Significant Between-treatment Difference Research Articles

Sufficiently Elevated Core Body Temperature May Be Necessary to Maintain Cerebral Blood Flow Response throughout the Morning

In comparison to a carbohydrate-rich breakfast, a nutritionally balanced breakfast reportedly leads to a higher core body temperature because of diet-induced thermogenesis (DIT) and also results in higher task performance. This study aimed to examine the relationships among the core body temperature, blood glucose level, cerebral blood flow, and cognitive performance when the core body temperature is raised to a similar extent as in DIT in the morning. This crossover study included 18 male participants who performed four sets of cognitive tests in the morning with four different foot baths and glucose intake conditions. In elevated body temperature (EBT) conditions, the core body temperature was increased by a foot bath at 42˚C or 39˚C, while in low body temperature (LBT) conditions, it was maintained at 35˚C by a foot bath; the participants received no glucose or two intakes of 20-g glucose for each thermal condition. In addition to the core body temperature measurement, the cerebral blood flow in the dorsolateral prefrontal cortex (DLPFC) was measured using near-infrared spectroscopy. Three blood collections were performed to measure the changes in blood glucose levels. The results revealed that in the EBT conditions, the core body temperature remained 0.3˚C - 0.5˚C higher than that at wake-up time, while the glucose intake conditions increased blood glucose levels which remained higher than those during fasting. No significant between-treatment difference was observed in the results of cognitive tests. However, the blood flow in the DLPFC increased during the second test period in the EBT/glucose and LBT/glucose conditions, whereas during the fourth test period, it increased solely in the EBT/glucose condition. Thus, in addition to the blood glucose level, an elevated core body temperature within the physiological range may be needed for long-term maintenance of the cerebral blood flow response.

A 12-month randomized controlled trial evaluating erythritol air-polishing versus curette/ultrasonic debridement of mandibular furcations in supportive periodontal therapy

BackgroundDue to complex morphology and limited access, the cleaning of the furcation area is extremely challenging. Therefore, novel therapeutic approaches need to be tested to potentially overcome debridement limitations. The aim of the present prospective 12-month study was to compare clinical and microbiological effects following erythritol air-polishing versus conventional mechanical debridement of furcation defects in a cohort of periodontal maintenance patients.MethodsTwenty patients with grade II mandibular molar furcation defects volunteered to enroll in this single-centre, examiner masked, randomized controlled trial. In a split-mouth study design, two furcation sites in each patient were randomly assigned to either receive subgingival debridement using erythritol air-polishing (test) or conventional ultrasonic/curette debridement (control) at baseline, and at 3, 6, 9 and 12 months. Probing depth, clinical attachment level and bleeding on probing were recorded at 3-month intervals. Subgingival microbiological samples obtained at baseline, 6 and 12 months were analyzed using checkerboard DNA–DNA hybridization. Discomfort from treatment was scored at 12 months using a visual analogue scale. The differences between treatments, and time-points, were tested using multilevel analysis (mixed effect models and robust variance estimates).ResultsA significant reduction in probing depth took place following both treatments (p < 0.001). Control sites experienced a significant mean gain in clinical attachment level of 0.5 mm (± 0.2) (p = 0.004), whereas a non-significant gain of 0.4 mm (± 0.3) was observed at test sites (p = 0.119). At 6 months, a significant between-treatment difference of 0.8 mm (± 0.4) was observed in favor of the control (p = 0.032). No significant between-treatment differences were observed in microbial load or composition. Notably, at 12 months patients experienced significantly less discomfort following air-polishing compared with control (p = 0.001).ConclusionsThe 12-month observations indicate that erythritol air-polishing and conventional mechanical debridement both support clinical improvements. A significant between-treatment difference in clinical attachment level was, however, detected in favour of control debridement at 6 months. In terms of patient comfort, erythritol air-polishing is superior.Trial Registration: The clinical trial was retrospectively registered in ClinicalTrial.gov with registration NCT04493398 (07/28/2020).

