What are the glycemic target and recommended diabetes medication adjustments for an adult with type 2 diabetes and chronic kidney disease based on estimated glomerular filtration rate?

Treatment of Diabetes in CKD Patients

Glycemic Targets

Individualized HbA1c targets should be set based on patient factors, but generally aim for <7% in most patients with diabetes and CKD, with less stringent targets (7.5-8%) for those at high risk of hypoglycemia or with limited life expectancy. 1

• Patients with CKD stages 3-5 have a 5-fold higher risk of severe hypoglycemia compared to those with normal renal function, making target individualization critical 2
• HbA1c accuracy decreases in advanced CKD due to altered red blood cell turnover; continuous glucose monitoring or frequent self-monitoring is preferred over sole reliance on HbA1c 2
• Monitor HbA1c every 3 months and reassess targets based on hypoglycemia risk, comorbidities, and disease duration 1, 2

First-Line Pharmacotherapy by eGFR Stage

eGFR ≥30 mL/min/1.73 m²

Metformin plus an SGLT2 inhibitor should be initiated as first-line therapy for all patients with type 2 diabetes and eGFR ≥30 mL/min/1.73 m². 1

• Metformin dosing:

  • eGFR ≥45 mL/min/1.73 m²: Continue standard dosing up to 2000 mg/day 3
  • eGFR 30-44 mL/min/1.73 m²: Reduce to maximum 1000 mg/day and recheck eGFR every 3-6 months 1, 3
  • eGFR <30 mL/min/1.73 m²: Discontinue immediately due to lactic acidosis risk 1, 3

• SGLT2 inhibitor initiation:

  • Start dapagliflozin 10 mg, empagliflozin 10 mg, or canagliflozin 100 mg daily when eGFR ≥20-30 mL/min/1.73 m² 1
  • Continue SGLT2 inhibitors even if eGFR falls below 45 mL/min/1.73 m² after initiation, as cardiorenal benefits persist despite reduced glucose-lowering efficacy 1, 3
  • SGLT2 inhibitors reduce cardiovascular death or heart failure hospitalization by 26-29%, kidney disease progression by 39-44%, and all-cause mortality by 31% 3
  • Expect a transient eGFR dip of 3-5 mL/min/1.73 m² in the first 1-4 weeks; this is hemodynamic and not harmful 3

eGFR 20-29 mL/min/1.73 m² (Stage 4 CKD)

Discontinue metformin and continue or initiate SGLT2 inhibitors for cardiorenal protection; insulin becomes the primary glucose-lowering agent. 1, 2

• Stop metformin completely at eGFR <30 mL/min/1.73 m² 3, 2
• SGLT2 inhibitors may be initiated at eGFR ≥20 mL/min/1.73 m² for cardiorenal benefit, though glucose-lowering effect is minimal 1, 3
• Start basal insulin (glargine, detemir, or NPH) at 10 units once daily or 0.1-0.2 units/kg/day 2
• Reduce total insulin dose by approximately 50% compared to patients with normal renal function due to decreased renal insulin clearance 2
• Titrate insulin by 2-4 units every 3 days based on fasting glucose, targeting 80-130 mg/dL 2

eGFR <20 mL/min/1.73 m² or Dialysis

Insulin is the preferred agent; SGLT2 inhibitors should not be initiated but may be continued if already prescribed. 3, 2

• Metformin is absolutely contraindicated 3
• SGLT2 inhibitors provide minimal glycemic effect but may offer residual cardiorenal benefit if already on therapy 3
• Intensive glucose monitoring is required due to markedly elevated hypoglycemia risk 2

Additional Glucose-Lowering Agents

When Metformin + SGLT2 Inhibitor Insufficient

Add a long-acting GLP-1 receptor agonist (semaglutide, dulaglutide, or liraglutide) as the preferred third agent. 1, 3

• GLP-1 receptor agonists require no renal dose adjustment at any eGFR level 3, 4
• They provide cardiovascular event reduction, particularly in patients with established atherosclerotic cardiovascular disease 1, 3
• GLP-1 receptor agonists are preferred over insulin in advanced CKD (eGFR <30 mL/min/1.73 m²) due to lower hypoglycemia risk, weight loss benefits, and cardiovascular protection 3
• When combining with insulin or sulfonylureas, reduce doses of these agents to minimize hypoglycemia risk 3

