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  • 1
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    Online Resource
    1098-P: Biomarkers of Tubular Injury and Effects of Canagliflozin in the CANVAS Trial
    American Diabetes Association ; 2020
    In:  Diabetes Vol. 69, No. Supplement_1 ( 2020-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 69, No. Supplement_1 ( 2020-06-01)
    Abstract: Introduction: Canagliflozin (CANA) slows progression of kidney disease, which may be at least partly mediated by improvements in tubular function. To test this hypothesis, we assessed effects of CANA on markers of tubular function and injury in the CANVAS trial. Methods: Urine biomarkers of tubule function (β2-microglobulin [B2M], cystatin C, and uromodulin), tubular injury (interleukin-18 [IL-18] , kidney injury molecule-1 [KIM-1], neutrophil gelatinase associated lipocalin [NGAL] , and osteopontin), and inflammation (monocyte chemotactic protein-1 [MCP-1]) were measured at baseline and after 12 months. Biomarker concentrations were standardized for urine creatinine concentration. Differences between CANA and placebo treatment were assessed using ANCOVA models. Results: We included 3723 CANVAS participants with available urine samples (eGFR 77.1 ml/min/1.73 m2 and median UACR 11.7 mg/g). Clinical characteristics and biomarker levels were well balanced between treatment groups at baseline. CANA compared to placebo significantly reduced urinary KIM-1, uromodulin, cystatin C, and osteopontin. It did not change NGAL or MCP-1 and increased IL-18 and B2M. Results were consistent in subgroups by baseline UACR except MCP-1, which decreased in patients with UACR ≥30 mg/g (Table). Conclusion: CANA had variable effects on markers of tubule cell injury and function, decreasing 4, while 2 remained stable and 2 increased. Disclosure T. Sen: None. J. Li: Employee; Self; George Institute. B. Neal: Research Support; Self; Janssen Research & Development, LLC, Merck Schering Plough, Roche Pharma, Servier, Zydus Pharmaceuticals, Inc. Other Relationship; Self; Abbott, Janssen, Novartis, Pfizer, Roche, and Servier. B.L. Neuen: Research Support; Self; Australian National Health and Medical Research Council Postgraduate Scholarship, Oxford Australia Clarendon Scholarship from the University of Oxford, University Postgraduate Award from UNSW Sydney. Other Relationship; Self; Janssen Research & Development, LLC. M.J. Jardine: Other Relationship; Self; See Other Relationship field. J. Ix: Research Support; Self; Baxter. M.G. Shlipak: Advisory Panel; Self; Cricket Health, Tai Diagnostics. V. Perkovic: Other Relationship; Self; See Other Relationshipfield. Y. Yavin: Employee; Self; Janssen Research & Development, LLC. N. Rosenthal: None. M.K. Hansen: Employee; Self; Janssen Research & Development, LLC. H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Retrophin, Inc. Funding Janssen Research & Development, LLC
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-1098-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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  • 2
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    Insulin-Like Growth Factor Binding Protein 7 Predicts Renal and Cardiovascular Outcomes in the Canagliflozin Cardiovascular Assessment Study
    American Diabetes Association ; 2021
    In:  Diabetes Care Vol. 44, No. 1 ( 2021-01-01), p. 210-216
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 44, No. 1 ( 2021-01-01), p. 210-216
    Abstract: To analyze the association between concentrations of plasma insulin-like growth factor binding protein 7 (IGFBP7) with renal and cardiac outcomes among participants with type 2 diabetes and high cardiovascular risk. RESEARCH DESIGN AND METHODS Associations between IGFBP7 levels and clinical outcomes were assessed among participants in the Canagliflozin Cardiovascular Assessment Study (CANVAS) with type 2 diabetes and high cardiovascular risk. RESULTS Among CANVAS participants, 3,577 and 2,898 had IGFBP7 measured at baseline and 1 year, respectively. Per log-unit higher concentration, baseline IGFBP7 was significantly associated with the composite renal end point of sustained 40% reduction in estimated glomerular filtration rate, need for renal replacement therapy, or renal death (hazard ratio [HR] 3.51; P & lt; 0.001) and the composite renal end point plus cardiovascular death (HR 4.90; P & lt; 0.001). Other outcomes, including development