What is the recommended treatment for a patient with diabetes mellitus and impaired renal function, as indicated by a low estimated Glomerular Filtration Rate (eGFR)?

Management of Diabetes with Impaired eGFR

For patients with diabetes and reduced eGFR, initiate an SGLT2 inhibitor (empagliflozin, canagliflozin, or dapagliflozin) if eGFR is 20-90 mL/min/1.73 m² to reduce chronic kidney disease progression and cardiovascular events, while optimizing glucose control (HbA1c <7%) and blood pressure, and adding ACE inhibitor or ARB therapy based on albuminuria status. 1

Immediate Assessment Required

Screen annually for both eGFR and urinary albumin-to-creatinine ratio (UACR) in all patients with type 2 diabetes to stratify risk and guide treatment intensity. 1

• Measure UACR from a spot urine sample (not 24-hour collection) and confirm abnormal results with 2 of 3 specimens over 3-6 months due to biological variability. 1
• Calculate eGFR using serum creatinine to stage kidney disease severity. 1
• Monitor serum potassium and creatinine levels when initiating or adjusting renin-angiotensin system blockers or diuretics. 1

Treatment Algorithm Based on eGFR and Albuminuria Status

Step 1: Optimize Glycemic Control

Target HbA1c <7.0% (53 mmol/mol) for most patients to reduce microvascular complications including diabetic kidney disease progression. 1

• More stringent targets (HbA1c <6.5%) may be appropriate for patients with short diabetes duration, long life expectancy, and no significant cardiovascular disease if achievable without hypoglycemia. 2
• Individualize HbA1c targets between 6.5-8.0% for patients with advanced CKD not on dialysis, considering risk of hypoglycemia and shortened erythrocyte lifespan affecting HbA1c accuracy when eGFR <30 mL/min/1.73 m². 1
• Intensive glycemic control reduces new-onset microalbuminuria by 34% in patients without baseline complications and by 43% in those with early complications. 2

Step 2: Blood Pressure Management

Target systolic blood pressure to 130 mmHg and <130 mmHg if tolerated, but not <120 mmHg in patients with diabetes and hypertension. 1

• Optimize blood pressure control to reduce risk or slow progression of diabetic kidney disease independent of glucose control. 1

Step 3: SGLT2 Inhibitor Therapy (Primary Nephroprotective Agent)

Initiate SGLT2 inhibitor therapy if eGFR is 20-90 mL/min/1.73 m² regardless of albuminuria status to reduce chronic kidney disease progression and cardiovascular events. 1

• Canagliflozin, empagliflozin, or dapagliflozin are recommended with Class I, Level B evidence for nephroprotection. 1
• The CREDENCE trial demonstrated 30% relative risk reduction in composite renal outcomes (end-stage renal disease, doubling of serum creatinine, or renal/cardiovascular death) with canagliflozin in patients with eGFR 30-90 mL/min/1.73 m². 1
• SGLT2 inhibitors can be used down to eGFR of 20 mL/min/1.73 m² based on recent evidence, though older guidelines cited 30 mL/min/1.73 m² as the threshold. 1
• Monitor for volume depletion, hypotension, and acute kidney injury, especially in elderly patients, those with eGFR <60 mL/min/1.73 m², or those on loop diuretics. 3
• Educate patients about lower limb care as SGLT2 inhibitors increase amputation risk, particularly in those with prior amputation, peripheral vascular disease, or neuropathy. 3

Step 4: ACE Inhibitor or ARB Therapy Based on Albuminuria

For UACR <30 mg/g (no albuminuria) with normal blood pressure: Do not initiate ACE inhibitor or ARB for primary prevention. 1

For UACR 30-299 mg/g (moderate albuminuria): Consider ACE inhibitor or ARB therapy, particularly if hypertensive. 1

For UACR ≥300 mg/g (severe albuminuria) or eGFR <60 mL/min/1.73 m²: Strongly recommend ACE inhibitor or ARB therapy. 1

• Use either ACE inhibitor or ARB, not both simultaneously, as dual renin-angiotensin system blockade increases risks of hypotension, hyperkalemia, and acute kidney injury without additional benefit. 4
• The VA NEPHRON-D trial demonstrated increased harm with combination lisinopril plus losartan versus monotherapy in diabetic nephropathy. 4
• Do not discontinue ACE inhibitor/ARB for creatinine increases ≤30% in the absence of volume depletion, as initial rises are expected and do not indicate harm. 1
• Monitor serum creatinine and potassium within 1-2 weeks after initiation or dose adjustment, then periodically thereafter. 1

Step 5: Additional Nephroprotective Agents

Consider GLP-1 receptor agonists (liraglutide or semaglutide) if eGFR >30 mL/min/1.73 m² for additional cardiovascular and renal protection. 1

Consider nonsteroidal mineralocorticoid receptor antagonist (finerenone) if eGFR ≥25 mL/min/1.73 m² in patients at increased cardiovascular risk or those unable to use SGLT2 inhibitors. 1

Step 6: Dietary Protein Restriction

Limit dietary protein intake to 0.8 g/kg/day (ideal body weight) for patients with non-dialysis-dependent CKD stage 3 or higher. 1

• Do not restrict protein below 0.8 g/kg/day as it does not improve glycemic measures, cardiovascular outcomes, or GFR decline. 1
• Sodium intake should be <2 g/day (or <90 mmol/day, or <5 g sodium chloride/day) to enhance blood pressure control and reduce proteinuria. 1

Monitoring Strategy Based on eGFR and Albuminuria

For eGFR ≥60 mL/min/1.73 m² with normal UACR:

• Recheck eGFR and UACR annually. 1

For eGFR 45-59 mL/min/1.73 m² or UACR 30-299 mg/g:

• Recheck eGFR and UACR every 6 months. 1
• Monitor for CKD complications including anemia, bone mineral disorders, and metabolic acidosis. 1

For eGFR 30-44 mL/min/1.73 m² or UACR ≥300 mg/g:

• Recheck eGFR and UACR every 3-4 months. 1
• Evaluate and manage CKD complications. 1
• Consider nephrology referral for advanced kidney disease or difficult management issues. 1

For eGFR <30 mL/min/1.73 m²:

• Refer to nephrologist for evaluation for renal replacement therapy planning. 1
• Recheck eGFR and UACR every 3 months or more frequently. 1

Critical Clinical Pitfalls to Avoid

Do not stop ACE inhibitor/ARB for modest creatinine increases (<30%) without evidence of volume depletion, as this represents expected hemodynamic changes and withdrawal eliminates nephroprotection. 1

Do not combine ACE inhibitor with ARB despite theoretical additive benefit, as the VA NEPHRON-D trial definitively showed increased harm without benefit in diabetic patients. 4

Albuminuria is a stronger predictor than eGFR alone for renal disease progression over 3 years, with macroalbuminuria having an odds ratio of 132.3 versus 9.0 for reduced eGFR. 5

Patients without albuminuria have <1% progression rate regardless of eGFR level, indicating that reduced eGFR adds risk only when albuminuria is present. 5, 6

The 24-month risk of progression is low (<8%) for patients with UACR <1000 mg/g regardless of eGFR, but rises steeply to 39.4% for eGFR <30 mL/min/1.73 m² combined with proteinuria ≥2000 mg/g. 7

Aim for ≥30% reduction in UACR as a treatment target when albuminuria ≥300 mg/g is present, as this degree of reduction slows CKD progression. 1

Recheck UACR within 6 months after intensifying therapy to assess treatment response and adjust management accordingly. 2