What is Guideline-Directed Medical Therapy (GDMT) for Chronic Kidney Disease (CKD)?

Guideline-Directed Medical Therapy (GDMT) for Chronic Kidney Disease

For patients with CKD, GDMT consists of four foundational medication classes: ACE inhibitors or ARBs for proteinuria reduction, SGLT2 inhibitors for kidney and cardiovascular protection, statins for cardiovascular risk reduction, and blood pressure control to target <140/90 mmHg. 1

Core Pharmacologic Interventions

SGLT2 Inhibitors (First-Line Therapy)

• SGLT2 inhibitors should be initiated in all patients with CKD stages G1-G4 (eGFR ≥20 mL/min/1.73 m²) to slow progression and reduce cardiovascular events. 1, 2
• These agents provide kidney protection through multiple mechanisms: reducing glomerular hyperfiltration via tubuloglomerular feedback, increasing diuretic efficacy when combined with loop diuretics, and shifting cardiac metabolism toward more efficient ketone utilization 1
• SGLT2 inhibitors are effective in patients both with and without diabetes 2
• In patients with type 2 diabetes and established cardiovascular disease or high cardiovascular risk, SGLT2 inhibitors prevent heart failure hospitalizations 1

ACE Inhibitors or ARBs

• ACE inhibitors or ARBs are recommended for all CKD patients with proteinuria (urinary albumin ≥300 mg/g), targeting a 30% or greater reduction in urinary albumin excretion. 3
• These agents slow CKD progression by reducing intraglomerular pressure through efferent arteriole vasodilation 1
• ARBs are preferred in patients intolerant to ACE inhibitors 1
• Common pitfall: Discontinuing these medications prematurely when serum creatinine rises 20-30% after initiation—this transient increase is expected and acceptable, reflecting hemodynamic changes rather than kidney injury 1

Statin Therapy (Mandatory for Cardiovascular Protection)

• In adults ≥50 years with eGFR <60 mL/min/1.73 m² (CKD stages G3a-G5), statin or statin/ezetimibe combination therapy is strongly recommended. 1
• For adults ≥50 years with eGFR ≥60 mL/min/1.73 m² (CKD stages G1-G2), statin monotherapy is recommended 1
• In adults 18-49 years with CKD, statins are recommended if they have coronary disease, diabetes, prior ischemic stroke, or 10-year cardiovascular risk >10% 1
• Consider PCSK-9 inhibitors in patients with CKD who have indications for their use 1
• Cardiovascular disease is the leading cause of mortality in CKD patients, making statin therapy non-negotiable. 4

Blood Pressure Management

• Target blood pressure <140/90 mmHg in all CKD patients to prevent progression and reduce cardiovascular events. 1
• Blood pressure control should be achieved using GDMT medications (ACE inhibitors/ARBs, beta-blockers if heart failure present) 1
• Consider 24-hour ambulatory blood pressure monitoring for accurate assessment 1

Additional Therapeutic Considerations

Mineralocorticoid Receptor Antagonists (MRAs)

• Finerenone (non-steroidal MRA) reduces cardiovascular and kidney outcomes in patients with CKD and type 2 diabetes. 1
• MRAs work synergistically with ACE inhibitors/ARBs by blocking aldosterone-mediated fibrosis and cardiac remodeling 1
• Monitor potassium levels closely, especially in advanced CKD (stages G4-G5) 1

Antiplatelet Therapy

• Low-dose aspirin is recommended for secondary prevention in CKD patients with established ischemic cardiovascular disease. 1
• Consider P2Y12 inhibitors if aspirin intolerance exists 1
• Aspirin is NOT recommended for primary prevention in CKD due to bleeding risk 1

Anticoagulation for Atrial Fibrillation

• Non-vitamin K antagonist oral anticoagulants (NOACs) are preferred over warfarin for thromboprophylaxis in atrial fibrillation in CKD stages G1-G4. 1
• NOAC dose adjustment based on eGFR is required, with particular caution in CKD stages G4-G5 1

Lifestyle and Dietary Modifications

Dietary Interventions

• Adopt a plant-based Mediterranean-style diet to reduce cardiovascular risk and complement pharmacologic therapy. 1, 4
• Limit alcohol, red meat, and high-fructose corn syrup intake 1, 4
• Sodium restriction supports blood pressure control and reduces proteinuria 1

Physical Activity

• Regular physical activity, maintaining normal weight, and avoiding smoking reduce future risk of heart failure and CKD progression. 1

Critical Implementation Strategies

Monitoring and Titration

• Uptitrate GDMT medications to maximally tolerated target doses rather than stopping at initial doses. 1
• The STRONG-HF study demonstrated that rapid uptitration (within 2 weeks) of quadruple GDMT reduces death and hospitalization, though this excluded patients with eGFR <30 mL/min/1.73 m² 1
• Accept transient increases in serum creatinine (up to 30%) and mild hyperkalemia (potassium <5.5 mEq/L) when initiating or uptitrating RAAS inhibitors 1

Addressing Therapeutic Inertia

• Prescription rates for GDMT remain suboptimal in CKD patients, with significant site-to-site variability. 5, 6, 7
• Patients without commercial health insurance coverage are less likely to receive SGLT2 inhibitors and GLP-1 receptor agonists 7
• Persistent prescribing (≥90 days) is substantially lower than initial prescribing, indicating need for systematic follow-up 7

Medications to AVOID in CKD

NSAIDs

• Never prescribe NSAIDs in CKD stage 3B or higher, even for short-term use, as they significantly increase risk of acute kidney injury and CKD progression. 4
• Alternative anti-inflammatory options include low-dose colchicine or short-course glucocorticoids 4

Erythropoietin-Stimulating Agents

• Erythropoietin-stimulating agents should NOT be used to improve morbidity and mortality in patients with heart failure and anemia. 1

Special Populations

CKD with Heart Failure

• In patients with heart failure and reduced ejection fraction (HFrEF) plus CKD, quadruple therapy includes: ACE inhibitor/ARB (or ARNI), beta-blocker, mineralocorticoid receptor antagonist, and SGLT2 inhibitor 1
• Beta-blockers reduce sympathetic nervous system activation and renin secretion, leading to long-term reduction in fibrosis and cardiac remodeling 1
• SGLT2 inhibitors enhance decongestion and diuretic efficacy when combined with loop diuretics 1

Advanced CKD (Stages G4-G5)

• Continue GDMT in advanced CKD unless contraindications develop 1
• More frequent monitoring of potassium and kidney function is required 1
• NOAC dosing requires careful adjustment, with consideration of warfarin in stage G5 1