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1. Leveraging mHealth for the Treatment and Management of PLHIV

Author

Kruse CS, Pacheco GJ, Rosenthal N, Kopp CJ, Omorotionmwan O, and Cruz JE

Subjects
mhealth, ehealth, telehealth, telemedicine, human immunodeficiency virus (hiv)., Public aspects of medicine, RA1-1270
Abstract

Clemens Scott Kruse, Gerardo J Pacheco, Noah Rosenthal, Caris J Kopp, Omosigho Omorotionmwan, John E Cruz Texas State University, School of Health Administration, 601 University Drive, San Marcos, TX, 78666, USACorrespondence: Clemens Scott Kruse, Email scottkruse@txstate.eduObjective: The objective of this systematic review was to analyze published literature from the last five years to assess facilitators and barriers to the adoption of mHealth as interventions to treat and manage HIV for PLHIV (people living with HIV). The primary outcomes were physical and mental conditions. The secondary outcomes were behavior based (substance use, care engagement, and healthy habits).Methods: Four databases (PubMed, CINAHL, Web of Science, and ScienceDirect) were queried on 9/2/2022 for peer-reviewed studies on the treatment and management of PLHIV with mHealth as the intervention. The review was conducted in accordance with the Kruse Protocol and reported in accordance with PRISMA 2020.Results: Five mHealth interventions were identified across 32 studies that resulted in improvements in physical health, mental health, care engagement, and behavior change. mHealth interventions offer both convenience and privacy, meet a digital preference, increase health knowledge, decrease healthcare utilization, and increase quality of life. Barriers are cost of technology and incentives, training of staff, security concerns, digital literacy gap, distribution of technology, technical issues, usability, and visual cues are not available over the phone.Conclusion: mHealth offers interventions to improve physical health, mental health, care engagement, and behavior for PLHIV. There are many advantages to this intervention and very few barriers to its adoption. The barriers are strong, however, and should be addressed through policy. Further research should focus on specific apps for younger versus older PLHIV, based on preferences and the digital literacy gap.Keywords: mHealth, eHealth, telehealth, telemedicine, human immunodeficiency virus, HIV

Published
2023

2. Genome wide conditional mouse knockout resources

Author

Kaloff, C, Anastassiadis, K, Ayadi, A, Baldock, R, Beig, J, Birling, M-C, Bradley, A, Brown, SDM, Bürger, A, Bushell, W, Chiani, F, Collins, FS, Doe, B, Eppig, JT, Finnell, RH, Fletcher, C, Flicek, P, Fray, M, Friedel, RH, Gambadoro, A, Gates, H, Hansen, J, Herault, Y, Hicks, GG, Hörlein, A, de Angelis, M Hrabé, Iyer, V, de Jong, PJ, Koscielny, G, Kühn, R, Liu, P, Lloyd, KCK, Lopez, RG, Marschall, S, Martínez, S, McKerlie, C, Meehan, T, von Melchner, H, Moore, M, Murray, SA, Nagy, A, Nutter, LMJ, Pavlovic, G, Pombero, A, Prosser, H, Ramirez-Solis, R, Ringwald, M, Rosen, B, Rosenthal, N, Rossant, J, Noppinger, P Ruiz, Ryder, E, Skarnes, WC, Schick, J, Schnütgen, F, Schofield, P, Seisenberger, C, Selloum, M, Smedley, D, Simpson, EM, Stewart, AF, Teboul, L, Valentini, GP Tocchini, Valenzuela, D, West, AP, and Wurst, W

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Human Genome, Biotechnology, Stem Cell Research, Stem Cell Research - Embryonic - Non-Human, Genetics, 2.6 Resources and infrastructure (aetiology), Generic health relevance, Neurosciences, Neurology & Neurosurgery, Pharmacology and pharmaceutical sciences
Abstract

The International Knockout Mouse Consortium (IKMC) developed high throughput gene trapping and gene targeting pipelines that produced mostly conditional mutations of more than 18,500 genes in C57BL/6N mouse embryonic stem (ES) cells which have been archived and are freely available to the research community as a frozen resource. From this unprecedented resource more than 6,000 mutant mouse strains have been produced by the IKMC and mostly the International Mouse Phenotyping Consortium (IMPC). In addition, a cre-driver resource was established including 250 inducible cre-driver mouse strains in a C57BL/6 background. Complementing the cre-driver resource, a collection of comprising 27 cre-driver rAAVs has also been produced. The resources can be easily accessed at the IKMC/IMPC web portal (www.mousephenotype.org). The IKMC/IMPC resource is a standardized reference library of mouse models with defined genetic backgrounds that enables the analysis of gene-disease associations in mice of different genetic makeup and should therefore have a major impact on biomedical research.

Published
2016

4. Cardiorenal protective effects of canagliflozin in CREDENCE according to glucose lowering.

Author

Charytan, DM, Mahaffey, KW, Jardine, MJ, Cannon, CP, Neal, B, Lambers Heerspink, HJ, Agarwal, R, Bakris, GL, de Zeeuw, D, Levin, A, Pollock, C, Zhang, H, Zinman, B, Rosenthal, N, Perkovic, V, Di Tanna, GL, Yu, J, Rogers, K, Arnott, C, Wheeler, DC, Charytan, DM, Mahaffey, KW, Jardine, MJ, Cannon, CP, Neal, B, Lambers Heerspink, HJ, Agarwal, R, Bakris, GL, de Zeeuw, D, Levin, A, Pollock, C, Zhang, H, Zinman, B, Rosenthal, N, Perkovic, V, Di Tanna, GL, Yu, J, Rogers, K, Arnott, C, and Wheeler, DC

Abstract

INTRODUCTION: Relationships between glycemic-lowering effects of sodium glucose co-transporter 2 inhibitors and impact on kidney and cardiovascular outcomes are uncertain. RESEARCH DESIGN AND METHODS: We analyzed 4395 individuals with prebaseline and postbaseline hemoglobin A1c (HbA1c) randomized to canagliflozin (n=2193) or placebo (n=2202) in The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial. Effects on HbA1c were assessed using mixed models. Mediation of treatment effects by achieved glycemic control was analyzed using proportional hazards regression with and without adjustment for achieved HbA1c. End points included combined kidney or cardiovascular death, end-stage kidney disease or doubling of serum creatinine (primary trial outcome), and individual end point components. RESULTS: HbA1c lowering was modified by baseline estimated glomerular filtration rate (eGFR). For baseline eGFR 60-90, 45-59, and 30-44 mL/min/1.73 m2, overall HbA1c (canagliflozin vs placebo) decreased by -0.24%, -0.14%, and -0.08% respectively and likelihood of >0.5% decrease in HbA1c decreased with ORs of 1.47 (95% CI 1.27 to 1.67), 1.12 (0.94 to 1.33) and 0.99 (0.83 to 1.18), respectively. Adjustment for postbaseline HbA1c marginally attenuated canagliflozin effects on primary and kidney composite outcomes: unadjusted HR 0.67 (95% CI 0.57 to 0.80) and 0.66 (95% CI 0.53 to 0.81); adjusted for week 13 HbA1c, HR 0.71 (95% CI 0.060 to 0.84) and 0.68 (95% CI 0.55 to 0.83). Results adjusted for time-varying HbA1c or HbA1c as a cubic spline were similar and consistent with preserved clinical benefits across a range of excellent and poor glycemic control. CONCLUSIONS: The glycemic effects of canagliflozin are attenuated at lower eGFR but effects on kidney and cardiac end points are preserved. Non-glycemic effects may be primarily responsible for the kidney and cardioprotective benefits of canagliflozin.22.

Published
2023

9. Multi-marker biomarker panel, adverse cardiovascular and kidney outcomes, and response to canagliflozin in the CANVAS Program

Author

Vaduganathan, M, Sattar, N, Xu, J, Butler, J, Mahaffey, KW, Neal, B, Shaw, W, Rosenthal, N, Pfeifer, M, Hansen, MK, and Januzzi, JL

Subjects
Science & Technology, Cardiac & Cardiovascular Systems, Cardiovascular System & Hematology, Cardiovascular System & Cardiology, Life Sciences & Biomedicine, 1102 Cardiorespiratory Medicine and Haematology
Abstract

Background/Introduction: Circulating biomarkers reflecting different mechanistic pathways may identify patients most likely to benefit from sodium glucose co-transporter 2 (SGLT2) inhibitors. Purpose: To determine if 3 biomarkers (high sensitivity cardiac troponin T [hs-cTnT], soluble ST2 [sST2], and insulin-like growth factor binding protein 7 [IGFBP7]) have prognostic implications or modify treatment response to canagliflozin in the CANVAS trial. Methods: Among 3,040 participants in the CANVAS trial with available biomarker data, we created a multi-marker panel assigning 1 point for each abnormally elevated level of hs-cTnT, sST2, and IGFBP7. We assessed its association with risk of cardiac and kidney outcomes, and whether each biomarker alone or as a multi-marker panel modified the treatment response to canagliflozin. Incremental discrimination was tested by comparing C-statistics of a base clinical model plus each individual biomarker (or multi-marker panel) vs. the base clinical model alone (age, eGFR, body mass index, systolic blood pressure, HbA1c, duration of diabetes, urine albumin:creatinine ratio, history of HF, and diuretic use). Results: Among placebo-treated participants, 38% had elevated levels of hs-cTnT ≥14 pg/mL, 7% had sST2 >35 ng/mL, and 49% had IGFBP7 >96.5ng/mL. Overall, 1,102 (36%), 1,051 (35%), 819 (27%), and 68 (2%) had 0, 1, 2, and 3 elevated biomarkers. Increasing numbers of elevated biomarkers independently predicted each cardiac and kidney outcome in a graded fashion and improved risk discrimination compared with clinical variables alone (C-statistic improvement by +0.04 to +0.06) (Figure). Canagliflozin reduced heart failure and kidney events regardless of baseline biomarker concentrations, however patients with elevated hs-cTnT appeared to derive greater relative benefit for major adverse cardiovascular events (MACE) compared with those with lower values (hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.61-0.97 vs. HR 1.10; 95% CI 0.83-1.44; Pinteraction=0.05). Similarly, patients with elevated IGFBP7 >96.5 ng/mL (HR 0.81; 95% CI 0.64-1.01) appeared to derive greater relative treatment effects for stroke compared with patients with normal IGFBP7 ≤96.5 ng/mL (HR 1.03; 95% CI 0.78-1.36; Pinteraction=0.05). Participants with an increasing number of abnormal circulating biomarkers appeared to have greatest relative reductions in MACE from canagliflozin treatment: 0 abnormal biomarkers (HR 0.94; 95% CI 0.63-1.39), 1 abnormal biomarker (HR 1.36; 95% CI 0.96-1.92), 2 abnormal biomarkers (HR 0.62; 95% CI 0.46-0.83), and 3 abnormal biomarkers (HR 0.44; 95% CI 0.19-1.01); Pinteraction trend=0.009. Conclusions: Circulating markers of myocardial injury and remodeling are frequently abnormal in patients with type 2 diabetes at high cardiovascular risk and may identify patients who may derive greater benefit from SGLT2 inhibitors.

Published
2021

10. Reasons Individuals Become School Administrators, School Counselors, and Teachers.

Author

Ribak-Rosenthal, N.

