Journal Club Kotkowski E, Price LR, Franklin C, Salazar M, Woolsey M, DeFronzo RA, Blangero J, Glahn DC, Fox PT. A neural signature of metabolic syndrome. Hum Brain Mapp. 2019 May 7. doi: 10.1002/hbm.24617. Heerspink HJL, Parving HH, Andress DL, Bakris G, Correa-Rotter R, Hou FF, Kitzman DW, Kohan D, Makino H, McMurray JJV, Melnick JZ, Miller MG, Pergola PE, Perkovic V, Tobe S, Yi T, Wigderson M, de Zeeuw D; SONAR Committees and Investigators. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial. Lancet. 2019 Apr 12. pii: S0140-6736(19)30772-X. doi: 10.1016/S0140-6736(19)30772-X. 埼玉医科大学 総合医療センター 内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田 昌文 Matsuda, Masafumi 2018年5月162日 8:30-8:55 ４階 カンファレンス室
Matsuda M, Liu Y, Mahankali S, Pu Y, Mahankali A, Wang J, DeFronzo RA, Fox PT, Gao JH : Altered hypothalamic function in response to glucose ingestion in obese humans. Diabetes 48:1801-1806, 1999.
1Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas 2Department of Radiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 3Methodology, Measurement and Statistical Analysis Center, Texas State University, San Marcos, Texas 4Texas Diabetes Institute, San Antonio, Texas 5Diabetes Research Unit and Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, Texas 6Genomics Computing Center, South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley, Brownsville, Texas 7Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 8Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, Hartford, Connecticut Hum Brain Mapp. 2019 May 7. doi: 10.1002/hbm.24617.
Aims/Hypothesis: That metabolic syndrome (MetS) is associated with age-related cognitive decline is well established. The neurobiological changes underlying these cognitive deficits, however, are not well understood. The goal of this study was to determine whether MetS is associated with regional differences in gray-matter volume (GMV) using a cross-sectional, between-group contrast design in a large, ethnically homogenous sample.
Methods: T1-weighted MRIs were sampled from the genetics of brain structure (GOBS) data archive for 208 Mexican-American participants: 104 participants met or exceeded standard criteria for MetS and 104 participants were age- and sex-matched metabolically healthy controls. Participants ranged in age from 18 to 74 years (37.3 ± 13.2 years, 56.7% female). Images were analyzed in a whole-brain, voxel-wise manner using voxel-based morphometry (VBM). Three contrast analyses were performed, a whole sample analysis of all 208 participants, and two post hoc half-sample analyses split by age along the median (35.5 years).
Figure 1 Participant selection pipeline from the original GOBS dataset applying MetS criteria scores based on a composite of the International Diabetes Federation (IDF) and National Cholesterol Education Program‐Adult Treatment Plan III (NCEP‐ATP III). Criteria for metabolically healthy control group was determined by including participants with a composite MetS score of ≤1.5. Criteria for MetS case group was determined by including participants fulfilling the WC criteria of the IDF and achieving a MetS score of ≥3.0. A few borderline individuals (3 controls and 6 MetS) were added to provide age‐ and sex‐matched symmetry in the final analysis
Results: Significant associations between MetS and decreased GMV were observed in multiple, spatially discrete brain regions including the posterior cerebellum, brainstem, orbitofrontal cortex, bilateral caudate nuclei, right parahippocampus, right amygdala, right insula, lingual gyrus, and right superior temporal gyrus. Age, as shown in the post hoc analyses, was demonstrated to be a significant covariate. A further functional interpretation of the structures exhibiting lower GMV in MetS reflected a significant involvement in reward perception, emotional valence, and reasoning.
Conclusions: Additional studies are needed to characterize the influence of MetS's individual clinical components on brain structure and to explore the bidirectional association between GMV and MetS.
Atrasentan is an experimental drug that is being studied for the treatment of various types of cancer, including non-small cell lung cancer. It is also being investigated as a therapy for diabetic kidney disease. It is an endothelin receptor antagonist selective for subtype A (ETA). While other drugs of this type (sitaxentan, ambrisentan) exploit the vasoconstrictive properties of endothelin and are mainly used for the treatment of pulmonary arterial hypertension, atrasentan blocks endothelin induced cell proliferation. https://en.wikipedia.org/wiki/Atrasentan endothelin receptor antagonists improved renal morphology and function and reduced albuminuria through multiple mechanisms, including attenuated damage to mesangial cells, podocytes, renal tubules, and the glycocalyx.
Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands (Prof H J L Heerspink PhD, Prof D de Zeeuw MD); Department of Medical Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark (Prof H-H Parving MD); Faculty of Health Science, Aarhus University, Aarhus, Denmark (Prof H-H Parving); Pharmaceutical Development, AbbVie, North Chicago, IL, USA (D L Andress MD, J Z Melnick MD, M G Miller PharmD, T Yi PhD, M Wigderson MD); American Society of Hypertension Comprehensive Hypertension Center, University of Chicago Medicine and Biological Sciences, Chicago, IL, USA (Prof G Bakris MD); National Medical Science and Nutrition Institute Salvador Zubirán, Mexico City, Mexico (Prof R Correa-Rotter MD); Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, Guangzhou, China (Prof F-F Hou MD); Wake Forest School of Medicine, Winston-Salem, NC, USA (D W Kitzman MD); Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, UT, USA (Prof D Kohan MD); Okayama University, Okayama, Japan (Prof H Makino MD); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK (J J V McMurray MD); Renal Associates PA, San Antonio, TX, USA (P E Pergola MD); George Institute for Global Health and University of New South Wales, Sydney, NSW, Australia (Prof V Perkovic MD); and Division of Nephrology, Sunnybrook Health Sciences Centre, University of Toronto and the Northern Ontario School of Medicine, Toronto, ON, Canada (Prof S Tobe MD) Lancet. 2019 Apr 12. pii: S0140-6736(19)30772-X. doi: 10.1016/S0140-6736(19)30772-X.
Background Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes.
Methods We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25–75 mL/min per 1·73 m2 of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days) or end-stage kidney disease (eGFR <15 mL/min per 1·73 m2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532.
Figure 1: Trial profile During the double-blind treatment period, 260 patients discontinued in the atrasentan group (111 adverse event, 37 withdrew consent, 14 were lost to follow-up, and 98 other) and 251 discontinued in the placebo group (94 adverse event, 58 withdrew consent, 21 lost to follow-up, and 78 other); some of these patients completed the study. *Reasons are not mutually exclusive. †Two patients who discontinued were later randomly assigned and included in the double-blind treatment period. ‡Adverse event, deterioration of the clinical status of the patient, investigator request, and other.
Figure 2: UACR, systolic blood pressure, BNP, and bodyweight during the study Geometric mean UACR (A), mean systolic blood pressure (B), geometric mean BNP (C), and mean bodyweight (D). Error bars are 95% CIs. Vertical dotted lines denote the start of the randomised treatment period. Patients who discontinued medication are included in figures but their data collected after 6-week post-treatment follow-up visit are excluded. BNP=brain natriuretic peptide. UACR=urine albumin-to-creatinine ratio.
Figure 3: Effects of atrasentan on the primary composite renal outcome and its components in responders Composite primary renal outcome (A), doubling of serum creatinine (B), and end-stage kidney disease (C) in the intention-to-treat population of responders. Calculated by Cox proportional hazard regression models.
Figure 4: Effects of atrasentan on the primary composite renal outcome in non-responders and all responders and non-responders combined Non-responders (A) and combined responders and non-responders (B). Primary composite renal outcome comprised doubling of serum creatinine and end-stage kidney disease. Calculated by Cox proportional hazard regression models. non-responders (UACR reduction of <30% during the enrichment period and no evidence of significant fluid retention)
Findings Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%) of 1325 patients in the atrasentan group and 105 (7·9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemiaadverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%) of 1325 patients in the atrasentan group and 34 (2·6%) of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%) patients in the atrasentan group and 52 (3·9%) in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65).
Interpretation Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding AbbVie.
Message 糖尿病性腎症のatrasentan、腎イベント発生を抑制 慢性腎臓病を合併した2型糖尿病患者を対象に、atrasentanの腎アウトカムに対する効果を二重盲検無作為化試験で検討（SONAR試験）。enrichment期間中にatrasentan投与が奏効した患者2648例をatrasentan群またはプラセボ群に割り付けた。 その結果、中央値2.2年の追跡で、主要複合評価項目（血清クレアチニンの2倍化または末期腎疾患［eGFR 15mL/分/1.73m2未満、慢性透析、腎移植、腎不全死］）発生率はatrasentan群6.0％、プラセボ群7.9％だった（ハザード比0.65、95％CI 0.49-0.88、P＝0.0047）。 https://www.m3.com/clinical/journal/20293