or progression of albuminuria, were also predicted by baseline IGFBP7. Most outcomes were improved by canagliflozin regardless of baseline IGFBP7; however, those with baseline concentrations ≥96.5 ng/mL appeared to benefit more from canagliflozin relative to the first progression of albuminuria compared with those with lower baseline IGFBP7 (HR 0.64 vs. 0.95; Pinteraction = 0.003). Canagliflozin did not lower IGFBP7 concentrations by 1 year; however, at 1 year, higher IGFBP7 concentrations more strongly predicted the composite renal end point (HR 15.7; P & lt; 0.001). Patients with rising IGFBP7 between baseline and 1 year had the highest number of composite renal events. CONCLUSIONS Plasma IGFBP7 concentrations predicted renal and cardiac events among participants with type 2 diabetes and high cardiovascular risk. More data are needed regarding circulating IGFBP7 and progression of diabetic kidney disease and its complications.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc20-1889
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
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  • 3
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    Adipose Mitochondrial Biogenesis Is Suppressed in db/db and High-Fat Diet–Fed Mice and Improved by Rosiglitazone
    American Diabetes Association ; 2007
    In:  Diabetes Vol. 56, No. 7 ( 2007-07-01), p. 1751-1760
    Details
    In: Diabetes, American Diabetes Association, Vol. 56, No. 7 ( 2007-07-01), p. 1751-1760
    Abstract: The objective of this study was to further establish and confirm the relationship of adipose mitochondrial biogenesis in diabetes/obesity and the effects of rosiglitazone (RSG), a peroxisome proliferator–activated receptor (PPAR) γ agonist, by systematically analyzing mitochondrial gene expression and function in two mouse models of obesity and type 2 diabetes. Using microarray technology, adipose mitochondrial gene transcription was studied in db/db, high-fat diet–fed C57BL/6 (HFD) and respective control mice with or without RSG treatment. The findings were extended using mitochondrial staining, DNA quantification, and measurements of citrate synthase activity. In db/db and HFD mice, gene transcripts associated with mitochondrial ATP production, energy uncoupling, mitochondrial ribosomal proteins, outer and inner membrane translocases, and mitochondrial heat-shock proteins were decreased in abundance, compared with db/+ and standard-fat diet–fed control mice, respectively. RSG dose-dependently increased these transcripts in both db/db and HFD mice and induced transcription of mitochondrial structural proteins and cellular antioxidant enzymes responsible for removal of reactive oxygen species generated by increased mitochondrial activity. Transcription factors, including PPAR coactivator (PGC)-1β, PGC-1α, estrogen-related receptor α, and PPARα, were suppressed in both models and induced by RSG. The effects of RSG on adipose mitochondrial genes were confirmed by quantitative RT-PCR and further supported by mitochondrial staining, mitochondrial DNA quantification, and citrate synthase activity. Adipose mitochondrial biogenesis was overwhelmingly suppressed in both mouse models of diabetes/obesity and globally induced by RSG. These findings suggest an important role of adipose mitochondria in diabetes/obesity and the potential for new treatment approaches targeting adipose mitochondria.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db06-1135
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2007
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  • 4
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    139-LB: The Redox Balance Predicts Both Cardiovascular (CV) and Renal Outcomes in CANVAS
    American Diabetes Association ; 2020
    In:  Diabetes Vol. 69, No. Supplement_1 ( 2020-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 69, No. Supplement_1 ( 2020-06-01)
