Trelagliptin

Overview

Trelagliptin (brand names Zafatek in Japan, Trelaglip in India) is an orally active, highly selective DPP-4 (dipeptidyl peptidase-4) inhibitor developed by Takeda. It is distinguished from all other DPP-4 inhibitors by its once-weekly dosing - no other oral antidiabetic drug in its class requires only one dose per week.

It was first approved in Japan in 2015 and more recently in India (2025). It has not been approved in the United States or European Union, where it is classified as a non-approved agent alongside gemigliptin, anagliptin, teneligliptin, omargliptin, evogliptin, and gosogliptin. - Katzung's Basic and Clinical Pharmacology, 16th Ed.

Mechanism of Action

The incretin axis is central to understanding trelagliptin:

An oral glucose load triggers release of gut incretins - primarily GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide) - from intestinal L and K cells respectively.
These incretins amplify glucose-induced insulin secretion from pancreatic beta cells in a glucose-dependent manner (reducing hypoglycemia risk compared to sulfonylureas).
GLP-1 also suppresses glucagon, delays gastric emptying, and reduces islet apoptosis.
DPP-4 rapidly degrades both GLP-1 and GIP, limiting their therapeutic window.

Trelagliptin inhibits DPP-4, preventing degradation of endogenous GLP-1 and GIP, thereby prolonging their action and enhancing insulin secretion, suppressing glucagon, and improving overall glycemic control. - Katzung's Basic and Clinical Pharmacology, 16th Ed.

Pharmacokinetics - What Enables Once-Weekly Dosing

This is what makes trelagliptin unique:

Parameter	Value
Formulation	Oral tablet (succinate salt)
Dose	100 mg once weekly
Half-life	~54.3 hours (vs. ~12 h for sitagliptin)
DPP-4 binding	Slow dissociation rate (~30 min), vs. sitagliptin (3.5 min) and vildagliptin (<2 min)
DPP-4 inhibition at day 7	77.4% maintained
Steady-state plasma levels	20-21.60 ng/mL, achieved by week 4
Molecular formula	C₂₂H₂₆FN₅O₆ (MW 475.5 g/mol)

The prolonged half-life combined with extremely slow DPP-4 enzyme dissociation is the structural basis for once-weekly efficacy.

Indications

Type 2 diabetes mellitus in adults
Primarily as add-on therapy when first-line metformin alone does not achieve glycemic targets
Can be used as first-line monotherapy when metformin is contraindicated or not tolerated
Can be combined with other oral antidiabetics, insulin, or GLP-1 receptor agonists

Efficacy

Reduces HbA1c and fasting plasma glucose (FPG) over the long term
A 2025 Phase 3 RCT (Dewan et al., PMID 40605903) comparing once-weekly trelagliptin vs. twice-daily vildagliptin in Indian T2DM patients found trelagliptin to be non-inferior to vildagliptin over 16 weeks in HbA1c reduction, with a slightly higher proportion of trelagliptin patients achieving HbA1c <7%
Reduces glycemic variability by maintaining sustained DPP-4 inhibition throughout the week

Safety Profile

Generally well tolerated
Low hypoglycemia risk - because GLP-1/GIP stimulate insulin only when glucose is elevated (glucose-dependent mechanism)
Adverse events are mild and comparable to other DPP-4 inhibitors
Class effects to monitor: nasopharyngitis, upper respiratory tract infection, rare pancreatitis (class concern for all DPP-4 inhibitors)
No major cardiovascular safety signals reported

Comparison with Other DPP-4 Inhibitors

Drug	Dosing	Approval Region
Sitagliptin	Once daily	US, EU, worldwide
Alogliptin	Once daily	US
Linagliptin	Once daily	US, EU
Vildagliptin	Twice daily	EU
Trelagliptin	Once weekly	Japan, India
Omargliptin	Once weekly	Japan

Clinical Relevance

The once-weekly oral dosing is clinically meaningful for:

Patients with poor adherence to daily medications
Elderly patients who find daily regimens difficult to manage
Patients who prefer weekly dosing aligned with other medications or clinic visits

A crossover study design (NCT03231709) confirmed patient preference for weekly DPP-4 inhibitor dosing over daily regimens in Japan.

Key takeaway: Trelagliptin is not novel in its mechanism (same DPP-4 inhibition as sitagliptin), but its structural design giving it a ~54-hour half-life and slow enzyme dissociation rate translates into a clinically differentiated once-weekly oral antidiabetic - currently approved only in Japan and India.

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