Abstract

Administered Reasons Individuals Give for Becoming Administrators, Counselors, or Teachers Questionnaire to 123 graduate students. Found that administrators, counselors, and teachers differed significantly on reasons they entered their respective professions. Administrators were more likely to mention money and prestige; counselors appeared more motivated by helping students; and teachers appeared motivated by security, good schedules, and good vacations. (NB)

Published
1994

12. Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: the CREDENCE trial

Author

Neuen B, Oshima M, Perkovic V, Agarwal R, Arnott C, Bakris G, Cannon C, Charytan D, Edwards R, Gorriz J, Jardine M, Levin A, Neal B, De Nicola L, Pollock C, Rosenthal N, Wheeler D, Mahaffey K, and Heerspink H

Abstract

AIMS: Hyperkalaemia is a common complication of type 2 diabetes mellitus (T2DM) and limits the optimal use of agents that block the renin-angiotensin-aldosterone system, particularly in patients with chronic kidney disease (CKD). In patients with CKD, sodium?glucose cotransporter 2 (SGLT2) inhibitors provide cardiorenal protection, but whether they affect the risk of hyperkalaemia remains uncertain. METHODS AND RESULTS: The CREDENCE trial randomized 4401 participants with T2DM and CKD to the SGLT2 inhibitor canagliflozin or matching placebo. In this post hoc analysis using an intention-to-treat approach, we assessed the effect of canagliflozin on a composite outcome of time to either investigator-reported hyperkalaemia or the initiation of potassium binders. We also analysed effects on central laboratory-determined hyper- and hypokalaemia (serum potassium =6.0 and

Published
2021

13. Effects of the SGLT2 inhibitor canagliflozin on plasma biomarkers TNFR-1, TNFR-2 and KIM-1 in the CANVAS trial

Author

Sen, T, Li, J, Neuen, BL, Neal, B, Arnott, C, Parikh, CR, Coca, SG, Perkovic, V, Mahaffey, KW, Yavin, Y, Rosenthal, N, Hansen, MK, Heerspink, HJL, Sen, T, Li, J, Neuen, BL, Neal, B, Arnott, C, Parikh, CR, Coca, SG, Perkovic, V, Mahaffey, KW, Yavin, Y, Rosenthal, N, Hansen, MK, and Heerspink, HJL

Abstract

Aims/hypothesis: Higher plasma concentrations of tumour necrosis factor receptor (TNFR)-1, TNFR-2 and kidney injury molecule-1 (KIM-1) have been found to be associated with higher risk of kidney failure in individuals with type 2 diabetes in previous studies. Whether drugs can reduce these biomarkers is not well established. We measured these biomarkers in samples of the CANVAS study and examined the effect of the sodium–glucose cotransporter 2 inhibitor canagliflozin on these biomarkers and assessed whether the early change in these biomarkers predict cardiovascular and kidney outcomes in individuals with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS). Methods: Biomarkers were measured with immunoassays (proprietary multiplex assay performed by RenalytixAI, New York, NY, USA) at baseline and years 1, 3 and 6. Mixed-effects models for repeated measures assessed the effect of canagliflozin vs placebo on the biomarkers. Associations of baseline levels and the early change (baseline to year 1) for each biomarker with the kidney outcome were assessed using multivariable-adjusted Cox regression. Results: In total, 3523/4330 (81.4%) of the CANVAS participants had available samples at baseline. Each doubling in baseline TNFR-1, TNFR-2 and KIM-1 was associated with a higher risk of kidney outcomes, with corresponding HRs of 3.7 (95% CI 2.3, 6.1; p < 0.01), 2.7 (95% CI 2.0, 3.6; p < 0.01) and 1.5 (95% CI 1.2, 1.8; p < 0.01), respectively. Canagliflozin reduced the level of the plasma biomarkers with differences in TNFR-1, TNFR-2 and KIM-1 between canagliflozin and placebo during follow-up of 2.8% (95% CI 3.4%, 1.3%; p < 0.01), 1.9% (95% CI 3.5%, 0.2%; p = 0.03) and 26.7% (95% CI 30.7%, 22.7%; p < 0.01), respectively. Within the canagliflozin treatment group, each 10% reduction in TNFR-1 and TNFR-2 at year 1 was associated with a lower risk of the kidney outcome (HR 0.8 [95% CI 0.7, 1.0; p = 0.02] and 0.9 [95% CI 0.9, 1.0; p < 0.01] respectively

Published
2021

14. Effects of canagliflozin on myocardial infarction: a post hoc analysis of the CANVAS Program and CREDENCE trial.

Author

Yu, J, Li, J, Leaver, PJ, Arnott, C, Huffman, MD, Udell, JA, Perkovic, V, Mahaffey, KW, de Zeeuw, D, Fulcher, G, Matthews, DR, Shaw, W, Rosenthal, N, Neal, B, Figtree, GA, Yu, J, Li, J, Leaver, PJ, Arnott, C, Huffman, MD, Udell, JA, Perkovic, V, Mahaffey, KW, de Zeeuw, D, Fulcher, G, Matthews, DR, Shaw, W, Rosenthal, N, Neal, B, and Figtree, GA

Abstract

AIMS: Given the benefits of sodium glucose co-transporter 2 inhibition (SGLT2i) in protecting against heart failure in diabetic patients, we sought to explore the potential impact of SGLT2i on the clinical features of patients presenting with myocardial infarction (MI) through a post-hoc analysis of CANVAS Program and CREDENCE trial. METHODS AND RESULTS: Individuals with type 2 diabetes and history or high risk of cardiovascular disease (CANVAS Program) or type 2 diabetes and chronic kidney disease (CREDENCE) were included. The intervention was Canagliflozin 100 or 300 mg (combined in the analysis) or placebo. MI events were adjudicated as ST-elevation myocardial infarction (STEMI), non-STEMI as well as type 1 MI or type 2 MI. 421 first MI events in the CANVAS Program and 178 first MI events in the CREDENCE trial were recorded (83 fatal, 128 STEMI, 431 non-STEMI, and 40 unknown). No benefit of canagliflozin compared with placebo on time to first MI event was observed (HR 0.89; 95% CI 0.75, 1.05). Canagliflozin was associated with lower risk for non-STEMI (HR 0.78; 95% CI 0.65, 0.95) but suggested a possible increase in STEMI (HR 1.55; 95% CI 1.06, 2.27), with no difference in risk of type 1 or type 2 MI. There was no change in fatal MI (HR 1.22, 95% CI 0.78, 1.93). CONCLUSIONS: Canagliflozin was not associated with a reduction in overall MI in the pooled CANVAS Program and CREDENCE trial population. The possible differential effect on STEMI and Non-STEMI observed in the CANVAS cohort warrants further investigation.

Published
2021

16. Insights from CREDENCE trial indicate an acute drop in estimated glomerular filtration rate during treatment with canagliflozin with implications for clinical practice

Author

Oshima, M, Jardine, MJ, Agarwal, R, Bakris, G, Cannon, CP, Charytan, DM, de Zeeuw, D, Edwards, R, Greene, T, Levin, A, Lim, SK, Mahaffey, KW, Neal, B, Pollock, C, Rosenthal, N, Wheeler, DC, Zhang, H, Zinman, B, Perkovic, V, Heerspink, HJL, Oshima, M, Jardine, MJ, Agarwal, R, Bakris, G, Cannon, CP, Charytan, DM, de Zeeuw, D, Edwards, R, Greene, T, Levin, A, Lim, SK, Mahaffey, KW, Neal, B, Pollock, C, Rosenthal, N, Wheeler, DC, Zhang, H, Zinman, B, Perkovic, V, and Heerspink, HJL

Abstract

Canagliflozin slows the progression of chronic kidney disease in patients with type 2 diabetes and induces a reversible acute drop in estimated glomerular filtration rate (eGFR), believed to be a hemodynamic effect. Predictors of the initial drop and its association with long-term eGFR trajectories and safety outcomes are unknown. To assess this, we performed a post-hoc analysis of 4289 participants in the CREDENCE trial with type 2 diabetes and chronic kidney disease equally split into treatment and placebo groups who had eGFR measured at both baseline and week three. The eGFR was categorized at week three as greater than a 10% decline; between 0 and 10% decline; and no decline. Long-term eGFR trajectories and safety outcomes were estimated in each category of acute eGFR change by linear mixed effects models and Cox regression after adjustment for baseline characteristics and medications use. Significantly more participants in the canagliflozin (45%) compared to the placebo (21%) group experienced an acute drop in eGFR over 10%. An over 30% drop occurred infrequently (4% of participants with canagliflozin and 2% with placebo). The odds ratio for a drop in eGFR over 10% with canagliflozin compared to placebo was significant at 3.03 (95% confidence interval 2.65, 3.47). Following the initial drop in eGFR, multivariable adjusted long-term eGFR trajectories, as well as overall and kidney safety profiles, in those treated with canagliflozin were similar across eGFR decline categories. Thus, although acute drops in eGFR over 10% occurred in nearly half of all participants following initiation of canagliflozin, the clinical benefit of canagliflozin was observed regardless. Additionally, safety outcomes were similar among subgroups of acute eGFR drop.

Published
2021

17. Insulin-Like Growth Factor Binding Protein 7 Predicts Renal and Cardiovascular Outcomes in the Canagliflozin Cardiovascular Assessment Study

Author

Januzzi, JL, Butler, J, Sattar, N, Xu, J, Shaw, W, Rosenthal, N, Pfeifer, M, Mahaffey, KW, Neal, B, Hansen, MK, Januzzi, JL, Butler, J, Sattar, N, Xu, J, Shaw, W, Rosenthal, N, Pfeifer, M, Mahaffey, KW, Neal, B, and Hansen, MK

Abstract

OBJECTIVE: 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 < 0.001) and the composite renal end point plus cardiovascular death (HR 4.90; P < 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 < 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.

Published
2021

18. Sodium-glucose co-transporter-2 inhibition and ocular outcomes in patients with type 2 diabetes: A systematic review and meta-analysis

Author

Li, C, Zhou, Z, Neuen, BL, Yu, J, Huang, Y, Young, T, Li, J, Li, L, Perkovic, V, Jardine, MJ, Keay, L, Markoulli, M, Rosenthal, N, Capuano, G, Yavin, Y, Neal, B, Arnott, C, Li, C, Zhou, Z, Neuen, BL, Yu, J, Huang, Y, Young, T, Li, J, Li, L, Perkovic, V, Jardine, MJ, Keay, L, Markoulli, M, Rosenthal, N, Capuano, G, Yavin, Y, Neal, B, and Arnott, C

Abstract

Sodium-glucose co-transporter-2 (SGLT2) inhibitors are effective for the treatment of macrovascular complications and nephropathy in type 2 diabetes, but effects on microvascular eye outcomes are unclear. We conducted a systematic review and meta-analysis of randomized placebo-controlled trials to evaluate the effect of SGLT2 inhibition on total ocular events and retinopathy in patients with type 2 diabetes. We searched MEDLINE and Embase for the period from database inception date to October 11, 2019. Two reviewers working independently extracted relevant data. Random-effects models with inverse variance weighting were selected to estimate summary risk ratios (RRs) and 95% confidence intervals (CIs). We included nine studies, involving 39 982 patients with a mean follow-up of 2.8 years. There were 1414 total ocular events, of which 624 were retinopathy events. SGLT2 inhibition was not associated with a change in the risk of total ocular events (RR 0.97, 95% CI 0.85, 1.11) or retinopathy (RR 0.98, 95% CI 0.84, 1.16), with consistent effects across studies (P for heterogeneity = 0.35 and 0.45, respectively). The effects of SGLT2 inhibition on eye disease in individuals with type 2 diabetes are probably null, although the available data cannot exclude small to moderate benefits or harms.