Associations between cognitions and functional decline in patients with major depressive disorder

Associations between cognitions and functional decline in patients with major depressive disorder

1033-P: Effects of Benaglutide on Weight Loss, Metabolic Changes, and Sexual Hormones in PCOS

Objective: Polycystic ovary syndrome (PCOS) is one the most common metabolic and endocrine disorders in women, which is always accompanied with obesity and insulin resistance (IR). Glucagon-like peptide-1 (GLP-1) has been investigated to decrease body weight and IR in PCOS, and it appears superior combined with metformin (MET) than MET alone. Benaglutide is the first human homologous GLP-1 drug. It had been shown in previous studies to reduce blood glucose and have effect on weight loss. The potential impact of preconception intervention with benaglutide on improving IR and weight loss in PCOS has not been evaluated yet. Methods: This is a 12-week open-label randomized clinical study.88 overweight/obese (OW/OB) patients with PCOS, who had already received MET 1000 mg Bid treatment for more than 3 months. They were randomized into two groups, to receive either benaglutide (BEN) 0.2 mg ih tid and MET 1000 mg bid (N=35, age: 27.6±5.7, BMI: 28.33±3.36 kg/m2, mean±s.d.) or exenatide (EXE) 10ug ih bid and MET 1000 mg bid (N=33, age: 27.7±6.5, BMI: 28.82±3.44 kg/m2) per day. We observed BMI, OGTT 0- and 2-hour blood glucose, HOMAIR, blood lipids and sexual hormones, at 0 and 12 weeks. Lifestyle intervention was promoted in both groups. Results: BMI had decreased in the BEN group 1.89±1.55 kg/m2 (p&amp;lt;0.05) compared with 1.83±1.17 kg/m2 (p&amp;lt;0.05) in the EXE group. OGTT 2-hour blood glucose was reduced 0.97±1.80 mmol/l (p&amp;lt;0.05) in the BEN group with 1.43±2.86 mmol/l (p&amp;lt;0.05) in the EXE group. In the BEN group, HOMAIR decreased 1.38±2.86 (p&amp;lt;0.05) as well as in the EXE group 1.61±2.08 (p&amp;lt;0.05), whereas measures of OGTT 0h blood glucose, blood lipids and sex hormones did not change. From all the indexes no significant between-treatment difference (p&amp;gt;0.05) were found in the two groups. Conclusions: Benaglutide combined with metformin treatment in overweight/obese women with PCOS appears superior decrease in BMI, OGTT 2-hour blood glucose and HOMAIR, the efficiencies were same as exenatide with metformin. Disclosure J. Chen: None. Q. Sun: None. M. Zhang: None. H. Tian: None. S. Chen: None.

Clinical efficacy of tadalafil compared to sildenafil in treatment of moderate to severe canine pulmonary hypertension: a pilot study

IntroductionCanine pulmonary hypertension (PH) is associated with high morbidity and mortality. Tadalafil, a phosphodiesterase-5 inhibitor used commonly in humans with PH, has not been evaluated in a clinical trial in dogs with naturally occurring PH. Our objectives were to compare the efficacy of tadalafil and sildenafil on PH assessed by peak tricuspid regurgitant flow velocity, estimated systolic pulmonary arterial pressure gradient, voluntary activity, quality of life, and safety profiles in dogs with moderate to severe PH. AnimalsTwenty-three dogs with echocardiographic evidence of moderate to severe PH were enrolled. MethodsA prospective short-term, randomized, double-blinded pilot study was carried out. Dogs with PH were randomly allocated to receive sildenafil or tadalafil for 2 weeks and assessed via echocardiography, activity monitors, and owner-reported outcomes. ResultsCollectively, phosphodiesterase-5 inhibition significantly decreased (improved) quality of life scores (p = 0.003) and visual analog score (p = 0.024) without significant between-treatment difference of these variables. Phosphodiesterase-5 inhibition did not significantly affect peak tricuspid regurgitant flow velocity (p = 0.056) or voluntary activity (p = 0.27). A total of 33% (7/21) of dogs experienced at least one adverse event during the study (tadalafil, n = 5; sildenafil, n = 2) with no significant difference between treatment type and incidence of adverse events (p = 0.36). DiscussionIn this pilot study, phosphodiesterase-5 inhibition led to apparent improvement in quality of life scores without documenting superiority of tadalafil over sildenafil. ConclusionTadalafil at a dose of 2 mg/kg once daily appears to be a viable alternative to sildenafil in dogs with moderate to severe PH.

