Randomized Controlled Trial Assessing the Impact of Tacrolimus Versus Cyclosporine on the Incidence of Posttransplant Diabetes Mellitus

Despite the high incidence of posttransplant diabetes mellitus (PTDM) among high-risk recipients, no studies have investigated its prevention by immunosuppression optimization. We conducted an open-label, multicenter, randomized trial testing whether a tacrolimus-based immunosuppression and rapid steroid withdrawal (SW) within 1 week (Tac-SW) or cyclosporine A (CsA) with steroid minimization (SM) (CsA-SM), decreased the incidence of PTDM compared with tacrolimus with SM (Tac-SM). All arms received basiliximab and mycophenolate mofetil. High risk was defined by age >60 or >45 years plus metabolic criteria based on body mass index, triglycerides, and high-density lipoprotein-cholesterol levels. The primary endpoint was the incidence of PTDM after 12 months. The study comprised 128 de novo renal transplant recipients without pretransplant diabetes (Tac-SW: 44, Tac-SM: 42, CsA-SM: 42). The 1-year incidence of PTDM in each arm was 37.8% for Tac-SW, 25.7% for Tac-SM, and 9.7% for CsA-SM (relative risk [RR] Tac-SW vs. CsA-SM 3.9 [1.2-12.4; P = 0.01]; RR Tac-SM vs. CsA-SM 2.7 [0.8-8.9; P = 0.1]). Antidiabetic therapy was required less commonly in the CsA-SM arm (P = 0.06); however, acute rejection rate was higher in CsA-SM arm (Tac-SW 11.4%, Tac-SM 4.8%, and CsA-SM 21.4% of patients; cumulative incidence P = 0.04). Graft and patient survival, and graft function were similar among arms. In high-risk patients, tacrolimus-based immunosuppression with SM provides the best balance between PTDM and acute rejection incidence

Contribution of Individual and Environmental Factors to Physical Activity Level among Spanish Adults

BACKGROUND: Lack of physical activity (PA) is a major risk for chronic disease and obesity. The main aims of the present study were to identify individual and environmental factors independently associated with PA and examine the relative contribution of these factors to PA level in Spanish adults. METHODOLOGY/PRINCIPAL FINDINGS: A population-based cross-sectional sample of 3,000 adults (18-75 years old) from Gran Canaria (Spain) was selected using a multistage stratified random sampling method. The participants were interviewed at home using a validated questionnaire to assess PA as well as individual and environmental factors. The data were analyzed using bivariate and multivariate logistic regression. One demographic variable (education), two cognitive (self-efficacy and perceived barriers), and one social environmental (organized format) were independently associated with PA in both genders. Odds ratios ranged between 1.76-2.07 in men and 1.35-2.50 in women (both p<0.05). Individual and environmental factors explained about one-third of the variance in PA level. CONCLUSIONS/SIGNIFICANCE: Self-efficacy and perceived barriers were the most significant factors to meet an adequate level of PA. The risk of insufficient PA was twofold greater in men with primary or lesser studies and who are employed. In women, living in rural environments increased the risk of insufficient PA. The promotion of organized PA may be an efficient way to increase the level of PA in the general population. Improvement in the access to sport facilities and places for PA is a prerequisite that may be insufficient and should be combined with strategies to improve self-efficacy and overcome perceived barriers in adulthood

Associations of environmental factors with the recommended level of physical activity.

<p>OR = Odds ratio to be sufficiently active; 95% CI = 95% confidence interval;</p>*<p>p<0.05;</p>a<p>Logistic Regression adjusted by <i>age; education; employment status; smoking; BMI; perceived health; indexes of self-efficacy, outcome expectations, barriers, social support and modelling; format of PA; availability of sport facilities, walking trails and parks; perceived access to facilities for PA; 8 characteristics of neighborhood; and town size</i>.</p>b<p>no availability of the specific type of facility;</p>c<p>Ausence of the specific attribute.</p

Basic characteristics of adults participants in Gran Canaria Physical Activity Study.

a<p>Age, Mean ± SD = 40.1±15.8 years-old;</p>b<p>Smoking, 18±11.3 cigarrettes;</p>c<p>BMI, 25.6±4.5 kg/m²; <i>% Active</i>, percentage of participants meeting public health recommendations of PA.</p

Percentage of the determination's coefficient explained by individual and environmental variables.

<p>Percentage of the determination's coefficient explained by individual and environmental variables.</p

Associations of individual factors with the recommended level of physical activity.

