Abstract Background Worldwide estimates of childhood overweight and obesity are as high as 43 million, and rates continue to increase each year. Researchers have taken interest in the childhood obesity epidemic and the impact of this condition across health domains. The consequences of childhood and adolescent obesity are extensive, including both medical and psychosocial comorbidities. Objective The purpose of this review was to consolidate and highlight the recent literature on the comorbidities associated with childhood obesity, both nationally and internationally. Methods PubMed and PsychINFO searches were conducted on childhood obesity and comorbidities. Results The initial search of the terms obesity and comorbidity yielded >5000 published articles. Limits were set to include studies on children and adolescents that were published in peer-reviewed journals from 2002 to 2012. These limits narrowed the search to 938. Review of those articles resulted in 79 that are included in this review. The major medical comorbidities associated with childhood obesity in the current literature are metabolic risk factors, asthma, and dental health issues. Major psychological comorbidities include internalizing and externalizing disorders, attention-deficit hyperactivity disorder, and sleep problems. Conclusions The high prevalence rates of childhood obesity have resulted in extensive research in this area. Limitations to the current childhood obesity literature include differential definitions of weight status and cut-off levels for metabolic risk factors across studies. Additionally, some results are based on self-report of diagnoses rather than chart reviews or physician diagnosis. Even so, there is substantial support for metabolic risk factors, internalizing disorders, attention-deficit hyperactivity disorder, and decreased health-related quality of life as comorbidities to obesity in childhood. Additional investigations on other diseases and conditions that might be associated with childhood obesity are warranted and intervention research in this area is critical.
Abstract Purpose The non–vitamin K antagonist oral anticoagulants (NOACs), dabigatran, rivaroxaban, and apixaban, provide several advantages over vitamin K antagonists, such as warfarin. Little is known about the trends of prescribing OACs in Canada. In this study we analyzed changes in prescription volumes for OAC drugs since the introduction of the NOACs in Canada overall, by province and by physician specialty. Methods Canadian prescription volumes for warfarin, dabigatran, rivaroxaban, and apixaban from January 2008 to June 2014 were obtained from the Canadian Compuscript Audit of IMS Health Canada Inc and were analyzed by physician specialty at the national and provincial levels. Total prescriptions by indication were calculated based on data from the Canadian Disease and Therapeutic Index for all OAC indications and for each commonly prescribed dose of dabigatran (75, 110, and 150 mg), rivaroxaban (10, 15, and 20 mg), and apixaban (2.5 and 5 mg). Findings The overall number of OAC prescriptions in Canada has increased annually since 2008. With the availability of the NOACs, the proportion of total OAC prescriptions attributable to warfarin has steadily decreased, from 99% in 2010 to 67% by June 2014, and the absolute number of warfarin prescriptions has been decreasing since February 2011. The greatest decline in proportionate warfarin prescriptions was in Ontario. In general, the increase of NOAC prescriptions coincided with the introduction of provinces’ reimbursement of NOAC prescription costs. The proportion of total OAC prescriptions represented by the NOACs varied by specialty, with the greatest proportionate prescribing found among orthopedic surgeons, cardiologists, and neurologists. Implications Since their approval, the NOACs have represented a growing share of total OAC prescriptions in Canada. This trend is expected to continue because the NOACs are given preference over warfarin in guidelines on stroke prevention in patients with atrial fibrillation, because of growing physician experience, and due to the emergence of potential new indications. An understanding of the current prescribing patterns will help to encourage knowledge translation and possibly influence policy/reimbursement strategies.
Background: The US Food and Drug Administration's guidance for industry document on patient-reported outcomes (PRO) defines content validity as "the extent to which the instrument measures the concept of interest" (FDA, 2009, p. 12). According to Strauss and Smith (2009), construct validity "is now generally viewed as a unifying form of validity for psychological measurements, subsuming both content and criterion validity" (p. 7). Hence, both qualitative and quantitative information are essential in evaluating the validity of measures. Methods: We review classical test theory and item response theory (IRT) approaches to evaluating PRO measures, including frequency of responses to each category of the items in a multi-item scale, the distribution of scale scores, floor and ceiling effects, the relationship between item response options and the total score, and the extent to which hypothesized "difficulty" (severity) order of items is represented by observed responses. Results: If a researcher has few qualitative data and wants to get preliminary information about the content validity of the instrument, then descriptive assessments using classical test theory should be the first step. As the sample size grows during subsequent stages of instrument development, confidence in the numerical estimates from Rasch and other IRT models (as well as those of classical test theory) would also grow. Conclusion: Classical test theory and IRT can be useful in providing a quantitative assessment of items and scales during the content-validity phase of PRO measure development. Depending on the particular type of measure and the specific circumstances, the classical test theory and/or the IRT should be considered to help maximize the content validity of PRO measures. (C) 2014 Elsevier HS Journals, Inc. All rights reserved.