Published
2021

19. Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: the CREDENCE trial

Author

Neuen, BL, Oshima, M, Perkovic, V, Agarwal, R, Arnott, C, Bakris, G, Cannon, CP, Charytan, DM, Edwards, R, Górriz, JL, Jardine, MJ, Levin, A, Neal, B, De Nicola, L, Pollock, C, Rosenthal, N, Wheeler, DC, Mahaffey, KW, Heerspink, HJL, Neuen, BL, Oshima, M, Perkovic, V, Agarwal, R, Arnott, C, Bakris, G, Cannon, CP, Charytan, DM, Edwards, R, Górriz, JL, Jardine, MJ, Levin, A, Neal, B, De Nicola, L, Pollock, C, Rosenthal, N, Wheeler, DC, Mahaffey, KW, and Heerspink, HJL

Abstract

AIMS : Hyperkalaemia is a common complication of type 2 diabetes mellitus (T2DM) and limits the optimal use of agents that block the renin-angiotensin-aldosterone system, particularly in patients with chronic kidney disease (CKD). In patients with CKD, sodium‒glucose cotransporter 2 (SGLT2) inhibitors provide cardiorenal protection, but whether they affect the risk of hyperkalaemia remains uncertain. METHODS AND RESULTS : The CREDENCE trial randomized 4401 participants with T2DM and CKD to the SGLT2 inhibitor canagliflozin or matching placebo. In this post hoc analysis using an intention-to-treat approach, we assessed the effect of canagliflozin on a composite outcome of time to either investigator-reported hyperkalaemia or the initiation of potassium binders. We also analysed effects on central laboratory-determined hyper- and hypokalaemia (serum potassium ≥6.0 and <3.5 mmol/L, respectively) and change in serum potassium. At baseline, the mean serum potassium in canagliflozin and placebo arms was 4.5 mmol/L; 4395 (99.9%) participants were receiving renin-angiotensin system blockade. The incidence of investigator-reported hyperkalaemia or initiation of potassium binders was lower with canagliflozin than with placebo [occurring in 32.7 vs. 41.9 participants per 1000 patient-years; hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.64-0.95, P = 0.014]. Canagliflozin similarly reduced the incidence of laboratory-determined hyperkalaemia (HR 0.77, 95% CI 0.61-0.98, P = 0.031), with no effect on the risk of hypokalaemia (HR 0.92, 95% CI 0.71-1.20, P = 0.53). The mean serum potassium over time with canagliflozin was similar to that of placebo. CONCLUSION : Among patients treated with renin-angiotensin-aldosterone system inhibitors, SGLT2 inhibition with canagliflozin may reduce the risk of hyperkalaemia in people with T2DM and CKD without increasing the risk of hypokalaemia.

Published
2021

21. Myocardial damage induced by a single high dose of isoproterenol in C57BL/6J mice triggers a persistent adaptive immune response against the heart

Author

Sattler, S, Baxan, N, Ng, FS, Benson, L, Boyle, J, Harding, S, Rosenthal, N, Medical Research Council (MRC), and British Heart Foundation

Subjects
Biochemistry & Molecular Biology, 0304 Medicinal and Biomolecular Chemistry, 1103 Clinical Sciences, 0601 Biochemistry and Cell Biology
Abstract

Heart failure is the common final pathway of several cardiovascular conditions and a major cause of morbidity and mortality worldwide. Aberrant activation of the adaptive immune system in response to myocardial necrosis has recently been implicated in the development of heart failure. The ß-adrenergic agonist isoproterenol-hydrochloride isused for its cardiac effects in a variety of different dosing regimens with high doses causing acute cardiomyocyte necrosis.To assess if isoproterenol-induced cardiomyocyte necrosistriggersan adaptive immune response against the heart, we treated C57BL/6J mice with a single intraperitoneal injection of 160mg/kg isoproterenol. We confirmed tissue damage reminiscent of human type 2 myocardial infarction. This is followed by an adaptive immune response targeting the heart as demonstrated by the activation of T cells, the presence of anti-heart auto-antibodies in the serum, as late as 12 weeks after initial challenge and IgG deposition in the myocardium. All of these are hallmark signs of an established autoimmune response. Adoptive transfer of splenocytes from isoproterenol-treated mice induces left ventricular dilation and impairs cardiac function in healthy recipients. In summary, a single administration of a high dose of isoproterenol is a suitable high-throughput model for future studies of the pathological mechanisms of anti-heart autoimmunity and to test potential immunomodulatory therapeutic approaches.

Published
2020

22. The effects of canagliflozin on heart failure and cardiovascular death by baseline participant characteristics: analysis of the CREDENCE trial

Author

de Zeeuw, D., Arnott, C., Li, J. -W., Cannon, C. P., Neuen, B. L., Heerspink, H. J. L., Neal, B., Charytan, D. M., Bakris, G., Chang, T. -H., Rosenthal, N., Zinman, B., Perkovic, V., Jardine, M. J., Mahaffey, K. W., Groningen Kidney Center (GKC), and Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET)

Subjects
Endocrinology & Metabolism, Science & Technology, 1114 Paediatrics and Reproductive Medicine, 1103 Clinical Sciences, Life Sciences & Biomedicine, 1117 Public Health and Health Services
Published
2020

29. Effect of Canagliflozin on Total Hospitalization for Heart Failure Events in Patients with Type 2 Diabetes and Chronic Kidney Disease

Author

Li, J, Jardine, MJ, Neal, B, Heerspink, HL, Cannon, C, Agarwal, R, Bakris, G, Charytan, DM, de Zeeuw, D, Edwards, R, Greene, T, Levin, A, Pollock, CA, Rosenthal, N, Wheeler, DC, Zhang, H, Zinman, B, Perkovic, V, Mahaffey, KW, Arnott, C, Li, J, Jardine, MJ, Neal, B, Heerspink, HL, Cannon, C, Agarwal, R, Bakris, G, Charytan, DM, de Zeeuw, D, Edwards, R, Greene, T, Levin, A, Pollock, CA, Rosenthal, N, Wheeler, DC, Zhang, H, Zinman, B, Perkovic, V, Mahaffey, KW, and Arnott, C

Published
2020

30. THE EFFECTS OF CANAGLIFLOZIN ON HEART FAILURE AND CARDIOVASCULAR DEATH BY BASELINE PARTICIPANT CHARACTERISTICS: ANALYSIS OF THE CREDENCE TRIAL

Author

Arnott, C, Li, J-W, Cannon, CP, Neuen, B, Heerspink, HL, Neal, B, Charytan, DM, Agarwal, R, Bakris, GL, De Zeeuw, D, Greene, T, Levin, A, Pollock, C, Chang, T, Rosenthal, N, Zhang, H, Zinman, B, Perkovic, V, Jardine, M, Mahaffey, K, Arnott, C, Li, J-W, Cannon, CP, Neuen, B, Heerspink, HL, Neal, B, Charytan, DM, Agarwal, R, Bakris, GL, De Zeeuw, D, Greene, T, Levin, A, Pollock, C, Chang, T, Rosenthal, N, Zhang, H, Zinman, B, Perkovic, V, Jardine, M, and Mahaffey, K

Published
2020

31. Effects of canagliflozin in patients with baseline eGFR <30 ml/min per 1.73 m2: Subgroup analysis of the randomized CREDENCE trial

Author

Bakris, G, Oshima, M, Mahaffey, KW, Agarwal, R, Cannon, CP, Capuano, G, Charytan, DM, de Zeeuw, D, Edwards, R, Greene, T, Heerspink, HJL, Levin, A, Neal, B, Oh, R, Pollock, C, Rosenthal, N, Wheeler, DC, Zhang, H, Zinman, B, Jardine, MJ, Perkovic, V, Bakris, G, Oshima, M, Mahaffey, KW, Agarwal, R, Cannon, CP, Capuano, G, Charytan, DM, de Zeeuw, D, Edwards, R, Greene, T, Heerspink, HJL, Levin, A, Neal, B, Oh, R, Pollock, C, Rosenthal, N, Wheeler, DC, Zhang, H, Zinman, B, Jardine, MJ, and Perkovic, V

Abstract

Background and objectives The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial demonstrated that the sodium glucose cotransporter 2 (SGLT2) inhibitor canagliflozin reduced the risk of kidney failure and cardiovascular events in participants with type 2 diabetes mellitus and CKD. Little is known about the use of SGLT2 inhibitors in patients with eGFR <30 ml/min per 1.73 m2. The participants in the CREDENCE study had type 2 diabetes mellitus, a urinary albumin-creatinine ratio >300–5000 mg/g, and an eGFR of 30 to <90 ml/min per 1.73 m2 at screening. This post hoc analysis evaluated participants with eGFR <30 ml/min per 1.73 m2 at randomization. Design, setting, participants, & measurements Effects of eGFR slope through week 130 were analyzed using a piecewise, linear, mixed-effects model. Efficacy was analyzed in the intention-to-treat population, on the basis of Cox proportional hazard models, and safety was analyzed in the on-treatment population. At randomization (an average of 29 days after screening), 174 of 4401 (4%) participants had an eGFR <30 ml/min per 1.73 m2 (mean [SD] eGFR, 26 [3] ml/min per 1.73 m2). Results From weeks 3 to 130, there was a 66% difference in the mean rate of eGFR decline with canagliflozin versus placebo (mean slopes,-1.30 versus-3.83 ml/min per 1.73 m2 per year; difference,-2.54 ml/min per 1.73 m2 per year; 95% confidence interval [CI], 0.90 to 4.17). Effects of canagliflozin on kidney, cardiovascular, and mortality outcomes were consistent for those with eGFR <30 and ≥30 ml/min per 1.73 m2 (all P interaction >0.20). The estimate for kidney failure in participants with eGFR <30 ml/min per 1.73 m2 (hazard ratio, 0.67; 95% CI, 0.35 to 1.27) was similar to those with eGFR ≥30 ml/min per 1.73 m2 (hazard ratio, 0.70; 95% CI, 0.54 to 0.91; P interaction=0.80). There was no imbalance in the rate of kidney-related adverse events or AKI associated with canagliflozin between participants

Published
2020

32. The effects of canagliflozin on heart failure and cardiovascular death by baseline participant characteristics: analysis of the CREDENCE trial

Author

de Zeeuw, D, Arnott, C, Li, J-W, Cannon, CP, Neuen, BL, Heerspink, HJL, Neal, B, Charytan, DM, Bakris, G, Chang, T-H, Rosenthal, N, Zinman, B, Perkovic, V, Jardine, MJ, Mahaffey, KW, de Zeeuw, D, Arnott, C, Li, J-W, Cannon, CP, Neuen, BL, Heerspink, HJL, Neal, B, Charytan, DM, Bakris, G, Chang, T-H, Rosenthal, N, Zinman, B, Perkovic, V, Jardine, MJ, and Mahaffey, KW

