Trelagliptin Side Effects: What Studies Report

What Trelagliptin Is, and Where Its Safety Data Come From

Trelagliptin is an orally administered dipeptidyl peptidase-4 (DPP-4) inhibitor given once weekly rather than once daily. A 2015 pharmacotherapy review described trelagliptin as the first novel once-weekly DPP-4 inhibitor developed for the treatment of type 2 diabetes mellitus and summarised its clinical development in Japan (PMID 26523434). A Japanese-language 2015 overview discussed once-weekly DPP-4 inhibitors as a dosing-frequency innovation within the same drug class (PMID 26666159). A 2025 article in an Indian journal introduced trelagliptin as a once-weekly DPP-4 inhibitor being made available in that setting (PMID 40955891).

Nearly all published human tolerability information for trelagliptin comes from randomised trials and post-marketing reviews in adults with type 2 diabetes, and the registration programme was conducted predominantly in Japanese patients, as a dedicated 2017 safety evaluation of trelagliptin in Japanese patients with type 2 diabetes mellitus set out (PMID 28829213). That context matters when reading any summary of adverse events: the reported event profile reflects a supervised prescription setting in people with diagnosed diabetes, not use in any other population.

Randomised Trial Tolerability: What Studies Report

Once-weekly trelagliptin compared with daily alogliptin

The pivotal comparison was a randomised, double-blind, phase 3 non-inferiority study in Japanese patients with type 2 diabetes that tested trelagliptin 100 mg once weekly against alogliptin 25 mg once daily and placebo, and researchers reported that trelagliptin was non-inferior to daily alogliptin for glycaemic control with a tolerability profile the investigators characterised as similar across the treatment groups (PMID 25609193). The study design — including a placebo arm — is the main reason the literature can compare trelagliptin-associated events against background event rates in the same trial population (PMID 25609193).

Switching from a once-daily DPP-4 inhibitor

An open-label, phase 3 exploratory study examined efficacy and safety when patients with type 2 diabetes mellitus were switched from a once-daily DPP-4 inhibitor to once-weekly oral trelagliptin, and the authors reported on both glycaemic parameters and treatment-emergent adverse events after the switch (PMID 28836351). Because the design was open-label and exploratory, the researchers framed the findings as descriptive rather than as a controlled safety comparison (PMID 28836351).

Combination with insulin therapy

A randomised phase IV study evaluated the efficacy and safety of trelagliptin used in combination with insulin therapy in Japanese patients with type 2 diabetes, and hypoglycaemia was among the adverse events assessed in that combination setting (PMID 29862617). Trials that add an incretin-based agent to insulin generally monitor low blood glucose closely, and the published report for trelagliptin plus insulin followed that pattern (PMID 29862617).

Severe renal impairment and end-stage renal disease

A separate randomised, phase 3 study assessed efficacy and safety of trelagliptin specifically in Japanese patients with type 2 diabetes who had severe renal impairment or end-stage renal disease, a group usually excluded from earlier trials (PMID 31389201). Renal-impairment studies of this kind exist because DPP-4 inhibitor exposure can change when kidney clearance is reduced, and the investigators reported both glycaemic and safety outcomes in that dedicated population (PMID 31389201). No dose figures for that population are reproduced here, because dosing decisions in renal disease are prescribing matters, not educational ones.

Pooled Safety Analyses: What Studies Report

A 2022 meta-analysis pooled randomised evidence on the once-weekly DPP-4 inhibitor trelagliptin in type 2 diabetes and examined safety alongside efficacy, with the researchers concluding that the pooled data supported comparability with control treatments rather than identifying a distinct new hazard (PMID 35344848). Meta-analyses of this size share a common limitation: the contributing trials were mostly short-to-medium duration and conducted in one country, which the pooled analysis of trelagliptin reflects (PMID 35344848).

The narrative safety evaluation published in 2017 approached the same question differently, reviewing the accumulated clinical and post-approval experience with trelagliptin in Japanese patients with type 2 diabetes and discussing how its weekly schedule interacts with tolerability considerations (PMID 28829213). Reviews of this type are useful for orientation but do not generate new incidence estimates, a distinction the authors of that safety evaluation preserved (PMID 28829213).

Class-Level DPP-4 Inhibitor Signals: What Studies Report

Several published questions about trelagliptin safety are really questions about the DPP-4 inhibitor class. The literature below concerns the class; it does not isolate trelagliptin, and readers should not assume a class finding transfers unchanged to one molecule.

Bullous pemphigoid

A 2020 meta-analysis of randomised controlled trials examined bullous pemphigoid — an autoimmune blistering skin condition — in patients treated with DPP-4 inhibitors, assembling the randomised evidence on that reported association (PMID 32236820). The analysis was conducted at class level across DPP-4 inhibitors, so it does not provide a trelagliptin-specific estimate (PMID 32236820).