Abstract Background: Evaluation of exenatide monotherapy in patients with type 2 diabetes may be of clinical interest based on improvements in glycemic control and weight that have been reported with the use of exenatide in combination with oral antidiabetic agents. Objective: The aim of this study was to evaluate the efficacy and tolerability of exenatide monotherapy in patients with type 2 diabetes naive to antidiabetic agents and whose disease was inadequately controlled with diet and exercise alone. Methods: This 24-week, double-blind, placebo-controlled, parallel-group study was conducted at 23 centers across the United States, Puerto Rico, Romania, Russia, and India. Patients aged ≥18 years with type 2 diabetes were randomly assigned to receive exenatide 5 µg, exenatide 10 µg, or placebo administered SC BID. Patients were instructed by investigators to maintain their individualized prestudy diet and exercise regimens throughout the study. Efficacy measures included: glycosylated hemoglobin (HbA1c ); fasting serum glucose (FSG); 6-point self-monitored blood glucose; percentages of patients achieving HbA1c values ≤6.5% and ≤7.0%; weight; and homeostasis model of β-cell function (HOMA-B, a clinical measure of pancreatic β-cell function). Tolerability measures included patient-reported adverse events, hypoglycemia, and blood pressure. Results: A total of 232 patients were included in the intent-to-treat population (130 men, 102 women; 68% white; mean [SD] age, 54  years; duration of type 2 diabetes, 2  years; weight, 86  kg; body mass index, 31  kg/m2 ; HbA1c , 7.8% [0.9%]). At end point, least-squares mean (SE) HbA1c reductions (%) from baseline were significantly greater with exenatide 5 and 10 µg than placebo (-0.7 [0.1] and -0.9 [0.1] vs -0.2 [0.1]; P = 0.003 and P < 0.001, respectively), as were FSG reductions (mg/dL) (-17.5 [4.0] and -18.7 [4.0] vs -5.2 [4.0]; P = 0.029 and P = 0.016, respectively). Changes in daily mean postprandial glucose excursions (mg/dL) from baseline to end point were significantly greater with exenatide 5 and 10 µg than placebo (-21.3 [2.7] and -24.7 [2.7] vs -8.3 [2.5]; both, P < 0.001). With exenatide 5 and 10 µg, 31% and 35% of patients achieved HbA1c ≤6.5% at end point versus 19% with placebo ( P = NS and P = 0.026, respectively), while 48% and 46% versus 29% achieved HbA1c ≤7.0% ( P = 0.024 and P = 0.036, respectively). Changes in weight (kg) at 24 weeks were greater with exenatide 5 and 10 ²g than placebo (-2.8 [0.3] and -3.1 [0.3] vs -1.4 [0.3]; P = 0.004 and P < 0.001, respectively). HOMA-B values increased from baseline to end point by 32% and 28% in the exenatide 5- and 10-µg groups, respectively, versus 6% for placebo. Improvements from baseline to end point in HOMA-B were significantly greater with exenatide 5 and 10 µg than placebo ( P = 0.002 and P = 0.010, respectively). Significant improvements in mean systolic and diastolic blood pressure (mm Hg) from baseline to end point were also observed with exenatide (systolic, both 5 and 10 µg, -3.7 [1.2] [ P = 0.037]; diastolic, 10 µg, -2.3 [0.7] [ P = 0.046]) versus placebo (systolic, -0.3 [1.2]; diastolic, -0.3 [0.7]). Overall, 25% of patients reported ≥1 treatment-emergent adverse event. Nausea was reported with the greatest incidence (5 µg, 3%; 10 µg, 13%; placebo, 0%; P = 0.010 for the combined exenatide group vs placebo). Most (88%) treatment-emergent adverse events were mild or moderate in intensity. Hypoglycemia was reported in 5%, 4%, and 1% of patients in the exenatide 5- and 10-µg and placebo groups, respectively ( P = NS), with no incidents of severe hypoglycemia reported. Conclusions: In these patients with type 2 diabetes naive to treatment with antidiabetic agents, exenatide monotherapy was associated with improved HbA1c , improved fasting and postprandial glucose control, reduced weight, improved β-cell function (HOMA-B), and improved blood pressure, and was well tolerated. These results suggest that exenatide monotherapy may provide a viable treatment option beyond diet and exercise and support further study of exenatide monotherapy in antidiabetic drug-naive patients with type 2 diabetes.
Objective: The efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy were assessed in patients with type 2 diabetes and inadequate glycemic control (glycosylated hemoglobin [HbA(1c)] >= 7% and = 18 years (Clinical-Trials. gov NCT00086502). At screening, all patients began a diet/exercise program that continued throughout the study period. Patients taking antihyperglycemic therapy other than ploglitazone underwent a washout of this therapy and entered an 8- to 14-week open-label ploglitazone dose-titration/stabilization period. Patients with an HbA(1c) >= 7% and = 7% and ! 10% entered the 2-week, single-blind, placebo run-in period directly. Thus, at the time of randomization, all patients were receiving ongoing pioglitazone (30 or 45 mg/d). Patients were randomized in a 1:1 ratio to receive sitagliptin 100 mg once daily or placebo for 24 weeks. The primary efficacy end point was the change from baseline in HbA(1c) at week 24. Secondary efficacy end points included the change from baseline in fasting plasma glucose (FPG), insulin, and proinsulin; the Homeostasis Model Assessment P-cell function and insulin-resistance indexes; the proinsulin/insulin ratio; the Quantitative Insulin Sensitivity Check Index; the percent changes from baseline in selected lipid parameters; the proportion of patients meeting the American Diabetes Association HbA(1c) goal of < 7.0%; the proportion of patients requiring metformin rescue therapy; and the time to the initiation of rescue therapy. Results: One hundred seventy-five patients were randomized to receive sitagliptin, and 178 were randomized to receive placebo. The mean (SD) baseline HbA(1c) value was 8.1% (0.8) in the sitagliptin group and 8.0% (0.8) in the placebo group. After 24 weeks, sitagliptin added to ploglitazone therapy was associated with significant reductions compared with placebo in HbA(1c) (between-treatment difference in least squares [LS] mean change from baseline: -0.70%; 95% CI, -0.85 to -0.54; P < 0.001) and FPG (-17.7 mg/dL; 95% CI, -24.3 to -11.0; P < 0.001). Mean HbA(1c) values at end point were 7.2% (0.9) and 7.8% (1.1) in the respective treatment groups, and the proportions of patients reaching a target HbA(1c) of < 7.0% were 45.4% and 23.0% (P < 0.001). Significant reductions in fasting serum proinsulin levels and the proinsulin/insulin ratio were seen with sitagliptin treatment compared with placebo (both, P < 0.01). Sitagliptin was generally well tolerated, with no increased risk of hypoglycemia compared with placebo (2 vs 0 patients, respectively). The number of patients discontinuing the study due to clinical adverse experiences (10 [5.7%] vs 2 [1.1%]) and the incidence of abdominal pain (3.4% vs 0%) were significantly greater in the sitagliptin group compared with the placebo group (both, P < 0.05). The LS mean change in body weight from baseline did not differ significantly between sitagliptin or placebo added to ploglitazone therapy (between-treatment difference in LS mean change from baseline: 0.2 kg; 95% CI, -0.5 to 1.0). Conclusion: In this 24-week study, sitagliptin 100 mg once daily added to ongoing pioglitazone therapy was effective and well tolerated in these patients with type 2 diabetes who had not achieved adequate glycemic control with pioglitazone alone.
