Atrasentan in Diabetic Kidney Disease
Primary Recommendation
Atrasentan is not recommended for routine clinical use in diabetic kidney disease, as it is not approved by regulatory authorities and is not included in current clinical practice guidelines for DKD management. While the SONAR trial demonstrated a 35% reduction in the composite renal endpoint (doubling of serum creatinine or end-stage kidney disease), this benefit must be weighed against increased risks of fluid retention and heart failure hospitalization 1.
Evidence from Clinical Trials
Efficacy Data
The SONAR trial (2019) showed that atrasentan 0.75 mg daily reduced the primary composite renal endpoint by 35% (HR 0.65,95% CI 0.49-0.88; p=0.0047) in patients with type 2 diabetes and CKD who were already receiving maximum tolerated renin-angiotensin system inhibition 1.
The trial enrolled 2,648 "responders" (patients who demonstrated ≥30% reduction in urinary albumin-to-creatinine ratio during a 6-week enrichment period) out of 4,711 patients who completed enrichment screening 1.
Atrasentan reduced albuminuria by 35-42% at the 0.75 mg and 1.75 mg doses compared to placebo over 8 weeks in earlier phase 2 studies 2.
The absolute benefit was greatest in patients with the lowest eGFR (<30 mL/min per 1.73 m²) and highest albuminuria (≥3000 mg/g), who had the highest baseline risk 3.
Safety Concerns
Hospital admission for heart failure occurred in 3.5% of patients in the atrasentan group versus 2.6% in the placebo group (HR 1.33,95% CI 0.85-2.07) 1.
Fluid retention and edema were more frequent with atrasentan, with 62% of edema events emerging during the first 4 weeks of treatment 2.
The risk of heart failure hospitalization was consistent across all subgroups of baseline eGFR and albuminuria, meaning even patients with less severe disease faced this increased risk 3.
Current Guideline-Recommended Therapy
First-Line Treatments
The 2022 Mayo Clinic Proceedings guideline recommends SGLT2 inhibitors and GLP-1 receptor agonists as the cornerstone of DKD management, providing both kidney and cardiovascular protective benefits 4.
KDIGO 2020 guidelines recommend ACE inhibitors or ARBs for patients with diabetes, hypertension, and albuminuria >30 mg/g, titrated to the highest approved dose that is tolerated 4.
SGLT2 inhibitors reduce the risk of kidney failure by 30-40% even when added to maximum ACE inhibitor/ARB therapy 5.
Why Atrasentan Is Not Included
Despite positive renal efficacy data, atrasentan has not been incorporated into KDOQI (2012), KDIGO (2020), or ADA guidelines for DKD management 4.
The enrichment design of SONAR (selecting only patients who responded to atrasentan during a run-in period) limits generalizability, as only 56% of patients who completed enrichment were "responders" eligible for randomization 6, 1.
The drug requires careful patient selection and monitoring that may not be practical in routine clinical practice 6.
Clinical Context and Practical Considerations
When Atrasentan Might Be Considered (Investigational)
If atrasentan were to become available, the SONAR trial data suggest it would theoretically be most beneficial in:
- Patients with type 2 diabetes and stage 3-4 CKD (eGFR 25-75 mL/min per 1.73 m²) 1.
- Those with macroalbuminuria (UACR 300-5000 mg/g) despite maximum tolerated RAS inhibition for ≥4 weeks 1.
- Patients who demonstrate ≥30% reduction in albuminuria during a trial period without developing significant fluid retention 1.
- Those at highest risk: eGFR <30 mL/min per 1.73 m² and UACR ≥3000 mg/g 3.
Critical Monitoring Requirements
- Close surveillance for fluid retention is essential, particularly during the first 4 weeks of treatment when 62% of edema events occur 2.
- Patients with pre-existing heart failure or volume overload should be excluded given the 33% increased relative risk of heart failure hospitalization 1.
- Hispanic patients showed greater UACR reductions (41-60%) compared to non-Hispanic patients (18-37%) in phase 2 studies, though this requires further characterization 2.
Common Pitfalls to Avoid
Do not use atrasentan as a substitute for proven therapies: SGLT2 inhibitors and RAS blockade remain the evidence-based standard of care with superior safety profiles 4, 5.
Do not overlook heart failure risk: The increased risk of heart failure hospitalization persists across all patient subgroups, regardless of baseline kidney function or albuminuria level 3.
Do not assume all patients will respond: The enrichment design means approximately 44% of patients did not achieve the ≥30% albuminuria reduction threshold needed to qualify as "responders" 6, 1.
Current Standard of Care
Until atrasentan receives regulatory approval and guideline endorsement, clinicians should focus on implementing the established four-pillar approach to DKD management:
- SGLT2 inhibitors for all patients with DKD regardless of glucose control 5
- ACE inhibitors or ARBs titrated to maximum tolerated dose 4
- GLP-1 receptor agonists for additional cardiovascular and kidney protection 4
- Finerenone (a selective mineralocorticoid receptor antagonist) if albuminuria persists after SGLT2 inhibitor initiation 5
These therapies have robust guideline support, proven mortality benefits, and more favorable safety profiles compared to the investigational use of atrasentan 4, 5.