive composite scores. However, we found worse performance in executive functions for T-allele carriers in the presence of arterial hypertension (β=−0.365, p=0.0077 and 0.031 after Bonferroni correction). This association was further modified by gender, showing the strongest association in hypertensive females (β=−0.500, p=0.0072 and 0.029 after Bonferroni correction). The effect of KIBRA on cognitive function seems to be complex and modified by gender and arterial hypertension.     

Disrupted Functional and Structural Networks in Cognitively Normal Elderly Subjects with the APOE ?4 Allele

As the Apolipoprotein E (APOE) ɛ4 allele is a major genetic risk factor for sporadic Alzheimer''s disease (AD), which has been suggested as a disconnection syndrome manifested by the disruption of white matter (WM) integrity and functional connectivity (FC), elucidating the subtle brain structural and functional network changes in cognitively normal ɛ4 carriers is essential for identifying sensitive neuroimaging based biomarkers and understanding the preclinical AD-related abnormality development. We first constructed functional network on the basis of resting-state functional magnetic resonance imaging and a structural network on the basis of diffusion tensor image. Using global, local and nodal efficiencies of these two networks, we then examined (i) the differences of functional and WM structural network between cognitively normal ɛ4 carriers and non-carriers simultaneously, (ii) the sensitivity of these indices as biomarkers, and (iii) their relationship to behavior measurements, as well as to cholesterol level. For ɛ4 carriers, we found reduced global efficiency significantly in WM and marginally in FC, regional FC dysfunctions mainly in medial temporal areas, and more widespread for WM network. Importantly, the right parahippocampal gyrus (PHG.R) was the only region with simultaneous functional and structural damage, and the nodal efficiency of PHG.R in WM network mediates the APOE ɛ4 effect on memory function. Finally, the cholesterol level correlated with WM network differently than with the functional network in ɛ4 carriers. Our results demonstrated ɛ4-specific abnormal structural and functional patterns, which may potentially serve as biomarkers for early detection before the onset of the disease.     

A randomized clinical trial evaluating the efficacy and safety of the once-weekly dipeptidyl peptidase-4 inhibitor omarigliptin in patients with type 2 diabetes inadequately controlled on metformin monotherapy

Objective: To examine the efficacy and safety of the once-weekly (q.w.) dipeptidyl peptidase-4 inhibitor, omarigliptin, in patients with type 2 diabetes (T2DM) and inadequate glycemic control on metformin monotherapy.

Methods: In a randomized, double-blind trial, patients with T2DM on a stable dose of metformin monotherapy (≥1500?mg/day) with glycated hemoglobin (HbA1c) of 7.0–10.5% were randomized to omarigliptin 25?mg q.w. or matching placebo (n?=?201 in both) for 24 weeks (primary timepoint) followed by an additional 80-week treatment period.

Results: At week 24, from a mean baseline HbA1c of 8.0–8.1%, the least squares (LS) mean (95% CI) change from baseline in HbA1c (primary end-point) was –0.54% (–0.69%, –0.40%) in the omarigliptin group and 0.00% (–0.14%, 0.15%) in the placebo group, for a between-group difference of –0.55% (–0.75%, –0.34%); p?p?=?.011) and –0.5 mmol/L (–0.9, –0.1) (p?=?.010), respectively. At week 24, the incidences of symptomatic hypoglycemia and subjects with one or more adverse event (AE), serious AEs, and discontinuations due to an AE were similar in the omarigliptin and placebo groups. Over 104 weeks, omarigliptin treatment provided a clinically meaningful reduction in HbA1c.

Conclusions: In patients with T2DM, adding omarigliptin 25?mg q.w. to metformin monotherapy improved glycemic control over 104 weeks and was generally welltolerated with a low risk of hypoglycemia.     

Effects of vildagliptin versus saxagliptin on daily acute glucose fluctuations in Chinese patients with T2DM inadequately controlled with a combination of metformin and sulfonylurea

Objective The present study aimed to compare the effects of the dipeptidyl peptidase-4 (DPP-4) inhibitors vildagliptin and saxagliptin on 24?hour acute glucose fluctuations in Chinese patients with type 2 diabetes mellitus (T2DM) inadequately controlled with a combination of metformin and sulfonylurea.