Abstract Background: Patients with elevated serum triglyceride (TG) levels often have elevations in non-high-density lipoprotein cholesterol (non-HDL-C) levels as well. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) has identified non-HDL-C as a secondary therapeutic target in these patients, but treatment goals may not be reached with statin monotherapy alone. Objective: This study evaluated the effects on non-HDL-C and other variables of adding prescription omega-3-acid ethyl esters (P-OM3; LovazaTM , formerly Omacor® [Reliant Pharmaceuticals, Inc., Liberty Corner, New Jersey]) to stable statin therapy in patients with persistent hypertriglyceridemia. Methods: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in adults who had received ≥8 weeks of stable statin therapy and had mean fasting TG levels ≥200 and <500 mg/dL and mean low-density lipoprotein cholesterol levels ⪯10% above their NCEP ATP III goal. The study regimen consisted of an initial 8 weeks of open-label simvastatin 40 mg/d and dietary counseling, followed by 8 weeks of randomized treatment with double-blind P-OM3 4 g/d plus simvastatin 40 mg/d or placebo plus simvastatin 40 mg/d. The main outcome measure was the percent change in non-HDL-C from baseline to the end of treatment. Results: The evaluable population included 254 patients, of whom 57.5% (146) were male and 95.7% (243) were white. The mean (SD) age of the population was 59.8 (10.4) years, and the mean weight was 92.0 (19.6) kg. At the end of treatment, the median percent change in non-HDL-C was significantly greater with P-OM3 plus simvastatin compared with placebo plus simvastatin (-9.0% vs -2.2%, respectively; P < 0.001). P-OM3 plus simvastatin was associated with significant reductions in TG (29.5% vs 6.3%) and very-low-density lipoprotein cholesterol (27.5% vs 7.2%), a significant increase in high-density lipoprotein cholesterol (HDL-C) (3.4% vs -1.2%), and a significant reduction in the total cholesterol:HDL-C ratio (9.6% vs 0.7%) (all, P < 0.001 vs placebo). Adverse events (AEs) reported by ≥1% of patients in the P-OM3 group that occurred with a higher frequency than in the group that received simvastatin alone were nasopharyngitis (4 [3.3%]), upper respiratory tract infection (4 [3.3%]), diarrhea (3 [2.5%]), and dyspepsia (3 [2.5%]). There was no significant difference in the frequency of AEs between groups. No serious AEs were considered treatment related. Conclusion: In these adult, mainly white patients with persistent hypertriglyceridemia, P-OM3 plus simvastatin and dietary counseling improved non-HDL-C and other lipid and lipoprotein parameters to a greater extent than simvastatin alone.
Abstract Purpose Guidelines recommend daptomycin combination therapy as an option for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia after vancomycin failure. Recent data suggest that combining daptomycin with a β-lactam may have unique benefits; however, there are very limited clinical data regarding the use of ceftaroline with daptomycin. Methods All 26 cases from the 10 medical centers in which ceftaroline plus daptomycin was used for treatment of documented refractory staphylococcal bacteremia from March 2011 to November 2012 were included. In vitro (synergy studies, binding assays, cathelicidin LL-37 killing assays), and in vivo (virulence assays using a murine subcutaneous infection model) studies examining the effects of ceftaroline with daptomycin were also performed. Findings Daptomycin plus ceftaroline was used in 26 cases of staphylococcal bacteremia (20 MRSA, 2 vancomycin-intermediate S aureus , 2 methicillin-susceptible S aureus [MSSA], 2 methicillin-resistant S epidermidis ). Bacteremia persisted for a median of 10 days (range, 3–23 days) on previous antimicrobial therapy. After daptomycin plus ceftaroline was started, the median time to bacteremia clearance was 2 days (range, 1–6 days). In vitro studies showed ceftaroline synergy against MRSA and enhanced MRSA killing by cathelicidin LL-37 and neutrophils. Ceftaroline also induced daptomycin binding in MSSA and MRSA to a comparable degree as nafcillin. MRSA grown in subinhibitory concentrations of ceftaroline showed attenuated virulence in a murine subcutaneous infection model. Implications Ceftaroline plus daptomycin may be an option to hasten clearance of refractory staphylococcal bacteremia. Ceftaroline offers dual benefit via synergy with both daptomycin and sensitization to innate host defense peptide cathelicidin LL37, which could attenuate virulence of the pathogen.
