Clinical utility of combinatorial pharmacogenomic testing in depression: A Canadian patient- and rater-blinded, randomized, controlled trial

The pharmacological treatment of depression consists of stages of trial and error, with less than 40% of patients achieving remission during first medication trial. However, in a large, randomized-controlled trial (RCT) in the U.S. (“GUIDED”), significant improvements in response and remission rates were observed in patients who received treatment guided by combinatorial pharmacogenomic testing, compared to treatment-as-usual (TAU). Here we present results from the Canadian “GAPP-MDD” RCT. This 52-week, 3-arm, multi-center, participant- and rater-blinded RCT evaluated clinical outcomes among patients with depression whose treatment was guided by combinatorial pharmacogenomic testing compared to TAU. The primary outcome was symptom improvement (change in 17-item Hamilton Depression Rating Scale, HAM-D17) at week 8. Secondary outcomes included response (≥50% decrease in HAM-D17) and remission (HAM-D17 ≤ 7) at week 8. Numerically, patients in the guided-care arm had greater symptom improvement (27.6% versus 22.7%), response (30.3% versus 22.7%), and remission rates (15.7% versus 8.3%) compared to TAU, although these differences were not statistically significant. Given that the GAPP-MDD trial was ultimately underpowered to detect statistically significant differences in patient outcomes, it was assessed in parallel with the larger GUIDED RCT. We observed that relative improvements in response and remission rates were consistent between the GAPP-MDD (33.0% response, 89.0% remission) and GUIDED (31.0% response, 51.0% remission) trials. Together with GUIDED, the results from the GAPP-MDD trial indicate that combinatorial pharmacogenomic testing can be an effective tool to help guide depression treatment in the context of the Canadian healthcare setting (ClinicalTrials.gov NCT02466477)

3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial

Background: Liraglutide 3·0 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes. Methods: In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3·0 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219. Findings: The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2·7 times longer with liraglutide than with placebo (95% CI 1·9 to 3·9, p<0·0001), corresponding with a hazard ratio of 0·21 (95% CI 0·13–0·34). Liraglutide induced greater weight loss than placebo at week 160 (–6·1 [SD 7·3] vs −1·9% [6·3]; estimated treatment difference −4·3%, 95% CI −4·9 to −3·7, p<0·0001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group. Interpretation: In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3·0 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes. Funding: Novo Nordisk, Denmark

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase&nbsp;1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation&nbsp;disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age&nbsp; 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score&nbsp; 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc&nbsp;= 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N&nbsp;= 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in&nbsp;Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in&nbsp;Asia&nbsp;and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Lifestyle mediates the role of nutrient-sensing pathways in cognitive aging:cellular and epidemiological evidence

Aging induces cellular and molecular changes including modification of stem cell pools. In particular, alterations in aging neural stem cells (NSCs) are linked to age-related cognitive decline which can be modulated by lifestyle. Nutrient-sensing pathways provide a molecular basis for the link between lifestyle and cognitive decline. Adopting a back-translation strategy using stem cell biology to inform epidemiological analyses, here we show associations between cellular readouts of NSC maintenance and expression levels of nutrient-sensing genes following NSC exposure to aging human serum as well as morphological and gene expression alterations following repeated passaging. Epidemiological analyses on the identified genes showed associations between polymorphisms in SIRT1 and ABTB1 and cognitive performance as well as interactions between SIRT1 genotype and physical activity and between GRB10 genotype and adherence to a Mediterranean diet. Our study contributes to the understanding of neural stem cell molecular mechanisms underlying human cognitive aging and hints at lifestyle modifiable factors

Phase 3 trial to evaluate the safety, tolerability, and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine, followed by 23-valent pneumococcal polysaccharide vaccine 6 months later, in at-risk adults 18–49 years of age (PNEU-DAY): A subgroup analysis by baseline risk factors

Immunocompetent adults with certain medical and behavioral factors are at increased risk of pneumococcal disease. In some countries, sequential vaccination with 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for at-risk adults. This subgroup analysis from a phase 3 study evaluated the safety, tolerability, and immunogenicity of sequential administration of either V114 (a 15-valent PCV containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F) or PCV13, followed 6 months later by PPSV23, in immunocompetent adults 18–49 years of age with pre-defined risk factors for pneumococcal disease. Safety and immunogenicity post-vaccination were analyzed by type and baseline number of risk factors for pneumococcal disease (1 and ≥2 risk factors). This analysis included 1,131 participants randomized 3:1 to receive either V114 or PCV13, followed by PPSV23. The majority (73.1%) of participants had at least one risk factor. Safety and tolerability profiles of V114 and PCV13 were similar across risk factor groups. V114 administered either alone or sequentially with PPSV23 6 months later was immunogenic for all 15 serotypes, including those not contained in PCV13, regardless of the number of baseline risk factors. V114 has the potential to broaden serotype coverage for at-risk adults