Published
2020

33. Effects of canagliflozin on anaemia in patients with type 2 diabetes and chronic kidney disease: a post-hoc analysis from the CREDENCE trial

Author

Oshima, M, Neuen, BL, Jardine, MJ, Bakris, G, Edwards, R, Levin, A, Mahaffey, KW, Neal, B, Pollock, C, Rosenthal, N, Wada, T, Wheeler, DC, Perkovic, V, Heerspink, HJL, Oshima, M, Neuen, BL, Jardine, MJ, Bakris, G, Edwards, R, Levin, A, Mahaffey, KW, Neal, B, Pollock, C, Rosenthal, N, Wada, T, Wheeler, DC, Perkovic, V, and Heerspink, HJL

Abstract

Background: Sodium-glucose co-transporter 2 inhibitors might enhance erythropoiesis and increase red blood cell mass. We assessed the long-term effects of canagliflozin on anaemia-related outcomes. Methods: In a post-hoc analysis of the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, we included patients with type 2 diabetes and chronic kidney disease who were randomly assigned to treatment with canagliflozin or placebo at 690 sites in 34 countries. We assessed the effects of canagliflozin versus matched placebo on haemoglobin and haematocrit using linear mixed-effects models. The primary outcome of this post-hoc analysis was a composite outcome of investigator-reported anaemia or treatment for anaemia, which was assessed using Kaplan-Meier analysis and Cox regression models. All analyses were done by intention to treat. Findings: Between March 24, 2014, and May 5, 2017, 4401 participants were randomly assigned to receive canagliflozin (100 mg; n=2202) or placebo (n=2199). At baseline, mean haemoglobin concentration was 132·0 g/L (SD 17·7), 1599 (36%) of 4401 participants had anaemia (defined as haemoglobin <130 g/L in men or <120 g/L in women), and 33 (<1%) of 4401 participants used erythropoiesis-stimulating agents. During a median follow-up period of 2·6 years (IQR 2·1–3·1), mean haemoglobin concentration was 7·1 g/L (95% CI 6·4–7·8) higher and haematocrit was 2·4% (2·2–2·6) higher in the canagliflozin group than the placebo group. Overall, 573 of 4401 participants had either an investigator-reported anaemia event or initiation of treatment for anaemia: 358 (8%) of 4401 participants reported anaemia events, 343 (8%) initiated iron preparations, 141 (3%) initiated erythropoiesis-stimulating agents, and 114 (2%) received blood transfusion. The risk of the composite outcome of anaemia events or initiation of treatment for anaemia was lower in the canagliflozin group than the placebo group (hazard ratio 0·

Published
2020

34. The effect of canagliflozin on amputation risk in the CANVAS program and the CREDENCE trial.

Author

Arnott, C, Huang, Y, Neuen, BL, Di Tanna, GL, Cannon, CP, Oh, R, Edwards, R, Kavalam, M, Rosenthal, N, Perkovic, V, Jardine, MJ, Mahaffey, K, Neal, B, Arnott, C, Huang, Y, Neuen, BL, Di Tanna, GL, Cannon, CP, Oh, R, Edwards, R, Kavalam, M, Rosenthal, N, Perkovic, V, Jardine, MJ, Mahaffey, K, and Neal, B

Abstract

AIM: To determine whether there was an explanation as to why the effects of the sodium-glucose co-transporter-2 (SGLT2) inhibitor canagliflozin on amputation risk vary between the CANVAS program and the CREDENCE trial. METHODS: We performed a pooled analysis of patient-level data from the CANVAS program and the CREDENCE trial. Patient characteristics associated with amputation risk were assessed in univariable and multivariable regression models and compared between studies. Effects of canagliflozin on amputation risk were determined from Cox proportional hazards models and compared between studies, subgroups and for a range of amputation outcomes. Effects over time were explored by cumulative event curves. RESULTS: In the CANVAS program (n = 10 142; median follow-up 2.4 years) and CREDENCE trial (n = 4401; median follow-up 2.5 years), 2.3% and 5.3% of participants, respectively, reported baseline amputation history. Key differences at baseline were the proportions with nephropathy (CREDENCE higher, 100% vs. 17.5%) and cardiovascular disease (CANVAS higher, 66% vs. 50%). There were 133 amputations in CREDENCE (3.0% annual event rate) and 187 amputations in CANVAS (1.8% annual event rate), with prior amputation being the strongest predictor of future amputation in both groups. Effects of canagliflozin on amputation risk were significantly different between trials (Pheterogeneity .02, I2 = 82%), but this was not explained by participant or trial differences. There was no evidence that foot disease management protocols instituted during CREDENCE ameliorated amputation risk. CONCLUSIONS: We identified no explanation for the difference in amputation risk between the CREDENCE trial and the CANVAS program. In the context of null effects of SGLT2 inhibition on amputation in CREDENCE and all other large trials, there is a possibility that the finding in CANVAS was the result of chance.

Published
2020

35. The effects of combination canagliflozin and glucagon-like peptide-1 receptor agonist therapy on intermediate markers of cardiovascular risk in the CANVAS program

Author

Arnott, C, Neuen, BL, Heerspink, HJL, Figtree, GA, Kosiborod, M, Lam, CS, Cannon, CP, Rosenthal, N, Shaw, W, Mahaffey, KW, Jardine, MJ, Perkovic, V, Neal, B, Arnott, C, Neuen, BL, Heerspink, HJL, Figtree, GA, Kosiborod, M, Lam, CS, Cannon, CP, Rosenthal, N, Shaw, W, Mahaffey, KW, Jardine, MJ, Perkovic, V, and Neal, B

Abstract

Background: Sodium glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP1-RA) reduce cardiovascular events, and improve intermediate markers of cardiometabolic health, in those with type 2 diabetes. We investigated these effects in the CANVAS Program. Methods and results: The CANVAS Program comprised 2 double-blind, randomized, placebo-controlled trials (CANVAS and CANVAS-R) done in patients with type 2 diabetes and elevated cardiovascular risk. Effects were estimated using mixed-effects models for continuous measures and Cox regression models for other outcomes. Randomized treatment by subgroup interaction terms were used to compare effects of canagliflozin versus placebo across subgroups defined by baseline use of GLP1-RA. There were 10,142 participants, of whom 407 (4%) were using GLP1-RA therapy at baseline. Those using GLP1-RA at baseline were less likely to have a history of cardiovascular disease (60.4% vs 65.8%), had a longer duration of diabetes (15.2 vs 13.5 years) and a higher body mass index (BMI; 35.6 vs 31.8 kg/m2) but were otherwise similar. There were greater reductions with canagliflozin versus placebo for HbA1c (−0.75% versus −0.58%; P =.0091), SBP (−6.26 versus −3.83 mmHg; P =.0018), and body weight (−3.79 versus −2.18 kg; P <.0001) in those on baseline GLP1-RA therapy. Effects across subgroups were similar for UACR (P =.21), eGFR slope (P =.72), major adverse cardiac events (P =.94) and total serious adverse events (P =.74). Conclusions: There may be a synergistic effect of SGLT2 inhibition when used on a background of GLP1-RA for intermediate cardiometabolic markers.

Published
2020

36. Renal, cardiovascular, and safety outcomes of canagliflozin by baseline kidney function: A secondary analysis of the CREDENCE randomized trial

Author

Jardine, MJ, Zhou, Z, Mahaffey, KW, Oshima, M, Agarwal, R, Bakris, G, Bajaj, HS, Bull, S, Cannon, CP, Charytan, DM, De Zeeuw, D, Di Tanna, GL, Greene, T, Heerspink, HJL, Levin, A, Neal, B, Pollock, C, Qiu, R, Sun, T, Wheeler, DC, Zhang, H, Zinman, B, Rosenthal, N, Perkovic, V, Jardine, MJ, Zhou, Z, Mahaffey, KW, Oshima, M, Agarwal, R, Bakris, G, Bajaj, HS, Bull, S, Cannon, CP, Charytan, DM, De Zeeuw, D, Di Tanna, GL, Greene, T, Heerspink, HJL, Levin, A, Neal, B, Pollock, C, Qiu, R, Sun, T, Wheeler, DC, Zhang, H, Zinman, B, Rosenthal, N, and Perkovic, V

Abstract

Background: Canagliflozin reduced renal and cardiovascular events in people with type 2 diabetes in the CREDENCE trial. We assessed efficacy and safety of canagliflozin by initial estimated glomerular filtration rate (eGFR). Methods: CREDENCE randomly assigned 4401 participants with an eGFR of 30 to <90 ml/min per 1.73 m2 and substantial albuminuria to canagliflozin 100 mg or placebo. We used Cox proportional hazards regression to analyze effects on renal and cardiovascular efficacy and safety outcomes within screening eGFR subgroups (30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m2) and linear mixed effects models to analyze the effects on eGFR slope. Results: At screening, 1313 (30%), 1279 (29%), and 1809 (41%) participants had an eGFR of 30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m2, respectively. The relative benefits of canagliflozin for renal and cardiovascular outcomes appeared consistent among eGFR subgroups (all P interaction >0.11). Subgroups with lower eGFRs, who were at greater risk, exhibited larger absolute benefits for renal outcomes. Canagliflozin's lack of effect on serious adverse events, amputations, and fractures appeared consistent among eGFR subgroups. In all subgroups, canagliflozin use led to an acute eGFR drop followed by relative stabilization of eGFR loss. Among those with an eGFR of 30 to <45 ml/min per 1.73 m2, canagliflozin led to an initial drop of 2.03 ml/min per 1.73 m2. Thereafter, decline in eGFR was slower in the canagliflozin versus placebo group (-1.72 versus -4.33 ml/min per 1.73 m2; between-group difference 2.61 ml/min per 1.73 m2). Conclusions: Canagliflozin safely reduced the risk of renal and cardiovascular events, with consistent results across eGFR subgroups, including the subgroup initiating treatment with an eGFR of 30 to <45 ml/min per 1.73 m2. Absolute benefits for renal outcomes were greatest in subgroups with lower eGFR.

Published
2020

38. Single cell sequencing reveals endothelial plasticity with transient mesenchymal activation after myocardial infarction

Author

Tombor, L, primary, John, D, additional, Glaser, S.F, additional, Luxan, G, additional, Forte, E, additional, Furtado, M, additional, Rosenthal, N, additional, Manavski, Y, additional, Fischer, A, additional, Muhly-Reinholz, M, additional, Looso, M, additional, Acker, T, additional, Harvey, R, additional, Abplanalp, A, additional, and Dimmeler, S, additional

Published
2020
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39. Persistent anti-heart autoimmunity causes cardiomyocyte damage in chronic heart failure

Author

Sintou, A, Rifai, SE, Mansfield, C, Rothery, S, Sanchez Alonso, J, Narodden, S, Sharma, K, Ferraro, E, Hasham, M, Swiatlowska, P, Harding, S, Rosenthal, N, Gorelik, J, and Sattler, S

Abstract

Although clinicians and researchers have long appreciated the detrimental effects of excessive acute inflammation after myocardial infarction (MI), less is known about the role of the adaptive immune system in MI complications including heart failure. Yet, abundant cardiac self-antigens released from necrotic cardiomyocytes in a highly inflammatory environment are likely to overwhelm peripheral mechanisms of immunological self-tolerance and adaptive auto-reactivity against the heart may cause ongoing tissue destruction and exacerbate progression to chronic heart failure (CHF). Here, we confirm that the adaptive immune system is indeed persistently active in CHF due to ischemic heart disease triggered by MI in rats. Heart draining mediastinal lymph nodes contain active secondary follicles with mature class-switched IgG2a positive cells, and mature anti-heart auto-antibodies binding to cardiac epitopes are still present in serum as late as 16 weeks after MI. When applied to healthy cardiomyocytes in vitro, humoral factors present in CHF serum promoted apoptosis, cytotoxicity and signs of hypertrophy. These findings directly implicate post-MI autoimmunity as an integral feature of CHF progression, constituting a roadblock to effective regeneration and a promising target for therapeutic intervention.

