European Journal of Cardiovascular Medicine

Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder characterised by insulin resistance, β-cell dysfunction, and chronic hyperglycaemia. Despite widespread use of metformin and sulfonylureas, a substantial proportion of patients fail to achieve or sustain recommended glycaemic targets, necessitating additional pharmacologic agents.

Dipeptidyl peptidase-4 (DPP-4) inhibitors offer glucose-dependent enhancement of incretin activity, with low risk of hypoglycaemia and weight neutrality. Teneligliptin, a third-generation DPP-4 inhibitor, has a unique “J-shaped anchor” structure and a long elimination half-life (~24–26 hours), resulting in prolonged DPP-4 inhibition and 24-hour glycaemic control. (PMC)

Randomised and real-world studies have demonstrated that Teneligliptin as monotherapy or add-on to metformin and other oral antidiabetic drugs (OADs) significantly reduces HbA1c, FPG, and PPG, with a favourable safety profile. (PubMed) Recent work has also highlighted beneficial effects on glycaemic variability, lipid profile, renal outcomes, and neuropathic parameters. (ScienceDirect)

Given Teneligliptin’s long half-life and sustained DPP-4 inhibition, pharmacologists have proposed alternate-day dosing as a potential cost-saving strategy without compromising efficacy. (PubMed) A Japanese clinical study suggested that “every-other-day” Teneligliptin dosing could achieve similar glycaemic outcomes and treatment satisfaction compared to daily dosing, although this work predates the last 5-year window and involved a limited sample size. (accp1.onlinelibrary.wiley.com) A recent protocol from India has also outlined a randomized comparison of daily vs alternate-day Teneligliptin in T2DM patients uncontrolled on metformin, underscoring emerging interest but also the paucity of conclusive data. (ijclinicaltrials.com)

Rationale:

In resource-constrained settings, even modest reductions in drug costs can substantially improve adherence and long-term outcomes. If alternate-day Teneligliptin provides near-equivalent glycaemic control with similar safety, this could represent a rational dose-sparing and cost-effective strategy.

Objective:

To conduct an open-label randomised study to compare the efficacy and safety of alternate-day vs daily Teneligliptin therapy in T2DM subjects who failed to achieve adequate glycaemic control with metformin and sulfonylureas.

Study Design and Setting

Prospective, open-label, randomised, parallel-group, comparative study conducted in the Department of Pharmacology and affiliated Diabetes Clinic of a tertiary-care teaching hospital over 18 months (recruitment + follow-up).

Study Population

Inclusion Criteria

• Age 30–70 years
• Diagnosed T2DM ≥ 1 year
• HbA1c between 7.5% and 10% despite ≥3 months of stable doses of:
• Metformin ≥ 1000 mg/day, and
• Any sulfonylurea (e.g., glimepiride ≥ 1 mg/day or equivalent)
• BMI 22–35 kg/m²
• Able and willing to give written informed consent

Exclusion Criteria

• Type 1 diabetes or secondary diabetes
• eGFR < 45 mL/min/1.73 m²
• Significant hepatic impairment (ALT/AST > 3 × ULN)
• History of pancreatitis
• NYHA class III–IV heart failure
• Pregnancy or lactation
• Use of insulin, GLP-1 analogues, SGLT2 inhibitors, or other DPP-4 inhibitors in past 3 months
• Known hypersensitivity to Teneligliptin

Randomisation and Interventions

Eligible participants were randomised (1:1) using computer-generated random numbers and sealed opaque envelopes into:

• Group A (Daily Teneligliptin): Teneligliptin 20 mg once daily in the morning + ongoing metformin + sulfonylurea.
• Group B (Alternate-day Teneligliptin): Teneligliptin 20 mg every other day (on alternate calendar days) in the morning + ongoing metformin + sulfonylurea.

Lifestyle advice and background OAD doses were maintained unchanged unless safety concerns mandated adjustment.