Research design and methods This was a 24 week, prospective, randomized, open-label, active-controlled study. Patients (N?=?73) with T2DM who had inadequate glycemic control (HbA1c 7.0%–10.0%) with a stable dosage of metformin plus gliclazide for more than 3 months were randomized to receive either vildagliptin 50?mg twice daily (BID, n?=?37) or saxagliptin 5?mg once daily (QD, n?=?36). Change in mean amplitude of glycemic excursions (MAGE) was assessed at the end of 24 weeks.

Results At baseline, the mean (±SD) age was 62.9?±?6.55 years, disease duration was 7.0?±?2.33 years, and HbA1c was 8.4?±?0.68%. After 24 weeks of treatment, the MAGE decreased from 5.81?±?1.16?mmol/L to 4.06?±?0.86?mmol/L (p<0.001) in the vildagliptin group and from 5.66?±?1.14?mmol/L to 4.79?±?1.25?mmol/L (p?=?0.003) in the saxagliptin group. The mean change in MAGE in the vildagliptin group was significantly greater than that in the saxagliptin group (1.74?±?0.48?mmol/L vs. 0.87?±?0.40?mmol/L, p<0.001). The mean change in HbA1c, from baseline to the study endpoint, in the vildagliptin and saxagliptin groups, was 1.22?±?0.40% and 1.07?±?0.36%, respectively, with no significant difference between the groups (p?=?0.091). The overall safety and tolerability of vildagliptin and saxagliptin were similar. The limitations of the study were a small number of patients and open-label administration of the study drug.

Conclusion Vildagliptin produced a significantly greater reduction in acute glucose fluctuations compared with saxagliptin when added to a dual combination of metformin and sulfonylurea in Chinese patients with T2DM.

Chinese clinical trial registration number ChiCTR-TRC-13003858.     

Prospective memory impairment in long-term opiate users

Rationale

Opiate use is associated with a range of neurological and cognitive deficits. However, to date, no studies have assessed whether these cognitive deficits extend to the ability to perform intended actions in the future (i.e. prospective memory). Reduced ability in this area might be anticipated due to impaired executive functions and episodic memory associated with long-term opiate use.

Objectives

The main objectives of this study are to assess the performance of long-term opiate users on a laboratory measure of prospective memory which closely simulates the types of prospective memory tasks encountered in everyday life (‘Virtual Week’) and to investigate the extent to which prospective memory performance is related to executive functions and episodic memory ability.

Methods

Twenty-six long-term heroin users enrolled in an opiate substitution program, and 30 controls with no previous history of drug use were tested on Virtual Week. Retrospective memory and executive functions were also assessed.

Results

Long-term opiate users were significantly impaired on prospective memory performance compared with controls (p?=?0.002, η² _p?=?0.17), and these deficits did not vary as a function of prospective memory task type (regular, irregular, event, time). The findings also suggest that retrospective memory difficulties contribute to the prospective memory difficulties seen in opiate users (r _s ?=?0.78, p?<?0.001) but that executive dysfunction is less influential.

Conclusions

Prospective memory is sensitive to long-term opiate use. Importantly, opiate users suffer from generalised deficits in prospective memory, regardless of the task demands, which may have significant implications for day-to-day functioning. These results may therefore contribute to the development of clinical intervention strategies to reduce the negative impact of prospective memory failures in daily life.     

A randomized,double-blind,non-inferiority trial evaluating the efficacy and safety of omarigliptin,a once-weekly DPP-4 inhibitor,or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy

Objective: To evaluate the efficacy and safety of adding the once-weekly DPP-4 inhibitor omarigliptin or the sulfonylurea glimepiride to the treatment regimen of patients with type 2 diabetes (T2DM) and inadequate glycemic control on metformin monotherapy.

Methods: Patients with T2DM and HbA1c ≥6.5% to ≤9.0% while on a stable dose of metformin (≥1500?mg/day) were randomized to omarigliptin 25?mg once-weekly (n?=?376) or glimepiride up to 6?mg once daily (n?=?375) for 54 weeks. The primary hypothesis was that omarigliptin is non-inferior to glimepiride in reducing HbA1c at week 54.