Published
2019

40. Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups

Author

Mahaffey, Kw, Jardine, Mj, Bompoint, S, Cannon, Cp, Neal, B, Heerspink, Hjl, Charytan, Dm, Edwards, R, Agarwal, R, Bakris, G, Bull, S, Capuano, G, de Zeeuw, D, Greene, T, Levin, A, Pollock, C, Sun, T, Wheeler, Dc, Yavin, Y, Zhang, H, Zinman, B, Rosenthal, N, Brenner, Bm, Perkovic, V, Guerrero, Raa, Aizenberg, D, Albisu, Jp, Alvarisqueta, A, Bartolacci, I, Berli, Ma, Bordonava, A, Calella, P, Cantero, Mc, Cartasegna, Lr, Cercos, E, Coloma, Gc, Colombo, H, Commendatore, V, Cuadrado, J, Cuneo, Ca, Cusumano, Am, Douthat, Wg, Dran, Rd, Farias, E, Fernandez, Mf, Finkelstein, H, Fragale, G, Fretes, Jo, Garcia, Nh, Gastaldi, A, Gelersztein, E, Glenny, Ja, Gonzalez, Jp, Colaso, Pdg, Goycoa, C, Greloni, Gc, Guinsburg, A, Hermida, S, Juncos, Li, Klyver, Mi, Kraft, F, Krynski, F, Lanchiotti, Pv, de la Fuente, Ral, Marchetta, N, Mele, P, Nicolai, S., Novoa, Pa, Orio, Si, Otreras, F, Oviedo, A, Raffaele, P, Resk, Jh, Rista, L, Papini, Nr, Sala, J, Santos, Jc, Schiavi, Lb, Sessa, H, Casabella, Ts, Ulla, Mr, Valdez, M, Vallejos, A, Villarino, A, Visco, Ve, Wassermann, A, Zaidman, Cj, Cheung, Nw, Droste, C, Fraser, I, Johnson, D, Mah, Pm, Nicholls, K, Packham, D, Proietto, J, Roberts, A, Roger, S, Tsang, V, Raduan, Ra, da Costa, Faa, Amodeo, C, Turatti, Laa, Bregman, R, Sanches, Fcc, Canani, Lh, Chacra, Ar, Cunha Borges, Jl, Vencio, Sac, Franco, Rjd, D'Avila, D, Portes, Ed, de Souza, P, Deboni, Lm, Fraige, F, Neto, Bg, Gomes, M, Kohara, Sk, Keitel, E, Saraiva, Jfk, Lisboa, Hrk, Contieri, Fld, Milagres, R, Montenegro, R, de Brito, Cm, Hissa, Mn, Sabbag, Arn, Noronha, I, Panarotto, D, Pecoits, R, Pereira, Ma, Saporito, W, Scotton, As, Schuch, T, de Almeida, Rs, Ramos, Cs, Felicio, Js, Thome, F, Hachmann, Jct, Yamada, S, Hayashida, Cy, Petry, Tbz, Zanella, Mt, Andreeva, V, Angelova, A, Dimitrov, S, Genadieva, V, Genova-Hristova, G, Hristozov, K, Kamenov, Z, Koundurdjiev, A, Lozanov, L, Margaritov, V, Nonchev, B, Rangelov, R, Shinkov, A., Temelkova, M, Velichkova, E, Yakov, A, Aggarwal, N, Aronson, R, Bajaj, H, Cherney, D, Chouinard, G, Conway, J, Cournoyer, S, Daroza, G, De Serres, S, Dube, F, Goldenberg, R, Gupta, A, Gupta, M, Henein, S, Khandwala, H, Leiter, L, Madore, F, Mcmahon, A, Muirhead, N, Pichette, V, Rabasa-Lhoret, R, Steele, A, Tangri, N, Torshizi, A, Woo, V, Zalunardo, Nadia, Fernandez Montenegro, Maria Alicia, Godoy Jorquera, Juan Gonzalo, Medina Farina, Marcelo, Saavedra Gajardo, Victor, Vejar, Margarita, Chen, Nan, Chen, Qinkai, Gan, Shenglian, Kong, Yaozhong, Detian, Li, Wenge, Li, Xuemei, Li, Lin, Hongli, Liu, Jian, Weiping, Lu, Mao, Hong, Ren, Yan, Song, Weihong, Sun, Jiao, Sun, Lin, Ping, Tu, Wang, Guixia, Yang, Jinkui, Yin, Aiping, Xueqing, Yu, Zhao, Minghui, Zheng, Hongguang, Accini Mendoza, Jose Luis, Arcos, Edgar, Avendano, Jorge, Diaz Ruiz, Jorge Ernesto Andres, Garcia Ortiz, Luis Hernando, Gonzalez, Alexander, Hernandez Triana, Eric, Diego Higuera, Juan, Malaver, Natalia, Ines Molina de Salazar, Dora, Rosero, Ricardo, Terront Lozano, Monica Alexandra, Valderrama Cometa, Luis, Valenzuela, Alex, Vargas Alonso, Ruben Dario, Villegas, Ivan, Yupanqui, Hernan, Bartaskova, Dagmar, Barton, Petr, Belobradkova, Jana, Dohnalova, Lenka, Drasnar, Tomas, Ferkl, Richard, Halciakova, Katarina, Klokocnikova, Vera, Kovar, Richard, Lastuvka, Jiri, Lukac, Martin, Pesickova, Satu, Peterka, Karel, Pumprla, Jiri, Rychlik, Ivan, Saudek, Frantisek, Tesar, Vladimir, Valis, Martin, Weiner, Pavel, Zemek, Stanislav, Alamartine, Eric, Borot, Sophie, Cariou, Bertrand, Dussol, Bertrand, Fauvel, Jean-Pierre, Gourdy, Pierre, Klein, Alexandre, Le Meur, Yannick, Penfornis, Alfred, Roussel, Ronan, Saulnier, Pierre-Jean, Thervet, Eric, Zaoui, Philippe, Burst, Volker, Faghih, Markus, Faulmann, Grit, Haller, Hermann, Jerwan-Keim, Reinhold, Maxeiner, Stephan, Paschen, Bjoern, Plassmann, Georg, Rose, Ludger, Gonzalez Orellana, Ronaldo Arturo, Paul Haase, Franklin, Moreira Diaz, Juan Pablo, Ramirez Roca, Luis Alberto, Sanchez Arenales, Jose Antonio, Sanchez Polo, Jose Vicente, Turcios Juarez, Erick, Csecsei, Gyongyi, Csiky, Botond, Danos, Peter, Deak, Laszlo, Dudas, Mihaly, Harcsa, Eleonora, Keltai, Katalin, Keresztesi, Sandor, Kiss, Konyves, Laszlo, Major, Lajos, Mileder, Margit, Molnar, Marta, Mucsi, Janos, Oroszlan, Tamas, Ory, Ivan, Paragh, Gyorgy, Peterfai, Eva, Petro, Gizella, Revesz, Katalin, Takacs, Robert, Vangel, Sandor, Vasas, Szilard, Zsom, Marianna, Abraham, Oomman, Bhushan, Raju Sree, Deepak, Dewan, Edwin, Fernando M., Gopalakrishnan, Natarajan, Gracious, Noble, Hansraj, Alva, Jain, Dinesh, Keshavamurthy, C. B., Khullar, Dinesh, Manisha, Sahay, Peringat, Jayameena, Prasad, Narayan, Satyanarayana, Rao K., Sreedhar, Reddy, Sreelatha, Melemadathil, Sudhakar, Bhimavarapu, Vyasam, Ramesh Chandra, Bonadonna, Riccardo, Castellino, Pietro, Ceriello, Antonio, Chiovato, Luca, De Cosmo, Salvatore, De Nicola, Luca, Derosa, Giuseppe, Di Carlo, Alberto, Di Cianni, Graziano, Frasca, Giovanni, Fuiano, Giorgio, Gambaro, Giovanni, Garibotto, Giacomo, Giorda, Carlo, Malberti, Fabio, Mandreoli, Marcora, Mannucci, Edoardo, Orsi, Emanuela, Piatti, Piermarco, Santoro, Domenico, Sasso, Ferdinando Carlo, Serviddio, Gaetano, Stella, Andrea, Trevisan, Roberto, Veronelli, Anna Maria, Zanoli, Luca, Akiyama, Hitoshi, Aoki, Hiromi, Asano, Akimichi, Iitsuka, Tadashi, Kajiyama, Shizuo, Kashine, Susumu, Kawada, Toshio, Kodera, Takamoto, Kono, Hiroshi, Koyama, Kazunori, Kumeda, Yasuro, Miyauchi, Shozo, Mizuyama, Kazuyuki, Niiya, Tetsuji, Oishi, Hiroko, Ota, Satoshi, Sakakibara, Terue, Takai, Masahiko, Tomonaga, Osamu, Tsujimoto, Mitsuru, Wada, Takashi, Wakasugi, Masakiyo, Wakida, Yasushi, Watanabe, Takayuki, Yamada, Masayo, Yanagida, Kazuhiro, Yanase, Toshihiko, and Yumita, Wataru

Subjects
Male, Risk, primary prevention, canagliflozin, clinical trial, diabetes mellitus, renal insufficiency, chronic, secondary prevention, renal insufficiency, Double-Blind Method, Original Research Articles, Humans, Sodium-Glucose Transporter 2 Inhibitors, Proportional Hazards Models, canagliflozin, clinical trial, diabetes mellitus, primary prevention, renal insufficiency, chronic, secondary prevention, Middle Aged, Placebo Effect, chronic, Treatment Outcome, Diabetes Mellitus, Type 2, Cardiovascular Diseases, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Kidney Failure, Chronic, Female
Abstract

Supplemental Digital Content is available in the text., Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67–0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49–0.94]) and secondary (HR, 0.85 [95% CI, 0.69–1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61–1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59–1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56–1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02065791.

