What are the considerations for using Tenegliptin (Dipeptidyl peptidase-4 inhibitor) in a patient with chronic kidney disease (CKD) and uncontrolled hyperglycemia on Mixtard (Insulin)?

Tenegliptin Use in Chronic Kidney Disease

Direct Recommendation

While tenegliptin is not specifically addressed in major international guidelines, DPP-4 inhibitors as a class can be used in CKD with appropriate dose adjustments, but they should NOT be first-line therapy when adding to insulin in patients with CKD—prioritize adding an SGLT2 inhibitor or GLP-1 receptor agonist instead for superior cardiorenal outcomes. 1

Treatment Hierarchy for Your Clinical Scenario

First-Line Addition to Insulin in CKD

• Add an SGLT2 inhibitor (if eGFR ≥20-25 mL/min/1.73 m²) as the preferred agent when intensifying therapy beyond insulin, as these provide proven cardiovascular death reduction, heart failure hospitalization reduction, and CKD progression prevention 1

• Add a GLP-1 receptor agonist (liraglutide, dulaglutide, or semaglutide) as the second preferred option, particularly if eGFR <30 mL/min/1.73 m² where SGLT2 inhibitor efficacy for glucose lowering is reduced, as GLP-1 RAs reduce major adverse cardiovascular events and slow eGFR decline 1

• Consider a DPP-4 inhibitor (including tenegliptin) only if SGLT2 inhibitors and GLP-1 RAs are contraindicated, not tolerated, or insufficient for glycemic control 1, 2

Critical Caveat About Combining Drug Classes

• Never combine DPP-4 inhibitors with GLP-1 receptor agonists—these are both incretin-based therapies and should not be used together 1

• When adding any glucose-lowering agent to insulin, reduce basal insulin dose by 20% to minimize hypoglycemia risk 1

Tenegliptin-Specific Considerations in CKD

Dosing Across CKD Stages

While tenegliptin is not mentioned in Western guidelines, it belongs to the DPP-4 inhibitor class where:

• Most DPP-4 inhibitors require dose reduction in CKD, with the exception of linagliptin which requires no adjustment 1, 2, 3

• For sitagliptin: 100 mg daily if eGFR ≥45; 50 mg daily if eGFR 30-44; 25 mg daily if eGFR <30 1, 2

• For alogliptin: 25 mg if eGFR >60; 12.5 mg if eGFR 30-60; 6.25 mg if eGFR <30 1, 2

• For saxagliptin: no adjustment if eGFR ≥45; maximum 2.5 mg daily if eGFR <45 1, 2

• For linagliptin: 5 mg daily regardless of renal function (preferred DPP-4 inhibitor in CKD) 1, 2, 3

Expected Efficacy in CKD

• DPP-4 inhibitors reduce HbA1c by approximately 0.4-0.9% in patients with CKD, similar to the general population 2, 4, 5

• A meta-analysis of 12 studies with 4,403 CKD patients showed a mean weighted HbA1c decline of -0.48% (95% CI -0.61 to -0.35) compared to placebo 5

• This glucose-lowering effect is less potent than GLP-1 receptor agonists or SGLT2 inhibitors 2

Safety Profile in CKD

• Minimal hypoglycemia risk when used as monotherapy, but risk increases approximately 50% when combined with sulfonylureas 2, 6

• When combined with insulin, hypoglycemia risk is elevated—monitor closely and reduce insulin dose by 20% at initiation 1, 6

• No cardiovascular benefit demonstrated in outcomes trials, unlike SGLT2 inhibitors and GLP-1 RAs 1, 2

• Cardiovascular safety is neutral for most DPP-4 inhibitors, though saxagliptin and alogliptin increase heart failure hospitalization risk by 27% and should be avoided in patients with heart failure 1, 2

• No increase in serious adverse events or mortality in CKD populations 5

Monitoring Requirements

• Monitor eGFR regularly to adjust DPP-4 inhibitor dosing as kidney function changes (except linagliptin) 1, 3

• Assess HbA1c within 3 months of initiating therapy to determine if further intensification is needed 2

• Increase frequency of glucose monitoring at home for the first 4 weeks, especially given background insulin therapy 1

• Monitor for hypoglycemia symptoms (lightheadedness, weakness, confusion) particularly in the first weeks after adding to insulin 1

Why SGLT2i or GLP-1 RA Should Be Prioritized Over DPP-4i

Proven Mortality and Morbidity Benefits

• SGLT2 inhibitors reduce cardiovascular death (HR 0.62-0.78 in major trials), heart failure hospitalization (HR 0.61-0.69), and CKD progression (HR 0.60-0.66) 1

• GLP-1 receptor agonists reduce major adverse cardiovascular events (HR 0.74-0.87) and slow eGFR decline, with greater benefit in patients with eGFR <60 mL/min/1.73 m² 1

• DPP-4 inhibitors show cardiovascular safety but NO cardiovascular benefit—they neither reduce nor increase cardiovascular events 1, 2

Renal Protection

• SGLT2 inhibitors reduce progression to CKD stage 3+ compared to DPP-4 inhibitors with a relative risk of 0.62 3

• GLP-1 RAs significantly reduce risk for composite kidney outcomes (macroalbuminuria, eGFR decline, progression to kidney failure) compared to placebo 1

• DPP-4 inhibitors may reduce albuminuria but have not demonstrated hard renal outcomes benefits 4

Common Pitfalls to Avoid

• Do not use DPP-4 inhibitors as first choice when SGLT2i or GLP-1 RA are appropriate—you miss the opportunity for cardiorenal protection 1

• Do not forget to reduce insulin dose by 20% when adding any glucose-lowering agent to avoid hypoglycemia 1

• Do not use saxagliptin or alogliptin in patients with heart failure risk or established heart failure 1, 2

• Do not combine DPP-4 inhibitors with GLP-1 receptor agonists—redundant mechanisms of action 1

• Do not assume all DPP-4 inhibitors have the same dosing in CKD—most require adjustment except linagliptin 1, 2, 3