What are the first-line and second-line treatment recommendations for patients with Chronic Kidney Disease (CKD)?

CKD Drug Management: First-Line and Second-Line Treatment Recommendations

For patients with CKD, SGLT2 inhibitors are the cornerstone first-line therapy for eGFR ≥20 mL/min/1.73 m², regardless of diabetes status, followed by RAS inhibitors for those with albuminuria and hypertension, with statins for all patients ≥50 years. 1

First-Line Drug Therapy

SGLT2 Inhibitors (Primary Foundation)

SGLT2 inhibitors should be initiated in all patients with CKD and eGFR ≥20 mL/min/1.73 m² (Grade 1A recommendation). 1 This applies to:

• Type 2 diabetes with CKD and eGFR ≥20 mL/min/1.73 m² (strongest indication) 1
• Non-diabetic CKD with eGFR ≥20 mL/min/1.73 m² and urine ACR ≥200 mg/g 1
• Heart failure patients, regardless of albuminuria level 1
• eGFR 20-45 mL/min/1.73 m² with ACR <200 mg/g (Grade 2B, weaker evidence but still recommended) 1

Prioritize these specific agents with proven kidney and cardiovascular benefits: 1

• Canagliflozin 100 mg daily
• Dapagliflozin 10 mg daily
• Empagliflozin 10 mg daily

Key implementation points:

• Continue SGLT2i even when eGFR falls below 20 mL/min/1.73 m² until dialysis or transplant 1
• Expect a reversible 3-5 mL/min/1.73 m² eGFR decline in first 4 weeks—this is NOT a reason to stop 1
• Withhold during prolonged fasting, surgery, or critical illness to reduce ketoacidosis risk 1

RAS Inhibitors (ACE Inhibitors or ARBs)

Start ACE inhibitor or ARB for patients with albuminuria (ACR ≥30 mg/g) and hypertension. 1, 2

Specific indications:

• Severe albuminuria (A3, ACR ≥300 mg/g) without diabetes: Initiate RASi 2
• Moderate albuminuria (A2, ACR 30-300 mg/g) without diabetes: Suggested 2
• Diabetes with moderate-to-severe albuminuria: Strongly recommended 2

Dosing strategy:

• Titrate to maximum tolerated dose—benefits proven at these doses 2
• Continue even when eGFR falls below 30 mL/min/1.73 m² 1
• Monitor creatinine and potassium within 2-4 weeks of initiation or dose increase 2
• Stop only if creatinine rises >30% within 4 weeks 2

Critical pitfall: Never combine ACE inhibitor + ARB + direct renin inhibitor—this triples adverse event risk 2

Statins

All patients ≥50 years with CKD require statin therapy. 1

• eGFR <60 mL/min/1.73 m²: Moderate-to-high intensity statin or statin/ezetimibe combination 2
• eGFR ≥60 mL/min/1.73 m²: Statin monotherapy 2

Metformin (Type 2 Diabetes Only)

Use metformin when eGFR ≥30 mL/min/1.73 m² in type 2 diabetes. 1 This serves as foundation therapy alongside SGLT2i for glycemic control.

Second-Line/Additional Risk-Based Therapy

Nonsteroidal Mineralocorticoid Receptor Antagonists (ns-MRA)

Add finerenone for type 2 diabetes patients with persistent albuminuria despite first-line therapy (Grade 2A). 1

Specific criteria:

• eGFR ≥25 mL/min/1.73 m²
• ACR ≥30 mg/g despite maximum tolerated RASi dose
• Normal serum potassium (<4.8 mEq/L)
• Already on RASi and SGLT2i 1

Rationale: Finerenone reduces both kidney progression (HR 0.82) and cardiovascular events (HR 0.86) with additive benefits to SGLT2i 1. The mechanisms are complementary—SGLT2i may even reduce hyperkalemia risk when combined with ns-MRA 1.

Monitoring: Check potassium regularly after initiation—14% develop hyperkalemia vs 6.9% on placebo 1

GLP-1 Receptor Agonists

Add long-acting GLP-1 RA when glycemic targets not met despite metformin + SGLT2i, or when those agents cannot be used (Grade 1B). 1

Prioritize agents with proven cardiovascular benefits: 1

• Start low dose and titrate slowly to minimize GI side effects
• Particularly useful for intentional weight loss in obese patients 1
• Never combine with DPP-4 inhibitors 1
• Reduce sulfonylurea/insulin doses to prevent hypoglycemia 1

Blood Pressure Control Beyond RASi

Target <140/90 mmHg for most CKD patients; consider <130/80 mmHg with albuminuria. 2

When RASi alone insufficient:

• Add dihydropyridine calcium channel blocker and/or diuretic 1
• All three classes often needed to reach target 1

Antiplatelet Therapy

Low-dose aspirin for secondary prevention in established cardiovascular disease. 1 Consider for primary prevention only in very high ASCVD risk.

Treatment Algorithm by Clinical Scenario

Type 2 Diabetes + CKD (eGFR ≥20):

1. SGLT2i + Metformin (if eGFR ≥30) + RASi (if albuminuria/HTN) + Statin 1
2. Add ns-MRA if ACR ≥30 mg/g persists 1
3. Add GLP-1 RA if glycemic targets unmet 1

Non-Diabetic CKD with ACR ≥200 mg/g:

1. SGLT2i + RASi (if HTN) + Statin 1, 2
2. Blood pressure optimization with CCB/diuretic as needed 2

CKD + Heart Failure:

1. SGLT2i (regardless of albuminuria) + RASi + Statin 1
2. Consider steroidal MRA for refractory HTN if eGFR ≥45 1

Common Pitfalls to Avoid

SGLT2i-related:

• Don't stop for initial eGFR dip—this is expected and protective long-term 1
• Counsel on genital hygiene to prevent mycotic infections 1
• Provide "sick day rules" for ketoacidosis prevention 1
• Consider reducing diuretics before starting if volume depletion risk 1

RASi-related:

• Don't stop prematurely for creatinine rise <30% 2
• Don't combine multiple RAS agents 2
• Monitor potassium closely, especially with ns-MRA 1, 2

Advanced CKD (eGFR <15):

• May consider dose reduction or stopping RASi to reduce uremic symptoms 2
• Continue SGLT2i until dialysis initiation 1

The evidence strongly supports this layered approach, with SGLT2i demonstrating the most robust kidney and cardiovascular protection across multiple trials (DAPA-CKD, EMPA-KIDNEY, CREDENCE) in both diabetic and non-diabetic populations 3, 4, 5. The addition of ns-MRA provides complementary protection through different mechanisms when residual risk persists 1.