Published
2019

41. Epicardial cell transfection with cationic polymeric nanocomplexes

Author

Brito, L, Mylonaki, I, Moroz, E, Grigsby, C, Smart, N, Rosenthal, N, Harding, SE, Stevens, MM, and British Heart Foundation

Subjects
Genetics & Heredity, Science & Technology, Biotechnology & Applied Microbiology, Medicine, Research & Experimental, 1004 Medical Biotechnology, fungi, 1103 Clinical Sciences, Research & Experimental Medicine, Life Sciences & Biomedicine, Biotechnology
Abstract

Paracrine signalling has been shown to contribute to heart regeneration after myocardial infarction (MI). As an important signalling regulatory centre, the epicardium is crucial for the heart development. Moreover, it is re-activated after MI, indicating its involvement in the response to this injury. This project aims to accomplish in situ transfection of the epicardium to stimulate the regenerative signalling pathways after MI. Here an in vitro proof of concept of epicardial cell transfection with nanocomplexes is presented. pABOL polyplexes, resulting from complexation of a bioreducible polymer with a GFP gene plasmid (pCAG-GFP), were able to transfect epicardial cells when added in suspension to the culture. The pCAG-GFP-pABOL polyplexes formulation was the most suitable when compared to Lipofectamine, Fugene or naked plasmid, revealing 45.9±9.7% of cell viability and 39.4±6.4% of transfection efficiency. Moreover, the freeze-drying of the pABOL polyplexes was tested. pABOL polyplexes formed in water and in the different sugar/surfactants HEPES buffers. The ζ-potential of these polyplexes ranged between +20 and +30mV. After the freeze-drying, pABOL polyplexes only maintained their transfection activity when formed in sugar-containing buffers. These preliminary results indicate for the first time the advantage of using pABOL polymer in comparison with standard transfection reagents for epicardial cells transfection and the possibility of retaining transfection activity of pABOL polyplexes when freeze-dried. Our final aim is to use nanoneedles, which can transfer substances to the epicardial layer alone, to deliver these polyplexes.

Published
2019

42. Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups Results From the Randomized CREDENCE Trial

