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1. Soft tissue echinococcosis: a report of two cases and review of the literature.

Author: Cannon, CP, Nelson, SD, Panosian, CB, Seeger, LL, Eilber, FR, and Eckardt, JJ
Subjects: Humans, Soft Tissue Infections, Echinococcosis, Tomography, X-Ray Computed, Magnetic Resonance Imaging, Adult, Middle Aged, Male, Digestive Diseases, Infectious Diseases, Rare Diseases, Tomography, X-Ray Computed, Orthopedics, Clinical Sciences
Abstract: Echinococcosis (hydatid cyst disease) is a zoonotic infection caused by the parasitic tapeworm Echinococcus. The larval stage of this parasite can implant in many organs of the body, most commonly the liver, and create internal budding cystic masses. Echinococcal cysts also can implant in soft tissues; however, a review of the literature revealed no published case with the patient initially presenting with a soft tissue mass. Two such cases are reported in the current study. Physicians who evaluate soft tissue masses, particularly in patients from Echinococcus-endemic areas, need to include echinococcosis in their differential diagnoses. The current treatment of choice for soft tissue echinococcosis is wide resection combined with perioperative medical therapy.
Published: 2001

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

Author: Charytan, DM, Mahaffey, KW, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Cannon, CP, Neal, B ; https://orcid.org/0000-0002-0490-7465, Lambers Heerspink, HJ, Agarwal, R, Bakris, GL, De Zeeuw, D, Levin, A, Pollock, C, Zhang, H, Zinman, B, Rosenthal, N, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Di Tanna, GL ; https://orcid.org/0000-0002-5470-3567, Yu, J ; https://orcid.org/0000-0002-7401-7580, Rogers, K, Arnott, C ; https://orcid.org/0000-0001-9370-9913, Wheeler, DC, Charytan, DM, Mahaffey, KW, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Cannon, CP, Neal, B ; https://orcid.org/0000-0002-0490-7465, Lambers Heerspink, HJ, Agarwal, R, Bakris, GL, De Zeeuw, D, Levin, A, Pollock, C, Zhang, H, Zinman, B, Rosenthal, N, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Di Tanna, GL ; https://orcid.org/0000-0002-5470-3567, Yu, J ; https://orcid.org/0000-0002-7401-7580, Rogers, K, Arnott, C ; https://orcid.org/0000-0001-9370-9913, 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 m 2, 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

3. Kidney and Cardiovascular Effects of Canagliflozin According to Age and Sex: A Post Hoc Analysis of the CREDENCE Randomized Clinical Trial

Author: Yi, TW, Smyth, B ; https://orcid.org/0000-0003-1838-3348, Di Tanna, GL ; https://orcid.org/0000-0002-5470-3567, Arnott, C ; https://orcid.org/0000-0001-9370-9913, Cardoza, K, Kang, A ; https://orcid.org/0000-0002-0300-1282, Pollock, C, Agarwal, R, Bakris, G, Charytan, DM, de Zeeuw, D, Heerspink, HJL, Neal, B ; https://orcid.org/0000-0002-0490-7465, Wheeler, DC, Cannon, CP, Zhang, H, Zinman, B, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Levin, A, Mahaffey, KW, Jardine, M ; https://orcid.org/0000-0002-0160-2375, Brenner, BM, Greene, T, Jardine, MJ, Meininger, G, Li, N, Kolesnyk, I, Aizenberg, D, Pecoits-Filho, R, Cherney, D, Obrador, G, Chertow, G, Chang, T, Hawley, C, Ji, L, Wada, T, Jha, V ; https://orcid.org/0000-0002-8015-9470, Lim, SK, Lim-Abrahan, MA, Santos, F, Chae, DW, Hwang, SJ, Vazelov, E, Rychlík, I, Hadjadj, S, Krane, V, Rosivall, L, De Nicola, L, Dreval, A, Nowicki, M, Schiller, A, Distiller, L, Górriz, JL, Kolesnyk, M, David, Wheeler, C, Guerrero, RAA, 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, PDCG, Goycoa, C, Greloni, GC, Guinsburg, A, Hermida, S, Juncos, LI, Klyver, MI, Kraft, F, Krynski, F, Lanchiotti, PV, Leon de la Fuente, RA, Marchetta, N, Mele, P, Nicolai, S, Novoa, PA, Orio, SI, Yi, TW, Smyth, B ; https://orcid.org/0000-0003-1838-3348, Di Tanna, GL ; https://orcid.org/0000-0002-5470-3567, Arnott, C ; https://orcid.org/0000-0001-9370-9913, Cardoza, K, Kang, A ; https://orcid.org/0000-0002-0300-1282, Pollock, C, Agarwal, R, Bakris, G, Charytan, DM, de Zeeuw, D, Heerspink, HJL, Neal, B ; https://orcid.org/0000-0002-0490-7465, Wheeler, DC, Cannon, CP, Zhang, H, Zinman, B, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Levin, A, Mahaffey, KW, Jardine, M ; https://orcid.org/0000-0002-0160-2375, Brenner, BM, Greene, T, Jardine, MJ, Meininger, G, Li, N, Kolesnyk, I, Aizenberg, D, Pecoits-Filho, R, Cherney, D, Obrador, G, Chertow, G, Chang, T, Hawley, C, Ji, L, Wada, T, Jha, V ; https://orcid.org/0000-0002-8015-9470, Lim, SK, Lim-Abrahan, MA, Santos, F, Chae, DW, Hwang, SJ, Vazelov, E, Rychlík, I, Hadjadj, S, Krane, V, Rosivall, L, De Nicola, L, Dreval, A, Nowicki, M, Schiller, A, Distiller, L, Górriz, JL, Kolesnyk, M, David, Wheeler, C, Guerrero, RAA, 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, PDCG, Goycoa, C, Greloni, GC, Guinsburg, A, Hermida, S, Juncos, LI, Klyver, MI, Kraft, F, Krynski, F, Lanchiotti, PV, Leon de la Fuente, RA, Marchetta, N, Mele, P, Nicolai, S, Novoa, PA, and Orio, SI
Abstract: Rationale & Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study. Study Design: Secondary analysis of a randomized controlled trial. Setting & Participants: Participants in the CREDENCE trial. Intervention: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo. Outcomes: Primary composite outcome of kidney failure, doubling of serum creatinine concentration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Outcomes were evaluated by age at baseline (<60, 60-69, and ≥70 years) and sex in the intention-to-treat population using Cox regression models. Results: The mean age of the cohort was 63.0 ± 9.2 years, and 34% were female. Older age and female sex were independently associated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (a composite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.48-0.82], and 0.89 [0.61-1.29] for ages <60, 60-69, and ≥70 years, respectively; P = 0.3 for interaction) or sexes (HRs, 0.71 [95% CI, 0.54-0.95] and 0.69 [0.56-0.84] in women and men, respectively; P = 0.8 for interaction). No differences in safety outcomes by age group or sex were observed. Limitations: This was a post hoc analysis with multiple comparisons. Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the
Published: 2023

4. Anacetrapib: potential for the prevention and treatment of coronary heart disease

Author: Steen DL, Khera AV, and Cannon CP
Subjects: Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Dylan L Steen,1 Amit V Khera,2 Christopher P Cannon1 1TIMI Study Group, Cardiovascular Division, 2Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA Abstract: Despite major advances in cardiovascular care in recent decades, atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Statins have been shown to reduce cardiovascular events by 25%–40% in a dose-dependent fashion; yet additional therapies are needed to reduce vascular disease progression and acute thrombotic events. In addition to low-density lipoprotein cholesterol (LDL-C) reduction, other lipid risk factors, such as low high-density lipoprotein cholesterol (HDL-C), have created interest as therapeutic targets to lower cardiovascular risk. However, the absence of compelling data for incremental benefit of non-LDL-centric therapies in the statin era has limited their clinical use. A novel class of compounds, cholesteryl ester transfer protein (CETP) inhibitors, has demonstrated many potentially beneficial lipid-modifying effects. While in vitro and animal data for CETP inhibition have been encouraging, the initial enthusiasm for the class has been tempered by the failure of two CETP inhibitors (torcetrapib and dalcetrapib) in Phase III trials to reduce cardiovascular outcomes. Anacetrapib, a compound that causes near-complete CETP inhibition, has among its effects, robust reductions in LDL-C and lipoprotein(a) as well as dramatic increases in HDL-C. The ability of anacetrapib to reduce coronary disease events is being tested in the Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL) trial (NCT01252953). Keywords: anacetrapib, cholesteryl ester transfer protein, cholesteryl ester transfer protein inhibitor, atherosclerosis
Published: 2013

5. Effect of Canagliflozin on Total Cardiovascular Burden in Patients With Diabetes and Chronic Kidney Disease: A Post Hoc Analysis From the CREDENCE Trial

Author: Li, JW ; https://orcid.org/0000-0002-4384-8226, Arnott, C ; https://orcid.org/0000-0001-9370-9913, Heerspink, HJL, Mbiostat, QL, Cannon, CP, Wheeler, DC, Charytan, DM, Barraclough, J ; https://orcid.org/0000-0002-5093-9900, Figtree, GA, Agarwal, R, Bakris, G, de Zeeuw, D, Greene, T, Levin, A, Pollock, C, Zhang, H, Zinman, B, Mahaffey, KW, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Neal, B ; https://orcid.org/0000-0002-0490-7465, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Li, JW ; https://orcid.org/0000-0002-4384-8226, Arnott, C ; https://orcid.org/0000-0001-9370-9913, Heerspink, HJL, Mbiostat, QL, Cannon, CP, Wheeler, DC, Charytan, DM, Barraclough, J ; https://orcid.org/0000-0002-5093-9900, Figtree, GA, Agarwal, R, Bakris, G, de Zeeuw, D, Greene, T, Levin, A, Pollock, C, Zhang, H, Zinman, B, Mahaffey, KW, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Neal, B ; https://orcid.org/0000-0002-0490-7465, and Jardine, MJ ; https://orcid.org/0000-0002-0160-2375
Abstract: BACKGROUND: The sodium-glucose cotransporter 2 inhibitor canagliflozin reduced the risk of first cardiovascular composite events in the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial. In this post hoc analysis, we evaluated the effect of canagliflozin on total (first and recurrent) cardiovascular events. METHODS AND RESULTS: The CREDENCE trial compared canagliflozin or matching placebo in 4401 patients with type 2 diabetes, albuminuria, and estimated glomerular filtration rate of 30 to <90 mL/min per 1.73 m2, over a median of 2.6 years. The primary outcome was analyzed as a composite of any cardiovascular event including myocardial infarction, stroke, hospitalization for heart failure, hospitalization for unstable angina, and cardiovascular death. Negative binomial regression models were used to assess the effect of canagliflozin on the net burden of cardiovascular events. During the trial, 634 patients had 883 cardiovascular events, of whom 472 (74%) had just 1 cardiovascular event and 162 (26%) had multiple cardiovascular events. Canagliflozin reduced first cardiovascular events by 26% (hazard ratio, 0.74 [95% CI, 0.63– 0.86]; P<0.001) and total cardiovascular events by 29% (incidence rate ratio, 0.71 [95% CI, 0.59– 0.86]; P<0.001). The absolute risk difference per 1000 patients treated over 2.5 years was −44 (95% CI, −67 to −21) first cardiovascular events and −73 (95% CI, −114 to −33) total events. CONCLUSIONS: Canagliflozin reduced cardiovascular events, with a larger absolute benefit for total cardiovascular than first cardiovascular events. These findings provide further support for the benefit of continuing canagliflozin therapy after an initial event to prevent recurrent cardiovascular events.
Published: 2022

