What are the recommended dosing adjustments for dipeptidyl peptidase‑4 inhibitors in adults with chronic kidney disease based on estimated glomerular filtration rate?

DPP-4 Inhibitor Dosing in Chronic Kidney Disease

Most DPP-4 inhibitors require dose reduction based on eGFR thresholds, with the critical exception of linagliptin, which requires no adjustment at any level of renal function. 1, 2

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Linagliptin: The Preferred DPP-4 Inhibitor in CKD

Linagliptin 5 mg once daily is the standard dose regardless of kidney function, including severe CKD (eGFR <30 mL/min/1.73 m²) and dialysis. 1, 2

• Linagliptin has minimal renal excretion and does not require dose adjustment at any eGFR level, making it the most straightforward choice for patients with fluctuating or advanced renal impairment. 1, 2
• Steady-state drug exposure increases only 40–42% in severe renal impairment, which is not clinically significant and does not necessitate dose reduction. 2
• The CARMELINA trial demonstrated cardiovascular safety (HR 1.02,95% CI 0.89–1.17) in patients with type 2 diabetes and severe renal impairment, including those on dialysis. 2

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Sitagliptin: Requires Stepwise Dose Reduction

Sitagliptin dosing must be adjusted when eGFR falls below 45 mL/min/1.73 m². 1, 2

Dosing Algorithm by eGFR:

• eGFR ≥45 mL/min/1.73 m²: 100 mg once daily (no adjustment needed) 1, 2

• eGFR 30–44 mL/min/1.73 m² (moderate CKD): 50 mg once daily 1, 2

• eGFR <30 mL/min/1.73 m² (severe CKD): 25 mg once daily 1, 2

• Dialysis: 25 mg once daily (administer without regard to timing of dialysis) 2

• Regular monitoring of renal function is required to adjust dosing appropriately. 2

• The TECOS trial demonstrated cardiovascular safety with neutral heart failure risk (HR 1.00,95% CI 0.83–1.20). 2

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Vildagliptin: Requires Dose Reduction in Moderate-to-Severe CKD

Vildagliptin dose must be reduced by half to 50 mg once daily when eGFR is <50 mL/min/1.73 m². 3

• eGFR ≥50 mL/min/1.73 m²: 50 mg twice daily (100 mg total daily dose) 3

• eGFR 30–50 mL/min/1.73 m² (moderate CKD): 50 mg once daily 3

• eGFR <30 mL/min/1.73 m² (severe CKD): 50 mg once daily 3

• Vildagliptin provides effective glycemic control with a favorable safety profile in moderate-to-severe renal failure. 3

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Saxagliptin: Requires Dose Reduction and Has Heart Failure Concerns

Saxagliptin requires dose reduction when eGFR is ≤45 mL/min/1.73 m² and should be avoided in patients with heart failure risk. 2

• eGFR >45 mL/min/1.73 m²: 5 mg once daily (no adjustment) 2

• eGFR ≤45 mL/min/1.73 m²: Maximum 2.5 mg once daily 2

• Critical safety concern: Saxagliptin increased heart failure hospitalization by 27% (HR 1.27,95% CI 1.07–1.51) in the SAVOR-TIMI 53 trial. 2

• Avoid saxagliptin in patients with established heart failure or high heart failure risk. 2

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Alogliptin: Requires Dose Reduction Based on eGFR

Alogliptin requires stepwise dose reduction as renal function declines. 2

• eGFR >60 mL/min/1.73 m²: 25 mg once daily 2

• eGFR 30–60 mL/min/1.73 m²: 12.5 mg once daily 2

• eGFR <30 mL/min/1.73 m²: 6.25 mg once daily 2

• Alogliptin has been associated with increased heart failure hospitalization risk and should be avoided in patients with heart failure. 2

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Clinical Efficacy in CKD

DPP-4 inhibitors reduce HbA1c by approximately 0.4–0.9% in patients with CKD, with efficacy similar to the general diabetic population. 1, 2, 4

• A meta-analysis of 12 studies (4,403 CKD patients) demonstrated a mean weighted HbA1c decline of -0.48% (95% CI -0.61 to -0.35) compared to placebo. 4
• DPP-4 inhibitors have minimal hypoglycemia risk when used as monotherapy, though risk increases approximately 50% when combined with sulfonylureas. 2, 5
• All DPP-4 inhibitors are weight-neutral. 2

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Safety Profile in CKD

DPP-4 inhibitors do not increase cardiovascular events, mortality, or severe adverse events in patients with CKD. 4, 6

• The odds ratio for mortality with DPP-4 inhibitors was 0.88 (95% CI 0.42–1.86) compared to placebo. 4
• The odds ratio for severe adverse effects was 0.86 (95% CI 0.65–1.15). 4
• Hypoglycemia risk is 21–80% higher compared to placebo but remains low overall, with severe hypoglycemia rates similar to placebo. 5

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Important Clinical Context: DPP-4 Inhibitors Are NOT First-Line in High-Risk Patients

For patients with established atherosclerotic cardiovascular disease, heart failure, or CKD with albuminuria (UACR ≥200 mg/g), SGLT2 inhibitors or GLP-1 receptor agonists are strongly preferred over DPP-4 inhibitors due to proven mortality and cardiovascular benefits. 1, 2

• KDIGO 2022 guidelines recommend metformin plus SGLT2 inhibitor as first-line therapy for patients with type 2 diabetes and CKD (eGFR ≥30 mL/min/1.73 m²). 1
• GLP-1 receptor agonists are the preferred additional agent when further glycemic control is needed. 1
• DPP-4 inhibitors are positioned as alternative agents when SGLT2 inhibitors and GLP-1 receptor agonists are contraindicated, not tolerated, or unaffordable. 1

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Practical Decision Algorithm

Step 1: Assess Patient Characteristics

• Check eGFR and albuminuria (UACR). 1
• Evaluate for established cardiovascular disease, heart failure, or high cardiovascular risk. 1

Step 2: Prioritize First-Line Agents

• If eGFR ≥30 mL/min/1.73 m²: Start metformin plus SGLT2 inhibitor. 1
• If additional glycemic control needed: Add GLP-1 receptor agonist. 1

Step 3: Consider DPP-4 Inhibitor Only If:

• SGLT2 inhibitor and GLP-1 receptor agonist are contraindicated, not tolerated, or cost-prohibitive. 1
• Patient has no established heart failure (avoid saxagliptin and alogliptin). 2

Step 4: Select Specific DPP-4 Inhibitor Based on eGFR:

• Any eGFR (including dialysis): Linagliptin 5 mg once daily (preferred for simplicity). 1, 2
• eGFR ≥45 mL/min/1.73 m²: Sitagliptin 100 mg once daily. 1, 2
• eGFR 30–44 mL/min/1.73 m²: Sitagliptin 50 mg once daily OR linagliptin 5 mg once daily. 1, 2
• eGFR <30 mL/min/1.73 m²: Sitagliptin 25 mg once daily OR linagliptin 5 mg once daily. 1, 2

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Common Pitfalls to Avoid

• Do not use saxagliptin or alogliptin in patients with heart failure or high heart failure risk. 2
• Do not rely on serum creatinine alone in elderly patients; always calculate eGFR to determine appropriate dosing. 2
• Do not prioritize DPP-4 inhibitors over SGLT2 inhibitors or GLP-1 receptor agonists in patients with cardiovascular disease or albuminuric CKD. 1, 2
• Remember that linagliptin is the only DPP-4 inhibitor that requires no dose adjustment, making it the simplest choice for patients with fluctuating or severe renal impairment. 1, 2