GLP-1 Receptor Agonist Liraglutide Increased IVF Pregnancy Rates in Obese Women with PCOS and Previous Poor Response to First-Line Reproductive Treatments

Objective: GLP-1 has been investigated in regulation of reproductive system in animal models. Current observations suggest that it directly regulates kisspeptin and GnRH expression and that ovaries express GLP-1 mRNA. Aim: To evaluate the impact of low dose liraglutide in combination with metformin compared to metformin alone on IVF pregnancy rate (PR) and cumulatively PR (IVF and spontaneous) in infertile obese women with PCOS who had been previously poor responders regarding weight reduction with lifestyle modification and resistant to first line reproductive treatments. Design/Participants/Methods: A prospective randomized open-label study was conducted with 28 infertile obese PCOS patients (aged 31,07±4,75 years, BMI 36,7±3,5 kg/m2, mean ± SD). They were assigned to metformin (MET) 1000 mg BID or combined MET 1000 mg BID and low dose liraglutide 1.2 mg QD s.c. (COMBI) for 12 weeks. Ovarian stimulation protocol was started after 4-week medication free period. Results: Patients in MET lost on average 7,0±6,0 kg (P&amp;lt;0.001) compared with 7,5± 3,9 kg loss in COMBI group (P&amp;lt;0.001), with no significant between-treatment difference (P=0,103). All treatment interventions resulted in significant reduction of visceral adipose tissue as assessed by DXA and reduction of HOMA-IR (p&amp;lt;0.001), with no significant difference regarding the treatment employed. After intervention, PR per ET was significantly higher in COMBI (85,7%) compared with MET (28,6%) (P=0.03). Moreover, cumulatively PR in time frame of 12 months in COMBI was 69,2% compared to 35,7% in MET. Conclusion: Short-term preconception intervention with low dose liraglutide as an add on to metformin was superior to metformin alone in increasing PR per ET and cumulative PR in infertile obese PCOS, despite comparable weight reduction in both arms. Potential direct crosstalk between GLP-1 and reproductive system needs further exploration. Disclosure A. Janez: None. M. Jensterle: None.

Liraglutide increases IVF pregnancy rates in obese PCOS women with poor response to first-line reproductive treatments: a pilot randomized study.

Glucagon-like peptide-1 (GLP-1) has been investigated in regulation of reproductive system in animal models. The potential impact of short-term preconception intervention with liraglutide on fertility potential in polycystic ovary syndrome (PCOS) has not been evaluated yet. A prospective randomized open-label study was conducted in 28 infertile obese PCOS patients (age: 31.07 ± 4.75, BMI: 36.7 ± 3.5 kg/m2, mean ± s.d.). They were assigned to metformin (MET) 1000 mg BID or to MET 1000 mg BID combined with low-dose liraglutide 1.2 mg QD s.c. (COMBI) for 12 weeks. Ovarian stimulation protocol was started after a 4-week medication-free period. The in vitro fertilization pregnancy rate (PR) was defined as the number of clinical pregnancies confirmed by ultrasound visualization of the fetal cardiac activity, divided by the total number of cycles performed or embryo transfers (ET). The spontaneous PR was followed for 12 months. Patients in the MET group on average lost 7.0 ± 6.0 kg (P = 0.001) compared with 7.5 ± 3.9 kg in the COMBI group (P < 0.001) with no significant between-treatment difference (P = 0.246). The PR per ET was significantly higher in the COMBI (85.7%) compared with the MET (28.6%) group (P = 0.03). The cumulative PR in the time frame of 12 months was 69.2% in the COMBI group compared to 35.7% in the MET group. Preconception intervention with low-dose liraglutide added to metformin is superior to metformin alone in increasing PRs per ET and cumulative PRs in infertile obese women with PCOS, despite comparable weight reduction in both groups. A potential impact of liraglutide on the reproductive system needs further exploration, in particular the GLP-1 impact on endometrial quality and receptivity.

Effects of Plasmalogen on Patients with Mild Cognitive Impairment: A Randomized, Placebo-Controlled Trial in Japan

Objective: It has been shown that plasmalogens (Pls) in the brain tissue and blood decrease among Alzheimer’s disease (AD) patients. We first confirmed the effects of Pls on animal AD models, and subsequently reported that the ingestion of 1 mg Pls was effective for AD patients in a randomized, placebo-controlled trial with mild cognitive impairment (MCI) or mild AD patients. The present study examined the efficacy of orally administered Pls on patients with MCI enrolled in the previous trial in terms of individual domains of the Mini Mental State Examination-Japanese (MMSE-J). Methods: The present analysis used 178 patients with MCI out of the 276 patients with either MCI or AD in the previously reported trial, and assessed the 24 week change in the domain-specific scores of the MMSE-J. Originally, the randomized, placebo-controlled trial was performed for 276 patients at age of 60-85 years who had the MMSE-J score of 20-27 points and the Geriatric Depression Scale-Short Version-Japanese Version (GDS-S-J) score of 5 points or less. The patients were randomly allocated to either a treatment with 1 mg of scallop-derived Pls daily or a placebo treatment. The primary outcome was a 24 week change in the MMSE-J. The registered number of the trial is UMI14945. Results: The MMSE-J total score improved statistically significantly in the Pls treatment but not in the placebo treatment, resulting in no significant between-treatment difference. With respect to one of the MMSE-J domains, orientation to place, the Pls treatment showed a significant improvement and the placebo treatment showed no such improvement; the between-treatment difference was statistically significant (p=0.003). The domain for orientation to time worsened significantly at endpoint in the placebo treatment, while the Pls treatment showed no worsening. However, the between-treatment difference failed to reach the statistical significance. No significant change was found in either treatment regarding the other MMSE-J domains. Conclusion: These findings suggest that oral administration of 1 mg Pls enhances cognitive function of MCI patients, especially orientation to place.