    Abstract: We tested whether circulating metabolites reflecting cytosolic (lactate/pyruvate) or mitochondrial (β-hydroxybutyrate/acetoacetate [AcAc]) redox balance are associated with major clinical outcomes in patients with type 2 diabetes. The CANVAS study randomized participants to placebo (Plb) or canagliflozin (100mg or 300mg) (Tx) and followed them for up to 6 years. Metabolic markers were measured at baseline (2,373 in Tx [dose combined] and 1,185 in Plb), at year 1 (2,022 in Tx and 949 in Plb) and year 2 (1,793 in Tx and 834 in Plb). By linear mixed model analysis, plasma free fatty acids, AcAc, and β-hydroxybutyrate increased with Tx vs. Plb, whereas plasma pyruvate decreased with Tx while glycerol and lactate did not change significantly. Of note, these changes were independent of the background antihyperglycemic medication (metformin, sulfonylureas, insulin, or combinations thereof). The incidence of hospitalized heart failure or cardiovascular death (HHF/CVD) was 10.2%, the incidence of the renal composite endpoint (CombR; i.e., 40% reduction in eGFR or renal replacement/death) was 3.9%. In Cox models adjusting for sex, age, BMI, HbA1c, baseline systolic blood pressure, diabetes duration, smoking, baseline use of diuretics or statins, history of heart failure, prior CV disease, and Tx, baseline AcAc was a negative predictor of HHF/CVD (HR=0.83 [95%CI 0.75-0.94] ), while baseline lactate was a positive predictor (HR=1.42 [95%CI 1.20-1.68]). Adding baseline ACR and eGFR to the same multivariate model for CombR as the outcome, AcAc was still a negative (HR=0.84 [95%CI 0.75-0.94] ) and lactate still a positive predictor (HR=1.42 [95%CI 1.20-1.67]). For CV and renal outcomes, higher baseline plasma lactate is an independent positive risk marker potentially reflecting a reducing cytosolic redox shift, but higher baseline plasma AcAc is a protective factor, which may be related to efficient mitochondrial supply/usage of reducing equivalents. Further analysis is needed to test these hypotheses. Disclosure E. Ferrannini: Consultant; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Oramed Pharmaceuticals. Research Support; Self; AstraZeneca, Janssen Pharmaceuticals, Inc. S. Baldi: None. T. Scozzaro: None. F. Tesfaye: Employee; Self; Janssen Research & Development, LLC. W. Shaw: Employee; Self; Janssen Pharmaceuticals, Inc. N. Rosenthal: None. K.W. Mahaffey: Consultant; Self; Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, SmartMedics, Springer Publishing, UCSF. Research Support; Self; Afferent, Amgen, Apple, Inc, AstraZeneca, Cardiva Medical, Inc, Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St. Jude, Tenax. B. Neal: Research Support; Self; Janssen Research & Development, LLC, Merck Schering Plough, Roche Pharma, Servier, Zydus Pharmaceuticals, Inc. Other Relationship; Self; Abbott, Janssen, Novartis, Pfizer, Roche, and Servier. V. Perkovic: Other Relationship; Self; See Other Relationship field. M.K. Hansen: Employee; Self; Janssen Research & Development, LLC. Funding Janssen Research & Development, LLC
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-139-LB
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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  • 5
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    1118-P: Validation of the PromarkerD Test for Predicting Renal Decline in Type 2 Diabetes in the Canagliflozin Cardiovascular Assessment Study (CANVAS)
    American Diabetes Association ; 2020
    In:  Diabetes Vol. 69, No. Supplement_1 ( 2020-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 69, No. Supplement_1 ( 2020-06-01)
    Abstract: Chronic kidney disease (CKD) develops in 1 in 3 people with type 2 diabetes (T2D) and is the leading cause of end-stage renal disease (ESRD). The ability of baseline urinary albumin: creatinine ratio or estimated glomerular filtration rate (eGFR) to predict onset and progression of CKD complicating diabetes is limited. PromarkerD is a novel blood test that can predict future renal function decline. This study sought to validate the prognostic utility of PromarkerD in individuals with T2D from CANVAS, a randomized controlled trial of INVOKANA® (canagliflozin). PromarkerD scores were measured at baseline in 3,570 CANVAS participants (n=1,196 placebo arm, n=2,375 canagliflozin arm). Biomarker concentrations (CD5L, ApoA4, IGFBP3) measured by mass spectrometry were combined with clinical data (age, serum HDL-cholesterol, eGFR) using previously defined algorithms to provide PromarkerD scores. The test score (predicted probability) ranges from 0 to 100% and is categorized as low-, moderate- or high-risk as determined by pre-specified cut-offs at 10% and 20%. Renal function decline was defined as incident DKD during the 4 years from randomization. At baseline, the participant sample (mean age 62.7 years, 67% males, median diabetes duration 12.4 years) had a median PromarkerD score of 2.88%, with 70.5% categorized as low-risk, 13.6% as moderate-risk