Abstract Objective Dapagliflozin is a highly selective, orally active inhibitor of renal sodium-glucose cotransporter 2 that reduces hyperglycemia by increasing urinary glucose excretion. The goal of this study was to evaluate dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes whose disease was inadequately controlled with diet and exercise. Methods In this Phase III, multicenter, parallel-group, double-blind study, drug-naive patients with glycosylated hemoglobin (HbA1c ) levels ≥7.0% to ≤10.5% (≥53–≤91 mmol/mol) were randomized (by using an interactive voice response system) to receive placebo (n = 132), dapagliflozin 5 mg (n = 128), or dapagliflozin 10 mg (n = 133). The primary end point was mean change from baseline in HbA1c level at week 24 (last-observation-carried-forward). Secondary end points included changes in fasting plasma glucose, 2-hour postprandial glucose, body weight, and other glycemic parameters. Results Baseline characteristics were balanced across groups. Most patients (89%) were Chinese, median disease duration was 0.2 year, and mean HbA1c level was 8.26%. Most patients (87%) completed the study. At week 24, mean reductions in HbA1c were −0.29% for placebo versus −1.04% and −1.11% for dapagliflozin 5 and 10 mg, respectively ( P < 0.0001 for both doses). Changes in fasting plasma glucose were 2.5, −25.1, and –31.6 mg/dL (0.14, −1.39, and −1.75 mmol/L) for placebo, dapagliflozin 5 mg, and dapagliflozin 10 mg. Changes in 2-hour postprandial glucose were 1.1, −46.8, and −54.9 mg/dL (0.06, −2.60, and −3.05 mmol/L). Reductions in body weight were −0.27, −1.64, and −2.25 kg. Proportions of patients achieving HbA1c levels <7.0% (53 mmol/mol) were 21.3%, 42.6%, and 49.8%. Adverse events (AEs) occurred in 63.6%, 61.7%, and 60.9% of patients, and serious AEs occurred in 1.5%, 3.9%, and 3.0% of patients. No deaths occurred. Hypoglycemia was uncommon (1.5%, 0.8%, and 0.8%); no hypoglycemic event led to discontinuation. Genital infections occurred in 0.8%, 3.1%, and 4.5% of patients and urinary tract infections in 3.0%, 3.9%, and 5.3% of patients. No AEs of renal infection or pyelonephritis were reported. No changes in renal function or AEs of renal failure occurred. Conclusions Compared with placebo, dapagliflozin 5 and 10 mg demonstrated clinically and statistically significant improvements in HbA1c levels after 24 weeks of treatment. Dose-dependent, statistically significant reductions in fasting plasma glucose, postprandial glucose, and weight were also observed for both doses compared with placebo. AEs and serious AEs were balanced across groups, with low rates of hypoglycemia and no increase in renal events. Genital infections and urinary tract infections were more common with dapagliflozin. Dapagliflozin as monotherapy in these drug-naive Asian patients was well tolerated, significantly improving glycemic control with the additional benefit of weight loss.
Abstract Purpose Patients with severe eosinophilic asthma often experience recurrent asthma exacerbations despite intensive inhaled corticosteroid therapy. In 2 previous double-blind studies (MENSA [NCT01691521] and SIRIUS [NCT01691508]), treatment with intravenous or subcutaneous mepolizumab was associated with significantly reduced annualized exacerbation rates and oral corticosteroid (OCS) requirements compared with placebo. The purpose of this study was to assess the long-term safety and efficacy of subcutaneous mepolizumab treatment in patients with severe eosinophilic asthma. Methods COSMOS was a 52-week, open-label extension study in patients who received mepolizumab or placebo in MENSA or SIRIUS. Patients received subcutaneous mepolizumab regardless of prior treatment allocation and continued to receive appropriate standard-of-care asthma therapy throughout. The primary objective was to assess the long-term safety of mepolizumab; end points included adverse events (AEs) and serious AEs (SAEs). Efficacy assessments included the annualized exacerbation rate and durability of response (defined as the exacerbation rate and OCS dose reduction when combined with MENSA and SIRIUS data, respectively). Findings In total, 558 (86%; previous mepolizumab: 358; previous placebo: 200) and 94 (14%; previous mepolizumab: 58, previous placebo: 36) patients experienced on-treatment AEs and SAEs, respectively. No fatal AEs were reported. Totals of 13 (2%) and 29 (4%) patients experienced systemic and local site reactions, respectively. There were no reports of mepolizumab-related anaphylaxis. Mepolizumab treatment was shown to exert a durable response, with patients who previously received mepolizumab in MENSA or SIRIUS maintaining reductions in exacerbation rate and OCS dosing throughout COSMOS. Patients who previously received placebo in MENSA or SIRIUS demonstrated improvements in these end points following treatment with mepolizumab in COSMOS. Implications These data demonstrate a favorable safety profile of mepolizumab and indicate a durable and stable effect over time, supporting long-term treatment in patients with severe eosinophilic asthma. ClinicalTrials.gov identifier: NCT01842607.
Abstract Background Infliximab is a chimeric monoclonal antibody against TNFα. The pharmacokinetic (PK) properties of infliximab have been studied in several adult patient populations, but a literature search identified no reported comparative population PK properties of this drug in pediatric patients. Objectives The current analysis applied population PK techniques to compare data on the PK properties of infliximab in pediatric and adult patients with moderately to severely active Crohn's disease (CD) from 2 Phase III studies. Methods This analysis used serum infliximab concentration data from 692 patients (112 children, 580 adults; age range, 6–76 years) from 2 Phase III clinical studies (REACH [A Randomized, Multicenter, Open-Label Study to Evaluate the Safety and Efficacy of Anti-TNF-α Chimeric Monoclonal Antibody in Pediatric Subjects with Moderate-to-Severe Crohn's Disease] and ACCENT I [A Crohn's Disease Clinical Trial Evaluating Infliximab in a New, Long-term Treatment Regimen]). PK models were developed separately for children, adults, and a combination of both. The combined population was used for establishing important covariates of infliximab PK properties in the combined CD population. Exploratory simulations using combined PK and covariate data were performed to expand the interpretation of the results in children. Results Based on the findings, in a typical child (who, based on the median values in REACH, weighs 42 kg, has a baseline serum albumin concentration [SAC] 3.8 mg/dL, and has not developed antibodies to infliximab [ATIs]) who is receiving infliximab and an immunomodulator, PK estimates (typical value [SE]) were as follows: clearance (CL), 5.43 (0.15) mL/kg/d; Vd in the central compartment (V1 ), 54.2 (1.15) mL/kg; Vd in the peripheral compartment (V2 ), 29.2 (2.03) mL/kg; and intercompartmental clearance (Q), 3.52 (0.71) mL/kg/d. Corresponding properties in a typical adult (weight, 68 kg; SAC, 4.1 mg/dL) were CL, 5.39 (0.13) mL/kg/d; V1 , 52.7 (0.49) mL/kg; V2 , 19.0 (1.53) mL/kg; and Q, 2.15 (0.39) mL/kg/d. V2 decreased as body weight increased, predicting a possible undercompensation for exposure with infliximab dosing per kg weight in lower-weight individuals. In pediatric and adult patients, CL was higher in those in whom ATIs developed or who had low baseline SAC. Concurrent immunomodulator use (purine antimetabolites or methotrexate) was associated with a 14% decrease in CL. In the pediatric and adult patients, observed trough serum infliximab concentrations, median infliximab t1/2 (in children, 13.2 days; and in adults, 12.4 days), and exploratory PK simulations predicted infliximab PK properties to be comparable between children and adults. Conclusions Infliximab PK properties appeared to be comparable between pediatric and adult patients with CD. Specifically, in this select population using nonlinear mixed effects modeling, infliximab CL increased as SAC decreased. CL also increased with ATI formation but decreased with immunomodulator coadministration. Although weight affects infliximab PK properties (total CL and total Vd increased with total body weight while per kg CL and Vd decrease with total body weight), age was not found to influence infliximab PK in the age range tested (6–76 years).