Results: The mean baseline HbA1c was 7.5% in the omarigliptin group and 7.4% in the glimepiride group. After 54 weeks, the least squares (LS) mean change from baseline in HbA1c was –0.30% in the omarigliptin group and –0.48% in the glimepiride group, with a between-group difference (95% CI) of 0.18% (0.06, 0.30), which met the pre-specified criterion for declaring non-inferiority. The incidence of symptomatic hypoglycemia was 5.3% in the omarigliptin group and 26.7% in the glimepiride group. With the exception of hypoglycemia, the incidences of adverse events and discontinuations were similar between treatment groups. Relative to baseline, omarigliptin was associated with a mean weight loss (?0.4?kg) and glimepiride a mean weight gain (+1.5?kg).

Conclusions: After 54 weeks, as add-on therapy to metformin, once-weekly omarigliptin was generally well tolerated and non-inferior to glimepiride in improving glycemic control, with a lower incidence of hypoglycemia and with weight loss vs weight gain.     

Association between hypoglycemia risk and hemoglobin A1C in patients with type 2 diabetes mellitus

Objective: To better manage type 2 diabetes mellitus (T2DM), the tradeoff between improved glycemic control and hypoglycemia should be evaluated. The purpose of this study was to assess the relationship between hypoglycemia and hemoglobin A1c (HbA1c) in a real-world population.

Research design and methods: Real-Life Effectiveness and Care Patterns of Diabetes Management (RECAP-DM) was a multi-center, observational study. Patients ≥30 years old using any oral anti-hyperglycemic agent were recruited from seven European and five Asian countries between 2006 and 2007. Hypoglycemia events were collected through patient-reported questionnaires. HbA1c data was collected through chart review. Logistic regression was performed to assess the relationship between hypoglycemia and the most proximate HbA1c levels adjusting for potential confounders (demographics, clinical variables, other medication use, and comorbid conditions).

Results: A total of 4399 patients were recruited and analyzed. Mean age was 60 years, 52% were male, and 75% were on sulfonylureas (S.U.s). Respectively, 37% or 42% of patients reported hypoglycemia in the past 6 (Asia) or 12 months (Europe) before recruitment. Prevalence of hypoglycemia increased significantly (33% to 40%) as HbA1c decreased (p?=?0.035). The same trend was also observed among S.U.-treated patients (p?<?0.01). After adjusting for confounders, hypoglycemia prevalence was significantly higher for HbA1c <7.0% (odds ratio [O.R.]?=?1.66 [95% C.I. 1.21, 2.28]; p?=?0.002) vs. HbA1c ≥10.0%.

Limitations: Our analyses pooled data from Asia and Europe, which differed in terms of the recall period for ascertaining hypoglycemia symptoms and the timing of latest HbA1c measure.

Conclusions: Lower HbA1c level was associated with higher hypoglycemia prevalence among S.U.-treated patients. HbA1c level should be taken into consideration when reporting hypoglycemia prevalence.     

APOE ��4 allele and CSF APOE on Cognition in HIV-Infected Subjects

The significance of the cerebrospinal fluid (CSF) Apolipoprotein E (APOE) level and whether it might have differential effects on brain function due to the presence of APOE ??4 allele(s) in HIV-infected patients are unknown. However, APOE ??4 allele has been associated with greater incidence of HIV-associated dementia and accelerated progression of HIV infection. Here, we show further evidence for the role of APOE ??4 in promoting cognitive impairment. We measured the APOE levels in the CSF of HIV-infected individuals. HIV+ subjects showed lower CSF APOE proteins than SN controls (?19%, p?=?0.03). While SN subjects with or without ??4 allele showed no difference in CSF APOE levels, ??4+ HIV+ subjects had similar levels to the SN subjects but higher levels than ??4? HIV+ subjects (+34%, p?=?0.01). Furthermore, while HIV+ subjects with ??2 or ??3 allele(s) showed a positive relationship between their CSF APOE levels and cognitive performance on the speed of processing domain (r?=?+0.35, p?=?0.05), ??4+ HIV+ subjects, in contrast, exhibited a negative relationship such that those with higher levels of CSF APOE(4) performed worse on the HIV Dementia Scale (r?=??0.61, p?=?0.02), had lower Global Cognitive Scores (r?=??0.57, p?=?0.03), and had poorer performance on tests involving learning (??4 allele x [APOE] interaction, p?=?0.01). Our findings also suggest that the relatively higher levels of CSF APOE in ??4+ HIV+ (having primarily APOE4 isoforms) may negatively impact the brain and lead to poorer cognitive outcomes, while those individuals without the ??4 allele (with primarily APOE2 or APOE3 isoforms) may show compensatory responses that lead to better cognitive performance.     