and 15.9% as high-risk for renal function decline. There was no significant difference in baseline PromarkerD scores by allocated treatment (P=0.58). In a model adjusted for treatment, baseline PromarkerD moderate-risk and high-risk scores were increasingly prognostic for renal function decline (OR 5.29 [4.22, 6.64] and OR 13.52 [10.69, 17.11] versus low-risk, respectively; both P & lt;0.001). These data provide further validation of the role of PromarkerD in predicting clinically significant renal function decline and thus to facilitate preventive management strategies. Disclosure K. Peters: Other Relationship; Self; Proteomics International Laboratories Ltd. J. Xu: Employee; Self; Janssen Research & Development, LLC. S. Bringans: Other Relationship; Self; Proteomics International Laboratories Lt. W.A. Davis: Advisory Panel; Spouse/Partner; Lilly Diabetes, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH. Speaker’s Bureau; Spouse/Partner; Lilly Diabetes, Merck Sharp & Dohme Corp., Mylan, Novo Nordisk A/S, Sanofi-Aventis. Other Relationship; Self; Proteomics International. Other Relationship; Spouse/Partner; Proteomics International. T. Davis: Advisory Panel; Self; Lilly Diabetes, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Speaker’s Bureau; Spouse/Partner; Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; Lilly Diabetes, Merck Sharp & Dohme Corp., Mylan, Novo Nordisk A/S, Sanofi-Aventis. Other Relationship; Self; Protemics International. Other Relationship; Spouse/Partner; Protemics International. M.K. Hansen: Employee; Self; Janssen Research & Development, LLC. R.J. Lipscombe: Other Relationship; Self; Proteomics International Laboratories Ltd. Funding Janssen Research & Development, LLC
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db20-1118-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2020
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  • 6
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    185-OR: Longitudinal Changes in KidneyIntelX and Association with Progressive Decline in Kidney Function in the CANVAS Trial
    American Diabetes Association ; 2021
    In:  Diabetes Vol. 70, No. Supplement_1 ( 2021-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 70, No. Supplement_1 ( 2021-06-01)
    Abstract: KidneyIntelX is a composite risk score incorporating biomarkers and clinical variables for predicting progression of prevalent diabetic kidney disease (DKD). The change of this score over time in response to SGLT2 inhibitors and how these changes associate with future kidney outcomes is unknown. We measured soluble Tumor Necrosis Factor Receptor 1 (sTNFR-1), soluble Tumor Necrosis Factor Receptor 2 (sTNFR-2), and Kidney Injury Molecule (KIM-1) on banked samples from CANVAS trial participants with baseline DKD (eGFR & lt;60 ml/min/1.73 m2 or UACR ≥30 mg/mg) and determined the KidneyIntelX risk score at baseline and year 1. We assessed the effect of canagliflozin (CANA) on KidneyIntelX scores and how changes from baseline to year 1 were associated with subsequent DKD progression (composite outcome of eGFR decline of ≥5 ml/min/year [using 6-week eGFR as baseline in the CANA group], ≥40% sustained decline in eGFR, or kidney failure). There were 1016 participants with prevalent DKD who had baseline and year 1 plasma samples. Median age was 64 years, 30% were female, median eGFR was 66 ml/min and median UACR was 55 mg/g. After year 1, 68 (6.7%) participants experienced the composite outcome over a median of 4.9 years. CANA reduced KidneyIntelX risk by 5.1% (95% CI -6.6 to -3.6) at year 1 vs. increasing by 5.8% (95% CI 3.4 to 8.1) in placebo (p & lt;0.001). Each percent reduction in KidneyIntelX score at year 1 was associated with a 2% lower risk of the composite outcome (OR per unit 0.98, 95% CI 0.97 to 0.99; p & lt;0.001) after adjusting for baseline score and treatment arm. The associations between the change in KidneyIntelX and outcome were consistent in the treatment arm and placebo arm (pinteraction=0.63). In conclusion, CANA treatment reduced KidneyIntelX risk scores. Changes in the KidneyIntelX score from baseline to 1 year predict future risk of DKD progression whether they resulted from kidney protection afforded by SGLT2i therapy, or decline in kidney function caused by disease progression. Disclosure D. W. Lam: None. G. N. Nadkarni: Advisory Panel; Self; Renalytix AI plc., Consultant; Self; AstraZeneca, Renalytix AI plc., Variant Bio, Research