DPP-4 Inhibitor Dosing in Impaired Renal Function
For patients with impaired renal function (eGFR <45 mL/min/1.73 m²), reduce saxagliptin to 2.5 mg once daily and sitagliptin to 50 mg daily (eGFR 30-44) or 25 mg daily (eGFR <30), while linagliptin requires no dose adjustment at any level of renal impairment. 1, 2
Dosing Algorithm by Renal Function
Normal to Mild Renal Impairment (eGFR ≥45 mL/min/1.73 m²)
- Saxagliptin: 2.5-5 mg once daily 1
- Sitagliptin: 100 mg once daily 2
- Linagliptin: 5 mg once daily (no adjustment needed) 2
Moderate Renal Impairment (eGFR 30-44 mL/min/1.73 m²)
- Saxagliptin: 2.5 mg once daily 1
- Sitagliptin: 50 mg once daily 2, 3
- Linagliptin: 5 mg once daily (no adjustment needed) 2
Severe Renal Impairment (eGFR <30 mL/min/1.73 m²)
- Saxagliptin: 2.5 mg once daily 1
- Sitagliptin: 25 mg once daily 2, 3
- Linagliptin: 5 mg once daily (no adjustment needed) 2
End-Stage Renal Disease (ESRD) on Hemodialysis
- Saxagliptin: 2.5 mg once daily, administered after hemodialysis 1
- Sitagliptin: 25 mg once daily, administered after hemodialysis 2
- Linagliptin: 5 mg once daily (no adjustment needed) 2
Critical Cardiovascular Safety Considerations
Saxagliptin should be avoided in patients with heart failure risk or established heart failure, as it increases heart failure hospitalization by 27% in the SAVOR-TIMI 53 trial. 4, 2 This is a Class III recommendation (not recommended) from the 2019 ESC Guidelines. 4
In contrast, sitagliptin and linagliptin have neutral effects on heart failure risk and may be considered in patients with heart failure. 4, 2
Drug Interaction Considerations
When saxagliptin is coadministered with strong CYP3A4/5 inhibitors (ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin), limit the dose to 2.5 mg once daily regardless of renal function. 1, 5 This is because saxagliptin is metabolized via CYP3A4/5, and these inhibitors significantly increase saxagliptin exposure. 5, 6
Sitagliptin and linagliptin are not substrates for CYP450 enzymes and do not require dose adjustment for drug interactions. 6
Practical Clinical Advantages of Linagliptin
Linagliptin is the preferred DPP-4 inhibitor for patients with any degree of renal impairment because it requires no dose adjustment across all stages of kidney disease, including ESRD. 2, 3 This eliminates the complexity of dose titration and reduces prescribing errors. 7
The steady-state exposure of linagliptin increases only 40-42% in severe renal impairment, which is not clinically significant and does not necessitate dose adjustment. 2 In contrast, saxagliptin and sitagliptin show significant increases in drug exposure requiring dose reductions. 6
Common Prescribing Errors to Avoid
A UK study found that 48% of patients with renal impairment were prescribed inappropriately high doses of saxagliptin, 43% for alogliptin, and 41% for sitagliptin at treatment initiation. 7 This likely reflects the complexity of different dosing requirements and lack of awareness of the need for dose adjustment. 7
Always assess renal function (eGFR) before initiating any DPP-4 inhibitor and periodically thereafter. 1 For saxagliptin and sitagliptin, failure to adjust doses in renal impairment leads to excessive drug exposure and potential adverse effects. 6
Long-Term Efficacy and Safety in Renal Impairment
A 52-week study demonstrated that saxagliptin 2.5 mg once daily provides sustained efficacy and good tolerability in patients with moderate to severe renal impairment and ESRD on hemodialysis. 8 The adjusted mean decrease in HbA1c was -0.73% compared to placebo (p<0.001), with similar rates of hypoglycemia (28% vs 29%). 8
Switching from other DPP-4 inhibitors to appropriately dosed sitagliptin (25 or 12.5 mg/day) in patients with renal dysfunction maintained glycemic control without altering renal function over 6 months. 9
Important Limitations
DPP-4 inhibitors should not be first-line therapy for patients with established atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease with albuminuria—in these populations, SGLT2 inhibitors or GLP-1 receptor agonists are strongly preferred due to proven cardiovascular and renal benefits. 2, 10
All DPP-4 inhibitors have neutral cardiovascular outcomes (no benefit, but safe) except saxagliptin, which increases heart failure hospitalization risk. 4, 2