Author

Mahaffey, KW, Jardine, MJ, Bompoint, S, Cannon, CP, Neal, B, Heerspink, HJL, Charytan, DM, Edwards, R, Agarwal, R, Bakris, G, Bull, S, Capuano, G, de Zeeuw, D, Greene, T, Levin, A, Pollock, C, Sun, T, Wheeler, DC, Yavin, Y, Zhang, H, Zinman, B, Rosenthal, N, Brenner, BM, Perkovic, V, Ahuad Guerrero, RA, Aizenberg, D, Pablo Albisu, J, Alvarisqueta, A, Bartolacci, I, Alberto Berli, M, Bordonava, A, Calella, P, Cecilia Cantero, M, Rodolfo Cartasegna, L, Cercos, E, Cecilia Coloma, G, Colombo, H, Commendatore, V, Cuadrado, J, Alberto Cuneo, C, Maria Cusumano, A, Guillermo Douthat, W, Dario Dran, R, Farias, E, Florencia Fernandez, M, Finkelstein, H, Fragale, G, Osvaldo Fretes, J, Horacio Garcia, N, Gastaldi, A, Gelersztein, E, Archibaldo Glenny, J, Pablo Gonzalez, J, Gonzalez Colaso, PDC, Goycoa, C, Cristian Greloni, G, Guinsburg, A, Hermida, S, Isaias Juncos, L, Isabel Klyver, M, Kraft, F, Krynski, F, Virginia Lanchiotti, P, Alfonso Leon de la Fuente, R, Marchetta, N, Mele, P, Nicolai, S, Antonio Novoa, P, Ines Orio, S, Otreras, F, Oviedo, A, Raffaele, P, Hector Resk, J, Rista, L, Rodriguez Papini, N, Sala, J, Santos, JC, Beatriz Schiavi, L, Sessa, H, Smith Casabella, T, Rosa Ulla, M, Valdez, M, Vallejos, A, Villarino, A, Esther Visco, V, Wassermann, A, Javier Zaidman, C, Cheung, NW, Droste, C, Fraser, I, Johnson, D, Mah, PM, Nicholls, K, Packham, D, Proietto, J, Roberts, A, Roger, S, Tsang, V, Raduan, RA, Alves da Costa, FA, Amodeo, C, Andreotti Turatti, LA, Bregman, R, Camelo Sanches, FC, Canani, LH, Chacra, AR, Cunha Borges, JL, Cunha Vencio, SA, da Silva Franco, RJ, d'Avila, D, Portes, EDS, de Souza, P, Deboni, LM, Fraige Filho, F, Geloneze Neto, B, Gomes, M, Kohara, SK, Keitel, E, Kerr Saraiva, JF, Kurtz Lisboa, HR, de Carvalho Contieri, FL, Milagres, R, Montenegro Junior, R, de Brito, CM, Hissa, MN, Nazario Sabbag, AR, Noronha, I, Panarotto, D, Pecoits Filho, R, Pereira, MA, Saporito, W, Scotton, AS, Schuch, T, de Almeida, RS, Ramos, CS, Felicio, JS, Thome, F, Tibes Hachmann, JC, Yamada, S, Hayashida, CY, Zanata Petry, TB, Zanella, MT, Andreeva, V, Angelova, A, Dimitrov, S, Genadieva, V, Genova-Hristova, G, Hristozov, K, Kamenov, Z, Koundurdjiev, A, Lozanov, L, Margaritov, V, Nonchev, B, Rangelov, R, Shinkov, A, Temelkova, M, Velichkova, E, Yakov, A, Aggarwal, N, Aronson, R, Bajaj, H, Cherney, D, Chouinard, G, Conway, J, Cournoyer, S, DaRoza, G, De Serres, S, Dube, F, Goldenberg, R, Gupta, A, Gupta, M, Henein, S, Khandwala, H, Leiter, L, Madore, F, McMahon, A, Muirhead, N, Pichette, V, Rabasa-Lhoret, R, Steele, A, Tangri, N, Torshizi, A, Woo, V, Zalunardo, N, Fernandez Montenegro, MA, Godoy Jorquera, JG, Medina Farina, M, Saavedra Gajardo, V, Vejar, M, Chen, N, Chen, Q, Gan, S, Kong, Y, Li, D, Li, W, Li, X, Lin, H, Liu, J, Lu, W, Mao, H, Ren, Y, Song, W, Sun, J, Sun, L, Tu, P, Wang, G, Yang, J, Yin, A, Yu, X, Zhao, M, Zheng, H, Accini Mendoza, JL, Arcos, E, Avendano, J, Diaz Ruiz, JEA, Garcia Ortiz, LH, Gonzalez, A, Hernandez Triana, E, Diego Higuera, J, Malaver, N, Ines Molina de Salazar, D, Rosero, R, Terront Lozano, MA, Valderrama Cometa, L, Valenzuela, A, Vargas Alonso, RD, Villegas, I, Yupanqui, H, Bartaskova, D, Barton, P, Belobradkova, J, Dohnalova, L, Drasnar, T, Ferkl, R, Halciakova, K, Klokocnikova, V, Kovar, R, Lastuvka, J, Lukac, M, Pesickova, S, Peterka, K, Pumprla, J, Rychlik, I, Saudek, F, Tesar, V, Valis, M, Weiner, P, Zemek, S, Alamartine, E, Borot, S, Cariou, B, Dussol, B, Fauvel, J-P, Gourdy, P, Klein, A, Le Meur, Y, Penfornis, A, Roussel, R, Saulnier, P-J, Thervet, E, Zaoui, P, Burst, V, Faghih, M, Faulmann, G, Haller, H, Jerwan-Keim, R, Maxeiner, S, Paschen, B, Plassmann, G, Rose, L, Gonzalez Orellana, RA, Paul Haase, F, Moreira Diaz, JP, Ramirez Roca, LA, Sanchez Arenales, JA, Sanchez Polo, JV, Turcios Juarez, E, Csecsei, G, Csiky, B, Danos, P, Deak, L, Dudas, M, Harcsa, E, Keltai, K, Keresztesi, S, Kiss, K, Konyves, L, Major, L, Mileder, M, Molnar, M, Mucsi, J, Oroszlan, T, Ory, I, Paragh, G, Peterfai, E, Petro, G, Revesz, K, Takacs, R, Vangel, S, Vasas, S, Zsom, M, Abraham, O, Bhushan, RS, Deepak, D, Edwin, FM, Gopalakrishnan, N, Gracious, N, Hansraj, A, Jain, D, Keshavamurthy, CB, Khullar, D, Manisha, S, Peringat, J, Prasad, N, Satyanarayana, RK, Sreedhar, R, Sreelatha, M, Sudhakar, B, Vyasam, RC, Bonadonna, R, Castellino, P, Ceriello, A, Chiovato, L, De Cosmo, S, De Nicola, L, Derosa, G, Di Carlo, A, Di Cianni, G, Frasca, G, Fuiano, G, Gambaro, G, Garibotto, G, Giorda, C, Malberti, F, Mandreoli, M, Mannucci, E, Orsi, E, Piatti, P, Santoro, D, Sasso, FC, Serviddio, G, Stella, A, Trevisan, R, Veronelli, AM, Zanoli, L, Akiyama, H, Aoki, H, Asano, A, Iitsuka, T, Kajiyama, S, Kashine, S, Kawada, T, Kodera, T, Kono, H, Koyama, K, Kumeda, Y, Miyauchi, S, Mizuyama, K, Niiya, T, Oishi, H, Ota, S, Sakakibara, T, Takai, M, Tomonaga, O, Tsujimoto, M, Wada, T, Wakasugi, M, Wakida, Y, Watanabe, T, Yamada, M, Yanagida, K, Yanase, T, Yumita, W, Gaupsiene, E, Kozloviene, D, Navickas, A, Urbanaviciene, E, Ghani, RA, Kadir, KA, Ali, N, Yusof, MDC, Gan, CL, Ismail, M, Kong, WY, Lam, SW, Lee, LY, Lim, SK, Loh, CL, Manocha, AB, Ng, KS, Ahmad, NNFN, Ratnasingam, V, Bin Shudim, SS, Vengadasalam, P, Abraira Munoz, LD, Alpizar Salazar, M, Baas Cruz, J, Burgos Soto, M, Chevaile Ramos, J, Chew Wong, A, Correa Rotter, JR, Diaz Escalante, T, Enriquez Sosa, FE, Flores Lozano, F, Flota Cervera, LF, Frenk Baron, P, Garcia Ballesteros, C, Gomez Rangel, JD, Herrera Jimenez, LE, Irizar Santana, SS, Jimenez Flores, F, Laviada Molina, H, Luna Ceballos, RI, del Campo Blanco, BM, Morales Franco, G, Moreno Loza, OT, Mustieles Rocha, C, Obrador Vera, G, Orozco Castellanos, R, Peralta Calcaneo, J, Reyes Rosano, MA, Rodriguez Pattzi, H, Rosas Guzman, J, Rucker Joerg, IE, Saavedra Sanchez, SB, Sanchez Mijangos, JH, Serrano Sanson, P, Tamayo y Orozco, JA, Tellez Chavez, E, Valdes Cepeda, A, Venegas Carrillo, L, Villagordoa Mesa, J, Zamarripa Escobedo, R, Baker, J, Noonan, P, Scott, R, Walker, R, Watson, E, Williams, M, Young, S, Abejuela, Z, Agra, J, Aquitania, G, Caringal, C, Comia, RS, Delos Santos, L, Gomez, O, Jimeno, C, Santos, F, Tan, G, Tolentino, M, Yao, C, Yap, YE, Ygpuara, MDL, Bijata-Bronisz, R, Hotlos, L, Januszewicz, A, Kaczmarek, B, Kaminska, A, Lazuka, L, Madej, A, Mazur, S, Mlodawska-Choluj, D, Nowicki, M, Orlowska-Kowalik, G, Popenda, G, Rewerska, B, Sowinski, D, Angelescu, LM, Anghel, V, Avram, R-I, Busegeanu, M-M, Cif, A, Cosma, D, Crisan, C, Demian, LD, Ferariu, IE, Halmagyi, I, Hancu, N, Munteanu, M, Negru, D, Onaca, AG, Petrica, L, Popa, AR, Ranetti, A-E, Serafinceanu, C, Toarba, C, Agafyina, A, Barbarash, O, Barysheva, O, Chizhov, D, Dobronravov, V, Dreval, A, Glinkina, I, Grineva, E, Khirmanov, V, Kolmakova, E, Koroleva, T, Kvitkova, L, Marasaev, V, Mkrtumyan, A, Morugova, T, Nagibovich, G, Nagibovich, O, Nedogoda, S, Osipova, I, Raskina, T, Samoylova, Y, Sazonova, O, Shamkhalova, M, Shutemova, E, Shwartz, Y, Uriasyev, O, Vorobyev, S, Zateyshchikova, A, Zateyshshikov, D, Zykova, T, Antic, S, Djordjevic, M, Kendereski, A, Lalic, K, Lalic, N, Popovic-Radinovic, V, Babikova, J, Benusova, O, Buganova, I, Culak, J, Dzupina, A, Dzuponova, J, Fulop, P, Ilavska, A, Martinka, E, Ochodnicka, Z, Pella, D, Smatanova, I, Ahmed, F, Badat, A, Breedt, J, Distiller, L, Govender, V, Govender, R, Joshi, M, Jurgens, J, Latiff, G, Lombard, L, Mookadam, M, Ngcakani, N, Nortje, H, Oosthuizen, H, Pillay-Ramaya, L, Prozesky, H, Reddy, J, Rheeder, P, Seeber, M, Chae, D-W, Cho, YM, Jeong, I-K, Kim, SG, Kim, YH, Kwon, H-S, Kwon, MJ, Lee, B-W, Lee, JE, Lee, M-K, Nam, M-S, Oh, K-H, Park, C-Y, Park, S-H, Yoon, KH, Alvarez Garcia, P, Asmarats Mercadal, L, Barrios, C, Cereto Castro, F, Cigarran Guldris, S, Dominguez Lopez, M, Egido de los Rios, J, Fernandez Fresnedo, G, Galan Serrano, A, Garcia, I, Gonzalez Martinez, FJ, Jodar Gimeno, JE, Lopez Mendoza, M, Malek Marin, T, Morales Portillo, C, Munar Vila, MA, Munoz Torres, M, Nieto Iglesias, J, Pantoja Perez, J, Perez Vera, M, Portoles Perez, JMY, Quesada Simon, MA, Simo Canonge, R, Soto Gonzalez, A, Terns Riera, M, Tinahones Madueno, FJ, Velo Plaza, M, Chang, C-T, Chuang, L-M, Hsia, T-L, Hsieh, C-H, Hwang, S-J, Lin, C-C, Lu, Y-C, Sheu, WH-H, Barna, O, Bilyk, SD, Botsyurko, V, Dudar, I, Fushtey, I, Godlevska, O, Golovchenko, O, Gyrina, O, Kazmirchuk, A, Kolesnyk, M, Komisarenko, I, Korzh, O, Kravchun, N, Legun, O, Mankovskyy, B, Martynyuk, L, Mostovoy, Y, Pashkovska, N, Pererva, L, Pertseva, T, Samoylov, O, Smirnov, I, Svyshchenko, Y, Tomashkevych, H, Topchii, I, Tryshchuk, N, Tseluyko, V, Vizir, V, Vlasenko, M, Zlova, T, Zub, L, Abusnana, S, Railey, M, Abouglila, K, Ainsworth, P, Ali, Z, Arutchelvam, V, Barnard, M, Bellary, S, Davies, E, Davies, M, Davies, S, Dawson, A, El Kossi, M, English, P, Fraser, D, Gnudi, L, Gunstone, A, Hall, T, Hanif, W, Jackson, A, Johnson, A, Joseph, F, Krishnan, S, Kumwenda, M, MacDougall, I, Nixon, P, O'Hare, J, Philip, S, Ramtoola, S, Saxena, M, Sennik, D, Simon, G, Singh, B, Stephens, J, Strzelecka, A, Symonds, R, Turner, W, Wahba, M, Wakeling, J, Wheeler, D, Winocour, P, Abdallah, J, Abdullah, R, Abramowitz, M, Acosta, I, Aiello, J, Akright, L, Akyea-Djamson, A, Alappan, R, Alicic, R, Al-Karadsheh, A, Allison, DC, Arauz-Pacheco, C, Arfeen, S, Arif, A, Arvind, M, Atray, N, Awad, A, Barnhill, P, Barranco, E, Barrera, C, Beacom, M, Behara, V, Belo, D, Bentley-Lewis, R, Berenguer, R, Bermudez, L, Bernardo, M, Biscoveanu, M, Bowman-Stroud, C, Brandon, D, Brusco, O, Busch, R, Canaan, Y, Chilito, A, Christensen, T, Christiano, C, Christofides, E, Chuateco, C, Cohen, K, Cohen, R, Cohen-Stein, D, Cook, C, Coyne, D, Daboul, N, Darwish, R, Daswani, A, Deck, K, Desouza, C, Dev, D, Dhillon, M, Dua, S, Eder, F, Elosegui, AM, El-Shahawy, M, Ervin, J, Esquenazi, A, Evans, J, Fishbane, S, Frias, J, Galindo-Ramos, E, Galphin, C, Ghazi, A, Gonzalez, E, Gorson, D, Gowda, A, Greco, B, Grubb, S, Gulati, R, Hammoud, J, Handelsman, S, Hartman, I, Hershon, K, Hiser, D, Hon, G, Jacob, R, Jaime, M, Jamal, A, Kaupke, C, Keightley, G, Kern, E, Khanna, R, Khitan, Z, Kim, S, Kopyt, N, Kovesdy, C, Krishna, G, (Jay) Kropp, J, Kumar, A, Kumar, J, Kumar, N, Kusnir, J, Lane, W, Lawrence, M, Lehrner, L, Lentz, J, Levinson, D, Lewis, D, Liss, K, Maddux, A, Maheshwari, H, Mandayam, S, Marar, I, Mehta, B, Middleton, J, Mordujovich, J, Moreda, R, Moustafa, M, Trenche, SM, Narayanan, M, Narvarte, J, Nassar, T, Newman, G, Nichol, B, Nicol, P, Nisnisan, J, Nossuli, AK, Obialo, C, Olelewe, S, Oliver, M, O'Shaughnessy, A, Padron, J, Pankhaniya, R, Parker, R, Patel, D, Patel, G, Patel, N, Pavon, H, Perez, A, Perez, C, Perlman, A, Pettis, K, Pharr, W, Phillips, A, Purighalla, R, Quesada-Suarez, L, Ranjan, R, Rastogi, S, Rendell, M, Rich, L, Robinson, M, Rodriguez, H, Rosas, S, Saba, F, Sankaram, R, Sarin, R, Schreiman, R, Scott, D, Sekkarie, M, Sensenbrenner, J, Shakeel, M, Shanik, M, Shaw, S, Smith, S, Solomon, R, Sprague, A, Spry, L, Suchinda, P, Sultan, S, Surampudi, P, Sussman, S, Tan, A, Terrelonge, A, Thompson, M, Trespalacios, F, Trippe, B, Trueba, P, Twahirwa, M, Updegrove, J, Van Buren, P, Vannorsdall, M, Varghese, F, Velasquez-Mieyer, P, Ventrapragada, S, Vukotic, G, Wadud, K, Warren, M, Watson, H, Watts, R, Weiner, D, Welker, J, Welsh, J, Williams, S, Zaniewski-Singh, M, Mahaffey, KW, Jardine, MJ, Bompoint, S, Cannon, CP, Neal, B, Heerspink, HJL, Charytan, DM, Edwards, R, Agarwal, R, Bakris, G, Bull, S, Capuano, G, de Zeeuw, D, Greene, T, Levin, A, Pollock, C, Sun, T, Wheeler, DC, Yavin, Y, Zhang, H, Zinman, B, Rosenthal, N, Brenner, BM, Perkovic, V, Ahuad Guerrero, RA, Aizenberg, D, Pablo Albisu, J, Alvarisqueta, A, Bartolacci, I, Alberto Berli, M, Bordonava, A, Calella, P, Cecilia Cantero, M, Rodolfo Cartasegna, L, Cercos, E, Cecilia Coloma, G, Colombo, H, Commendatore, V, Cuadrado, J, Alberto Cuneo, C, Maria Cusumano, A, Guillermo Douthat, W, Dario Dran, R, Farias, E, Florencia Fernandez, M, Finkelstein, H, Fragale, G, Osvaldo Fretes, J, Horacio Garcia, N, Gastaldi, A, Gelersztein, E, Archibaldo Glenny, J, Pablo Gonzalez, J, Gonzalez Colaso, PDC, Goycoa, C, Cristian Greloni, G, Guinsburg, A, Hermida, S, Isaias Juncos, L, Isabel Klyver, M, Kraft, F, Krynski, F, Virginia Lanchiotti, P, Alfonso Leon de la Fuente, R, Marchetta, N, Mele, P, Nicolai, S, Antonio Novoa, P, Ines Orio, S, Otreras, F, Oviedo, A, Raffaele, P, Hector Resk, J, Rista, L, Rodriguez Papini, N, Sala, J, Santos, JC, Beatriz Schiavi, L, Sessa, H, Smith Casabella, T, Rosa Ulla, M, Valdez, M, Vallejos, A, Villarino, A, Esther Visco, V, Wassermann, A, Javier Zaidman, C, Cheung, NW, Droste, C, Fraser, I, Johnson, D, Mah, PM, Nicholls, K, Packham, D, Proietto, J, Roberts, A, Roger, S, Tsang, V, Raduan, RA, Alves da Costa, FA, Amodeo, C, Andreotti Turatti, LA, Bregman, R, Camelo Sanches, FC, Canani, LH, Chacra, AR, Cunha Borges, JL, Cunha Vencio, SA, da Silva Franco, RJ, d'Avila, D, Portes, EDS, de Souza, P, Deboni, LM, Fraige Filho, F, Geloneze Neto, B, Gomes, M, Kohara, SK, Keitel, E, Kerr Saraiva, JF, Kurtz Lisboa, HR, de Carvalho Contieri, FL, Milagres, R, Montenegro Junior, R, de Brito, CM, Hissa, MN, Nazario Sabbag, AR, Noronha, I, Panarotto, D, Pecoits Filho, R, Pereira, MA, Saporito, W, Scotton, AS, Schuch, T, de Almeida, RS, Ramos, CS, Felicio, JS, Thome, F, Tibes Hachmann, JC, Yamada, S, Hayashida, CY, Zanata Petry, TB, Zanella, MT, Andreeva, V, Angelova, A, Dimitrov, S, Genadieva, V, Genova-Hristova, G, Hristozov, K, Kamenov, Z, Koundurdjiev, A, Lozanov, L, Margaritov, V, Nonchev, B, Rangelov, R, Shinkov, A, Temelkova, M, Velichkova, E, Yakov, A, Aggarwal, N, Aronson, R, Bajaj, H, Cherney, D, Chouinard, G, Conway, J, Cournoyer, S, DaRoza, G, De Serres, S, Dube, F, Goldenberg, R, Gupta, A, Gupta, M, Henein, S, Khandwala, H, Leiter, L, Madore, F, McMahon, A, Muirhead, N, Pichette, V, Rabasa-Lhoret, R, Steele, A, Tangri, N, Torshizi, A, Woo, V, Zalunardo, N, Fernandez Montenegro, MA, Godoy Jorquera, JG, Medina Farina, M, Saavedra Gajardo, V, Vejar, M, Chen, N, Chen, Q, Gan, S, Kong, Y, Li, D, Li, W, Li, X, Lin, H, Liu, J, Lu, W, Mao, H, Ren, Y, Song, W, Sun, J, Sun, L, Tu, P, Wang, G, Yang, J, Yin, A, Yu, X, Zhao, M, Zheng, H, Accini Mendoza, JL, Arcos, E, Avendano, J, Diaz Ruiz, JEA, Garcia Ortiz, LH, Gonzalez, A, Hernandez Triana, E, Diego Higuera, J, Malaver, N, Ines Molina de Salazar, D, Rosero, R, Terront Lozano, MA, Valderrama Cometa, L, Valenzuela, A, Vargas Alonso, RD, Villegas, I, Yupanqui, H, Bartaskova, D, Barton, P, Belobradkova, J, Dohnalova, L, Drasnar, T, Ferkl, R, Halciakova, K, Klokocnikova, V, Kovar, R, Lastuvka, J, Lukac, M, Pesickova, S, Peterka, K, Pumprla, J, Rychlik, I, Saudek, F, Tesar, V, Valis, M, Weiner, P, Zemek, S, Alamartine, E, Borot, S, Cariou, B, Dussol, B, Fauvel, J-P, Gourdy, P, Klein, A, Le Meur, Y, Penfornis, A, Roussel, R, Saulnier, P-J, Thervet, E, Zaoui, P, Burst, V, Faghih, M, Faulmann, G, Haller, H, Jerwan-Keim, R, Maxeiner, S, Paschen, B, Plassmann, G, Rose, L, Gonzalez Orellana, RA, Paul Haase, F, Moreira Diaz, JP, Ramirez Roca, LA, Sanchez Arenales, JA, Sanchez Polo, JV, Turcios Juarez, E, Csecsei, G, Csiky, B, Danos, P, Deak, L, Dudas, M, Harcsa, E, Keltai, K, Keresztesi, S, Kiss, K, Konyves, L, Major, L, Mileder, M, Molnar, M, Mucsi, J, Oroszlan, T, Ory, I, Paragh, G, Peterfai, E, Petro, G, Revesz, K, Takacs, R, Vangel, S, Vasas, S, Zsom, M, Abraham, O, Bhushan, RS, Deepak, D, Edwin, FM, Gopalakrishnan, N, Gracious, N, Hansraj, A, Jain, D, Keshavamurthy, CB, Khullar, D, Manisha, S, Peringat, J, Prasad, N, Satyanarayana, RK, Sreedhar, R, Sreelatha, M, Sudhakar, B, Vyasam, RC, Bonadonna, R, Castellino, P, Ceriello, A, Chiovato, L, De Cosmo, S, De Nicola, L, Derosa, G, Di Carlo, A, Di Cianni, G, Frasca, G, Fuiano, G, Gambaro, G, Garibotto, G, Giorda, C, Malberti, F, Mandreoli, M, Mannucci, E, Orsi, E, Piatti, P, Santoro, D, Sasso, FC, Serviddio, G, Stella, A, Trevisan, R, Veronelli, AM, Zanoli, L, Akiyama, H, Aoki, H, Asano, A, Iitsuka, T, Kajiyama, S, Kashine, S, Kawada, T, Kodera, T, Kono, H, Koyama, K, Kumeda, Y, Miyauchi, S, Mizuyama, K, Niiya, T, Oishi, H, Ota, S, Sakakibara, T, Takai, M, Tomonaga, O, Tsujimoto, M, Wada, T, Wakasugi, M, Wakida, Y, Watanabe, T, Yamada, M, Yanagida, K, Yanase, T, Yumita, W, Gaupsiene, E, Kozloviene, D, Navickas, A, Urbanaviciene, E, Ghani, RA, Kadir, KA, Ali, N, Yusof, MDC, Gan, CL, Ismail, M, Kong, WY, Lam, SW, Lee, LY, Lim, SK, Loh, CL, Manocha, AB, Ng, KS, Ahmad, NNFN, Ratnasingam, V, Bin Shudim, SS, Vengadasalam, P, Abraira Munoz, LD, Alpizar Salazar, M, Baas Cruz, J, Burgos Soto, M, Chevaile Ramos, J, Chew Wong, A, Correa Rotter, JR, Diaz Escalante, T, Enriquez Sosa, FE, Flores Lozano, F, Flota Cervera, LF, Frenk Baron, P, Garcia Ballesteros, C, Gomez Rangel, JD, Herrera Jimenez, LE, Irizar Santana, SS, Jimenez Flores, F, Laviada Molina, H, Luna Ceballos, RI, del Campo Blanco, BM, Morales Franco, G, Moreno Loza, OT, Mustieles Rocha, C, Obrador Vera, G, Orozco Castellanos, R, Peralta Calcaneo, J, Reyes Rosano, MA, Rodriguez Pattzi, H, Rosas Guzman, J, Rucker Joerg, IE, Saavedra Sanchez, SB, Sanchez Mijangos, JH, Serrano Sanson, P, Tamayo y Orozco, JA, Tellez Chavez, E, Valdes Cepeda, A, Venegas Carrillo, L, Villagordoa Mesa, J, Zamarripa Escobedo, R, Baker, J, Noonan, P, Scott, R, Walker, R, Watson, E, Williams, M, Young, S, Abejuela, Z, Agra, J, Aquitania, G, Caringal, C, Comia, RS, Delos Santos, L, Gomez, O, Jimeno, C, Santos, F, Tan, G, Tolentino, M, Yao, C, Yap, YE, Ygpuara, MDL, Bijata-Bronisz, R, Hotlos, L, Januszewicz, A, Kaczmarek, B, Kaminska, A, Lazuka, L, Madej, A, Mazur, S, Mlodawska-Choluj, D, Nowicki, M, Orlowska-Kowalik, G, Popenda, G, Rewerska, B, Sowinski, D, Angelescu, LM, Anghel, V, Avram, R-I, Busegeanu, M-M, Cif, A, Cosma, D, Crisan, C, Demian, LD, Ferariu, IE, Halmagyi, I, Hancu, N, Munteanu, M, Negru, D, Onaca, AG, Petrica, L, Popa, AR, Ranetti, A-E, Serafinceanu, C, Toarba, C, Agafyina, A, Barbarash, O, Barysheva, O, Chizhov, D, 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Abstract