Implementation of a pharmacist-led diabetes management service in an endocrinology clinic

BackgroundDiabetes is a complicated health condition that can lead to significant health complications. Pharmacists are in an ideal position to make therapeutic interventions, provide clinical education, and can provide necessary follow-up to evaluate response to therapy for patients with diabetes.ObjectivesThe primary objective of this study is to evaluate the mean change in hemoglobin A1c (HbA1c) in patients receiving short-term diabetes management services from a clinical pharmacist through collaborative drug therapy management.MethodsThis study is a single-center retrospective chart review of patients with diabetes who have been referred by their endocrinologist to the clinical pharmacist for short-term intensification of pharmacologic management of hyperglycemia. Patients included in the study completed at least 2 visits with the pharmacist during the study period. The primary outcome was to evaluate the mean absolute change in HbA1c at 3-6 months from baseline.ResultsData were collected from 117 patients. The average age was 55 years (19-91 years, SD ± 14.5), 65 patients (55.6%) were female, average duration of diabetes was 14.9 years (0.5-49 years, SD ± 9.9), 21 patients (17.9%) had type 1 diabetes, 96 patients (82.1%) had type 2 diabetes, and 88 patients (75.2%) had a baseline HbA1c of at least 8.5%. On average, patients reduced their HbA1c by 2.0% (P < 0.001) at 3-6 months. For patients with a baseline HbA1c of at least 8.5%, they experienced a 2.5% (P < 0.001) reduction in HbA1c at 3-6 months.ConclusionThe addition of a clinical pharmacist within the endocrinology practice was associated with significant improvements in glycemic control for those referred. This short-term, intensive service model demonstrates that patients can achieve significant reductions in HbA1c with temporary support from a clinical pharmacist.     

Trajectories of glycemic control with clinical pharmacy specialist management of veterans with type 2 diabetes

BackgroundImproved control of glycemic control likely lowers the risk of diabetes complications and clinical pharmacy specialist (CPS) services can improve glycemic control. Though the pattern of control may also matter in terms of outcomes.ObjectivesThe objective of this study was to examine the longitudinal trajectories of HbA1c among a large population of Veterans with type 2 diabetes who received CPS-led diabetes management.MethodsThis is an observational, multicenter cohort study of Veterans with type-2 diabetes managed by CPSs between 7/1/2013 and 7/1/2017 with baseline glycosylated hemoglobin (HbA1c) level ≥8%. Two years of HbA1c measurements were used to group patients into distinct patterns of HbA1c trajectories over time using group-based trajectory modeling. Characteristics associated with successful HbA1c trajectories and association of assigned trajectories with all-cause and diabetes-related hospitalizations were analyzed using logistic regression.ResultsA total of 4119 Veterans were included and able to be successfully segmented into six distinct HbA1c trajectory groups over time: High Gradually Decreasing (n = 325, 7.9%), Moderate Early Decline (n = 1692, 41.1%), Large Early Decline (n = 231, 5.6%), Uncontrolled Stable (n = 1468, 35.6%), Early Decline/Subsequent Increase (n = 266, 6.5%), and Very Uncontrolled Stable (n = 137, 3.3%). The distinguishing factor between successful and less successful trajectories appears to be the progress made within the first six months of pharmacist management.ConclusionsSignificant variability exists in the pattern of glycemic control over time of type 2 diabetes patients managed by clinical pharmacy specialists. Limited resources should be first prioritized to managing patients with very elevated HbA1c and into the first six months of CPS management.     

Improved glycemic control with weight loss and a low risk of hypoglycemia with insulin detemir: insights from the Italian cohort of the PREDICTIVE study after 6-month observation in type 2 diabetic subjects

Objective: PREDICTIVE (Predictable Results and Experience in Diabetes through Intensification and Control to Target: an International Variability Evaluation) is a large, multinational, open-label, prospective, observational study addressed to assess the efficacy and safety of insulin detemir in clinical practice. This paper reports 26 weeks of follow-up data, from 1298 type 2 diabetes patients from Italy.