Abstract Purpose The aim of this analysis was to establish the safety profile and tolerability of empagliflozin in patients with type 2 diabetes mellitus (T2DM) according to pooled data from several clinical trials. Methods Pooled data were analyzed from patients with T2DM treated with placebo (n = 3695), empagliflozin 10 mg (n = 3806), or empagliflozin 25 mg (n = 4782) in 17 randomized, Phase I, II, and III clinical trials plus 6 extension studies. Adverse events (AEs) were assessed descriptively in patients who took ≥1 dose of the study drug. AE incidence rates per 100 patient-years were calculated to adjust for differences in drug exposure across trials. Findings Total exposure was 3254, 3840, and 5649 patient-years in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg groups, respectively. The incidence of any AEs, AEs leading to treatment discontinuation, severe AEs, and serious AEs was no higher in patients treated with empagliflozin than with placebo. Empagliflozin was not associated with an increased risk of hypoglycemia versus placebo, except in patients on background sulfonylurea and/or insulin. The incidence of events consistent with urinary tract infection was similar across treatment groups (9.4–11.3/100 patient-years); 0.4%, 0.2%, and 0.3% of patients in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg groups, respectively, had urinary tract infections that required or prolonged hospitalization. The incidence of events consistent with genital infection was higher in patients treated with empagliflozin (4.7 and 5.0/100 patient-years for empagliflozin 10 and 25 mg, respectively) than placebo (1.3/100 patient-years), but only 0.1%, 0.1%, and 75 years (4.4 vs 2.3 and 2.5/100 patient-years, respectively). The incidences of bone fractures, malignancies, decreased renal function, hepatic injury, venous thromboembolic events, and diabetic ketoacidosis were low and similar across the treatment groups. Implications In this predefined analysis that was based on >9000 patient-years’ exposure to empagliflozin, empagliflozin 10 mg, and empagliflozin 25 mg were well tolerated in patients with T2DM.
Abstract Background: Hypertension guidelines recommend the use of 2 agents having complementary mechanisms of action when >1 agent is needed to achieve blood pressure (BP) goals. Objective: The aim of this study was to compare the efficacy and tolerability of combinations of olmesartan medoxomil (OM) and amlodipine besylate with those of the component monotherapies in patients with mild to severe hypertension. Methods: This was a multicenter, randomized, doubleblind, placebo-controlled, factorial study. Patients who were naive to antihypertensive therapy or who underwent a washout of previous antihypertensive therapy for up to 2 weeks and had a seated diastolic BP (SeDBP) of 95 to 120 mm Hg were randomized to receive 1 of the following for 8 weeks: OM 10, 20, or 40 mg; amlodipine (AML) 5 or 10 mg; each possible combination of OM and AML; or placebo. The primary end point was the change from baseline in SeDBP at week 8, with secondary end points including the change in seated systolic blood pressure (SeSBP), the proportion of patients reaching the BP goal (<140/90 mm Hg; <130/80 mm Hg for patients with diabetes), and the proportions of the intention-to-treat population reaching BP thresholds of <120/80, <130/80, <130/85, and <140/90 mm Hg. Safety and tolerability were also evaluated, with a particular focus on the incidence and severity of edema. Results: Of the 1940 randomized patients, 54.3% were male. The mean age of the study population was 54.0 years and 19.8% were aged ≥65 years. The mean baseline BP was 164/102 mm Hg, and 79.3% of patients had stage 2 hypertension. Combination therapy with OM and AML was associated with dose-dependent reductions in SeDBP (from −13.8 mm Hg with OM/AML 10/5 mg to −19.0 mm Hg with OM/AML 40/10 mg) and SeSBP (from −23.6 mm Hg with OM/AML 20/5 mg to −30.1 mm Hg with OM/AML 40/10 mg) that were significantly greater than the reductions with the corresponding component monotherapies ( P < 0.001). At week 8, the number of patients achieving the BP goal ranged from 57 of 163 (35.0%) to 84 of 158 (53.2%) in the combination-therapy groups, from 32 of 160 (20.0%) to 58 of 160 (36.3%) in the OM monotherapy groups, and from 34 of 161 (21.1%) to 53 of 163 (32.5%) in the AML monotherapy groups ( P < 0.005, combination therapies vs component monotherapies), compared with 14 of 160 (8.8%) in the placebo group. Achievement of the BP thresholds was highest in the combination-therapy groups, with 56.3% and 54.0% of patients achieving a BP <140/90 mm Hg with OM/AML 20/10 and 40/10 mg, respectively. Combination therapy was generally well tolerated, and no unexpected safety concerns emerged in the course of the study. The most common adverse events were edema (ranging from 9.9% [OM 20 mg] to 36.8% [AML 10 mg], compared with 12.3% with placebo) and headache (ranging from 2.5% [OM/AML 10/5 mg] to 8.7% [OM 20 mg], compared with 14.2% with placebo). Conclusion: The combination of OM and AML was effective and well tolerated in this adult population with hypertension.