6. Canagliflozin and atrial fibrillation in type 2 diabetes mellitus: A secondary analysis from the CANVAS Program and CREDENCE trial and meta-analysis

Author: Li, C, Yu, J ; https://orcid.org/0000-0002-7401-7580, Hockham, C ; https://orcid.org/0000-0003-2126-5350, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Neuen, BL ; https://orcid.org/0000-0001-9276-8380, Badve, SV ; https://orcid.org/0000-0003-2269-312X, Houston, L ; https://orcid.org/0000-0003-0825-0373, Lee, VYJ ; https://orcid.org/0000-0002-9118-9835, Barraclough, JY ; https://orcid.org/0000-0002-5093-9900, Fletcher, RA, Mahaffey, KW, Heerspink, HJL, Cannon, CP, Neal, B ; https://orcid.org/0000-0002-0490-7465, Arnott, C ; https://orcid.org/0000-0001-9370-9913, Li, C, Yu, J ; https://orcid.org/0000-0002-7401-7580, Hockham, C ; https://orcid.org/0000-0003-2126-5350, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Neuen, BL ; https://orcid.org/0000-0001-9276-8380, Badve, SV ; https://orcid.org/0000-0003-2269-312X, Houston, L ; https://orcid.org/0000-0003-0825-0373, Lee, VYJ ; https://orcid.org/0000-0002-9118-9835, Barraclough, JY ; https://orcid.org/0000-0002-5093-9900, Fletcher, RA, Mahaffey, KW, Heerspink, HJL, Cannon, CP, Neal, B ; https://orcid.org/0000-0002-0490-7465, and Arnott, C ; https://orcid.org/0000-0001-9370-9913
Abstract: Aim: To assess the effects of canagliflozin on the incidence of atrial fibrillation/atrial flutter (AF/AFL) and other key cardiorenal outcomes in a pooled analysis of the CANVAS and CREDENCE trials. Materials and Methods: Participants with type 2 diabetes and high risk of cardiovascular disease or chronic kidney disease were included and randomly assigned to canagliflozin or placebo. We explored the effects of canagliflozin on the incidence of first AF/AFL events and AF/AFL-related complications (ischaemic stroke/transient ischaemic attack/hospitalization for heart failure). Major adverse cardiovascular events and a renal-specific outcome by baseline AF/AFL status were analysed using Cox regression models. Results: Overall, 354 participants experienced a first AF/AFL event. Canagliflozin had no detectable effect on AF/AFL (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.67-1.02) compared with placebo. Subgroup analysis, however, suggested a possible reduction in AF/AFL in those with no AF/AFL history (HR 0.78, 95% CI 0.62-0.99). Canagliflozin was also associated with a reduction in AF/AFL-related complications (HR 0.74, 95% CI 0.65-0.86). There was no evidence of treatment heterogeneity by baseline AF/AFL history for other key cardiorenal outcomes (all Pinteraction > 0.14). Meta-analysis of five sodium-glucose cotransporter-2 (SGLT2) inhibitor trials demonstrated a 19% reduction in AF/AFL events with active treatment (HR 0.81, 95% CI 0.72-0.92). Conclusions: Overall, a significant effect of canagliflozin on the incidence of AF/AFL events could not be shown, however, a possible reduction in AF/AFL events in those with no prior history requires further investigation. Meta-analysis suggests SGLT2 inhibition reduces AF/AFL incidence.
Published: 2022

7. Cardiovascular Effects of Canagliflozin in Relation to Renal Function and Albuminuria

Author: Sarraju, A, Bakris, G, Cannon, CP, Cherney, D, Damaraju, CV, Figtree, GA, Gogate, J, Greene, T, Heerspink, HJL, Januzzi, JL, Neal, B ; https://orcid.org/0000-0002-0490-7465, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Blais, J, Kosiborod, M, Levin, A, Lingvay, I, Weir, MR, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Mahaffey, KW, Sarraju, A, Bakris, G, Cannon, CP, Cherney, D, Damaraju, CV, Figtree, GA, Gogate, J, Greene, T, Heerspink, HJL, Januzzi, JL, Neal, B ; https://orcid.org/0000-0002-0490-7465, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Blais, J, Kosiborod, M, Levin, A, Lingvay, I, Weir, MR, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, and Mahaffey, KW
Abstract: Background: People with type 2 diabetes mellitus (T2DM) have elevated cardiovascular (CV) risk, including for hospitalization for heart failure (HHF). Canagliflozin reduced CV and kidney events in patients with T2DM and high CV risk or nephropathy in the CANVAS (CANagliflozin cardioVascular Assessment Study) Program and the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial. Objectives: The aim of this study was to assess the effects of canagliflozin on CV outcomes according to baseline estimated glomerular filtration rate (eGFR) and urine albumin:creatinine ratio (UACR) in pooled patient-level data from the CANVAS Program and CREDENCE trial. Methods: Canagliflozin effects on CV death or HHF were assessed by baseline eGFR (<45, 45-60, and >60 mL/min/1.73 m2) and UACR (<30, 30-300, and >300 mg/g). HRs and 95% CIs were estimated by using Cox regression models overall and according to subgroups. Results: A total of 14,543 participants from the CANVAS Program (N = 10,142) and the CREDENCE (N = 4,401) trial were included, with a mean age of 63 years, 35% female, 75% White, 13.2% with baseline eGFR <45 mL/min/1.73 m2, and 31.9% with UACR >300 mg/g. Rates of CV death or HHF increased as eGFR declined and/or UACR increased. Canagliflozin significantly reduced CV death or HHF compared with placebo (19.4 vs 28.0 events per 1,000 patient-years; HR: 0.70; 95% CI: 0.62-0.79), with consistent results across eGFR and UACR categories (all P interaction >0.40). Conclusions: Risk of CV death or HHF was higher in those with lower baseline eGFR and/or higher UACR. Canagliflozin consistently reduced CV death or HHF in participants with T2DM and high CV risk or nephropathy regardless of baseline renal function or level of albuminuria. (Canagliflozin Cardiovascular Assessment Study [CANVAS], NCT01032629; A Study of the Effects of Canagliflozin [JNJ-24831754] on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus [CA
Published: 2022

8. Cardiovascular and renal outcomes with canagliflozin in patients with peripheral arterial disease: Data from the CANVAS Program and CREDENCE trial

Author: Barraclough, JY ; https://orcid.org/0000-0002-5093-9900, Yu, J ; https://orcid.org/0000-0002-7401-7580, Figtree, GA, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Heerspink, HJL, Neuen, BL ; https://orcid.org/0000-0001-9276-8380, Cannon, CP, Mahaffey, KW, Schutte, AE ; https://orcid.org/0000-0001-9217-4937, Neal, B ; https://orcid.org/0000-0002-0490-7465, Arnott, C ; https://orcid.org/0000-0001-9370-9913, Barraclough, JY ; https://orcid.org/0000-0002-5093-9900, Yu, J ; https://orcid.org/0000-0002-7401-7580, Figtree, GA, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Heerspink, HJL, Neuen, BL ; https://orcid.org/0000-0001-9276-8380, Cannon, CP, Mahaffey, KW, Schutte, AE ; https://orcid.org/0000-0001-9217-4937, Neal, B ; https://orcid.org/0000-0002-0490-7465, and Arnott, C ; https://orcid.org/0000-0001-9370-9913
Abstract: Aim: To define the proportional and absolute benefits of the sodium-glucose co-transporter-2 inhibitor canagliflozin in patients with type 2 diabetes (T2D) with and without peripheral arterial disease (PAD). Materials and Methods: We pooled individual participant data from the CANVAS Program (n = 10 142) and CREDENCE trial (n = 4401). In this post hoc analysis, the main outcomes of interest were major adverse cardiovascular events (MACE: non-fatal myocardial infarction, non-fatal stroke or cardiovascular death), kidney outcomes, and extended major adverse limb events (MALE). Cox proportional hazards models were used to assess canagliflozin treatment effects in those with and without PAD. Absolute risk reductions per 1000 patients treated for 2.5 years were estimated using Poisson regression. Results: Of 14 543 participants, 3159 (21.7%) had PAD at baseline. In patients with PAD, canagliflozin reduced MACE (hazard ratio, 0.76; 95% confidence interval, 0.62-0.92), with similar relative benefits for other cardiovascular and kidney outcomes in participants with or without PAD at baseline (all Pinteraction >.268). There was no increase in the relative risk of extended MALE with canagliflozin, irrespective of baseline PAD history (Pinteraction >.864). The absolute benefits of canagliflozin were greater in those with PAD. Conclusions: Patients with T2D and PAD derived similar relative cardiorenal benefits from canagliflozin treatment but higher absolute benefits compared with those without PAD, with no increase in extended MALE.
Published: 2022

9. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

Author: Perkovic, V., Jardine, M. J., Neal, B., Bompoint, S., Heerspink, H. J. L., Charytan, D. M., Edwards, R., Agarwal, R., Bakris, G., Bull, S., Cannon, C. P., Capuano, G., Chu, P. -L., De Zeeuw, D., Greene, T., Levin, A., Pollock, C., Wheeler, D. C., Yavin, Y., Zhang, H., Zinman, B., Meininger, G., Brenner, B. M., Mahaffey, K. W., Perkovic, V, Mahaffey, Kw, Agarwal, R, Bakris, G, Brenner, Bm, Cannon, Cp, Charytan, Dm, de Zeeuw, D, Greene, T, Jardine, Mj, Heerspink, Hjl, Levin, A, Meininger, G, Neal, B, Pollock, C, Wheeler, Dc, Zhang, H, Zinman, B, Mcguire, Dk, Holman, R, Home, P, Scharfstein, D, Parfrey, P, Shahinfar, S, August, P, Chang, T, Sinha, Ad, Januzzi, J, Kolansky, D, Amerena, J, Hillis, G, Gorelick, P, Kissela, B, Kasner, S, Lindley, R, Fulcher, G, Ounadjela, S, Hufert, K, von Ingersleben, G, Gaglia, J, Harris, R, Hudson, M, Turchin, A, Cheifetz, A, Sheth, S, Feuerstein, J, Cohen, S, Jardine, M, Li, N, Kolesnyk, I, Aizenberg, D, Pecoits-Filho, R, Cherney, D 3rd, Obrador, G, Chertow, G, Hawley, C, Ji, L, Wada, T, Jha, V, Lim, Sk, Lim-Abrahan, Ma, Santos, F, Chae, Dw, Hwang, Sj, Vazelov, E, Rychlík, I, Hadjadj, S, Krane, V, Rosivall, L, De Nicola, L, Dreval, A, Nowicki, M, Schiller, A, Distiller, L, Górriz, Jl, Kolesnyk, M, Morren, F, Goykhman, S, David, C, Yost, L, Wang, H, Hettiarachchi, M, Thimmaiah, R, Koppolu, D, George, S, Schmidt, M, Ignjatovic, J, Chapin, L, Travis, K, Destree, M, Sood, V, Coffee, L, De Brouwer, K, Zaviriukha, V, Starzec, A, Koizumi, M, Lin, G, Chen, E, Lin, P, Leia, C, Mascaro, D, Amigo, A, Limos, A, Abrahamsen, I, Jaffer, S, Ahuad Guerrero RA, 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, Gonzalez Colaso PDC, Goycoa, C, Greloni, Gc, Guinsburg, A, Hermida, S, Juncos, Li, Klyver, Mi, Kraft, F, Krynski, F, Lanchiotti, Pv, Leon de la Fuente RA, Marchetta, N, Mele, P, Nicolai, S, Novoa, Pa, Orio, Si, Otreras, F, Oviedo, A, Raffaele, P, Resk, Jh, Rista, L, Rodriguez Papini, N, Sala, J, Santos, Jc, Schiavi, Lb, Sessa, H, Smith Casabella, T, 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, Alves da Costa FA, Amodeo, C, Andreotti Turatti LA, Bregman, R, Camelo Sanches FC, Canani, Lh, Chacra, Ar, Cunha Borges JL, Cunha Vêncio SA, da Silva Franco RJ, D'Avila, D, de Souza Portes, E, de Souza, P, Deboni, Lm, Filho, Ff, Geloneze Neto, B, Gomes, M, Kohara, Sk, Keitel, E, Kerr Saraiva JF, Kurtz Lisboa HR, de Carvalho Contieri FL, Milagres, R, Montenegro Junior, R, Moreira de Brito, C, Nazzer Hissa, M, Nazario Sabbag ÂR, Noronha, I, Panarotto, D, Pecoits Filho, R, Pereira, Ma, Saporito, W, Scotton, As, Schuch, T, Simões de Almeida, R, Slompo Ramos, C, Soares Felício, J, Thomé, F, Tibes Hachmann JC, Yamada, S, Yoiti Hayashida, C, 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, Chouinard, G, Conway, J, Cournoyer, S, Daroza, G, De Serres, S, Dubé, 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, Fernández Montenegro MA, Godoy Jorquera JG, Medina Fariña, 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, Higuera, Jd, Malaver, N, Molina de Salazar DI, 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, Jp, Gourdy, P, Klein, A, Le Meur, Y, Penfornis, A, Roussel, R, Saulnier, Pj, 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, Haase, Fp, Moreira Diaz JP, Ramirez Roca LA, Sánchez 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, Derosa, G, Di Carlo, A, Di Cianni, G, Frascà, 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, Wakasugi, M, Wakida, Y, Watanabe, T, Yamada, M, Yanagida, K, Yanase, T, Yumita, W, Gaupsiene, E, Kozloviene, D, Navickas, A, Urbanaviciene, E, Abdul Ghani, R, Abdul Kadir, K, Ali, N, Che Yusof MD, Gan, Cl, Ismail, M, Kong, Wy, Lam, Sw, Lee, Ly, Loh, Cl, Manocha, Ab, Ng, Ks, Nik Ahmad NNF, Ratnasingam, V, Bin Shudim SS, Vengadasalam, P, Abraira Munoz LD, Salazar, Ma, Cruz, Jb, Soto, Mb, Ramos, Jc, Wong, Ac, 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 Florez, F, Laviada Molina, H, Luna Ceballos RI, Martin Del Camp Blanco, B, 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, Saaveddra Sanchez SB, Sanchez Mijangos JH, Serrano Sanson, P, Tamayo, Y Orozco JA, Tellez Chavez, E, Valdes Depeda, 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, 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, Orlowska-Kowalik, G, Popenda, G, Rewerska, B, Sowinski, D, Angelescu, Lm, Anghel, V, Avram, Ri, Busegeanu, Mm, 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, Ae, Serafinceanu, C, Toarba, C, Agafyina, A, Barbarash, O, Barysheva, O, Chizhov, D, Dobronravov, V, 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, 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, Cho, Ym, Jeong, Ik, Kim, Sg, Kim, Yh, Kwon, Hs, Kwon, Mj, Lee, Bw, Lee, J, Lee, Mk, Nam, Ms, Oh, Kh, Park, Cy, Park, Sh, Yoon, Kh, Alvarez Garcia, P, Asmarats Mercadal, L, Barrios, C, Cereto Castro, F, Cigarran Guldris, S, Dominquez Lopez, M, Egido de Los Rios, J, Fernandez Fresnedo, G, Galan Serrano, A, Garcia, I, Gonzalez Martinez FJ, Jodar Gimeno JE, Muñoz Lopez Mendoza, M, Malek Marin, T, Morales Portillo, C, Munar Vila MA, Muñoz Torres, M, Nieto Iglesias, J, Pantoja Perez, J, Perez Vera, M, Portoles Perez JM, Quesada Simón MA, Simo Canonge, R, Soto Gonzalez, A, Terns Riera, M, Tinahones Madueno FJ, Plaza, Mv, Chang, Ct, Chuang, Lm, Hsia, Tl, Hsieh, Ch, Lin, Cc, Lu, Yc, Sheu, Wh, Barna, O, Bilyk, Sd, Botsyurko, V, Dudar, I, Fushtey, I, Godlevska, O, Golovchenko, O, Gyrina, O, Kazmirchuk, A, 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, 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, Mujica Trenche, S, 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., Perkovic, Vlado, Jardine, Meg J, Neal, Bruce, Bompoint, Severine, Heerspink, Hiddo J L, Charytan, David M, Edwards, Robert, Agarwal, Rajiv, Bakris, George, Bull, Scott, Cannon, Christopher P, Capuano, George, Chu, Pei-Ling, de Zeeuw, Dick, Greene, Tom, Levin, Adeera, Pollock, Carol, Wheeler, David C, Yavin, Yshai, Zhang, Hong, Zinman, Bernard, Meininger, Gary, Brenner, Barry M, Mahaffey, Kenneth W, collaborator: Perkovic, V, Mahaffey, Kw, Agarwal, R, Bakris, G, Brenner, Bm, Cannon, Cp, Charytan, Dm, de Zeeuw, D, Greene, T, Jardine, Mj, Heerspink, Hjl, Levin, A, Meininger, G, Neal, B, Pollock, C, Wheeler, Dc, Zhang, H, Zinman, B, Mcguire, Dk, Holman, R, Home, P, Scharfstein, D, Parfrey, P, Shahinfar, S, August, P, Chang, T, Sinha, Ad, Januzzi, J, Kolansky, D, Amerena, J, Hillis, G, Gorelick, P, Kissela, B, Kasner, S, Lindley, R, Fulcher, G, Ounadjela, S, Hufert, K, von Ingersleben, G, Gaglia, J, Harris, R, Hudson, M, Turchin, A, Cheifetz, A, Sheth, S, Feuerstein, J, Cohen, S, Jardine, M, Li, N, Kolesnyk, I, Aizenberg, D, Pecoits-Filho, R, Cherney, D 3rd, Obrador, G, Chertow, G, Hawley, C, Ji, L, Wada, T, Jha, V, Lim, Sk, Lim-Abrahan, Ma, Santos, F, Chae, Dw, Hwang, Sj, Vazelov, E, Rychlík, I, Hadjadj, S, Krane, V, Rosivall, L, De Nicola, L, Dreval, A, Nowicki, M, Schiller, A, Distiller, L, Górriz, Jl, Kolesnyk, M, Morren, F, Goykhman, S, David, C, Yost, L, Wang, H, Hettiarachchi, M, Thimmaiah, R, Koppolu, D, George, S, Schmidt, M, Ignjatovic, J, Chapin, L, Travis, K, Destree, M, Sood, V, Coffee, L, De Brouwer, K, Zaviriukha, V, Starzec, A, Koizumi, M, Lin, G, Chen, E, Lin, P, Leia, C, Mascaro, D, Amigo, A, Limos, A, Abrahamsen, I, Jaffer, S, Ahuad Guerrero, Ra, 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, Gonzalez Colaso, Pdc, Goycoa, C, Greloni, Gc, Guinsburg, A, Hermida, S, Juncos, Li, Klyver, Mi, Kraft, F, Krynski, F, Lanchiotti, Pv, Leon de la Fuente, Ra, Marchetta, N, Mele, P, Nicolai, S, Novoa, Pa, Orio, Si, Otreras, F, Oviedo, A, Raffaele, P, Resk, Jh, Rista, L, Rodriguez Papini, N, Sala, J, Santos, Jc, Schiavi, Lb, Sessa, H, Smith Casabella, T, 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, Alves da Costa, Fa, Amodeo, C, Andreotti Turatti, La, Bregman, R, Camelo Sanches, Fc, Canani, Lh, Chacra, Ar, Cunha Borges, Jl, Cunha Vêncio, Sa, da Silva Franco, Rj, D'Avila, D, de Souza Portes, E, de Souza, P, Deboni, Lm, Filho, Ff, Geloneze Neto, B, Gomes, M, Kohara, Sk, Keitel, E, Kerr Saraiva, Jf, Kurtz Lisboa, Hr, de Carvalho Contieri, Fl, Milagres, R, Montenegro Junior, R, Moreira de Brito, C, Nazzer Hissa, M, Nazario Sabbag, Âr, Noronha, I, Panarotto, D, Pecoits Filho, R, Pereira, Ma, Saporito, W, Scotton, A, Schuch, T, Simões de Almeida, R, Slompo Ramos, C, Soares Felício, J, Thomé, F, Tibes Hachmann, Jc, Yamada, S, Yoiti Hayashida, C, 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, Chouinard, G, Conway, J, Cournoyer, S, Daroza, G, De Serres, S, Dubé, 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, Fernández Montenegro, Ma, Godoy Jorquera, Jg, Medina Fariña, 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, Higuera, Jd, Malaver, N, Molina de Salazar, Di, 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, Jp, Gourdy, P, Klein, A, Le Meur, Y, Penfornis, A, Roussel, R, Saulnier, Pj, 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, Haase, Fp, Moreira Diaz, Jp, Ramirez Roca, La, Sánchez 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, R, 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, Derosa, G, Di Carlo, A, Di Cianni, G, Frascà, 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 et al, Groningen Kidney Center (GKC), and Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET)
Subjects: Aged, Canagliflozin, Cardiovascular Diseases, Creatinine, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Double-Blind Method, Female, Follow-Up Studies, Glomerular Filtration Rate, Humans, Kidney Failure, Chronic, Male, Middle Aged, Sodium-Glucose Transporter 2 Inhibitors, Type 2 diabetes, 030204 cardiovascular system & hematology, Diabetic nephropathy, Kidney Failure, chemistry.chemical_compound, 0302 clinical medicine, 030212 general & internal medicine, 03.02. Klinikai orvostan, Dapagliflozin, Chronic, 11 Medical and Health Sciences, EMPAGLIFLOZIN, General Medicine, Life Sciences & Biomedicine, Type 2, medicine.drug, medicine.medical_specialty, Nephropathy, 03 medical and health sciences, Medicine, General & Internal, Internal medicine, Diabetes mellitus, General & Internal Medicine, CREDENCE Trial Investigators, medicine, Diabetes Mellitus, Science & Technology, business.industry, urogenital system, diabetic nephropathy, Type 2 Diabetes Mellitus, KIDNEY-DISEASE, medicine.disease, chemistry, business, Kidney disease
Abstract: BACKGROUND: Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS: In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin-angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of
Published: 2019

10. Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease

Author: Bhatt, Dl, Szarek, M, Pitt, B, Cannon, Cp, Leiter, La, Mcguire, Dk, Lewis, Jb, Riddle, Mc, Inzucchi, Se, Kosiborod, Mn, Cherney, Dzi, Dwyer, Jp, Scirica, Bm, Bailey, Cj, Díaz, R, Ray, Kk, Udell, Ja, Lopes, Rd, Lapuerta, P, Steg, Gabriel, P, and Lauro, D
Subjects: Male, SAXAGLIPTIN, 030204 cardiovascular system & hematology, Saxagliptin, MELLITUS, chemistry.chemical_compound, 0302 clinical medicine, Settore MED/13, Glycosides, 030212 general & internal medicine, 11 Medical and Health Sciences, RISK, SGLT2 INHIBITOR, OUTCOMES, Kidney, EMPAGLIFLOZIN, General Medicine, Middle Aged, Hospitalization, medicine.anatomical_structure, Cardiovascular Diseases, HEART-FAILURE, Diarrhea/chemically induced, Female, OUTPATIENTS, Life Sciences & Biomedicine, Diarrhea, medicine.medical_specialty, SCORED Investigators, Mycoses/etiology, Diabetic ketoacidosis, Renal Insufficiency, Chronic/complications, Glycosides/adverse effects, Diabetic Ketoacidosis, 03 medical and health sciences, Medicine, General & Internal, Sodium-Glucose Transporter 1, Double-Blind Method, General & Internal Medicine, Internal medicine, Diabetes mellitus, medicine, Empagliflozin, Humans, Renal Insufficiency, Chronic, Sodium-Glucose Transporter 2 Inhibitors, Aged, Hospitalization/statistics & numerical data, Science & Technology, Diabetic Ketoacidosis/chemically induced, urogenital system, business.industry, MORTALITY, Cardiovascular Diseases/epidemiology, Diabetes Mellitus, Type 2/complications, Sodium-Glucose Transporter 2 Inhibitors/adverse effects, medicine.disease, CARDIOVASCULAR EVENT RATES, Clinical trial, Mycoses, chemistry, Diabetes Mellitus, Type 2, Sodium-Glucose Transporter 1/antagonists & inhibitors, Heart failure, business, Kidney disease
Abstract: In a trial involving 10,584 patients with diabetes and chronic kidney disease, sotagliflozin resulted in fewer total deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure than placebo. Diarrhea, mycotic infections, and diabetic ketoacidosis occurred with sotagliflozin. Background The efficacy and safety of sodium-glucose cotransporter 2 inhibitors such as sotagliflozin in preventing cardiovascular events in patients with diabetes with chronic kidney disease with or without albuminuria have not been well studied. Methods We conducted a multicenter, double-blind trial in which patients with type 2 diabetes mellitus (glycated hemoglobin level, >= 7%), chronic kidney disease (estimated glomerular filtration rate, 25 to 60 ml per minute per 1.73 m(2) of body-surface area), and risks for cardiovascular disease were randomly assigned in a 1:1 ratio to receive sotagliflozin or placebo. The primary end point was changed during the trial to the composite of the total number of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure. The trial ended early owing to loss of funding. Results Of 19,188 patients screened, 10,584 were enrolled, with 5292 assigned to the sotagliflozin group and 5292 assigned to the placebo group, and followed for a median of 16 months. The rate of primary end-point events was 5.6 events per 100 patient-years in the sotagliflozin group and 7.5 events per 100 patient-years in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.63 to 0.88; P
Published: 2021
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11. Ertugliflozin and slope of chronic egfr prespecified analyses from the randomized vertis cv trial

Author: Cherney, Dzi, Cosentino, F, Dagogo-Jack, S, Mcguire, Dk, Pratley, R, Frederich, R, Maldonado, M, Liu, Cc, Liu, J, Pong, A, Cannon, Cp, VERTIS CV Investigators, Lembo, G, Pugliese, G., Cherney, D. Z. I., Cosentino, F., Dagogo-Jack, S., Mcguire, D. K., Pratley, R., Frederich, R., Maldonado, M., Liu, C. -C., Liu, J., Pong, A., Cannon, C. P., and Paolisso, G
Subjects: Male, medicine.medical_specialty, type 2 diabetes mellitu, Epidemiology, type 2 diabetes mellitus, Population, Urology, Renal function, clinical trial, diabetic nephropathy, glomerular filtration rate, renal function decline, renal protection, sodium-glucose cotransporter 2 inhibitor, Critical Care and Intensive Care Medicine, Placebo, Diabetic nephropathy, Sodium-Glucose Transporter 2, medicine, Humans, Hypoglycemic Agents, education, Sodium-Glucose Transporter 2 Inhibitors, Aged, Transplantation, education.field_of_study, business.industry, Type 2 Diabetes Mellitus, Original Articles, Middle Aged, Bridged Bicyclo Compounds, Heterocyclic, medicine.disease, Confidence interval, Clinical trial, Diabetes Mellitus, Type 2, Nephrology, Atherosclerosi, Diabetic Nephropathie, Female, business, Human, Kidney disease
Abstract: BACKGROUND AND OBJECTIVES: A reduction in the rate of eGFR decline, with preservation of ≥0.75 ml/min per 1.73 m(2) per year, has been proposed as a surrogate for kidney disease progression. We report results from prespecified analyses assessing effects of ertugliflozin versus placebo on eGFR slope from the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes (VERTIS CV) trial (NCT01986881). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease were randomized to placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg (1:1:1). The analyses compared the effect of ertugliflozin (pooled doses, n=5499) versus placebo (n=2747) on eGFR slope per week and per year by random coefficient models. Study periods (weeks 0–6 and weeks 6–52) and total and chronic slopes (week 0 or week 6 to weeks 104, 156, 208, and 260) were modeled separately and by baseline kidney status. RESULTS: In the overall population, for weeks 0–6, the least squares mean eGFR slopes (ml/min per 1.73 m(2) per week [95% confidence interval (95% CI)]) were −0.07 (−0.16 to 0.03) and −0.54 (−0.61 to −0.48) for the placebo and ertugliflozin groups, respectively; the difference was −0.47 (−0.59 to −0.36). During weeks 6–52, least squares mean eGFR slopes (ml/min per 1.73 m(2) per year [95% CI]) were −0.12 (−0.70 to 0.46) and 1.62 (1.21 to 2.02) for the placebo and ertugliflozin groups, respectively; the difference was 1.74 (1.03 to 2.45). For weeks 6–156, least squares mean eGFR slopes (ml/min per 1.73 m(2) per year [95% CI]) were −1.51 (−1.70 to −1.32) and −0.32 (−0.45 to −0.19) for the placebo and ertugliflozin groups, respectively; the difference was 1.19 (0.95 to 1.42). During weeks 0–156, the placebo-adjusted difference in least squares mean slope was 1.06 (0.85 to 1.27). These findings were consistent by baseline kidney status. CONCLUSIONS: Ertugliflozin has a favorable placebo-adjusted eGFR slope >0.75 ml/min per 1.73 m(2) per year, documenting the kidney function preservation underlying the clinical benefits of ertugliflozin on kidney disease progression in patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: US National Library of Medicine, ClinicalTrials.gov NCT01986881. Date of trial registration: November 13, 2013.
Published: 2021

12. Corrigendum

Author: Yu, J, Arnott, C, Neuen, BL ; https://orcid.org/0000-0001-9276-8380, Heersprink, HL, Mahaffey, KW, Cannon, CP, Khan, SS, Baldridge, AS, Shah, SJ, Huang, Y, Li, C, Figtree, GA, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Neal, B ; https://orcid.org/0000-0002-0490-7465, Huffman, MD ; https://orcid.org/0000-0001-7412-2519, Yu, J, Arnott, C, Neuen, BL ; https://orcid.org/0000-0001-9276-8380, Heersprink, HL, Mahaffey, KW, Cannon, CP, Khan, SS, Baldridge, AS, Shah, SJ, Huang, Y, Li, C, Figtree, GA, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Neal, B ; https://orcid.org/0000-0002-0490-7465, and Huffman, MD ; https://orcid.org/0000-0001-7412-2519
Published: 2021

13. Effects of canagliflozin on hyperkalaemia and serum potassium in people with diabetes and chronic kidney disease: insights from the CREDENCE trial

Author: Neuen, BL, Oshima, M, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Arnott, C ; https://orcid.org/0000-0001-9370-9913, Bakris, G, Cannon, CP, Charytan, DM, Jardine, M ; https://orcid.org/0000-0002-0160-2375, Levin, A, Neal, B ; https://orcid.org/0000-0002-0490-7465, Pollock, C, Wheeler, DC, Mahaffey, KW, Heerspink, HJL, Neuen, BL, Oshima, M, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Arnott, C ; https://orcid.org/0000-0001-9370-9913, Bakris, G, Cannon, CP, Charytan, DM, Jardine, M ; https://orcid.org/0000-0002-0160-2375, Levin, A, Neal, B ; https://orcid.org/0000-0002-0490-7465, Pollock, C, Wheeler, DC, Mahaffey, KW, and Heerspink, HJL
Published: 2021

14. Cardiovascular and renal outcomes with canagliflozin according to baseline diuretic use: a post hoc analysis from the CANVAS Program

Author: Yu, J ; https://orcid.org/0000-0002-7401-7580, Arnott, C ; https://orcid.org/0000-0001-9370-9913, Neuen, BL ; https://orcid.org/0000-0001-9276-8380, Heersprink, HL, Mahaffey, KW, Cannon, CP, Khan, SS, Baldridge, AS, Shah, SJ, Huang, Y, Li, C, Figtree, GA, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Neal, B ; https://orcid.org/0000-0002-0490-7465, Huffman, MD ; https://orcid.org/0000-0001-7412-2519, Yu, J ; https://orcid.org/0000-0002-7401-7580, Arnott, C ; https://orcid.org/0000-0001-9370-9913, Neuen, BL ; https://orcid.org/0000-0001-9276-8380, Heersprink, HL, Mahaffey, KW, Cannon, CP, Khan, SS, Baldridge, AS, Shah, SJ, Huang, Y, Li, C, Figtree, GA, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Neal, B ; https://orcid.org/0000-0002-0490-7465, and Huffman, MD ; https://orcid.org/0000-0001-7412-2519
Abstract: Aims: The CANVAS Program identified the effect of canagliflozin on major adverse cardiovascular events (MACE) differed according to whether participants were using diuretics at study commencement. We sought to further evaluate this finding related to baseline differences, treatment effects, safety, and risk factor changes. Methods and results: The CANVAS Program enrolled 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk. Participants were randomized to canagliflozin or placebo and followed for a mean of 188 weeks. The primary outcome was major cardiovascular events, a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included multiple cardiovascular, renal, and safety events. In this post hoc subgroup analysis, participants were categorized according to baseline use of any diuretic. The effect on outcomes was compared using Cox proportional hazards models, while risk factor changes were compared using mixed-effect models. At baseline, 4490 (44.3%) participants were using a diuretic. Compared with those not using a diuretic, participants using a diuretic were more likely to be older (mean age ± standard deviation, 64.3 ± 8.0 vs. 62.5 ± 8.3), be female (38.9% vs. 33.4%), and have heart failure (19.6% vs. 10.3%) (all Pdifference < 0.0001). The effect of canagliflozin on major cardiovascular events was greater for those using diuretic at baseline than for those who were not [adjusted hazard ratio 0.65 (95% confidence interval 0.54–0.78) vs. adjusted hazard ratio 1.13 (95% confidence interval 0.93–1.36), Pheterogeneity < 0.0001]. Changes in most risk factors, including blood pressure, body weight, and urine albumin-to-creatinine ratio, were similar between groups (all Pdifference > 0.11), although the effect of canagliflozin on haemoglobin A1c reduction was slightly weaker in participants using compared with not using diuretics at baseline (−0.52% vs. −0.64%, Pheterogeneity = 0.0007). Ov
Published: 2021

