Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation and Study of Diabetic Nephropathy with Atrasentan: what was learned about the treatment of diabetic kidney disease with canagliflozin and atrasentan?

Abstract

In April 2019, two major Phase 3 randomized clinical trials were published that assessed primary renal outcomes in diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM). The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) tested an already available antidiabetic drug, canagliflozin, and the Study of Diabetic Nephropathy with Atrasentan (SONAR) tested a novel molecule, the endothelin-1 receptor blocker atrasentan, both on top of renin-angiotensin system blockade. Both trials demonstrated significant nephroprotection in patients with overt DKD (albuminuria >300 mg/g urinary creatinine) for combined primary endpoints of end-stage kidney disease (ESKD), doubling of serum creatinine or death from renal or cardiovascular causes in CREDENCE {hazard ratio [HR] 0.70 [95% confidence interval (CI) 0.59-0.82]} and ESKD and doubling of serum creatinine in SONAR [HR 0.65 (95% CI 0.49-0.88)]. Canagliflozin also decreased the secondary renal endpoint ESKD, doubling of serum creatinine or renal death [HR 0.66 (95% CI 0.53-0.81)], which was similar in nature and impact to the primary endpoint in SONAR. In addition, canagliflozin decreased a secondary endpoint of cardiovascular death or hospitalization for heart failure [HR 0.69 (95% CI 0.57-0.83)], whereas atrasentan had no significant impact on a secondary cardiovascular composite endpoint or on hospital admissions for heart failure and, despite restrictive exclusion criteria, there was a non-significant trend towards more frequent episodes of heart failure. Based on these results, canagliflozin will likely be approved for the indication of treating DKD in T2DM and the estimated glomerular filtration rate threshold for prescribing it will be lifted, whereas the future and place of atrasentan in the treatment of DKD remain unclear.

Keywords: albuminuria; atrasentan; canagliflozin; chronic kidney disease; diabetic kidney disease; endothelin; sodium-glucose cotransporter-2 (SGLT2) inhibitor.

FIGURE 1

CKD G (GFR) and A (albuminuria) categories of patients enrolled in RCTs for current DKD therapies, cardiovascular SGLT2i trials, CANVAS and SONAR. Data from references [1, 2, 4, 20–23]. Data presented as mean ± SD and albuminuria data as median (IQR). The percentage of patients with eGFR <60 mL/min/1.73 m² was 25.9, 22.7 and 9.11% in EMPA-REG, CANVAS and DECLARE, respectively. For albuminuria >300 mg/g, the percentages were 11, 7.1 and 6.8%, respectively.

FIGURE 2

Efficacy of nephroprotective therapies. (A) Relative risk or HR for primary endpoint (IDNT and RENAAL: doubling of the serum creatinine concentration, ESRD or death; CANVAS: doubling of the serum creatinine concentration, ESRD or cardiovascular or renal death). SONAR was omitted because the primary endpoint did not include death. (B) Relative risk or HR for key renal endpoints explored in all the trials. The original IDNT manuscript did not provide the combined doubling of the serum creatinine concentration and ESRD endpoint. (C) Residual risk for key renal endpoints. In IDNT, the residual risk per 100 person-years was estimated from mean follow-up and percentage of patients with events. Data from references [2–4]. The comparator for RENAAL and IDNT was placebo/absence of RAS blockade, whereas the comparator for CREDENCE and SONAR was placebo + RAS blockade.

FIGURE 3

Cardiovascular safety of SGLT2i and atrasentan. Data from (A) cardiovascular outcome trials enrolling T2DM patients at high cardiovascular risk (CANVAS Program, DECLARE-TIMI and EMPA-REG OUTCOME) [20, 33, 40] and (B) trials enrolling patients with DKD (CANVAS and SONAR) [2, 20] are presented. MACE: major cardiovascular events: cardiovascular death, myocardial infarction or stroke.