Abstract Purpose The microbiome modulates numerous aspects of human physiology and is a crucial factor in the development of various human diseases. Vitamin D deficiency and downregulation of the vitamin D receptor (VDR) are also associated with the pathogenesis of diseases such as inflammatory bowel disease, cancers, obesity, diabetes, and asthma. VDR is a nuclear receptor that regulates the expression of antimicrobial peptides and autophagy regulator ATG16L1. Vitamin D may promote a balanced intestinal microbiome and improve glucose homeostasis in diabetes. However, how VDR regulates microbiome is not well known. In the current study, we hypothesize that VDR status regulates the composition and functions of the intestinal bacterial community. Methods Fecal and cecal stool samples were harvested from Vdr knockout ( Vdr−/− ) and wild-type mice for bacterial DNA and then sequenced with 454 pyrosequencing. The sequences were denoised and clustered into operational taxonomic units, then queried against the National Center for Biotechnology Information database. Metagenomics were analyzed, and the abundances of genes involved in metabolic pathways were compared by reference to the Kyoto Encyclopedia of Genes and Genomes and Clusters of Orthologous Groups databases. Findings In the Vdr−/− mice, Lactobacillus was depleted in the fecal stool, whereas Clostridium and Bacteroides were enriched. Bacterial taxa along the Sphingobacteria-to-Sphingobacteriaceae lineage were enriched, but no genera reached statistical significance. In the cecal stool, Alistipes and Odoribacter were depleted, and Eggerthella was enriched. Notably, all of the taxa upstream of Eggerthella remained unchanged. A comparison of Vdr−/− and wild-type samples revealed 40 (26 enriched, 14 depleted) and 72 (41 enriched, 31 depleted) functional modules that were significantly altered in the cecal and fecal microbiomes, respectively (both, P < 0.05), due to the loss of Vdr. In addition to phylogenetic differences in gut microbiome with different intestinal origins, we identify several important pathways, such as nucleotide-binding oligomerization domain–like receptor, affected by Vdr status, including amino acid, carbohydrate, and fatty acid synthesis and metabolism, detoxification, infections, signal transduction, and cancer and other diseases. Implications Our study fills knowledge gaps by having investigated the microbial profile affected by VDR. Insights from our findings can be exploited to develop novel strategies to treat or prevent various diseases by restoring VDR function and healthy microbe–host interactions.
Abstract Background: Preclinical and clinical studies have suggested that milnacipran, a dual norepinephrine-serotonin reuptake inhibitor, may be efficacious in the treatment of fibromyalgia (FM). Objective: This study was conducted to evaluate the efficacy and tolerability of milnacipran in treating the multiple domains of FM. Methods: This was a multicenter, double-blind, placebo-controlled trial. Adult patients (age 18–70 years) who met 1990 American College of Rheumatology criteria for FM were randomized to receive milnacipran 100 mg/d, milnacipran 200 mg/d, or placebo for 15 weeks. Because this was a pivotal registration trial, the primary end points were chosen to investigate efficacy for 2 potential indications: the treatment of FM and the treatment of FM pain. Thus, the 2 primary efficacy end points were rates of FM composite responders and FM pain composite responders. FM composite responders were defined as patients concurrently experiencing clinically meaningful improvements in the following 3 domain criteria: pain (≥30% improvement, as recorded in an electronic diary); patients' global status (a rating of very much improved or much improved on the Patient Global Impression of Change [PGIC] scale); and physical function (a ≥6-point improvement on the 36-item Short-Form Health Survey [SF-36] Physical Component Summary score). FM pain composite responders were defined as those who met the pain and PGIC criteria. Adverse events reported by patients or observed by investigators were recorded throughout the trial. Results: Of 2270 patients screened, 1196 were randomized to receive milnacipran 100 mg/d (n = 399), milnacipran 200 mg/d (n = 396), or placebo (n = 401). The majority of patients were female (96.2%) and white (93.5%). The population had a mean age of 50.2 years, a mean baseline weight of 180.8 pounds, and a mean baseline body mass index of 30.6 kg/m2 . Compared with placebo, significantly greater proportions of milnacipran-treated patients were FM composite responders (100 mg/d: P = 0.01; 200 mg/d: P = 0.02) and FM pain composite responders (100 mg/d: P = 0.03; 200 mg/d: P = 0.004). Milnacipran was associated with significant improvements in pain after 1 week of treatment (100 mg/d: P = 0.004; 200 mg/d: P = 0.04), as well as significant improvements in multiple secondary efficacy end points, including global status (PGIC: P <0.001 for both doses), physical function (SF-36 physical functioning domain—100 mg/d: P < 0.001; 200 mg/d: P = 0.02), and fatigue (Multidimensional Fatigue Inventory— 100 mg/d: P = 0.04). The most commonly reported adverse events with milnacipran were nausea (100 mg/d, 34.3%; 200 mg/d, 37.6%), headache (18.0% and 17.7%, respectively), and constipation (14.3% and 17.9%). Adverse events resulted in premature study discontinuation in 19.5% and 23.7% of those who received milnacipran 100 and 200 mg/d, respectively, compared with 9.5% of placebo recipients. Conclusion: In these adult patients with FM, both doses of milnacipran (100 and 200 mg/d) were associated with significant improvements in pain and other symptoms. Clinical Trials Identification Number: NCT00098124.