15. Kidney, cardiovascular, and safety outcomes of canagliflozin according to baseline albuminuria a credence secondary analysis

Author: Jardine, M ; https://orcid.org/0000-0002-0160-2375, Zhou, Z ; https://orcid.org/0000-0001-6543-7113, Lambers Heerspink, HJ, Hockham, C ; https://orcid.org/0000-0003-2126-5350, Li, Q ; https://orcid.org/0000-0002-4384-8226, Agarwal, R, Bakris, GL, Cannon, CP, Charytan, DM, Greene, T, Levin, A, Li, JW, Neuen, BL ; https://orcid.org/0000-0001-9276-8380, Neal, B ; https://orcid.org/0000-0002-0490-7465, Oh, R, Oshima, M, Pollock, C, Wheeler, DC, de Zeeuw, D, Zhang, H, Zinman, B, Mahaffey, KW, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Jardine, M ; https://orcid.org/0000-0002-0160-2375, Zhou, Z ; https://orcid.org/0000-0001-6543-7113, Lambers Heerspink, HJ, Hockham, C ; https://orcid.org/0000-0003-2126-5350, Li, Q ; https://orcid.org/0000-0002-4384-8226, Agarwal, R, Bakris, GL, Cannon, CP, Charytan, DM, Greene, T, Levin, A, Li, JW, Neuen, BL ; https://orcid.org/0000-0001-9276-8380, Neal, B ; https://orcid.org/0000-0002-0490-7465, Oh, R, Oshima, M, Pollock, C, Wheeler, DC, de Zeeuw, D, Zhang, H, Zinman, B, Mahaffey, KW, and Perkovic, V ; https://orcid.org/0000-0002-4257-7620
Abstract: Background and objectives The kidney protective effects of renin-angiotensin system inhibitors are greater in people with higher levels of albuminuria at treatment initiation. Whether this applies to sodium-glucose cotransporter 2 (SGLT2) inhibitors is uncertain, particularly in patients with a very high urine albumin-to-creatinine ratio (UACR; ≥3000 mg/g). We examined the association between baseline UACR and the effects of the SGLT2 inhibitor, canagliflozin, on efficacy and safety outcomes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) randomized controlled trial. Design, setting, participants, & measurements The study enrolled 4401 participants with type 2 diabetes, an eGFR of 30 to <90 ml/min per 1.73 m2, and UACR of >300 to 5000 mg/g. Using Cox proportional hazards regression, we examined the relative and absolute effects of canagliflozin on kidney, cardiovascular, and safety outcomes according to a baseline UACR of ≤1000 mg/g (n=2348), >1000 to <3000 mg/g (n=1547), and ≥3000 mg/g (n=506). In addition, we examined the effects of canagliflozin on UACR itself, eGFR slope, and the intermediate outcomes of glycated hemoglobin, body weight, and systolic BP. Results Overall, higher UACR was associated with higher rates of kidney and cardiovascular events. Canagliflozin reduced efficacy outcomes for all UACR levels, with no evidence that relative benefits varied between levels. For example, canagliflozin reduced the primary composite outcome by 24% (hazard ratio [HR], 0.76; 95% confidence interval [95% CI], 0.56 to 1.04) in the lowest UACR subgroup, 28% (HR, 0.72; 95% CI, 0.56 to 0.93) in the UACR subgroup >1000 to <3000 mg/g, and 37% (HR, 0.63; 95% CI, 0.47 to 0.84) in the highest subgroup (Pheterogeneity=0.55). Absolute risk reductions for kidney outcomes were greater in participants with higher baseline albuminuria; the number of primary composite events prevented across ascending UACR categories wer
Published: 2021

16. Blood Pressure Effects of Canagliflozin and Clinical Outcomes in Type 2 Diabetes and Chronic Kidney Disease: Insights From the CREDENCE Trial

Author: Ye, N, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Oshima, M, Hockham, C ; https://orcid.org/0000-0003-2126-5350, Heerspink, HJL, Agarwal, R, Bakris, G, Schutte, AE ; https://orcid.org/0000-0001-9217-4937, Arnott, C ; https://orcid.org/0000-0001-9370-9913, Chang, TI, Górriz, JL, Cannon, CP, Charytan, DM, De Zeeuw, D, Levin, A, Mahaffey, KW, Neal, B ; https://orcid.org/0000-0002-0490-7465, Pollock, C, Wheeler, DC, Luca Di Tanna, G, Cheng, H, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Neuen, BL ; https://orcid.org/0000-0001-9276-8380, Di Tanna, Gian Luca ; https://orcid.org/0000-0002-5470-3567, Ye, N, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Oshima, M, Hockham, C ; https://orcid.org/0000-0003-2126-5350, Heerspink, HJL, Agarwal, R, Bakris, G, Schutte, AE ; https://orcid.org/0000-0001-9217-4937, Arnott, C ; https://orcid.org/0000-0001-9370-9913, Chang, TI, Górriz, JL, Cannon, CP, Charytan, DM, De Zeeuw, D, Levin, A, Mahaffey, KW, Neal, B ; https://orcid.org/0000-0002-0490-7465, Pollock, C, Wheeler, DC, Luca Di Tanna, G, Cheng, H, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Neuen, BL ; https://orcid.org/0000-0001-9276-8380, and Di Tanna, Gian Luca ; https://orcid.org/0000-0002-5470-3567
Abstract: Background: People with type 2 diabetes and chronic kidney disease experience a high burden of hypertension, but the magnitude and consistency of blood pressure (BP) lowering with canagliflozin in this population are uncertain. Whether the effects of canagliflozin on kidney and cardiovascular outcomes vary by baseline BP or BP-lowering therapy is also unknown. Methods: The CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) randomized people with type 2 diabetes and chronic kidney disease to canagliflozin or placebo. In a post hoc analysis, we investigated the effect of canagliflozin on systolic BP across subgroups defined by baseline systolic BP, number of BP-lowering drug classes, and history of apparent treatment-resistant hypertension (BP ≥130/80 mm Hg while receiving ≥3 classes of BP-lowering drugs, including a diuretic). We also assessed whether effects on clinical outcomes differed across these subgroups. Results: The trial included 4401 participants, of whom 3361 (76.4%) had baseline systolic BP ≥130 mm Hg, and 1371 (31.2%) had resistant hypertension. By week 3, canagliflozin reduced systolic BP by 3.50 mm Hg (95% CI, -4.27 to -2.72), an effect maintained over the duration of the trial, with similar reductions across BP and BP-lowering therapy subgroups (all P interaction ≥0.05). Canagliflozin also reduced the need for initiation of additional BP-lowering agents during the trial (hazard ratio, 0.68 [95% CI, 0.61-0.75]). The effect of canagliflozin on kidney failure, doubling of serum creatinine, or death caused by kidney or cardiovascular disease (hazard ratio, 0.70 [95% CI, 0.59-0.82]) was consistent across BP and BP-lowering therapy subgroups (all P interaction ≥0.35), as were effects on other key kidney, cardiovascular, and safety outcomes. Conclusions: In people with type 2 diabetes and chronic kidney disease, canagliflozin lowers systolic BP across all BP-defined subgroups and reduces the need for
Published: 2021

17. Effects of canagliflozin on cardiovascular, renal, and safety outcomes in participants with type 2 diabetes and chronic kidney disease according to history of heart failure: Results from the CREDENCE trial

Author: Sarraju, A, Li, JW, Cannon, CP, Chang, TI, Agarwal, R, Bakris, G, Charytan, DM, de Zeeuw, D, Greene, T, Heerspink, HJL, Levin, A, Neal, B ; https://orcid.org/0000-0002-0490-7465, Pollock, C, Wheeler, DC, Yavin, Y, Zhang, H, Zinman, B, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Jardine, M ; https://orcid.org/0000-0002-0160-2375, Mahaffey, KW, Sarraju, A, Li, JW, Cannon, CP, Chang, TI, Agarwal, R, Bakris, G, Charytan, DM, de Zeeuw, D, Greene, T, Heerspink, HJL, Levin, A, Neal, B ; https://orcid.org/0000-0002-0490-7465, Pollock, C, Wheeler, DC, Yavin, Y, Zhang, H, Zinman, B, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Jardine, M ; https://orcid.org/0000-0002-0160-2375, and Mahaffey, KW
Abstract: We aimed to assess the efficacy and safety of canagliflozin in patients with type 2 diabetes and nephropathy according to prior history of heart failure in the Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) trial. We found that participants with a prior history of heart failure at baseline (15%) were more likely to be older, female, white, have a history of atherosclerotic cardiovascular disease, and use diuretics and beta blockers (all P < .001), and that, compared with placebo, canagliflozin safely reduced renal and cardiovascular events with consistent effects in patients with and without a prior history of heart failure (all efficacy P interaction >.150). These results support the efficacy and safety of canagliflozin in patients with type 2 diabetes and nephropathy regardless of prior history of heart failure.
Published: 2021

18. Effect of SGLT2 inhibitors on stroke and atrial fibrillation in diabetic kidney disease: Results from the CREDENCE trial and meta-analysis

Author: Zhou, Z ; https://orcid.org/0000-0001-6543-7113, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Li, Q ; https://orcid.org/0000-0002-4384-8226, Neuen, BL ; https://orcid.org/0000-0001-9276-8380, Cannon, CP, De Zeeuw, D, Edwards, R, Levin, A, Mahaffey, KW, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Neal, B ; https://orcid.org/0000-0002-0490-7465, Lindley, RI, 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, Del Carmen Gonzalez Colaso, P, 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, Borges, JLC, Vêncio, SAC, Da Silva Franco, RJ, D'Avila, D, De Souza Portes, E, De Souza, P, Phillips, Andrea, Zhou, Z ; https://orcid.org/0000-0001-6543-7113, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Li, Q ; https://orcid.org/0000-0002-4384-8226, Neuen, BL ; https://orcid.org/0000-0001-9276-8380, Cannon, CP, De Zeeuw, D, Edwards, R, Levin, A, Mahaffey, KW, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Neal, B ; https://orcid.org/0000-0002-0490-7465, Lindley, RI, 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, Del Carmen Gonzalez Colaso, P, 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, Borges, JLC, Vêncio, SAC, Da Silva Franco, RJ, D'Avila, D, De Souza Portes, E, De Souza, P, and Phillips, Andrea
Abstract: BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-Analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus. METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-Analysis. RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: Total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]). CONCLUSIONS: Although we found no clear effect
Published: 2021

19. 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 ; https://orcid.org/0000-0002-0160-2375, Agarwal, R, Bakris, G, Cannon, CP, Charytan, DM, de Zeeuw, D, Edwards, R, Greene, T, Levin, A, Lim, SK, Mahaffey, KW, Neal, B ; https://orcid.org/0000-0002-0490-7465, Pollock, C, Rosenthal, N, Wheeler, DC, Zhang, H, Zinman, B, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Heerspink, HJL, Oshima, M, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Agarwal, R, Bakris, G, Cannon, CP, Charytan, DM, de Zeeuw, D, Edwards, R, Greene, T, Levin, A, Lim, SK, Mahaffey, KW, Neal, B ; https://orcid.org/0000-0002-0490-7465, Pollock, C, Rosenthal, N, Wheeler, DC, Zhang, H, Zinman, B, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, 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