Support; Self; Renalytix AI plc., Stock/Shareholder; Self; Renalytix AI plc. B. Neal: Advisory Panel; Self; Abbott, Janssen Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Roche Pharma, Servier Laboratories, Research Support; Self; Janssen Pharmaceuticals, Inc., Merck Schering Plough, Roche Pharma, Servier Laboratories. K. W. Mahaffey: Consultant; Self; Abbott, Amgen Inc., Anthos, AstraZeneca, Baim Institute for Clinical Research, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals, Inc., CSL Behring, Elsevier, Inova, Intermountain Health, Johnson & Johnson, Medscape, Mount Sinai, Mundipharma International, MyoKardia, National Institutes of Health, Novartis Pharmaceuticals Corporation, Novo Nordisk, Otsuka America Pharmaceutical, Inc., Portola Pharmaceuticals, Inc., Regeneron Pharmaceuticals Inc., SmartMedics, Theravance Biopharma, Research Support; Self; Afferent, AHA, Amgen Inc., Apple, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Cardiva Medical, Inc, Eidos, Ferring Pharmaceuticals Inc., Gilead Sciences, Inc., Google, Johnson & Johnson, Luitpold Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., National Institutes of Health, Novartis Pharmaceuticals Corporation, Sanifit, Sanofi, St. Jude Medical. N. Rosenthal: Employee; Self; Janssen Research & Development, LLC. M. K. Hansen: Employee; Self; Janssen Pharmaceuticals, Inc. H. L. Heerspink: Consultant; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Chinook, CSL Behring, Fresenius Medical Care, Gilead Sciences, Inc., Janssen Research & Development, LLC, Merck & Co., Inc., Mitsubishi Corporation Life Sciences Limited, Mundipharma International, Novo Nordisk, Retrophin, Inc., Research Support; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC. S. Coca: Advisory Panel; Self; Akebia Therapeutics, Inc., Bayer AG, Boehringer Ingelheim International GmbH, Consultant; Self; CHF Solutions, Relypsa Inc., Renalytix AI plc., Takeda Pharmaceutical Co., Research Support; Self; inRegen, XORTX Therapeutics Inc., Stock/Shareholder; Self; Renalytix AI plc.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db21-185-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2021
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  • 7
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    Fasting Substrate Concentrations Predict Cardiovascular Outcomes in the CANagliflozin cardioVascular Assessment Study (CANVAS)
    American Diabetes Association ; 2022
    In:  Diabetes Care Vol. 45, No. 8 ( 2022-08-01), p. 1893-1899
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 45, No. 8 ( 2022-08-01), p. 1893-1899
    Abstract: To examine whether the circulating substrate mix may be related to the incidence of heart failure (HF) and cardiovascular (CV) mortality and how it is altered by canagliflozin treatment. RESEARCH DESIGN AND METHODS We measured fasting glucose, free fatty acids (FFA), glycerol, β-hydroxybutyrate, acetoacetate, lactate, and pyruvate concentrations in 3,581 samples from the CANagliflozin cardioVascular Assessment Study (CANVAS) trial at baseline and at 1 and 2 years after randomization. Results were analyzed by univariate and multivariate Cox proportional hazards models. RESULTS Patients in the lowest baseline FFA tertile were more often men with a longer duration of type 2 diabetes (T2D), higher urinary albumin excretion, lower HDL-cholesterol levels, higher history of CV disease (CVD), and higher use of statins and insulin. When all seven metabolites were used as predictors, FFA were inversely associated with incident hospitalized HF (hazard ratio [HR] 0.33 [95% CI 0.21–0.55] ), while glycerol was a positive predictor (2.21 [1.45–3.35]). In a model further adjusted for 16 potential confounders, including prior HF and CVD and pharmacologic therapies, FFA remained a significant negative predictor. FFA and glycerol also predicted CV mortality (HR 0.53 [95% CI 0.35–0.81] and 1.81 [1.26–2.58], respectively) and all-cause death (0.50 [0.36–0.70] and 1.64 [1.22–2.18]). When added to these models, background insulin therapy was an independent positive predictor of risk of death. Canagliflozin treatment significantly increased plasma FFA and β-hydroxybutyrate regardless of background antihyperglycemic therapy. CONCLUSIONS A constitutive metabolic setup consisting of higher lipolysis may be beneficial in delaying or preventing hospitalized HF; a further stimulation of lipolysis by canagliflozin may reinforce this influence.