PS 17-54 EFFECTS OF CILNIDIPINE VERSUS ATENOLOL ON LEFT VENTRICULAR DIASTOLIC FUNCTION AND HYPERTROPHY IN ESSENTIAL HYPERTENSION - CANDLE TRIAL

Objective: Effects of Cilnidipine versus Atenolol on Left Ventricular Diastolic Function and Hypertrophy in Essential Hypertension (CANDLE) study was designed as a prospective, randomized, double-blind, parallel-group to test whether cilnidipine achieves greater left ventricular (LV) mass reduction and improves LV diastolic function than does atenolol. Design and method: Seventy-two patients with uncomplicated essential hypertension and increased LV mass index at screening echocardiography (55 ± 2 years; 59% male; BP 157 ± 4/99 ± 3 mmHg) were enrolled and were randomly assigned and forced-titrated to 20 mg/d cilnidipine or 100 mg of atenolol treatment for 36 weeks. Echocardiography, 24-hours ambulatory blood pressure monitoring, biochemical studies including N-terminal pro-B-type natriuretic peptide and 24-hours urine protein and microalbumin were measured at baseline and after 36-weeks therapy. Results: Clinical examination and blinded echocardiogram in a per-protocol analysis of 28 cilnidipine-treated and 26 atenolol-treated patients revealed similar reductions in systolic/diastolic pressure (−16.5/8.9 versus −23.9/14.8 mmHg, both P > 0.05) and LV mass index (−21.4 versus −19.5 g/m2, both P > 0.05). No significant between-treatment difference was detected in population subsets defined by monotherapy treatment, sex, age, or severity of baseline hypertrophy. Similarly, there was no between-treatment difference in change in biochemical parameters. As we expected, cilnidipine-treated group showed lesser reduction on night-time heart rate (−2.4 versus −5.6 %, p = 0.021) rather than atenolol-treated group. Interestingly, cilnidipine-treated group showed reduction on left atrial (LA) volume index but on the contrary, atenolol-treated group showed more enlarged LA after treatment (−5.1 versus 7.3 %, p = 0.035). Conclusions: Both cilnidipine and atenolol similarly and effectively reduced blood pressure and LV mass index. However, only cilnidipine reduced LA volume index, whereas atenolol increased. Cilnidipine may provide more beneficial effect on the management in essential hypertension with diastolic dysfunction.

Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial

SummaryBACKGROUNDTwelve months of oral cyclophosphamide (CYC) has been shown to alter the progression of scleroderma-related interstitial lung disease (SSc-ILD) when compared to placebo. However, toxicity was a concern and without continued treatment the efficacy disappeared by 24 months. We hypothesized that a two-year course of mycophenolate mofetil (MMF) would be safer, better tolerated and produce longer lasting improvements than CYC.METHODSPatients with SSc-ILD meeting defined dyspnea, pulmonary function and high-resolution computed tomography (HRCT) criteria were randomized in a double-blind, two-arm trial at 14 medical centers. MMF (target dose 1500 mg twice daily) was administered for 24 months in one arm and oral CYC (target dose 2·0 mg/kg/day) administered for 12 months followed by placebo for 12 months in the other arm. The primary endpoint, change in forced vital capacity as a percent of the predicted normal value (FVC %) over the course of 24 months, was assessed in a modified intention-to-treat analysis using an inferential joint model combining a mixed effects model for longitudinal outcomes and a survival model to handle non-ignorable missing data. The study was registered with ClinicalTrials.gov, number NCT00883129, and is closed.RESULTSBetween November, 2009, and January, 2013, 142 patients were randomized. 126 patients (63 MMF; 63 CYC) with acceptable baseline HRCT studies and at least one outcome measure were included in the analysis. The adjusted FVC % (primary endpoint) improved from baseline to 24 months by 2.17 in the MMF arm (95% CI, 0.53–3.84) and 2·86 in the CYC arm (95% confidence interval 1·19–4·58) with no significant between-treatment difference (p=0·24), indicating that the trial was negative for the primary endpoint. However, in a post-hoc analysis of the primary endpoint, within-treatment improvements from baseline to 24 months were noted in both the CYC and MMF arms. A greater number of patients on CYC than on MMF prematurely withdrew from study drug (32 vs 20) and failed treatment (2 vs 0), and the time to stopping treatment was significantly shorter in the CYC arm (p=0·019). Sixteen deaths occurred (11 CYC; 5 MMF) with most due to progressive ILD. Leukopenia (30 vs 4 patients) and thrombocytopenia (4 vs 0 patients) occurred more often in patients treated with CYC. In post-hoc analyses, within- (but not between-) treatment improvements were also noted in defined secondary outcomes including skin score, dyspnea and whole-lung HRCT scores.INTERPRETATIONTreatment of SSc-ILD with MMF for two years or CYC for one year both resulted in significant improvements in pre-specified measures of lung function, dyspnea, lung imaging, and skin disease over the 2-year course of the study. While MMF was better tolerated and associated with less toxicity, the hypothesis that it would have greater efficacy at 24 months than CYC was not confirmed. These findings support the potential clinical impact of both CYC and MMF for progressive SSc-ILD, as well as the current preference for MMF due to its better tolerability and toxicity profile.FUNDINGNational Heart, Lung and Blood Institute/National Institutes of Health with drug supply provided by Hoffmann-La Roche/Genentech.

Femoral strength in osteoporotic women treated with teriparatide or alendronate

To gain insight into the clinical effect of teriparatide and alendronate on the hip, we performed non-linear finite element analysis of quantitative computed tomography (QCT) scans from 48 women who had participated in a randomized, double-blind clinical trial comparing the effects of 18-month treatment of teriparatide 20 μg/d or alendronate 10mg/d. The QCT scans, obtained at baseline, 6, and 18 months, were analyzed for volumetric bone mineral density (BMD) of trabecular bone, the peripheral bone (defined as all the cortical bone plus any endosteal trabecular bone within 3 mm of the periosteal surface), and the integral bone (both trabecular and peripheral), and for overall femoral strength in response to a simulated sideways fall. At 18 months, we found in the women treated with teriparatide that trabecular volumetric BMD increased versus baseline (+4.6%, p<0.001), peripheral volumetric BMD decreased (-1.1%, p<0.05), integral volumetric BMD (+1.0%, p=0.38) and femoral strength (+5.4%, p=0.06) did not change significantly, but the ratio of strength to integral volumetric BMD ratio increased (+4.0%, p=0.04). An increase in the ratio of strength to integral volumetric BMD indicates that overall femoral strength, compared to baseline, increased more than did integral density. For the women treated with alendronate, there were small (<1.0%) but non-significant changes compared to baseline in all these parameters. The only significant between-treatment difference was in the change in trabecular volumetric BMD (p<0.005); related, we also found that, for a given change in peripheral volumetric BMD, femoral strength increased more for teriparatide than for alendronate (p=0.02). We conclude that, despite different compartmental volumetric BMD responses for these two treatments, we could not detect any overall difference in change in femoral strength between the two treatments, although femoral strength increased more than integral volumetric BMD after treatment with teriparatide.

Long-term low-dose erythromycin in patients with unexplained chronic cough: a double-blind placebo controlled trial

AimsUnexplained chronic cough is a common condition with no satisfactory treatments. Previous work has suggested that cough may be linked to neutrophilic airway inflammation. This study tested the hypothesis that...