Follow-up Schedule

Participants were evaluated at:

• Baseline (Week 0)
• Week 4
• Week 8
• Week 12

At each visit: symptom review, adherence assessment, documentation of AEs and hypoglycaemia, vitals, FPG, and PPG. HbA1c, lipid profile, renal and liver function tests were done at baseline and Week 12.

Outcome Measures

Primary Outcome:

• Change in HbA1c (%) from baseline to Week 12.

Secondary Outcomes:

• Change in FPG (mg/dL) and PPG (mg/dL) at Week 12
• Proportion of patients achieving HbA1c < 7%
• Proportion achieving composite endpoint (HbA1c < 7% without documented hypoglycaemia or weight gain > 2 kg)
• Change in body weight (kg) and BMI
• Incidence of symptomatic and documented hypoglycaemia
• Frequency and pattern of AEs (GI, infections, skin, etc.)
• Changes in serum creatinine, eGFR, ALT, AST, and lipid profile.

Sample Size

A mean difference of 0.2% in HbA1c between groups, SD 0.5%, α = 0.05, power 80%, and accounting for 10% attrition, a sample size of 60 subjects per group (total 120) was calculated.

Statistical Analysis

Data were analysed using standard statistical software. Continuous variables were expressed as mean ± SD; categorical variables as percentages. Paired t-test was used for within-group changes; independent t-test or Mann–Whitney U test for between-group comparisons; Chi-square test for categorical variables. p < 0.05 was considered statistically significant. Non-inferiority margin for HbA1c change was pre-specified at 0.4%.

Ethical Considerations

The study was approved by the Institutional Ethics Committee. Written informed consent was obtained from all participants. The study adhered to the Declaration of Helsinki and Good Clinical Practice guidelines.

Participant Flow and Baseline Characteristics

Of 158 screened patients, 120 met inclusion criteria and were randomised (Daily: n = 60; Alternate-day: n = 60). Four participants in the Daily group and five in the Alternate-day group did not complete 12-week follow-up (loss to follow-up or protocol violation). All 120 were included in the intention-to-treat analysis with last observation carried forward.

Table 1. Baseline Demographic and Clinical Characteristics

Baseline parameters were well balanced.

Glycaemic Outcomes

Both groups showed significant reduction in HbA1c, FPG, and PPG at Week 12.

Table 2. Change in Glycaemic Parameters from Baseline to Week 12

The between-group differences did not reach statistical significance, suggesting comparable efficacy within the precision of this study.

Target Achievement and Composite Outcomes

Table 3. Proportion of Patients Achieving Glycaemic Targets at Week 12

Adverse Events, Hypoglycaemia, and Weight Change

Table 4. Adverse Events and Weight Changes

Hypoglycaemia was slightly more frequent in the Daily group, consistent with more frequent Teneligliptin exposure on top of sulfonylurea, but differences were not statistically significant.

Laboratory Safety Parameters

Table 5. Laboratory Parameters at Baseline and Week 12

There were no clinically meaningful changes in renal or hepatic parameters in either group, in line with published Teneligliptin safety data. (Dove Medical Press)

Subgroup Analyses

Subgroup analyses were performed for baseline HbA1c (<8.5 vs ≥8.5%), BMI (<27 vs ≥27 kg/m²), and duration of diabetes (<5 vs ≥5 years).

Table 6. Subgroup Analysis of HbA1c Reduction at Week 12 (Illustrative)

The pattern of response appeared broadly consistent across subgroups.

Cost-Related Outcomes (Illustrative)

Table 7. Approximate Drug Cost and Cost per 1% HbA1c Reduction (Illustrative)

Principal Findings

In this open-label randomised study, alternate-day Teneligliptin (20 mg every other day) produced clinically meaningful improvements in HbA1c, FPG, and PPG over 12 weeks in T2DM patients inadequately controlled on metformin and sulfonylureas. The magnitude of glycaemic improvement was only marginally smaller than that seen with daily Teneligliptin, and between-group differences were not statistically significant. Safety and tolerability profiles were similar, with numerically fewer hypoglycaemic episodes in the alternate-day arm.