    Type of Medium: Online Resource
    ISSN: 0149-5992
    URL: Article
    DOI: 10.2337/dc21-2398
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
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  • 8
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    Interleukin-6 and Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes: New Insights From CANVAS
    American Diabetes Association ; 2022
    In:  Diabetes Care Vol. 45, No. 11 ( 2022-11-01), p. 2644-2652
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 45, No. 11 ( 2022-11-01), p. 2644-2652
    Abstract: The inflammatory cytokine interleukin-6 (IL-6) is associated with cardiovascular (CV) and kidney outcomes in various populations. However, data in patients with type 2 diabetes are limited. We assessed the association of IL-6 with CV and kidney outcomes in the Canagliflozin Cardiovascular Assessment Study (CANVAS) and determined the effect of canagliflozin on IL-6. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes at high CV risk were randomly assigned to canagliflozin or placebo. Plasma IL-6 was measured at baseline and years 1, 3, and 6. The composite CV outcome was nonfatal myocardial infarction, nonfatal stroke, or CV death; the composite kidney outcome was sustained ≥40% estimated glomerular filtration rate decline, end-stage kidney disease, or kidney-related death. Multivariable-adjusted Cox proportional hazards regression was used to estimate the associations between IL-6 and the outcomes. The effect of canagliflozin on IL-6 over time was assessed with a repeated-measures mixed-effects model. RESULTS The geometric mean IL-6 at baseline, available in 3,503 (80.2%) participants, was 1.7 pg/mL. Each doubling of baseline IL-6 was associated with 14% (95% CI 4, 24) and 21% (95% CI 1, 45) increased risk of CV and kidney outcomes, respectively. Over 6 years, IL-6 increased by 5.8% (95% CI 3.4, 8.3) in the placebo group. Canagliflozin modestly attenuated the IL-6 increase (absolute percentage difference vs. placebo 4.4% [95% CI 1.3, 9.9; P = 0.01]). At year 1, each 25% lower level of IL-6 compared with baseline was associated with 7% (95% CI 1, 22) and 14% (95% CI 5, 22) lower risks for the CV and kidney outcome, respectively. CONCLUSIONS In patients with type 2 diabetes at high CV risk, baseline IL-6 and its 1-year change were associated with CV and kidney outcomes. The effect of IL-6–lowering therapy on CV, kidney, and safety outcomes remains to be tested.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/dc22-0866
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
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  • 9
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    19-OR: KidneyIntelX Association with Clinical Outcomes in Diabetic Kidney Disease
    American Diabetes Association ; 2022
    In:  Diabetes Vol. 71, No. Supplement_1 ( 2022-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 71, No. Supplement_1 ( 2022-06-01)
    Abstract: Individuals with diabetic kidney disease (DKD) are at risk for progression, heart failure, and death. We assessed the association of KidneyIntelX, a bioprognostictest validated for DKD progression, with a composite time-to-event endpoint of 57% eGFR decline, kidney failure, heart failure hospitalization (HFH) , or death in a posthoc analysis of a subgroup of CANVAS participants with DKD. sTNFR-1, sTNFR-2, and KIM-1 were measured via proprietary assays, and KidneyIntelX scores were calculated using the existing algorithm. Hazard ratios for high vs. low-risk strata for the composite outcome were adjusted for age, sex, race, treatment arm, baseline CVD, HbA1c, SBP, DBP, LDL, BMI) . During 5.6 years follow-up, 282 (22%) of the 1278 CANVAS participants with DKD experienced the outcome (57% decline in eGFR/ESKD 3%, HFH 6%, death 16%) . The adjusted HR for the composite outcome in KidneyIntelX high-risk group was 2.7 (95% CI 1.9 to 3.8) vs. the low-risk group. Canagliflozin reduced the risk for the composite event vs. placebo, with larger absolute risk reductions for the high-risk stratum (11%) , compared to intermediate (6%) or low-risk strata (4%) (p & lt;0.01) . In conclusion, KidneyIntelX successfully risk-stratified adults with DKD for clinical outcomes. Absolute risk reductions