5-Year Survival in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia in a Randomized, Phase III Trial of Fludarabine Plus Cyclophosphamide With or Without Oblimersen

A randomized trial of oblimersen plus fludarabine/cyclophosphamide (OBL-FC; n = 120) versus FC (n = 121) was conducted in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). The primary end point was met: the complete response (CR) rate, defined as complete or nodular partial response, was significantly greater with OBL-FC than with FC (17% v 7%; P = .025). Among patients with CR, response duration was significantly longer with OBL-FC than with FC (median not reached; > 36 months v 22 months; P = .03). Maximum benefit with OBL-FC, including a four-fold increase in CR rate and a survival benefit with 3 years of follow-up (hazard ratio, 0.53; P = .05), was observed in patients with fludarabine-sensitive disease. We evaluated long-term survival and poststudy CLL therapy among all randomly assigned patients. Poststudy CLL treatment information was collected. Patients were observed for survival for up to 5 years from the date of random assignment. Poststudy CLL treatment was balanced between arms. Intent-to-treat analysis of 5-year survival showed no significant between-treatment difference (hazard ratio, 0.87; P = .34). Among the greater than 40% of patients with complete or partial remission, a significant 5-year survival benefit was observed with OBL-FC (hazard ratio, 0.60; P = .038). Among patients with fludarabine-sensitive disease who had previously demonstrated maximum benefit with OBL-FC, the previously observed survival benefit improved: a 50% reduction in the risk of death was observed (P = .004). In relapsed/refractory CLL, OBL combined with FC offers patients who achieve complete or partial remission, as well as those who have fludarabine-sensitive disease, a significant survival benefit.

Effect of olanzapine on cognition during treatment of behavioral and psychiatric symptoms in patients with dementia: a post‐hoc analysis

This study was conducted to determine the effect of olanzapine treatment on cognition in elderly patients with behavioral and psychiatric symptoms (BPSD) associated with dementia. This was a post-hoc analysis of three randomized double-blind, clinical trials of olanzapine (n = 682) vs placebo (n = 257) in dementia patients with BPSD in long-term or continuing-care settings. One study was 6 weeks long; the other two were 10 weeks duration, and their data were combined. Patients were subgrouped according to baseline Mini Mental State Examination (MMSE) scores: Group I = 23-26; Group II = 19-22; Group III = 14-18; Group IV = 7-13; Group V = 1-6. BPSD was assessed by the Neuropsychiatric Inventory (NPI). Within-treatment group cognitive decline in patients was significant in the combined studies, but not in the 6-week study. Between-treatment cognitive changes were non-significant in the 6-week study, but showed a statistical trend in the combined studies (olanzapine, -0.78 +/- 0.19 vs placebo, -0.32 +/- 0.25; p = 0.06). In the subgroup analysis, there was a significant between-treatment difference in cognitive changes in MMSE subgroup IV in the combined studies (olanzapine, -0.63 +/- 0.26 vs placebo, 0.27 +/- 0.41, p = 0.04). Improvement in BPSD was correlated with better cognitive outcome (r = -0.2; p < 0.01). Although the overall differences in cognitive changes in patients treated with olanzapine vs placebo were small and non-significant, negative effects on cognition in some patients cannot be excluded, especially in patients with more pronounced cognitive decline or whose behavioral and psychiatric symptoms are not responding to treatment.

Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes

Type 2 diabetes is difficult to manage in patients with a long history of disease requiring insulin therapy. Moreover, addition of most currently available oral antidiabetic agents increases the risk of hypoglycaemia. Vildagliptin is a dipeptidyl peptidase-IV inhibitor, which improves glycaemic control by increasing pancreatic beta cell responsiveness to glucose and suppressing inappropriate glucagon secretion. This study assessed the efficacy and tolerability of vildagliptin added to insulin therapy in patients with type 2 diabetes. This was a multicentre, 24-week, double-blind, randomised, placebo-controlled, parallel-group study in patients with type 2 diabetes that was inadequately controlled (HbA(1c) = 7.5-11%) by insulin. Patients received vildagliptin (n = 144; 50 mg twice daily) or placebo (n = 152) while continuing insulin therapy. Baseline HbA(1c) averaged 8.4 +/- 0.1% in both groups. The adjusted mean change from baseline to endpoint (AMDelta) in HbA(1c) was -0.5 +/- 0.1% and -0.2 +/- 0.1% in patients receiving vildagliptin or placebo, respectively, with a significant between-treatment difference (p = 0.01). In patients aged >/=65 years, the AMDelta HbA(1c) was -0.7 +/- 0.1% in the vildagliptin group vs -0.1 +/- 0.1% in the placebo group (p < 0.001). The incidence of adverse events was similar in the vildagliptin (81.3%) and placebo (82.9%) groups. However, hypoglycaemic events were less common (p < 0.001) and less severe (p < 0.05) in patients receiving vildagliptin than in those receiving placebo. Vildagliptin decreases HbA(1c) in patients whose type 2 diabetes is poorly controlled with high doses of insulin. Addition of vildagliptin to insulin therapy is also associated with reduced confirmed and severe hypoglycaemia. ClinicalTrials.gov ID no.: NCT 00099931.