Background: The second-generation antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and other compounds with different mechanisms of action. All second-generation antidepressants are metabolized in the liver by the cytochrome P450 (CYP) enzyme system. Concomitant intake of inhibitors or inducers of the CYP isozymes involved in the biotransformation of specific antidepressants may alter plasma concentrations of these agents, although this effect is unlikely to be associated with clinically relevant interactions. Rather, concern about drug interactions with second-generation antidepressants is based on their in vitro potential to inhibit >= 1 CYP isozyme. Objective: The goal of this article was to review the current literature on clinically relevant pharmacokinetic drug interactions with second-generation antidepressants. Methods: A search of MEDLINE and EMBASE was conducted for original research and review articles published in English between January 1985 and February 2008. Among the search terms were drug interactions, second-generation antidepressants, newer antidepressants, SSRIs, SNRIs, fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, escitalopram, venlafaxine, duloxetine, mirtazapine, reboxetine, bupropion, nefazodone, pharmacokinetics, drug metabolism, and cytochrome P450. Only articles published in peer-reviewed journals were included, and meeting abstracts were excluded. The reference lists of relevant articles were hand-searched for additional publications. Results: Second-generation antidepressants differ in their potential for pharmacokinetic drug interactions. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, fluvoxamine markedly inhibits CYP1A2 and CYP2C19, and nefazodone is a substantial inhibitor of CYP3A4. Therefore, clinically relevant interactions may be expected when these antidepressants are coadministered with substrates of the pertinent isozymes, particularly those with a narrow therapeutic index. Duloxetine and bupropion are moderate inhibitors of CYP2D6, and sertraline may cause Significant inhibition of this isoform, but only at high doses. Citalopram, escitalopram, venlafaxine, mirtazapine, and reboxetine are weak or negligible inhibitors of CYP isozymes in vitro and are less likely than other second-generation antidepressants to interact with co-administered medications. Conclusions: Second-generation antidepressants are not equivalent in their potential for pharmacokinetic drug interactions. Although interactions may be predictable in specific circumstances, use of an antidepressant with a more favorable drug-interaction profile may be justified.
Abstract Background Past national surveys indicate that use of herbs and dietary supplements rose rapidly in the United States during the 1990s and early 2000s. Additional research is needed to determine whether this growth rate and associated patterns of use have persisted over time. Objectives The objectives of this study were: (1) to assess population and subpopulation changes in rates of herb and supplement use; and (2) to assess changes in rates of disclosure of herb and supplement use to conventional medical providers. Methods This study used data from the 2002 (n = 30,427) and 2007 (n = 22,657) Adult Complementary and Alternative Medicine File to the National Health Interview Survey (NHIS). Weighted group and subgroup comparisons used the Wald χ2 tests to compare differences in herb and supplement use between 2002 and 2007. Results The number of adults in the United States that ever used herbs or supplements grew slightly, from 50.6 million in 2002 to 55.1 million in 2007. However, the proportion of adults who reported use of herbs or supplements in the past 12 months dropped significantly: from 18.9% in 2002 to 17.9% in 2007 ( P < 0.05). Subpopulation comparisons revealed that younger adults were less likely to use herbs and supplements in 2007 (17.6%) than in 2002 (20.0%), whereas older adults (ie, those aged ≥65 years) were more likely to do so (19.5% in 2007 vs. 13.2% in 2002). Racial and ethnic minorities also reported a significant decline in recent use. The proportion of respondents that disclosed herb or supplement use to their physician or another conventional medical professional rose, from 33.4% in 2002 to 45.4% in 2007. However, <1% of recent herb and supplement users disclosed this use to their pharmacist. Limitations of this research are that the 2 national data sets were not directly comparable and that questionnaires in the 2 surveys assessed were not identical. Conclusions Herbal preparations and dietary supplements remain popular in the United States, but the user population and patterns of use are changing. Ongoing surveillance of this health behavior is a public health priority.
Abstract Purpose Exosomes are small (30- to 100-nm) vesicles secreted by all cell types in culture and found in most body fluids. A mean of 1 mL of blood serum, derived from healthy donors, contains approximately 1012 exosomes. Depending on the disease, the number of exosomes can fluctuate. Concentration of exosomes in the bloodstream and all other body fluids is extremely high. Several B-cell surface antigens (CD19, CD20, CD22, CD23, CD24, CD37, CD40, and HLA-DR) and the common leukocyte antigen CD45 are interesting in terms of immunotherapy of hematologic malignant neoplasms. The established standard for exosome isolation is ultracentrifugation. However, this method cannot discriminate between exosome subpopulations and other nanovesicles. The main purpose of this study was to characterize CD81+ and CD63+ subpopulations of exosomes in terms of these surface markers after release from various types of B-cell lymphoma cell lines using an easy and reliable method of immunomagnetic separation. Methods Western blotting, flow cytometry, and electron microscopy were used to compare the total preenriched extracellular vesicle (EV) pool to each fraction of vesicles after specific isolation, using magnetic beads conjugated with antibodies raised against the exosome markers CD63 and CD81. Findings Magnetic bead–based isolation is a convenient method to study and compare subpopulations of exosomes released from B-cell lymphoma cells. The data indicated that the specifically isolated vesicles differed from the total preenriched EV pool. CD19, CD20, CD24, CD37, and HLA-DR, but not CD22, CD23, CD40, and CD45, are expressed on exosomes from B-cell lymphoma cell lines with large heterogeneity among the different B-cell lymphoma cell lines. Interestingly, these B-cell lymphoma–derived EVs are able to rescue lymphoma cells from rituximab-induced complement-dependent cytotoxicity. Implications Distribution of exosomes that contain CD19, CD20, CD24, CD37, and HLA-DR may intercept immunotherapy directed against these antigens, which is important to be aware of for optimal treatment. The use of an immunomagnetic separation platform enables easy isolation and characterization of exosome subpopulations for further studies of the exosome biology to understand the potential for therapeutic and diagnostic use.