Research design and methods: In this observational study, the primary end point was the incidence of serious adverse drug reactions (SADRs), including major hypoglycemia. Secondary end points were: hemoglobin A1c (HbA1c), mean self-monitored fasting glucose, within-patient fasting glucose variability and body weight change.

Results: Insulin detemir significantly improved glycemic control, with a decrease in mean HbA1c, fasting glucose and within-patient fasting glucose variability. Interestingly, the improvements in glycemic control occurred in association with a small, but significant reduction in weight. The safety results of this study showed that 26 weeks of treatment with insulin detemir was associated with a very low rate of SADRs (only 14 events), which mainly consisted of hypoglycemia (78%, of which 42% were major hypoglycemia).

Conclusions: Insulin detemir improves glycemic control, with low risk of hypoglycemia, no weight gain and an excellent safety profile; these data support the overall findings of PREDICTIVE.     

Dose-dependent retrograde facilitation of verbal memory in healthy elderly after acute oral lorazepam administration

Rationale Retrograde facilitation (RF) refers to a paradoxical phenomenon in which recall of information presented before acute administration of agents generally associated with anterograde amnestic and sedative effects, such as benzodiazepines, is enhanced relative to a placebo condition. However, it is unclear whether this effect occurs in elderly individuals and if it is influenced by plasma drug levels, baseline cognitive function, or genetic factors such as the APOE e-4 allele, that may modulate drug-induced cognitive toxicity.Objectives To determine if acute oral doses of lorazepam (0.5 mg, 1 mg) produced RF in elderly individuals exposed to interference tasks, and the variables associated with RF.Materials and methods Sixty-four cognitively intact and highly educated (>12 years) older adults (mean age, 66.09 years) participated in a placebo-controlled double-blind crossover study. The Buschke Selective Reminding Test was used to assess RF and amnestic effects for verbal memory. Self-ratings of mood states were also obtained.Results Lorazepam administration resulted in significant dose-dependent RF, i.e., better recall of pre-drug word lists compared to placebo [F(1,63)= 15.358; p<0.001 and F(1,63)= 46.163; p<0.001 for 0.5 and 1 mg lorazepam, respectively]. Also, more of the pre-drug words were recalled in the 1.0-mg-lorazepam condition relative to the 0.5-mg-lorazepam condition [F(1,63)=29.498; p<0.001]. In both the 0.5 and 1 mg lorazepam conditions, participants who exhibited high RF experienced significantly greater lorazepam-induced memory impairments over time [F(3,61)=2.901; p<0.05; F(3,61)=2.698; p<0.05; 0.5 and 1 mg lorazepam, respectively]. Also, in the 1-mg-lorazepam condition, participants who exhibited high RF reported significantly greater drowsiness relative to participants who showed less RF [t(62)=−2.521; p<0.05]. RF was not significantly associated with age, the APOE ɛ4 allele, years of education, global cognitive status, vocabulary scores, or a memory index score.Conclusion In healthy elderly, acute oral lorazepam administration resulted in dose-dependent RF, which was associated with greater anterograde amnestic and sedative effects.This study was supported by NIMH Grant MH056994.     

Consequences of delaying treatment intensification in type 2 diabetes: evidence from a UK database