Nateglinide or gliclazide in combination with metformin for treatment of patients with type 2 diabetes mellitus inadequately controlled on maximum doses of metformin alone: 1‐year trial results

To compare long-term efficacy and safety of nateglinide plus metformin with those of gliclazide plus metformin in patients with type 2 diabetes not adequately controlled with metformin monotherapy. Double-blind, double-dummy, multicentre study extended to a total of 52 weeks. Patients with inadequate glucose control on maximal doses of metformin were randomized to nateglinide (N = 133) or gliclazide (N = 129) add-on treatment. After the initial 6-month study, the majority of patients in the nateglinide group [n = 112 (93.3%)] and in the gliclazide group [n = 101 (92.7%)] entered a 6-month, double-blind, extension study. There was no significant difference between treatment regimens in haemoglobin Alc (HbA1c) change from baseline to 52 weeks (-0.14% for nateglinide vs. -0.27% for gliclazide; p = 0.396). Proportions of patients achieving an endpoint HbA1c of <7% were similar (40 vs. 47.4%) for nateglinide and gliclazide groups. There was no significant between-treatment difference in fasting plasma glucose change from baseline to 52 weeks (nateglinide: -0.2 mmol/l and gliclazide: -0.7 mmol/l; p = 0.096). The decreases in prandial plasma glucose area under the curve(0-4 h) from baseline were -3.26 and -1.86 h x mmol/l in the nateglinide and the gliclazide groups respectively, and the change was statistically significant in the nateglinide group only (p = 0.006). Initial insulin response to a meal was augmented with nateglinide treatment only, without between-treatment difference in 2-h insulin response. The overall rate of hypoglycaemic events was similar with nateglinide and gliclazide combinations with metformin. Nateglinide plus metformin treatment was not associated with weight gain. No significant difference was seen between nateglinide plus metformin and gliclazide plus metformin in terms of HbA1c. Treatment with nateglinide plus metformin for up to 12 months was not associated with weight gain.

Once-daily Insulin Glargine Administration in the Morning Compared to Bedtime in Combination with Morning Glimepiride in Patients with Type 2 Diabetes: An Assessment of Treatment Flexibility

To compare the incidence of nocturnal hypoglycemia and glycemic control following bedtime or morning insulin glargine (LANTUS; glargine) plus glimepiride. In this 24-week, multinational, open, randomized study, 624 patients with type 2 diabetes poorly controlled on oral therapy received morning or bedtime glargine plus morning glimepiride (2, 3 or 4 mg) titrated to a target fasting blood glucose level < or = 5.5 mmol/l. The incidence of nocturnal hypoglycemia was equivalent between the two groups, with morning glargine non-inferior to bedtime (13.0 VS. 14.9 % of patients; between-treatment difference -1.9 %; one-sided 95 % confidence interval -100 %; 2.84 %). At endpoint, similar improvements in glycemic control were observed with morning compared to bedtime glargine: HbA1c: -1.65 +/- 1.21 VS. -1.57 +/- 1.16 %; p = 0.42; fasting blood glucose: -4.25 +/- 2.82 VS. -4.48 +/- 2.75 mmol/l; p = 0.08. The endpoint mean daily glargine dose was comparable (34.7 +/- 17.4 VS. 32.4 +/- 17.0 IU; p = 0.15), and there was no significant between-treatment difference in the change in body weight (2.1 VS. 1.8 kg; p = 0.39). Once-daily glargine can be administered in a flexible morning or bedtime regimen (plus morning glimepiride) to achieve good glycemic control without any difference in hypoglycemia.

Combined esterified estrogens and methyltestosterone versus esterified estrogens alone in the treatment of loss of sexual interest in surgically menopausal women