BACKGROUND: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). METHODS: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. RESULTS: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). CONCLUSIONS: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02065791.

Published
2019

49. IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1

Author

Musaro, A, McCullagh, K. J, Naya, F. J, Olson, E. N, and Rosenthal, N

Subjects
Life Sciences (General)
Abstract

Localized synthesis of insulin-like growth factors (IGFs) has been broadly implicated in skeletal muscle growth, hypertrophy and regeneration. Virally delivered IGF-1 genes induce local skeletal muscle hypertrophy and attenuate age-related skeletal muscle atrophy, restoring and improving muscle mass and strength in mice. Here we show that the molecular pathways underlying the hypertrophic action of IGF-1 in skeletal muscle are similar to those responsible for cardiac hypertrophy. Transfected IGF-1 gene expression in postmitotic skeletal myocytes activates calcineurin-mediated calcium signalling by inducing calcineurin transcripts and nuclear localization of calcineurin protein. Expression of activated calcineurin mimics the effects of IGF-1, whereas expression of a dominant-negative calcineurin mutant or addition of cyclosporin, a calcineurin inhibitor, represses myocyte differentiation and hypertrophy. Either IGF-1 or activated calcineurin induces expression of the transcription factor GATA-2, which accumulates in a subset of myocyte nuclei, where it associates with calcineurin and a specific dephosphorylated isoform of the transcription factor NF-ATc1. Thus, IGF-1 induces calcineurin-mediated signalling and activation of GATA-2, a marker of skeletal muscle hypertrophy, which cooperates with selected NF-ATc isoforms to activate gene expression programs.

Published
1999
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50. Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function data from the CANVAS program

Author

Neuen, BL, Ohkuma, T, Neal, B, Matthews, DR, De Zeeuw, D, Mahaffey, KW, Fulcher, G, Desai, M, Li, Q, Deng, H, Rosenthal, N, Jardine, MJ, Bakris, G, Perkovic, V, Neuen, BL, Ohkuma, T, Neal, B, Matthews, DR, De Zeeuw, D, Mahaffey, KW, Fulcher, G, Desai, M, Li, Q, Deng, H, Rosenthal, N, Jardine, MJ, Bakris, G, and Perkovic, V

Abstract

BACKGROUND: Canagliflozin is approved for glucose lowering in type 2 diabetes and confers cardiovascular and renal benefits. We sought to assess whether it had benefits in people with chronic kidney disease, including those with an estimated glomerular filtration rate (eGFR) between 30 and 45 mL/min/1.73 m2 in whom the drug is not currently approved for use. METHODS: The CANVAS Program randomized 10 142 participants with type 2 diabetes and eGFR >30 mL/min/1.73 m2 to canagliflozin or placebo. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, with other cardiovascular, renal, and safety outcomes. This secondary analysis describes outcomes in participants with and without chronic kidney disease, defined as eGFR <60 and ≥60 mL/min/1.73 m2, and according to baseline kidney function (eGFR <45, 45 to <60, 60 to <90, and ≥90 mL/min/1.73 m2). RESULTS: At baseline, 2039 (20.1%) participants had an eGFR <60 mL/min/1.73 m2, 71.6% of whom had a history of cardiovascular disease. The effect of canagliflozin on the primary outcome was similar in people with chronic kidney disease (hazard ratio, 0.70; 95% CI, 0.55-0.90) and those with preserved kidney function (hazard ratio, 0.92; 95% CI, 0.79-1.07; P heterogeneity = 0.08). Relative effects on most cardiovascular and renal outcomes were similar across eGFR subgroups, with possible heterogeneity suggested only for the outcome of fatal/ nonfatal stroke (P heterogeneity = 0.01), as were results for almost all safety outcomes. CONCLUSIONS: The effects of canagliflozin on cardiovascular and renal outcomes were not modified by baseline level of kidney function in people with type 2 diabetes and a history or high risk of cardiovascular disease down to eGFR levels of 30 mL/min/1.73 m2. Reassessing current limitations on the use of canagliflozin in chronic kidney disease may allow additional individuals to benefit from this therapy.

Published
2018

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