Abstract Background: Patients with hypertension may require a combination of ≥2 antihypertensive agents to achieve blood pressure (BP) control. Objective: The aim of this study was to determine whether a triple combination of olmesartan medoxomil (OM), amlodipine besylate (AML), and hydrochlorothiazide (HCTZ) had a clinically significant benefit compared with dual combinations of the individual components in patients with moderate to severe hypertension. Methods: This was a multicenter, randomized, doubleblind, parallel-group study in which triple combination treatment with OM 40 mg + AML 10 mg + HCTZ 25 mg was compared with dual combinations of the individual components—OM 40 mg/AML 10 mg in fixed-dose combination, OM 40 mg/HCTZ 25 mg in fixed-dose combination, and AML 10 mg + HCTZ 25 mg—in patients aged ≥18 years who had a mean seated BP ≥140/100 mm Hg or ≥160/90 mm Hg. The study consisted of a 3-week washout period with no study medication and a 12-week double-blind treatment period. In the first 2 weeks of the double-blind treatment period, all patients were randomized to receive dual combination treatment or placebo. All patients assigned to a dual combination treatment group continued the assigned treatment until week 4, and all patients assigned to placebo were switched at week 2 to receive 1 of the dual combination treatments until week 4. At week 4, patients either continued dual combination treatment or switched to triple combination treatment until week 12. The primary end point was the change in seated diastolic BP (SeDBP) from baseline to week 12; SeDBP reduction of ≥2 mm Hg was considered a clinically significant benefit. Secondary efficacy end points included the change in seated systolic BP (SeSBP) at week 12 and the percentages of patients achieving BP targets of <140/90 mm Hg, <120/80 mm Hg, SeSBP <140 mm Hg, and SeDBP <90 mm Hg at week 12. The tolerability of the treatments was also evaluated based on adverse events (AEs), clinical laboratory evaluations (chemistry, hematology, and urinalysis), physical examinations, and 12-lead ECGs. Results: The 2492 randomized patients (52.9% male, 66.8% white, 30.4% black) had a mean (SD) age of 55.1 (10.9) years and a mean weight of 96.0 (22.9) kg. Diabetes was present in 15.5% of the population, chronic cardiovascular disease in 9.1%, and chronic kidney disease in 4.1%. At baseline, the mean SeBP was 168.5/100.9 mm Hg. At week 12, triple combination treatment was associated with significantly greater least squares mean reductions in SeBP compared with the dual combinations (SeDBP: −21.8 vs −15.1 to −18.0 mm Hg, respectively [ P < 0.001]; SeSBP: −37.1 vs −27.5 to −30.0 mm Hg [ P < 0.001]). A significantly higher proportion of patients receiving triple combination treatment reached BP targets compared with the dual combinations at week 12 ( P < 0.001). The proportions of patients reaching the BP target of <140/90 mm Hg at week 12 was 69.9% in the triple combination treatment group and 52.9%, 53.4%, and 41.1% in the treatment groups receiving OM 40 mg/AML 10 mg, OM 40 mg/HCTZ 25 mg, and AML 10 mg + HCTZ 25 mg, respectively ( P < 0.001, triple combination vs each dual combination). The incidence of treatment-emergent AEs (TEAEs) was 58.4% for triple combination treatment and 51.7% to 58.9% for the dual combinations; most TEAEs were mild or moderate in severity. The most common TEAEs in the triple combination treatment group were dizziness (9.9%), peripheral edema (7.7%), and headache (6.4%). In total, 52 patients (2.3%) discontinued the study due to TEAEs—6 (1.0%) in the OM 40 mg/AML 10 mg group, 12 (2.1%) in the OM 40 mg/HCTZ 25 mg group, 11 (2.0%) in the AML 10 mg + HCTZ 25 mg group, and 23 (4.0%) in the OM 40 mg + AML 10 mg + HCTZ 25 mg group. Thirty-two patients (1.4%)–4 (0.7%), 5 (0.9%), 5 (0.9%), and 18 (3.1%) in the respective treatment groups—discontinued the study due to drug-related TEAEs. Conclusions: In these adult patients with moderate to severe hypertension, triple combination treatment with OM 40 mg + AML 10 mg + HCTZ 25 mg was associated with significant BP reductions compared with dual combinations of the individual components. All treatments were generally well tolerated. ClinicalTrials. gov identifier: NCT00649389.
Abstract Background A novel omega-3 formulation in free fatty acid form (OM3-FFA) has as much as 4-fold greater bioavailability than ethyl ester forms and reduces triglyceride (TG) levels in patients with severe hypertriglyceridemia. Objective This study was designed to evaluate the efficacy of adding OM3-FFA (2 or 4 g/d) to statin therapy for lowering non–HDL-C and TG levels in subjects with persistent hypertriglyceridemia and at high risk for cardiovascular disease. Methods In this double-blind, parallel-group study, 647 diet-stable patients with fasting TG levels ≥200 mg/dL and <500 mg/dL (treated with a maximally tolerated dose of statin or statin with ezetimibe) and at high risk for cardiovascular disease were randomized to 6 weeks of treatment with capsules of control (olive oil [OO]) 4 g/d, OM3-FFA 2 g/d (plus 2 g/d OO), or OM3-FFA 4 g/d. Assessments included fasting serum levels of lipids and apolipoproteins (apo); plasma concentrations of eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, and arachidonic acid; and laboratory safety values and adverse events. Results In the 627 subjects in the intention to treat sample, non–HDL-C levels were reduced with OM3-FFA 2 g/d and OM3-FFA 4 g/d (–3.9% and –6.9%, respectively) compared with OO (–0.9%) (both, P < 0.05), as were TG levels (–14.6% and –20.6%, respectively, vs –5.9%; both, P < 0.001). LDL-C levels increased with OM3-FFA 2 g/d (4.6%) compared with OO (1.1%) ( P = 0.025) but not with OM3-FFA 4 g/d (1.3%). Total cholesterol and VLDL-C concentrations were reduced compared with OO with both OM3-FFA dosages, and the total cholesterol/HDL-C ratio and apo AI and apo B levels were significantly lowered with OM3-FFA 4 g/d only (all at least P < 0.05). Percent changes from baseline in HDL-C did not differ between OO and either OM3-FFA group. Plasma concentrations of docosahexaenoic acid, eicosapentaenoic acid, and docosapentaenoic acid were significantly increased and arachidonic acid was significantly reduced in both OM3-FFA treatment groups compared with the OO responses (all, P < 0.001). Withdrawals related to treatment-emergent adverse events ranged from 0.9% with OO to 3.2% with OM3-FFA 4 g/d. Conclusions OM3-FFA was well tolerated and lowered non–HDL-C and TG levels at both 2- and 4-g/d dosages in patients with persistent hypertriglyceridemia taking a statin, with the 4-g/d dosage providing incremental improvements compared with 2 g/d. ClinicalTrials.gov identifier: NCT01408303.