BackgroundCanagliflozin is a sodium–glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on cardiovascular, renal, and safety outcomes. MethodsThe CANVAS Program integrated data from two trials involving a total of 10,142 participants with type 2 diabetes and high cardiovascular risk. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. ResultsThe mean age of the participants was 63.3 years, 35.8% were women, the mean duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease. The rate of the primary outcome was lower with canagliflozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio, 0.86; 95% c...

/pdf/canagliflozin-and-cardiovascular-and-renal-events-in-type-2-2rzuupndw9.pdf

Canagliflozin and cardiovascular and renal events in type 2 diabetes

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...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1811744

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

https://minerva-access.unimelb.edu.au/bitstream/handle/11343/238777/Global, regional, and national burden of chronic kidney.pdf

Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) 

Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR) 

ABI
: ankle-brachial index

/pdf/2016-esc-eas-guidelines-for-the-management-of-dyslipidaemias-3oe2qnm09b.pdf

2016 ESC/EAS Guidelines for the Management of Dyslipidaemias

KDOQI Clinical Practice Guideline for Vascular Access: 2019 Update.

Multifaceted Quality Improvement Interventions to Prevent Hemodialysis Catheter-Related Bloodstream Infections: A Systematic Review.

AKI occurs in up to 21% of hospitalized patients, affecting about 13.3 million people a year globally, and has significant effects on short- and long-term morbidity and mortality ([1][1]). The long-term sequelae of AKI are many, and include higher rates of mortality and CKD. The role of recurrent

Forever Starts Now: Effects of Glucose-Lowering Therapies on Acute Kidney Injury


 
 
 IgA nephropathy (IgAN) is the leading cause of primary glomerulonephritis. Approximately 30-45% of IgAN patients progress to ESKD over a period of 20-25 years and proteinuria is the strongest predictor of disease progression. Endothelin A (ETA) receptor activation drives proteinuria, kidney inflammation and fibrosis. Atrasentan, a potent and selective ETA antagonist, has potential to reduce proteinuria and preserve kidney function in IgAN. Interim results of a phase 2, open-label study in patients with IgAN (AFFINITY, NCT04573920) demonstrated that atrasentan was well tolerated and resulted in clinically meaningful and sustained proteinuria reductions in patients receiving a maximally tolerated and optimized dose of a RAS inhibitor (RASi; Kim et al. 2022, ASN Kidney Week FC052). Sodium glucose cotransporter-2 inhibitors (SGLT2is) are approved for use in adults with CKD at risk of kidney disease progression. In a post-hoc analysis of a global phase 3 study in patients with type 2 diabetes and CKD (SONAR), 6 week treatment with SGLT2i and atrasentan (n = 14) resulted in greater reductions in albuminuria (change in UACR from baseline −54.7%, 95%CI −64.6 to −42.0) compared to atrasentan alone (change in UACR from baseline −37.6%, 95%CI −45.9 to −28.0), suggesting independent and additive effects of both drug classes (Heerspink et al. 2021, Kidney Intl). The ASSIST study will evaluate the safety and efficacy of atrasentan vs. placebo in adults with IgAN and persistent proteinuria while on stable background SGLT2i and RASi therapy.
 
 
 
 The ASSIST trial is a randomized, double-blind, placebo-controlled, crossover clinical trial. Approximately 52 patients with biopsy-proven IgAN and eGFR ≥ 30 mL/min/1.73 m2 (CKD-epi) who are receiving maximally tolerated RASi for at least 12 weeks prior to screening will be enrolled. Patients on a stable dose of SGLT2i prior to screening (SGLT2i stable) must have total urine protein of >0.5 grams/day at screening. Patients who are not currently on SGLT2i or are not on a stable dose of SGLT2i must have a total urine protein of >0.85 grams/day at screening and enter a run-in period during which they receive SGLT2i for 8 weeks (SGLT2i run-in), after which they must have a total urine protein of >0.5 grams/day confirmed at the Week-1 visit (Figure). Choice of SGLT2i will be at the discretion of the principal investigator and per local treatment standards. Thereafter, all eligible patients will be randomized 1:1 to sequence AB or sequence BA in which they will receive 0.75 mg atrasentan once daily (QD) during one period and placebo during the other period. Randomization will be stratified by SGLT2i status (stable vs run-in). All subjects will enter Treatment Period 1 for 12 weeks, followed by a 12-week washout period, and then Treatment Period 2 for 24 weeks. Following the end of treatment, patients will have follow-up evaluations for safety approximately 4 weeks after the end of treatment. Fifty-two subjects will provide approximately 83% power using a two-sided pairwise test (α 0.05) to detect a treatment effect of at least 0.288 in natural log transformed UPCR (25% reduction) between atrasentan and placebo.
 
 
 
 Primary and secondary endpoints are change in proteinuria (UPCR from 24-hr collection) from baseline to week 12 and week 24, respectively. Type, incidence, severity, seriousness, and relatedness of adverse events will be evaluated. Change in eGFR from baseline to week 24 in Treatment Period 2 will be evaluated as an exploratory endpoint.
 
 
 
 Atrasentan is a potent and selective ETA antagonist. Interim results from the AFFINITY Phase 2 open-label study demonstrated that atrasentan resulted in sustained, clinically meaningful reductions in proteinuria in patients with IgAN. The phase 2 ASSIST study will examine the effects of atrasentan in combination with SGLT2i in patients with IgAN who are also receiving maximally tolerated RASi.


/pdf/4341-assist-study-design-a-randomized-double-blind-placebo-305bg715.pdf

#4341 assist study design: a randomized, double-blind, placebo-controlled, crossover study of atrasentan in patients with iga nephropathy (igan) on sglt2i

Sradha Kotwal

Papers

Multifaceted Quality Improvement Interventions to Prevent Hemodialysis Catheter-Related Bloodstream Infections: A Systematic Review.

Forever Starts Now: Effects of Glucose-Lowering Therapies on Acute Kidney Injury

#4341 assist study design: a randomized, double-blind, placebo-controlled, crossover study of atrasentan in patients with iga nephropathy (igan) on sglt2i