<p>OR = Odds ratio to be sufficiently active; 95% CI = 95% confidence interval; * p<0.05;</p>a<p>Logistic Regression adjusted by <i>age; education; employment status; smoking; BMI; perceived health; indexes of self-efficacy, outcome expectations, barriers, social support and modelling; format of PA; availability of sport facilities, walking trails and parks; perceived access to facilities for PA; 8 characteristics of neighborhood; and town size</i>.</p>b<p>for each increase of 1 year;</p>c<p>for each increase of 10 cigarretes;</p>d<p>for each increase of 1 kg/m²;</p>e<p>all cognitive variables as ordinal scales.</p

Randomized Controlled Trial Assessing the Impact of Tacrolimus Versus Cyclosporine on the Incidence of Posttransplant Diabetes Mellitus

Despite the high incidence of posttransplant diabetes mellitus (PTDM) among high-risk recipients, no studies have investigated its prevention by immunosuppression optimization. We conducted an open-label, multicenter, randomized trial testing whether a tacrolimus-based immunosuppression and rapid steroid withdrawal (SW) within 1 week (Tac-SW) or cyclosporine A (CsA) with steroid minimization (SM) (CsA-SM), decreased the incidence of PTDM compared with tacrolimus with SM (Tac-SM). All arms received basiliximab and mycophenolate mofetil. High risk was defined by age >60 or >45 years plus metabolic criteria based on body mass index, triglycerides, and high-density lipoprotein-cholesterol levels. The primary endpoint was the incidence of PTDM after 12 months. The study comprised 128 de novo renal transplant recipients without pretransplant diabetes (Tac-SW: 44, Tac-SM: 42, CsA-SM: 42). The 1-year incidence of PTDM in each arm was 37.8% for Tac-SW, 25.7% for Tac-SM, and 9.7% for CsA-SM (relative risk [RR] Tac-SW vs. CsA-SM 3.9 [1.2-12.4; P = 0.01]; RR Tac-SM vs. CsA-SM 2.7 [0.8-8.9; P = 0.1]). Antidiabetic therapy was required less commonly in the CsA-SM arm (P = 0.06); however, acute rejection rate was higher in CsA-SM arm (Tac-SW 11.4%, Tac-SM 4.8%, and CsA-SM 21.4% of patients; cumulative incidence P = 0.04). Graft and patient survival, and graft function were similar among arms. In high-risk patients, tacrolimus-based immunosuppression with SM provides the best balance between PTDM and acute rejection incidence

Odanacatib for the treatment of postmenopausal osteoporosis : Results of the LOFT multicentre, randomised, double-blind, placebo-controlled trial and LOFT Extension study

Background Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis. Methods The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between −2·5 and −4·0 if no previous radiographic vertebral fracture, or between −1·5 and −4·0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than −4·0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66). Findings Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36·5 months (IQR 34·43–40·15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47·6 months, IQR 35·45–60·06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3·7% (251/6770) versus 7·8% (542/6910), hazard ratio (HR) 0·46, 95% CI 0·40–0·53; hip fractures 0·8% (65/8043) versus 1·6% (125/8028), 0·53, 0·39–0·71; non-vertebral fractures 5·1% (412/8043) versus 6·7% (541/8028), 0·77, 0·68–0·87; all p<0·0001. Combined results from LOFT plus LOFT Extension for cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 4·9% (341/6909) versus 9·6% (675/7011), HR 0·48, 95% CI 0·42–0·55; hip fractures 1·1% (86/8043) versus 2·0% (162/8028), 0·52, 0·40–0·67; non-vertebral fractures 6·4% (512/8043) versus 8·4% (675/8028), 0·74, 0·66–0·83; all p<0·0001. In LOFT, the composite cardiovascular endpoint of cardiovascular death, myocardial infarction, or stroke occurred in 273 (3·4%) of 8043 patients in the odanacatib group versus 245 (3·1%) of 8028 in the placebo group (HR 1·12, 95% CI 0·95–1·34; p=0·18). New-onset atrial fibrillation or flutter occurred in 112 (1·4%) of 8043 patients in the odanacatib group versus 96 (1·2%) of 8028 in the placebo group (HR 1·18, 0·90–1·55; p=0·24). Odanacatib was associated with an increased risk of stroke (1·7% [136/8043] vs 1·3% [104/8028], HR 1·32, 1·02–1·70; p=0·034), but not myocardial infarction (0·7% [60/8043] vs 0·9% [74/8028], HR 0·82, 0·58–1·15; p=0·26). The HR for all-cause mortality was 1·13 (5·0% [401/8043] vs 4·4% [356/8028], 0·98–1·30; p=0·10). When data from LOFT Extension were included, the composite of cardiovascular death, myocardial infarction, or stroke occurred in significantly more patients in the odanacatib group than in the placebo group (401 [5·0%] of 8043 vs 343 [4·3%] of 8028, HR 1·17, 1·02–1·36; p=0·029, as did stroke (2·3% [187/8043] vs 1·7% [137/8028], HR 1·37, 1·10–1·71; p=0·0051). Interpretation Odanacatib reduced the risk of fracture, but was associated with an increased risk of cardiovascular events, specifically stroke, in postmenopausal women with osteoporosis. Based on the overall balance between benefit and risk, the study's sponsor decided that they would no longer pursue development of odanacatib for treatment of osteoporosis