What is the stepwise approach to treating a patient with chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM), and established cardiovascular disease?

Stepwise Treatment Approach for CKD with T2DM and Established CVD

For patients with CKD, type 2 diabetes, and established cardiovascular disease, initiate a comprehensive four-pillar pharmacologic approach immediately: (1) SGLT2 inhibitor continued until dialysis, (2) metformin if eGFR ≥30 mL/min/1.73 m², (3) RAS inhibitor at maximum tolerated dose, and (4) high-intensity statin, alongside lifestyle modifications targeting blood pressure <120 mmHg systolic. 1, 2

Step 1: Foundation - Lifestyle Modifications

• Exercise: 150 minutes per week of moderate-intensity physical activity, or to a level compatible with cardiovascular and physical tolerance 2
• Diet: Adopt a plant-based "Mediterranean-style" diet with higher consumption of plant-based foods compared to animal-based foods and lower consumption of ultraprocessed foods 1, 2
• Protein intake: Maintain 0.8 g/kg body weight/day in adults with CKD G3-G5 2
• Smoking cessation: Mandatory for all patients 1
• Weight management: Address obesity through dietary and exercise interventions 1

Step 2: First-Line Pharmacologic Therapy (Initiate Simultaneously)

Pillar 1: SGLT2 Inhibitor

• Initiate immediately in all patients with T2DM and CKD when eGFR ≥20 mL/min/1.73 m² 1
• Continue until dialysis or transplantation is initiated 2
• Do not wait for glycemic targets to be unmet—organ protection is independent of baseline HbA1c 1
• Can be added to existing antihyperglycemic medications 1

Pillar 2: Metformin

• Initiate or continue if eGFR ≥30 mL/min/1.73 m² 1
• Dose adjustments: 1
  • eGFR ≥60: Standard dosing (immediate release: 500-850 mg once daily, titrate to maximum dose)
  • eGFR 45-59: Initiate at half the dose, titrate to half of maximum recommended dose
  • eGFR 30-44: Initiate at half the dose, titrate to half of maximum recommended dose
  • eGFR <30: Discontinue; do not initiate
• Monitor eGFR at least every 3-6 months when eGFR 30-59 mL/min/1.73 m² 1
• Monitor vitamin B12 levels due to deficiency risk 1

Pillar 3: RAS Inhibition (ACE Inhibitor or ARB)

• Initiate and titrate to maximum approved tolerated dose in all patients with hypertension and/or albuminuria 1, 2
• Target systolic blood pressure <120 mmHg 2
• Monitoring protocol: 1
  • Check serum creatinine and potassium within 2-4 weeks after starting or changing dose
  • Continue therapy unless creatinine rises >30% within 4 weeks
  • If hyperkalemia develops: review concurrent drugs, moderate potassium intake, consider diuretics, sodium bicarbonate, or GI cation exchangers before reducing dose
  • If creatinine rises >30%: review for causes of AKI, correct volume depletion, reassess concomitant medications (diuretics, NSAIDs), consider renal artery stenosis

Pillar 4: High-Intensity Statin

• Initiate high-intensity statin for secondary prevention in all patients with established ASCVD 1
• For patients aged ≥50 years with eGFR <60 mL/min/1.73 m²: use statin or statin/ezetimibe combination 1
• Choose statin-based regimens to maximize absolute reduction in LDL cholesterol 1

Step 3: Additional Glucose-Lowering Therapy (If Glycemic Targets Not Met)

• GLP-1 receptor agonist (long-acting): Preferred if metformin and SGLT2i are insufficient to meet individualized glycemic targets 1
• Alternative options if GLP-1 RA not suitable: DPP-4 inhibitors, TZD, insulin (based on patient factors including eGFR, weight goals, hypoglycemia risk, cost) 1

Step 4: Advanced Cardio-Renal Protection

Nonsteroidal Mineralocorticoid Receptor Antagonist (ns-MRA)

• Add to first-line therapy for patients with T2DM and persistent albuminuria >30 mg/g (>3 mg/mmol) despite optimal therapy, indicating high residual risk 1, 2

Additional Lipid Management

• Ezetimibe: Consider adding to statin if LDL targets not met 1, 2
• PCSK-9 inhibitors: Consider for patients with CKD who have an indication based on ASCVD risk and attained LDL cholesterol concentrations 1, 2

Step 5: Cardiovascular Disease-Specific Management

Antiplatelet Therapy

• Low-dose aspirin: Recommended for secondary prevention in all patients with established ischemic cardiovascular disease 1
• Consider P2Y12 inhibitors if aspirin intolerance 1

Atrial Fibrillation Management (If Present)

• Non-vitamin K antagonist oral anticoagulants (NOACs): Preferred over warfarin for thromboprophylaxis in CKD G1-G4 1, 2
• NOAC dose adjustment for GFR is required, with caution at CKD G4-G5 1
• Use opportunistic pulse-based screening when measuring BP, followed by wearable device or Holter ECG if indicated 1

Coronary Artery Disease Management

• For stable stress-test confirmed ischemic heart disease: initial conservative approach using intensive medical therapy is appropriate 1
• Invasive strategy may be preferable for acute/unstable coronary disease, unacceptable angina, left ventricular systolic dysfunction attributable to ischemia, or left main disease 1

Step 6: Regular Monitoring and Reassessment

• Risk factor reassessment every 3-6 months: 1, 2
  • eGFR and serum creatinine
  • Urine albumin-to-creatinine ratio (UACR)
  • Blood pressure
  • Lipid panel
  • HbA1c
  • Serum potassium
  • Vitamin B12 (if on metformin)
• Estimate 10-year cardiovascular risk using a validated risk tool 1

Critical Pitfalls to Avoid

• Never prescribe NSAIDs in CKD patients due to nephrotoxicity risk causing acute kidney injury, progressive GFR loss, electrolyte derangements, hypervolemia, and worsening heart failure and hypertension 2, 3
• For acute gout or inflammatory conditions, use low-dose colchicine or glucocorticoids instead 2
• Do not use agents to lower serum uric acid in patients with asymptomatic hyperuricemia to delay CKD progression 1, 2
• Avoid high protein intake (>1.3 g/kg/day) as it accelerates CKD progression 2
• Do not delay SGLT2i initiation waiting for glycemic control issues—start immediately for organ protection 1
• Do not stop RAS inhibitors prematurely for mild hyperkalemia or creatinine elevation <30%—manage these complications first 1
• Advise contraception in women receiving ACE inhibitor or ARB therapy; discontinue in women considering pregnancy or who become pregnant 1