Objective: Type 2 diabetes mellitus (TD2M) treatment focuses on achieving glycemic control, with HbA1c targeted at 6.5–7.5%. Clinicians commonly delay treatment intensification despite patients failing glycemic targets. This study evaluated longitudinal clinical and cost outcomes in patients failing metformin monotherapy using electronic medical records. Research design and methods: Adults with incident T2DM were identified in the UK Clinical Practice Research Datalink (CPRD) from 1 January 2000 to 31 March 2014. Patients were initiated on metformin monotherapy but had not reached target (HbA1c <7%). Patients were grouped by time to intensification of second-line therapy from first recorded HbA1c ≥7%: Group A, rapid intensification within 365 days; Group B, delayed intensification days 366–1824; Group C, never intensified. Patients were followed from day 366 for 5 years until end of study, switch to insulin, migration or death. Main outcome measures: The study evaluated baseline clinical and medication characteristics which were re-evaluated each year, including HbA1c, weight, cholesterol and concomitant prescribing. Results: A total of 6710 patients were included (Group A 2647, Group B 2452, Group C 1611). Group A achieved a significant decline in HbA1c at 1 year post-index date compared to Groups B and C (?1.13% Group A; +0.26% Group B, +0.16% Group C). A significantly higher proportion of patients achieved HbA1c target?<?7% in Group A (Group A [45.8%]; Group B [19.1%], p?<?0.0001). Using an adjusted hazard model, Group A was found to achieve the HbA1c target from the index date significantly faster than Group B (hazard ratio 3.25 [95% CI 2.87–3.69]). The most commonly prescribed second-line medications were sulfonylureas in Groups A and B throughout observation and were associated with significant weight gain (+1.3?kg per patient) in the adjusted models. Conclusions: Patients who were rapidly intensified achieved a maintained reduction in HbA1c faster than those with delayed intensification or no second-line therapy, despite a higher baseline HbA1c.     

Efficacy and safety of teneligliptin add-on to insulin monotherapy in Japanese patients with type 2 diabetes mellitus: a 16-week,randomized, double-blind,placebo-controlled trial with an open-label period

Objective: To assess the efficacy and safety of teneligliptin as add-on to insulin monotherapy in patients with type 2 diabetes mellitus (T2DM).

Research design and methods: In a 16-week, double-blind period, 148 Japanese T2DM patients with inadequate glycemic control with insulin and diet/exercise therapies were randomized to placebo or teneligliptin 20 mg. In a subsequent 36-week, open-label period, all patients received teneligliptin once daily. The primary outcome measure was change in HbA1c at the end of the double-blind period.

Results: The difference between placebo and teneligliptin in change in HbA1c in the double-blind period (least squares mean ± SE) was ?0.80% ± 0.11%; teneligliptin was superior (ANCOVA, P < 0.001). The HbA1c-lowering effect of teneligliptin was maintained throughout the open-label period. The incidence of adverse events was 53.5% with placebo and 44.2% with teneligliptin in the double-blind period, 66.7% in the placebo/teneligliptin group in the open-label period, and 77.9% in the teneligliptin/teneligliptin group over both double-blind/open-label periods. The incidence of hypoglycemic symptoms was 11.1% in the placebo/teneligliptin group in the open-label period and 27.3% in the teneligliptin/teneligliptin group over both double-blind/open-label periods.

Conclusion: Teneligliptin was effective and well tolerated in Japanese T2DM patients with inadequate glycemic control.

Clinical trial registration: NCT02081599     

Statins worsen glycemic control of T2DM in target LDL-c level and LDL-c reduction dependent manners: a meta-analysis

Objective: Recent studies demonstrated that a low target low-density lipoprotein cholesterol (LDL-c) level, high LDL-c reduction and high dose of statin therapy increased incident diabetes. This study aimed to explore how statin therapy influences glycemic control in type 2 diabetes mellitus (T2DM).

Methods: Medline, Embase, and Cochrane Central were searched for randomized control trials inT2DM. Trials with target LDL-c levels of ≤2.6 mmol/L or LDL-c reduction of ≥30% were analyzed. Then, we calculated mean differences in glycosylated hemoglobin (HbA1c) and fasting blood glucose via stratified LDL-c level, relative LDL-c reduction and statin dose.

Results: In total, trials involving 6,875 participants (3,619 statins, 3,256 controls) were included. Meta-analysis showed that detrimental effect of intensive LDL-c lowering statin therapy on HbA1c (SMD 0.10%; 95% CI 0.05, 0.15; p = 0.000) was more severe than all statin trials analyzed together (SMD 0.07%; 95% CI 0.02, 0.12; p = 0.005). Stratified analyses revealed that the effects on HbA1c became increasingly significant as target LDL-c level decreased and LDL-c reduction increased. Low baseline LDL-c and endpoint LDL-c levels were risk factors involved in increasing HbA1c level during statin therapy.

Conclusions: Statin therapy worsens the glycemic control of T2DM in target LDL-c level and LDL-c reduction dependent manners.