What is the appropriate use and monitoring of Trelagliptin for a patient with type 2 diabetes?

Trelagliptin for Type 2 Diabetes

Overview and Clinical Positioning

Trelagliptin is a once-weekly oral DPP-4 inhibitor approved in Japan that should NOT be prioritized in the treatment algorithm for type 2 diabetes, as major international guidelines recommend against adding DPP-4 inhibitors to metformin due to lack of mortality or morbidity benefit. 1, 2

While trelagliptin demonstrates efficacy and safety in clinical trials, DPP-4 inhibitors as a class are inferior to SGLT-2 inhibitors and GLP-1 receptor agonists for reducing mortality and cardiovascular events. 1, 2

When Trelagliptin Might Be Considered

Trelagliptin may have a limited role in specific clinical scenarios where preferred agents cannot be used:

Patient Selection Criteria

• Patients who cannot tolerate or afford SGLT-2 inhibitors or GLP-1 receptor agonists 1, 2
• Patients requiring low hypoglycemia risk without cardiovascular disease, heart failure, or chronic kidney disease 3
• Patients with compliance challenges who might benefit from once-weekly dosing 4, 5
• Patients with any degree of renal impairment, as trelagliptin requires no dose adjustment 3

Contraindications to Prioritized Therapy

• Cost constraints preventing access to SGLT-2 inhibitors or GLP-1 receptor agonists 1
• Severe renal impairment (eGFR <15 ml/min/1.73 m²) where SGLT-2 inhibitors are contraindicated 6

Dosing and Administration

Standard Dosing

• Trelagliptin 100 mg orally once weekly, taken before breakfast 5, 7, 8
• No dose adjustment required for any degree of renal or hepatic impairment 4, 5

Switching from Daily DPP-4 Inhibitors

• Direct switch from once-daily DPP-4 inhibitors (such as sitagliptin) to trelagliptin 100 mg weekly is safe without washout period 7
• Glycemic control remains stable during the transition 7

Efficacy Profile

Glycemic Control

• HbA1c reduction of 0.25% to 0.74% depending on baseline control and combination therapy 5
• Non-inferior to daily alogliptin 25 mg with similar HbA1c reduction of approximately 0.33-0.45% 8
• Maintains stable glycemic control with reduced glycemic variability 9

Comparative Efficacy

• Less potent than GLP-1 receptor agonists or SGLT-2 inhibitors for glucose-lowering 6, 3
• Similar efficacy to other DPP-4 inhibitors (sitagliptin, alogliptin, linagliptin) 3, 8

Combination Therapy

Approved Combinations

• Monotherapy with diet and exercise 5
• Combination with sulfonylureas 5
• Combination with glinides 5
• Combination with α-glucosidase inhibitors 5
• Combination with biguanides (metformin) 5
• Combination with thiazolidinediones 5

Critical Safety Warning

• When combining with sulfonylureas or insulin, hypoglycemia risk increases approximately 50% 6, 3
• If SGLT-2 inhibitors or GLP-1 agonists achieve adequate glycemic control, reduce or discontinue sulfonylureas to avoid severe hypoglycemia 1, 2

Safety Profile

Common Adverse Events

• 79.8% of patients experience at least one adverse event with monotherapy, though most are mild or moderate 5
• No specific serious adverse events reported in clinical trials 4
• No hypoglycemia reported with trelagliptin monotherapy 8

Cardiovascular Safety

• DPP-4 inhibitors as a class show cardiovascular safety but NO cardiovascular benefit 3
• Unlike SGLT-2 inhibitors and GLP-1 receptor agonists, trelagliptin does not reduce cardiovascular death, heart failure hospitalization, or major adverse cardiovascular events 6, 3

Tolerability

• Well tolerated in both monotherapy and combination therapy 4, 5
• Adverse event profile similar to once-daily DPP-4 inhibitors 4

Monitoring Requirements

Glycemic Monitoring

• Target HbA1c between 7% and 8% for most adults 1, 2
• Reassess HbA1c within 3 months of initiating therapy 3
• Self-monitoring of blood glucose likely unnecessary when combined with metformin alone due to minimal hypoglycemia risk 1, 2

Renal Function

• Monitor eGFR for all patients with type 2 diabetes and CKD 6
• Unlike other DPP-4 inhibitors, trelagliptin requires no dose adjustment regardless of renal function 3

Long-term Monitoring

• Reassess medication regimen every 3-6 months 1
• Monitor for vitamin B12 deficiency with long-term metformin use (>4 years) 6

Critical Clinical Caveats

When NOT to Use Trelagliptin

• Patients with established atherosclerotic cardiovascular disease—use SGLT-2 inhibitors or GLP-1 receptor agonists instead 3, 1, 2
• Patients with heart failure—use SGLT-2 inhibitors instead 6
• Patients with chronic kidney disease with albuminuria—use SGLT-2 inhibitors or GLP-1 receptor agonists instead 3, 1, 2
• Patients requiring significant weight loss—use GLP-1 receptor agonists instead 1

Treatment Algorithm Position

• First-line: Metformin plus lifestyle modifications 1, 2
• Second-line: Add SGLT-2 inhibitor or GLP-1 receptor agonist (NOT DPP-4 inhibitor) 1, 2
• Trelagliptin only considered when preferred agents are contraindicated, not tolerated, or unaffordable 6

Deintensification Strategy

• Deintensify treatment when HbA1c falls below 6.5% to prevent hypoglycemia 1, 2
• When adequate glycemic control is achieved, reduce or discontinue sulfonylureas or long-acting insulins 1, 2

Advantages Over Daily DPP-4 Inhibitors

• Once-weekly dosing may improve medication adherence compared to daily DPP-4 inhibitors 4, 5
• No dose adjustment required in renal impairment, unlike sitagliptin which requires dose reduction when eGFR <45 ml/min/1.73 m² 3
• Maintains stable DPP-4 inhibition throughout the week 9