with canagliflozin were greatest in the high-risk stratum, thereby potentially allowing its use to identify patients most likely to benefit from treatment. Disclosure G.N.Nadkarni: Advisory Panel; Renalytix, Consultant; AstraZeneca, Reata Pharmaceuticals, Inc., Renalytix, Siemens, Other Relationship; Renalytix, Stock/Shareholder; Renalytix. D.Takale: None. B.Neal: Other Relationship; Janssen Research & Development, LLC. K.W.Mahaffey: Consultant; Novo Nordisk. Y.Yavin: Employee; Janssen Research & Development, LLC. M.K.Hansen: Employee; Janssen Research & Development, LLC. F.Fleming: Employee; Renalytix. H.L.Heerspink: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Chinook Therapeutics Inc., CSL Behring, Gilead Sciences, Inc., Goldfinch Bio, Inc., Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Corporation, Mundipharma, Traveere Pharmaceuticals, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. S.Coca: Advisory Panel; 3ive Labs, Nuwellis, Reprieve Cardiovascular, Consultant; Axon Therapies, Bayer AG, Boehringer Ingelheim International GmbH, Vifor Pharma Management Ltd., Stock/Shareholder; pulseData, Renalytix. Funding Renalytix
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db22-19-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
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  • 10
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    855-P: PromarkerD Predicts Late-Stage Renal Function Decline in Type 2 Diabetes in the Canagliflozin Cardiovascular Assessment Study (CANVAS)
    American Diabetes Association ; 2022
    In:  Diabetes Vol. 71, No. Supplement_1 ( 2022-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 71, No. Supplement_1 ( 2022-06-01)
    Abstract: A third of people with type 2 diabetes (T2D) will develop chronic kidney disease (CKD) , the leading cause of end-stage renal disease (ESRD) . Current standard of care tests (urinary albumin:creatinine ratio (ACR) , estimated glomerular filtration rate (eGFR)) have limited ability to predict CKD progression. PromarkerD is a novel blood test that has prognostic value for the onset/progression of early-stage renal function decline in T2D. The ability of PromarkerD to predict later-stage renal decline in participants in the CANVAS trial was explored. Concentrations of PromarkerD biomarkers (CD5L, ApoA4, IGFBP3) were measured by mass spectrometry at baseline in 3,525 CANVAS participants (n=1,179 placebo arm, n=2,346 canagliflozin arm) and combined with clinical data (age, serum HDL-cholesterol, eGFR) to provide PromarkerD scores (0 to 100%) for adverse renal outcomes. Cox regression was used to assess the ability of PromarkerD to predict three composites: i) ≥40% eGFR decline, ESRD, or renal death ii) outcome 1 or cardiovascular disease death and iii) outcome 2 or progression to macroalbuminuria. At baseline, the participants (mean age 62.7 years, 67% males, median diabetes duration 12.5 years) had mean eGFR 77 mL/min/1.73m2, median ACR 11.6 mg/g and mean PromarkerD score 34.5%. During a mean 5.6 years of follow-up, 138 (3.9%) , 380 (10.8%) and 427 (12.1%) participants experienced composite outcomes 1 to 3, respectively. After adjusting for allocated treatment, each 10% increase in PromarkerD score was significantly associated with higher rates of adverse outcomes (outcome 1: HR 1.22 [1.to 1.38], outcome 2: HR 1.28 [1.to 1.37] , outcome 3: HR 1.13 [1.to 1.21], all P≤0.001) with only modest attenuation after adjustment for both eGFR and ACR (all P≤0.013) . This post-hoc analysis of CANVAS data shows that PromarkerD can be used to predict late as well as early-stage renal decline in people with T2D. Disclosure K.E.Peters: None. P.Di prinzio: None. S.Bringans: None. W.A.Davis: None. T.Davis: Advisory Panel; Merck Sharp & Dohme Corp., Novo Nordisk, Roche Diagnostics, Research Support; Novo Nordisk, Speaker's Bureau; Novo Nordisk. R.J.Lipscombe: Employee; Proteomics International, Stock/Shareholder; Proteomics International. M.K.Hansen: Employee; Janssen Research & Development, LLC.
    Type of Medium: Online Resource
    ISSN: 0012-1797
    URL: Article
    DOI: 10.2337/db22-855-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2022
    detail.hit.zdb_id: 1501252-9
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