DPP-4 Inhibitors as Alternative Agents

DPP-4 inhibitors should be used only when SGLT2 inhibitors and GLP-1 receptor agonists are unsuitable due to contraindications, intolerance, or cost. 3, 4

• Linagliptin 5 mg daily is preferred across all eGFR levels, including dialysis, as it requires no dose adjustment 3, 4
• Sitagliptin requires renal dose adjustment:
  • eGFR ≥45 mL/min/1.73 m²: 100 mg daily 4
  • eGFR 30-44 mL/min/1.73 m²: 50 mg daily 4
  • eGFR <30 mL/min/1.73 m²: 25 mg daily 4
• DPP-4 inhibitors reduce HbA1c by 0.4-0.9% with minimal hypoglycemia risk as monotherapy 4
• Avoid saxagliptin and alogliptin due to increased heart failure hospitalization risk 4, 2

Medications to Avoid or Use with Extreme Caution

Sulfonylureas (including gliclazide) should be discontinued and replaced with guideline-directed therapy. 3

• Sulfonylureas lack cardiovascular and renal protection compared to SGLT2 inhibitors and GLP-1 receptor agonists 3
• They significantly increase hypoglycemia risk, particularly when combined with SGLT2 inhibitors 3
• If cost constraints necessitate sulfonylurea use, glipizide 2.5 mg daily may be considered with close monitoring in eGFR 30-60 mL/min/1.73 m² 2
• Glyburide and first-generation sulfonylureas must be avoided due to metabolite accumulation and severe hypoglycemia risk 2

Comprehensive Cardiorenal Risk Management

Blood Pressure Control

RAS blockade (ACE inhibitor or ARB) is first-line therapy for patients with albuminuria and hypertension. 1

• Do not discontinue RAS blockade for creatinine increases ≤30% in the absence of volume depletion 1, 2
• Monitor serum creatinine and potassium every 3-6 months when eGFR <60 mL/min/1.73 m² 1
• Add dihydropyridine calcium channel blockers and/or diuretics if needed to achieve individualized blood pressure targets 1

Additional Risk-Based Therapy

For patients with type 2 diabetes, eGFR ≥25 mL/min/1.73 m², and persistent albuminuria ≥30 mg/g despite first-line therapy, add a nonsteroidal mineralocorticoid receptor antagonist (finerenone). 1

• Nonsteroidal MRAs reduce CKD progression and cardiovascular events in high-risk patients 1
• Monitor potassium closely, as hyperkalemia is the primary safety concern 1

Lipid Management

All patients with type 2 diabetes and CKD should receive statin therapy regardless of baseline LDL cholesterol. 1

• Add ezetimibe, PCSK9 inhibitor, or icosapent ethyl based on ASCVD risk and lipid levels 1
• Consider antiplatelet therapy for secondary prevention in those with established cardiovascular disease 1

Lifestyle Modifications

Recommend at least 150 minutes per week of moderate-intensity physical activity, sodium intake <2 g/day, and protein intake of 0.8 g/kg body weight per day for non-dialysis CKD. 1, 3

• Physical activity reduces HbA1c by approximately 0.4-1.0% 3
• Protein restriction helps slow CKD progression in stages 3-5 1
• Patients on dialysis require higher protein intake to prevent protein-energy wasting 1

Monitoring and Nephrology Referral

Refer to nephrology when eGFR <30 mL/min/1.73 m², continuously increasing albuminuria, rapidly progressing kidney disease, or uncertainty about etiology. 1

• Reassess risk factors every 3-6 months, including eGFR, urine albumin-to-creatinine ratio, HbA1c, blood pressure, and lipids 1
• Use continuous glucose monitoring or frequent self-monitoring (at least pre-breakfast and bedtime) in advanced CKD rather than relying solely on HbA1c 2

Common Pitfalls to Avoid

• Do not continue sulfonylureas when adding SGLT2 inhibitors, as this combination increases hypoglycemia risk without additional benefit 3
• Do not stop SGLT2 inhibitors if eGFR falls below 45 mL/min/1.73 m² after initiation; cardiorenal benefits persist 1, 3
• Do not withhold GLP-1 receptor agonists solely because eGFR <30 mL/min/1.73 m²; they are safe and effective in advanced CKD 3
• Do not use metformin at eGFR <30 mL/min/1.73 m² under any circumstances 3, 2
• Do not prioritize DPP-4 inhibitors over SGLT2 inhibitors or GLP-1 receptor agonists in patients with established cardiovascular disease, heart failure, or albuminuric CKD 3, 4