Aspiration pneumonia reporting signal

A 2020 disproportionality analysis using the Japanese spontaneous reporting system investigated an association between DPP-4 inhibitors and aspiration pneumonia (PMID 31822955). Spontaneous reporting databases capture suspected events submitted by clinicians and patients, and disproportionality methods detect statistical imbalance rather than establish causation — a constraint intrinsic to the design used in that Japanese pharmacovigilance analysis (PMID 31822955).

Cardiovascular events and mortality

An extensive 2021 meta-analysis of randomised controlled trials evaluated cardiovascular events and all-cause mortality in patients with type 2 diabetes treated with DPP-4 inhibitors (PMID 34364771). That analysis pooled the class as a whole; trelagliptin does not have its own dedicated long-term cardiovascular outcome trial in the verified literature reviewed here, and the class-level pooling in that meta-analysis is what the evidence base currently offers (PMID 34364771).

Study Map

What the Published Literature Does Not Cover

Several gaps are worth stating plainly as absences rather than leaving implied:

• Non-diabetic populations. The verified literature reviewed here studied trelagliptin in adults with type 2 diabetes, including a dedicated Japanese safety evaluation (PMID 28829213). No published human safety data describe trelagliptin in people without diabetes, in athletic or body-composition contexts, or in healthy volunteers outside registration pharmacology.
• Geographic breadth. The pivotal non-inferiority trial and the insulin-combination and renal-impairment studies were conducted in Japanese patients (PMID 25609193, PMID 29862617, PMID 31389201). Broader-population data remain limited, and a 2025 article discussed trelagliptin's introduction in India as a newer step in that geographic expansion (PMID 40955891).
• Molecule-specific long-term outcomes. Cardiovascular and mortality evidence for DPP-4 inhibition has been pooled at class level rather than for trelagliptin alone (PMID 34364771).
• Rare dermatological and respiratory events. Bullous pemphigoid and aspiration pneumonia have been examined for DPP-4 inhibitors as a group, not for trelagliptin individually (PMID 32236820, PMID 31822955).

How to Read Adverse-Event Reports

Three reading habits help when comparing the sources above. First, controlled trials with a placebo arm, such as the phase 3 non-inferiority study, allow event rates to be interpreted against background rates in the same population (PMID 25609193). Second, combination settings change expected event patterns, which is why a trial of trelagliptin with insulin is reported separately from monotherapy work (PMID 29862617). Third, signal-detection studies answer a narrower question than trials: the Japanese spontaneous reporting analysis screened for statistical imbalance in reported aspiration pneumonia rather than measuring risk in a randomised cohort (PMID 31822955).

This page is for educational purposes only and is not medical advice; consult a licensed physician about any medication, symptom or laboratory result. Trelagliptin is a prescription medicine in the jurisdictions where it is approved, and nothing here describes how it should be used.

References

• Once-weekly trelagliptin versus daily alogliptin in Japanese patients with type 2 diabetes: a randomised, double-blind, phase 3, non-inferiority study (The Lancet Diabetes & Endocrinology, 2015)
• First novel once-weekly DPP-4 inhibitor, trelagliptin, for the treatment of type 2 diabetes mellitus (Expert Opinion on Pharmacotherapy, 2015)
• [Once-weekly DPP-4 inhibitor] (Nihon Rinsho, 2015)
• Safety evaluation of trelagliptin in the treatment of Japanese type 2 diabetes mellitus patients (Expert Opinion on Drug Safety, 2017)
• Efficacy and safety of once-weekly oral trelagliptin switched from once-daily dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes mellitus: An open-label, phase 3 exploratory study (Journal of Diabetes Investigation, 2018)
• Efficacy and safety of trelagliptin in combination with insulin therapy in Japanese patients with type 2 diabetes: Results from a randomized, Phase IV study (Diabetes, Obesity & Metabolism, 2018)
• Efficacy and safety of trelagliptin in Japanese patients with type 2 diabetes with severe renal impairment or end-stage renal disease: Results from a randomized, phase 3 study (Journal of Diabetes Investigation, 2020)
• Association between dipeptidyl peptidase-4 inhibitor and aspiration pneumonia: disproportionality analysis using the spontaneous reporting system in Japan (European Journal of Clinical Pharmacology, 2020)
• Bullous pemphigoid and dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized controlled trials (Endocrine, 2020)
• Cardiovascular events and all-cause mortality in patients with type 2 diabetes treated with dipeptidyl peptidase-4 inhibitors: An extensive meta-analysis of randomized controlled trials (Nutrition, Metabolism and Cardiovascular Diseases, 2021)
• Safety and efficacy of once weekly dipeptidyl-peptidase-4 inhibitor trelagliptin in type-2 diabetes: A meta-analysis (Diabetes & Metabolic Syndrome, 2022)
• Introducing a Novel Once-weekly Dipeptidyl Peptidase 4 Inhibitor: Trelagliptin in India (Journal of the Association of Physicians of India, 2025)