20. Effects of canagliflozin on hyperkalaemia and serum potassium in people with diabetes and chronic kidney disease: insights from the CREDENCE trial

Author: Neuen, BL ; https://orcid.org/0000-0001-9276-8380, Oshima, M, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Arnott, C ; https://orcid.org/0000-0001-9370-9913, Bakris, G, Cannon, CP, Charytan, DM, Jardine, M ; https://orcid.org/0000-0002-0160-2375, Levin, A, Neal, B ; https://orcid.org/0000-0002-0490-7465, Pollock, C, Wheeler, DC, Mahaffey, KW, Heerspink, HJL, Neuen, BL ; https://orcid.org/0000-0001-9276-8380, Oshima, M, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Arnott, C ; https://orcid.org/0000-0001-9370-9913, Bakris, G, Cannon, CP, Charytan, DM, Jardine, M ; https://orcid.org/0000-0002-0160-2375, Levin, A, Neal, B ; https://orcid.org/0000-0002-0490-7465, Pollock, C, Wheeler, DC, Mahaffey, KW, and Heerspink, HJL
Abstract: 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 (RAAS), 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. We sought to assess the effect of canagliflozin on hyperkalaemia and other potassium-related outcomes in people with T2DM and CKD by conducting a post-hoc analysis of the CREDENCE trial. 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. Canagliflozin reduced the risk of investigator-reported hyperkalaemia or initiation of potassium binders (HR 0.78, 95% CI 0.64–0.95, p=0.014; Figure 1). The incidence of laboratory-determined hyperkalaemia was similarly reduced (HR 0.77, 95% CI 0.61–0.98, p=0.031; Figure 2); the risk of hypokalaemia (HR 0.92, 95% CI 0.71–1.20, p=0.53) was not increased. Mean serum potassium over time with canagliflozin was similar to that of placebo. Among patients treated with RAAS 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. Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: The CREDENCE trial

Author: Neuen, BL ; https://orcid.org/0000-0001-9276-8380, Oshima, M, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Agarwal, R, Arnott, C ; https://orcid.org/0000-0001-9370-9913, Bakris, G, Cannon, CP, Charytan, DM, Edwards, R, Górriz, JL, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Levin, A, Neal, B ; https://orcid.org/0000-0002-0490-7465, De Nicola, L, Pollock, C, Rosenthal, N, Wheeler, DC, Mahaffey, KW, Heerspink, HJL, Neuen, BL ; https://orcid.org/0000-0001-9276-8380, Oshima, M, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Agarwal, R, Arnott, C ; https://orcid.org/0000-0001-9370-9913, Bakris, G, Cannon, CP, Charytan, DM, Edwards, R, Górriz, JL, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Levin, A, Neal, B ; https://orcid.org/0000-0002-0490-7465, 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

22. The effect of sex on the efficacy and safety of dual antithrombotic therapy with dabigatran versus triple therapy with warfarin after PCI in patients with atrial fibrillation (a RE-DUAL PCI subgroup analysis and comparison to other dual antithrombotic therapy trials)

Author: Eccleston, DS, Kim, JM, ten Berg, JM, Steg, PG, Bhatt, DL, Hohnloser, SH, de Veer, A, Nordaby, M, Miede, C, Kimura, T, Lip, GYH, Oldgren, J, Cannon, CP, Eccleston, DS, Kim, JM, ten Berg, JM, Steg, PG, Bhatt, DL, Hohnloser, SH, de Veer, A, Nordaby, M, Miede, C, Kimura, T, Lip, GYH, Oldgren, J, and Cannon, CP
Abstract: BACKGROUND: The RE-DUAL PCI trial demonstrated that in patients with nonvalvular atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI), dual therapy with dabigatran and a P2Y12 inhibitor, either clopidogrel or ticagrelor, reduced the risk of bleeding without an increased risk of thromboembolic events as compared to triple therapy with warfarin in addition to a P2Y12 inhibitor and aspirin. What remains unclear is whether this effect is consistent between males and females undergoing PCI. HYPOTHESIS: The reduction in risk of bleeding without increased risk of thromboembolic events with dual therapy with dabigatran and a P2Y12 inhibitor in comparison to triple therapy with warfarin, a P2Y12 inhibitor and aspirin is consistent in females and males. METHODS: The primary safety endpoint was the first International Society on Thrombosis and Hemostasis (ISTH) major bleeding event (MBE) or clinically relevant non-major bleeding event (CRNMBE). The efficacy endpoint was the composite of death, thromboembolic event (stroke, myocardial infarction, and systemic embolism) or unplanned revascularization. Cox proportional hazard regression analyses were applied to calculate corresponding hazard ratios and interaction p values for each endpoint. RESULTS: A total of 655 women and 2070 men were enrolled. The risk of major or CRNM bleeding was lower with both dabigatran 110 mg dual therapy and dabigatran 150 mg dual therapy compared with warfarin triple therapy in female and male patients (for 110 mg: females: HR 0.69, 95% CI 0.47-1.01, males: HR 0.46, 95% CI 0.37-0.59, interaction p value: 0.084 and for 150 mg: females HR 0.74, 95% CI 0.48-1.16, males HR 0.71, 95% CI 0.56-0.90, interaction p value: 0.83). There was also no detectable difference in the composite efficacy endpoint of death, thromboembolic events or unplanned revascularization between dabigatran dual therapy and warfarin triple therapy, with no statistically significant interaction between sex and
Published: 2021

23. Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease Results From the CREDENCE Trial and Meta-Analysis

Author: Zhou, Z, Jardine, MJ, Li, Q, Neuen, BL, Cannon, CP, de Zeeuw, D, Edwards, R, Levin, A, Mahaffey, KW, Perkovic, V, Neal, B, Lindley, RI, Zhou, Z, Jardine, MJ, Li, Q, Neuen, BL, Cannon, CP, de Zeeuw, D, Edwards, R, Levin, A, Mahaffey, KW, Perkovic, V, Neal, B, and Lindley, RI
Abstract: BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus. METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis. RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (<45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]). CONCLUSIONS: Although we found no clear effect
Published: 2021

24. Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes

Author: Cannon, Cp, Pratley, R, Dagogo-Jack, S, Mancuso, J, Huyck, S, Masiukiewicz, U, Charbonnel, B, Frederich, R, Gallo, S, Cosentino, F, Shih, Wj, Gantz, I, Terra, Sg, Cherney, Dzi, Mcguire, Dk, VERTIS CV Investigators, Pugliese, G, Lembo, G, Cannon, C. P., Pratley, R., Dagogo-Jack, S., Mancuso, J., Huyck, S., Masiukiewicz, U., Charbonnel, B., Frederich, R., Gallo, S., Cosentino, F., Shih, W. J., Paolisso, G, Gantz, I., Terra, S. G., Cherney, D. Z. I., and Mcguire, D. K.
Subjects: Male, medicine.medical_specialty, ertugliflozin, MEDLINE, type 2 diabetes, cardiovascular disease, Type 2 diabetes, 030204 cardiovascular system & hematology, law.invention, Placebos, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Double-Blind Method, law, Internal medicine, Diabetes mellitus, Humans, Medicine, Diabetic Nephropathies, 030212 general & internal medicine, Sodium-Glucose Transporter 2 Inhibitors, Placebo, Aged, urogenital system, business.industry, General Medicine, Middle Aged, Atherosclerosis, medicine.disease, Bridged Bicyclo Compounds, Heterocyclic, Hospitalization, Equivalence Trial, Multicenter study, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Atherosclerosi, Diabetic Nephropathie, Ertugliflozin, Female, business, Cardiovascular outcomes, Human
Abstract: The cardiovascular effects of ertugliflozin, an inhibitor of sodium-glucose cotransporter 2, have not been established.In a multicenter, double-blind trial, we randomly assigned patients with type 2 diabetes and atherosclerotic cardiovascular disease to receive 5 mg or 15 mg of ertugliflozin or placebo once daily. With the data from the two ertugliflozin dose groups pooled for analysis, the primary objective was to show the noninferiority of ertugliflozin to placebo with respect to the primary outcome, major adverse cardiovascular events (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The noninferiority margin was 1.3 (upper boundary of a 95.6% confidence interval for the hazard ratio [ertugliflozin vs. placebo] for major adverse cardiovascular events). The first key secondary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure.A total of 8246 patients underwent randomization and were followed for a mean of 3.5 years. Among 8238 patients who received at least one dose of ertugliflozin or placebo, a major adverse cardiovascular event occurred in 653 of 5493 patients (11.9%) in the ertugliflozin group and in 327 of 2745 patients (11.9%) in the placebo group (hazard ratio, 0.97; 95.6% confidence interval [CI], 0.85 to 1.11; P0.001 for noninferiority). Death from cardiovascular causes or hospitalization for heart failure occurred in 444 of 5499 patients (8.1%) in the ertugliflozin group and in 250 of 2747 patients (9.1%) in the placebo group (hazard ratio, 0.88; 95.8% CI, 0.75 to 1.03; P = 0.11 for superiority). The hazard ratio for death from cardiovascular causes was 0.92 (95.8% CI, 0.77 to 1.11), and the hazard ratio for death from renal causes, renal replacement therapy, or doubling of the serum creatinine level was 0.81 (95.8% CI, 0.63 to 1.04). Amputations were performed in 54 patients (2.0%) who received the 5-mg dose of ertugliflozin and in 57 patients (2.1%) who received the 15-mg dose, as compared with 45 patients (1.6%) who received placebo.Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, ertugliflozin was noninferior to placebo with respect to major adverse cardiovascular events. (Funded by Merck SharpDohme and Pfizer; VERTIS CV ClinicalTrials.gov number, NCT01986881.).
Published: 2020

25. 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 ; https://orcid.org/0000-0002-0490-7465, Oh, R, Pollock, C, Rosenthal, N, Wheeler, DC, Zhang, H, Zinman, B, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, 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 ; https://orcid.org/0000-0002-0490-7465, Oh, R, Pollock, C, Rosenthal, N, Wheeler, DC, Zhang, H, Zinman, B, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, and Perkovic, V ; https://orcid.org/0000-0002-4257-7620
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

26. 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 ; https://orcid.org/0000-0001-9370-9913, Li, J-W, Cannon, CP, Neuen, BL ; https://orcid.org/0000-0001-9276-8380, Heerspink, HJL, Neal, B ; https://orcid.org/0000-0002-0490-7465, Charytan, DM, Bakris, G, Chang, T-H, Rosenthal, N, Zinman, B, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Mahaffey, KW, de Zeeuw, D, Arnott, C ; https://orcid.org/0000-0001-9370-9913, Li, J-W, Cannon, CP, Neuen, BL ; https://orcid.org/0000-0001-9276-8380, Heerspink, HJL, Neal, B ; https://orcid.org/0000-0002-0490-7465, Charytan, DM, Bakris, G, Chang, T-H, Rosenthal, N, Zinman, B, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, and Mahaffey, KW
Published: 2020

27. Sodium-Glucose Cotransporter 2 Inhibition for the Prevention of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis

Author: Arnott, C ; https://orcid.org/0000-0001-9370-9913, Li, Q, Kang, A ; https://orcid.org/0000-0002-0300-1282, Neuen, BL ; https://orcid.org/0000-0001-9276-8380, Bompoint, S, Lam, CSP, Rodgers, A ; https://orcid.org/0000-0003-1282-1896, Mahaffey, KW, Cannon, CP, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Neal, B ; https://orcid.org/0000-0002-0490-7465, Arnott, C ; https://orcid.org/0000-0001-9370-9913, Li, Q, Kang, A ; https://orcid.org/0000-0002-0300-1282, Neuen, BL ; https://orcid.org/0000-0001-9276-8380, Bompoint, S, Lam, CSP, Rodgers, A ; https://orcid.org/0000-0003-1282-1896, Mahaffey, KW, Cannon, CP, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, and Neal, B ; https://orcid.org/0000-0002-0490-7465
Abstract: Background: Several trials have demonstrated protective effects from inhibition of sodium-glucose cotransporter 2 among patients with type 2 diabetes mellitus. There is uncertainty about the consistency of the cardiovascular benefits achieved across patient subsets. Methods and Results: We included 4 large-scale trials of sodium-glucose cotransporter 2 inhibition compared with placebo in patients with diabetes mellitus that reported effects on cardiovascular outcomes overall and for participant subgroups defined at baseline by cardiovascular disease, reduced kidney function, and heart failure. Fixed effects models with inverse variance weighting were used to estimate summary hazard ratios and 95% CIs. There were 38 723 patients from 4 trials, with a mean 2.9 years of follow-up. Of the patients, 22 870 (59%) had cardiovascular disease, 7754 (20%) had reduced kidney function, and 4543 (12%) had heart failure. There were 3828 major adverse cardiac events. There was overall benefit for major adverse cardiac events (0.88; 95% CI, 0.82–0.94; P<0.001) and no evidence that the effects of sodium-glucose cotransporter 2 inhibition varied across patient subgroups, defined by the presence of cardiovascular disease or heart failure at baseline (all P interaction >0.252; I2<25%). All patient subgroups benefited with respect to hospitalization for heart failure (all P interaction>0.302; I2<10%), cardiovascular death (all P interaction>0.167; I2<50%), and death from any cause (all P interaction>0.354; I2=0%). The only difference in effects across subgroups was for stroke, with protection observed among those with reduced kidney function but not those with preserved kidney function (P interaction=0.020; I2=81%). Conclusions: Sodium-glucose cotransporter 2 inhibitors protect against cardiovascular disease and death in diverse subsets of patients with type 2 diabetes mellitus regardless of cardiovascular disease history.
Published: 2020

28. 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 ; https://orcid.org/0000-0001-9370-9913, Neuen, BL ; https://orcid.org/0000-0001-9276-8380, Heerspink, HJL, Figtree, GA, Kosiborod, M, Lam, CS, Cannon, CP, Rosenthal, N, Shaw, W, Mahaffey, KW, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Neal, B ; https://orcid.org/0000-0002-0490-7465, Arnott, C ; https://orcid.org/0000-0001-9370-9913, Neuen, BL ; https://orcid.org/0000-0001-9276-8380, Heerspink, HJL, Figtree, GA, Kosiborod, M, Lam, CS, Cannon, CP, Rosenthal, N, Shaw, W, Mahaffey, KW, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, and Neal, B ; https://orcid.org/0000-0002-0490-7465
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

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

Author: Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Zhou, Z ; https://orcid.org/0000-0001-6543-7113, Mahaffey, KW, Oshima, M, Agarwal, R, Bakris, G, Bajaj, HS, Bull, S, Cannon, CP, Charytan, DM, De Zeeuw, D, Di Tanna, GL ; https://orcid.org/0000-0002-5470-3567, Greene, T, Heerspink, HJL, Levin, A, Neal, B ; https://orcid.org/0000-0002-0490-7465, Pollock, C, Qiu, R, Sun, T, Wheeler, DC, Zhang, H, Zinman, B, Rosenthal, N, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Zhou, Z ; https://orcid.org/0000-0001-6543-7113, Mahaffey, KW, Oshima, M, Agarwal, R, Bakris, G, Bajaj, HS, Bull, S, Cannon, CP, Charytan, DM, De Zeeuw, D, Di Tanna, GL ; https://orcid.org/0000-0002-5470-3567, Greene, T, Heerspink, HJL, Levin, A, Neal, B ; https://orcid.org/0000-0002-0490-7465, Pollock, C, Qiu, R, Sun, T, Wheeler, DC, Zhang, H, Zinman, B, Rosenthal, N, and Perkovic, V ; https://orcid.org/0000-0002-4257-7620
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

30. 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

31. 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, 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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, and Zaniewski-Singh, M
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

32. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

Author: Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Neal, B ; https://orcid.org/0000-0002-0490-7465, Bompoint, S, Heerspink, HJL, Charytan, DM, Edwards, R, Agarwal, R, Bakris, G, Bull, S, Cannon, CP, Capuano, G, Chu, PL, De Zeeuw, D, Greene, T, Levin, A, Pollock, C, Wheeler, DC, Yavin, Y, Zhang, H, Zinman, B, Meininger, G, Brenner, BM, Mahaffey, KW, Jha, Vivekanand ; https://orcid.org/0000-0002-8015-9470, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Neal, B ; https://orcid.org/0000-0002-0490-7465, Bompoint, S, Heerspink, HJL, Charytan, DM, Edwards, R, Agarwal, R, Bakris, G, Bull, S, Cannon, CP, Capuano, G, Chu, PL, De Zeeuw, D, Greene, T, Levin, A, Pollock, C, Wheeler, DC, Yavin, Y, Zhang, H, Zinman, B, Meininger, G, Brenner, BM, Mahaffey, KW, and Jha, Vivekanand ; https://orcid.org/0000-0002-8015-9470
Abstract: BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular dea
Published: 2019

33. The canagliflozin and renal endpoints in diabetes with established nephropathy clinical evaluation (CREDENCE) study rationale, design, and baseline characteristics

Author: Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Mahaffey, KW, Neal, B ; https://orcid.org/0000-0002-0490-7465, Agarwal, R, Bakris, GL, Brenner, BM, Bull, S, Cannon, CP, Charytan, DM, De Zeeuw, D, Edwards, R, Greene, T, Heerspink, HJL, Levin, A, Pollock, C, Wheeler, DC, Xie, J, Zhang, H, Zinman, B, Desai, M, Perkovic, V ; https://orcid.org/0000-0002-4257-7620, Jardine, MJ ; https://orcid.org/0000-0002-0160-2375, Mahaffey, KW, Neal, B ; https://orcid.org/0000-0002-0490-7465, Agarwal, R, Bakris, GL, Brenner, BM, Bull, S, Cannon, CP, Charytan, DM, De Zeeuw, D, Edwards, R, Greene, T, Heerspink, HJL, Levin, A, Pollock, C, Wheeler, DC, Xie, J, Zhang, H, Zinman, B, Desai, M, and Perkovic, V ; https://orcid.org/0000-0002-4257-7620
Abstract: © 2017 S. Karger AG, Basel. Background: People with diabetes and kidney disease have a high risk of cardiovascular events and progression of kidney disease. Sodium glucose co-transporter 2 inhibitors lower plasma glucose by reducing the uptake of filtered glucose in the kidney tubule, leading to increased urinary glucose excretion. They have been repeatedly shown to induce modest natriuresis and reduce HbA1c, blood pressure, weight, and albuminuria in patients with type 2 diabetes. However, the effects of these agents on kidney and cardiovascular events have not been extensively studied in patients with type 2 diabetes and established kidney disease. Methods: The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial aims to compare the efficacy and safety of canagliflozin versus placebo at preventing clinically important kidney and cardiovascular outcomes in patients with diabetes and established kidney disease. CREDENCE is a randomized, double- blind, event-driven, placebo-controlled trial set in in 34 countries with a projected duration of 5.5 years and enrolling 4,401 adults with type 2 diabetes, estimated glomerular filtration rate =30 to <90 mL/min/1.73 m2, and albuminuria (urinary albumin:creatinine ratio >300 to =5,000 mg/g). The study has 90% power to detect a 20% reduction in the risk of the primary outcome (a = 0.05), the composite of end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death. Conclusion: CREDENCE will provide definitive evidence about the effects of canagliflozin on renal (and cardiovascular) outcomes in patients with type 2 diabetes and established kidney disease. Trial Registration: EudraCT number: 2013-004494-28; ClinicalTrials.gov identifier: NCT02065791.
Published: 2018

34. The relative safety and efficacy of clopidogrel in women and men: Meta-analysis of 79,613 patients enrolled in CREDO, CURE, CLARITY-TIMI 28, COMMIT, and CHARISMA

Author: Berger, JS, Bhatt, DL, Cannon, CP, Chen, Z, Jones, JB, Mehta, SR, Sabatine, MS, Steinhubl, SR, Topol, EJ, and Berger, PB
Published: 2016

35. Prevention of post-operative atrial fibrillation by statin pre-treatment in patients undergoing cardiac surgery: a collaborative patient level meta-analysis of 11 randomized studies

Author: Patti G., Cannon CP, Mega S., Bennet R., Ray KK, Cavallari I, Ricottini E., Chello M., Di Sciascio G., MANNACIO, VITO ANTONIO, Patti, G., Cannon, Cp, Mega, S., Bennet, R., Ray, Kk, Cavallari, I, Ricottini, E., Chello, M., Mannacio, VITO ANTONIO, and Di Sciascio, G.
Published: 2012

36. A comparison of the health status and psychological distress of partners of patients with a left ventricular assist device versus an implantable cardioverter defibrillator

Author: Brouwers, CJ, Caliskan, Kadir, de Jonge, N, Theuns, Dominic, Constantinescu, Alina, Young, QR, Cannon, CP, Denollet, J, Pedersen, Susanne, Cardiothoracic Surgery, and Cardiology
Published: 2015

37. Impact of Empagliflozin on Blood Pressure in Patients with Type 2 Diabetes Mellitus and Hypertension by Background Antihypertensive Medication

Author: Mancia, G, Cannon, C, Tikkanen, I, Zeller, C, Ley, L, Woerle, H, Broedl, U, Johansen, O, Cannon, CP, Woerle, HJ, Broedl, UC, Johansen, OE, Mancia, G, Cannon, C, Tikkanen, I, Zeller, C, Ley, L, Woerle, H, Broedl, U, Johansen, O, Cannon, CP, Woerle, HJ, Broedl, UC, and Johansen, OE
Abstract: In the EMPA-REG BP trial, empagliflozin 10 mg and 25 mg once daily reduced glycohemoglobin, blood pressure (BP), and weight versus placebo in patients with type 2 diabetes mellitus and hypertension. Patients received placebo (n=271), empagliflozin 10 mg (n=276), or empagliflozin 25 mg (n=276) for 12 weeks (n=full analysis set). This present analysis investigated changes from baseline to week 12 in mean 24-hour systolic BP (SBP) and diastolic BP (DBP) in patients receiving 0, 1, or ≥2 antihypertensive medications and patients receiving/not receiving diuretics or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. Compared with placebo, empagliflozin 10 mg and 25 mg reduced mean 24-hour SBP/DBP in patients receiving 0 (10 mg: -3.89/-2.58 mm Hg; 25 mg: -3.77/-2.45 mm Hg), 1 (10 mg: -4.74/-1.97 mm Hg; 25 mg: -4.27/-1.81 mm Hg), or ≥2 (10 mg: -2.36/-0.68 mm Hg; 25 mg: -4.17/-1.54 mm Hg) antihypertensives. The effect of empagliflozin was not significantly different between subgroups by number of antihypertensives for changes in SBP (interaction P value 0.448) or DBP (interaction P value 0.498). Empagliflozin reduced 24-hour mean SBP/DBP irrespective of diuretic or angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, with no significant difference between subgroups by use/no use of diuretics (interaction P values 0.380 [systolic]; 0.240 [diastolic]) or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (interaction P values 0.900 [systolic]; 0.359 [diastolic]). In conclusion, in patients with type 2 diabetes mellitus and hypertension, empagliflozin for 12 weeks reduced SBP and DBP versus placebo, irrespective of the number of antihypertensives and use of diuretics or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. Clinical Trial Registration - URL: https://clinicaltrials.gov. Unique identifier: NCT01370005.
Published: 2016

38. Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes

Author: White, WB, Cannon, CP, Heller, SR, Nissen, SE, Bergenstal, RM, Bakris, GL, Perez, AT, Fleck, PR, Mehta, CR, Kupfer, S, Wilson, C, Cushman, WC Zannad, F, and Knežević, Aleksandar
Abstract: To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies. We assessed cardiovascular outcomes with alogliptin, a new inhibitor of dipeptidyl peptidase 4 (DPP-4), as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome. We randomly assigned patients with type 2 diabetes and either an acute myocar - dial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days to receive alogliptin or placebo in addition to existing antihyperglycemic and cardiovascular drug therapy. The study design was a double-blind, noninferiority trial with a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point of a composite of death from cardiovascular causes, nonfatal myo - cardial infarction, or nonfatal stroke. A total of 5380 patients underwent randomization and were followed for up to 40 months (median, 18 months). A primary end-point event occurred in 305 patients assigned to alogliptin (11.3%) and in 316 patients assigned to placebo (11.8%) (haz - ard ratio, 0.96 ; upper boundary of the one-sided repeated confidence interval, 1.16 ; P
Published: 2013

39. BP reduction with the sodium glucose co-transporter 2 inhibitor (SGLT-2i) empagliflozin (EMPA) in type 2 diabetes (T2D) is similar in treatment naïve as in those on one or ≥2 antihypertensive agents – further insights from a dedicated 24h ABPM study

Author: Mancia, G, primary, Cannon, CP, additional, Tikkanen, I, additional, Zeller, C, additional, Ley, L, additional, Hach, T, additional, Woerle, HJ, additional, Broedl, UC, additional, and Johansen, OE, additional
Published: 2015
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40. Empagliflozin, ein Inhibitor des natriumabhängigen Glukose-Co-Transporters SGLT2, senkt den Blutdruck und Marker für arterielle Steifigkeit sowie den Gefäßwiderstand bei Typ-2-Diabetes

Author: Chilton, R, primary, Tikkanen, I, additional, Cannon, CP, additional, Crowe, S, additional, Hach, T, additional, Woerle, HJ, additional, Broedl, UC, additional, and Johansen, OE, additional
Published: 2015
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41. Effect of Rosiglitazone on Progression of Coronary Atherosclerosis in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease

Author: Gerstein, HC, Ratner, RE, Cannon, CP, Serruys, PWJC (Patrick), Garcia Garcia, Hector, Es, Gerrit-anne, Kolatkar, NS, Kravitz, BG, Miller, DM, Huang, C, Fitzgerald, PJ, Nesto, RW, and Cardiology
Subjects: SDG 3 - Good Health and Well-being
Abstract: Background-Rosiglitazone has several properties that may affect progression of atherosclerosis. The Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Diabetes Patients With Cardiovascular History (APPROACH) study was undertaken to determine the effect of the thiazolidinedione rosiglitazone on coronary atherosclerosis as assessed by intravascular ultrasound compared with the sulfonylurea glipizide. Methods and Results-This was a randomized, double-blind, controlled 18-month study in 672 patients aged 30 to 80 years with established type 2 diabetes mellitus treated by lifestyle, 1 oral agent, or submaximal doses of 2 oral agents who had at least 1 atherosclerotic plaque with 10% to 50% luminal narrowing in a coronary artery that had not undergone intervention during a clinically indicated coronary angiography or percutaneous coronary intervention. The primary outcome was change in percent atheroma volume in the longest and least angulated epicardial coronary artery that had not undergone intervention. Secondary outcomes included change in normalized total atheroma volume and change in total atheroma volume in the most diseased baseline 10-mm segment. Rosiglitazone did not significantly reduce the primary outcome of percent atheroma volume compared with glipizide (-0.64%; 95% confidence interval, -1.46 to 0.17; P=0.12). The secondary outcome of normalized total atheroma volume was significantly reduced by rosiglitazone compared with glipizide (-5.1 mm(3); 95% confidence interval, -10.0 to -0.3; P=0.04); however, no significant difference between groups was observed for the change in total atheroma volume within the most diseased baseline 10-mm segment (-1.7 mm(3); 95% confidence interval, -3.9 to 0.5; P=0.13). Conclusions-Rosiglitazone did not significantly decrease the primary end point of progression of coronary atherosclerosis more than glipizide in patients with type 2 diabetes mellitus and coronary atherosclerosis.
Published: 2010

42. National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine Practice Guidelines: analytical issues for biochemical markers of acute coronary syndromes

Author: Morrow, David A., Cannon, CP, Jesse, Robert L., Newby, L. Kristin, Ravkilde, Jan, Storrow, Alan B., Wu, Alan H.B., Christenson, Robert H., Apple, Fred. S., Francis, Gary, and Tang, Wilson
Published: 2007

43. Collaborative meta-analysis of individual participant data from observationalstudies of Lp-PLA2 and cardiovascular diseases

Author: THE LP PLA STUDIES COLLABORATION, Ballantyne, C, Cushman, M, Psaty, B, Furberg, C, Khaw, Kt, Sandhu, M, Oldgren, J, Rossi, Gianpaolo, Maiolino, G, Cesari, M, Lenzini, Livia, James, Sk, Rimm, E, Collins, R, Anderson, J, Koenig, W, Brenner, H, Rothenbacher, D, Berglund, G, Persson, M, Berger, P, Brilakis, E, Mcconnell, Jp, Sacco, R, Elkind, M, Talmud, P, Cannon, Cp, Packard, C, BARRETT CONNOR, E, Hofman, A, Kardys, I, Witteman, Jc, Criqui, M, Corsetti, Jp, Rainwater, Dl, Moss, Aj, Robins, S, Bloomfield, H, Collins, D, WASSERTHEIL SMOLLER, S, Ridker, P, Danesh, J, Gu, D, Nelson, Jj, Thompson, S, Zalewski, A, Zariffa, N, DI ANGELANTONIO, E, Kaptoge, S, Thompson, A, Walker, M, Watson, S, and Wood, A.
Published: 2007

44. American college of cardiology key data elements and definitions for measuring the clinical management and joutcomes of patiens with acute coronary syndromes

Author: ACC writing committee,, Cannon, CP, Simoons, Maarten, and Cardiology
Published: 2001

45. Early invasive vs conservative treatment strategies in women and men with unstable angina and non-ST-segment elevation myocardial infarction : A meta-analysis

Author: ODonoghue, M, Boden, WE, Braunwald, E, Cannon, CP, Clayton, TC, de Winter, RJ, Fox, KA, Lagerqvist, B, McCullough, PA, Murphy, SA, Spacek, R, Swahn, Eva, Wallentin, L, Windhausen, F, Sabatine, MS, ODonoghue, M, Boden, WE, Braunwald, E, Cannon, CP, Clayton, TC, de Winter, RJ, Fox, KA, Lagerqvist, B, McCullough, PA, Murphy, SA, Spacek, R, Swahn, Eva, Wallentin, L, Windhausen, F, and Sabatine, MS
Abstract: Context: Although an invasive strategy is frequently used in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS), data from some trials suggest that this strategy may not benefit women. Objective: To conduct a meta-analysis of randomized trials to compare the effects of an invasive vs conservative strategy in women and men with NSTE ACS. Data Sources: Trials were identified through a computerized literature search of the MEDLINE and Cochrane databases (1970-April 2008) using the search terms invasive strategy, conservative strategy, selective invasive strategy, acute coronary syndromes, non-ST-elevation myocardial infarction, and unstable angina. Study Selection: Randomized clinical trials comparing an invasive vs conservative treatment strategy in patients with NSTE ACS. Data Extraction: The principal investigators for each trial provided the sex-specific incidences of death, myocardial infarction (MI), and rehospitalization with ACS through 12 months of follow-up. Data Synthesis: Data were combined across 8 trials (3075 women and 7075 men). The odds ratio (OR) for the composite of death, MI, or ACS for invasive vs conservative strategy in women was 0.81 (95% confidence interval [CI], 0.65-1.01, 21.1% vs 25.0%) and in men was 0.73 (95% CI, 0.55-0.98, 21.2% vs 26.3%) without significant heterogeneity between sexes (P for interaction = .26). Among biomarker-positive women, an invasive strategy was associated with a 33% lower odds of death, MI, or ACS (OR, 0.67, 95% CI, 0.50-0.88) and a nonsignificant 23% lower odds of death or MI (OR, 0.77, 95% CI, 0.47-1.25). In contrast, an invasive strategy was not associated with a significant reduction in the triple composite end point in biomarker-negative women (OR, 0.94, 95% CI, 0.61-1.44, P for interaction = .36) and was associated with a nonsignificant35%higher odds of death or MI (OR, 1.35, 95% CI, 0.78-2.35, P for interaction = .08). Among men, the OR for death, MI, or ACS was 0.56 (95% CI, 0.46-0.6
Published: 2008
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46. CV3: INFLUENCE OF DIABETES AND BASELINE ST-SEGMENT CHANGE STATUS ON THE COST-EFFECTIVENESS OF AN EARLY INVASIVE VS. CONSERVATIVE STRATEGY FOR THE TREATMENT OF ACUTE CORONARY SYNDROMES:APPLICATION OF A NET-BENEFIT REGRESSION APPROACH TO DATA FROM THE TACTICS-TIMI 18 TRIAL

Author: Mahoney, EM, primary, Chu, H, additional, Jurkovitz, CT, additional, Cannon, CP, additional, Alexander, C, additional, Nag, S, additional, and Weintraub, WS, additional
Published: 2003
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47. Influence of insurance type on the use of procedures, medications, and hospital outcome in patients with unstable angina

Author: Every, NR., primary, Cannon, CP., additional, and C, Granger, additional
Published: 1999
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48. Ticagrelor versus clopidogrel in elderly patients with acute coronary syndromes: a substudy from the Prospective Randomized PLATelet Inhibition and Patient Outcomes (PLATO) trial.

Author: Husted S, James S, Becker RC, Horrow J, Katus H, Storey RF, Cannon CP, Heras M, Lopes RD, Morais J, Mahaffey KW, Bach RG, Wojdyla D, Wallentin L, and PLATO study group
Published: 2012

49. Guideline Adherence After ST-Segment Elevation Versus Non-ST Segment Elevation Myocardial Infarction.

Author: Somma KA, Bhatt DL, Fonarow GC, Cannon CP, Cox M, Laskey W, Peacock WF, Hernandez AF, Peterson ED, Schwamm L, and Saxon LA
Published: 2012
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50. Trends in patients hospitalized with heart failure and preserved left ventricular ejection fraction: prevalence, therapies, and outcomes.

Author: Steinberg BA, Zhao X, Heidenreich PA, Peterson ED, Bhatt DL, Cannon CP, Hernandez AF, Fonarow GC, and Get With the Guidelines Scientific Advisory Committee and Investigators
Published: 2012
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