To compare the effect of esterified estrogens and methyltestosterone versus esterified estrogens alone on diminished sexual interest in surgically menopausal women. This randomized, double-blind study compared the effect of combined esterified estrogens (1.25 mg) and methyltestosterone (2.5 mg) (EE/MT) versus esterified estrogens (1.25 mg) alone (EE) for 8 weeks. Several different sexual function questionnaires were used to measure response to therapy. Changes from baseline in sexual interest/function and hormone levels were evaluated after 4 and 8 weeks of treatment. A total of 102 women were randomized into the study; 52 (age range, 32-61 years) to EE/MT and 50 (age range, 33-62 years) to EE. After 8 weeks, significant differences between treatments were not seen in the Changes in Sexual Functioning Questionnaire (CSFQ-F-C) sexual desire/interest subscale score, the primary efficacy variable. In contrast statistically significant between-treatment differences were found for several secondary efficacy variables including Menopausal Sexual Interest Questionnaire (MSIQ) sexual interest/desire score, CSFQ-F-C arousal/erection subscale score and Women's Health Questionnaire sexual functioning subscale score. The mean serum concentration of bioavailable and free testosterone significantly increased, approximately doubling between baseline and the end of the study in patients receiving EE/MT, with a significant (P < 0.001) between-treatment difference. The mean serum concentration of sex hormone-binding globulin significantly decreased to less than one third of the pretreatment levels in patients receiving EE/MT (P < 0.001). Both treatments were well tolerated. The mixed results seen with the different sexual function questionnaires may be due to the CSFQ-F-C's lack of specificity for this population. Increased levels of bioavailable and free testosterone paralleled the improved MSIQ item scores. Both the EE and EE/MT treatments were well tolerated.

Antipsychotic Drug Effects on Brain Morphology in First-Episode Psychosis

Pathomorphologic brain changes occurring as early as first-episode schizophrenia have been extensively described. Longitudinal studies have demonstrated that these changes may be progressive and associated with clinical outcome. This raises the possibility that antipsychotics might alter such pathomorphologic progression in early-stage schizophrenia. To test a priori hypotheses that olanzapine-treated patients have less change over time in whole brain gray matter volumes and lateral ventricle volumes than haloperidol-treated patients and that gray matter and lateral ventricle volume changes are associated with changes in psychopathology and neurocognition. Longitudinal, randomized, controlled, multisite, double-blind study. Patients treated and followed up for up to 104 weeks. Neurocognitive and magnetic resonance imaging (MRI) assessments performed at weeks 0 (baseline), 12, 24, 52, and 104. Mixed-models analyses with time-dependent covariates evaluated treatment effects on MRI end points and explored relationships between MRI, psychopathologic, and neurocognitive outcomes. Fourteen academic medical centers (United States, 11; Canada, 1; Netherlands, 1; England, 1). Patients with first-episode psychosis (DSM-IV) and healthy volunteers. Random allocation to a conventional antipsychotic, haloperidol (2-20 mg/d), or an atypical antipsychotic, olanzapine (5-20 mg/d). Brain volume changes assessed by MRI. Of 263 randomized patients, 161 had baseline and at least 1 postbaseline MRI evaluation. Haloperidol-treated patients exhibited significant decreases in gray matter volume, whereas olanzapine-treated patients did not. A matched sample of healthy volunteers (n = 58) examined contemporaneously showed no change in gray matter volume. Patients with first-episode psychosis exhibited a significant between-treatment difference in MRI volume changes. Haloperidol was associated with significant reductions in gray matter volume, whereas olanzapine was not. Post hoc analyses suggested that treatment effects on brain volume and psychopathology of schizophrenia may be associated. The differential treatment effects on brain morphology could be due to haloperidol-associated toxicity or greater therapeutic effects of olanzapine.

Directional coronary atherectomy plus stent implantation vs. left internal mammary artery bypass grafting for isolated proximal stenosis of the left anterior descending coronary artery

The aim of this study was to compare the short- (< 30 days) and long-term (> or = 30 days) clinical outcomes of left internal mammary artery bypass grafting (LIMA-LAD) and directional coronary atherectomy plus stent implantation (DCA + stent) in the treatment of isolated proximal left anterior descending coronary (LAD) lesions. One hundred and twenty-six patients underwent LIMA-LAD and 132 consecutive patients underwent DCA + stenting. The primary endpoint was the incidence of short- and long-term major adverse cardiac events (MACE); the secondary endpoints included any periprocedural events and long-term target vessel revascularization (TVR). We found no significant between-treatment difference in the occurrence of short-term MACE, and the long-term MACE rate per 100 person-years was 3.0 in the LIMA-LAD group and 4.6 in the DCA + stent group. After 5-year follow-up, 79% of the patients in the DCA + stent group and 89% of those in the LIMA-LAD group were still MACE-free. The risk of any periprocedural events was six times lower in the DCA + stent group, and the risk of TVR was six times higher. We conclude that both procedures lead to good short- and long-term follow-up results in isolated proximal LAD disease. As fewer periprocedural events and more TVRs occur after DCA + stenting than after LIMA-LAD, they can be considered valuable alternatives to each other.