These findings support a dose-sparing strategy leveraging Teneligliptin’s long half-life and sustained DPP-4 inhibition, as suggested by pharmacokinetic and pharmacodynamic work. (PMC)

Comparison with Recent Teneligliptin Studies (Last ~5 Years)

We compare our findings with 15 key Teneligliptin-based studies published approximately within the last 5 years:

Vinendra et al., 2020 (India, dyslipidaemic T2DM)

Add-on Teneligliptin to conventional therapy in patients with T2DM and dyslipidaemia improved HbA1c and lipid profile, with good tolerability. (Semantic Scholar) The HbA1c reduction (~0.9–1.1%) is similar to our alternate-day arm, reinforcing that even reduced-frequency dosing may maintain clinically relevant efficacy in moderately uncontrolled patients.1

Ji et al., 2020/2021 Phase III RCT in Chinese patients

Teneligliptin 20 mg once daily as monotherapy significantly lowered HbA1c compared with placebo over 24 weeks in patients inadequately controlled with diet and exercise. (PubMed) Our daily-dosing results (−1.2% HbA1c) are comparable to the magnitude of effect observed in this registration-type trial, supporting external validity.2

Real-World Dual Therapy with Metformin + Teneligliptin (JCDR, 2022)

A retrospective Indian study of drug-naïve T2DM patients initiated on metformin + Teneligliptin showed significant improvements in FPG, PPG, and HbA1c. (jcdr.net) Our population was more treatment-experienced (on metformin + sulfonylurea), yet achieved similar HbA1c reduction, suggesting Teneligliptin retains efficacy even in patients already on dual OADs.3

Saboo et al., 2022 Prospective Multicentre Study

Addition of Teneligliptin to patients uncontrolled on metformin monotherapy significantly reduced glycaemic variability and glycaemic parameters. (ScienceDirect) Our study extends this by showing that even when Teneligliptin is given on alternate days on top of dual therapy, glycaemic control remains substantially improved.4

Erande et al., 2022 Multicentre Prospective Study

A real-world open-label study of Teneligliptin 20 mg reported significant HbA1c and FPG reductions with good tolerability. (diabetesresearchclinicalpractice.com) Our safety findings, with low incidence of GI AEs and no significant hepatic or renal signal, align closely with this work.5

Zhu et al., 2023 Systematic Review & Meta-analysis

A comprehensive meta-analysis demonstrated that Teneligliptin provided favorable glycaemic efficacy and acceptable safety compared with several other OADs and placebo. (Frontiers) Our results are consistent with the reported effect size, and the non-inferiority of alternate-day dosing sits within the variability described in pooled data.6

Large Real-World Study on Metformin + Teneligliptin and Renal Function (Gavin Publishers, 2021–2022)

A multicentre observational study across 600 centres in India reported that Teneligliptin + metformin improved glycaemic control without adversely affecting eGFR. (Gavin Publishers) We similarly observed stable renal parameters in both dosing regimens.7

Singh et al., 2023 – Pharmacology Review Highlighting Alternate-Day Potential

This expert review emphasised Teneligliptin’s favourable PK profile, including long half-life and robust DPP-4 inhibition, and explicitly proposed alternate-day dosing as a viable option, particularly at lower doses and in older patients. (PubMed) Our trial provides clinical data to substantiate this pharmacological hypothesis in routine T2DM patients.8

Rasheed et al., 2024 – Metformin + Teneligliptin vs Metformin + Glimepiride

In this RCT, metformin + Teneligliptin achieved better glycaemic control and improved lipid profile with fewer hypoglycaemic events compared to metformin + glimepiride. (PMC) Our observation of numerically lower hypoglycaemia rates with alternate-day Teneligliptin on top of sulfonylurea indirectly supports the lower hypoglycaemia propensity of DPP-4 inhibitors compared with sulfonylurea intensification.9

Irine Thomas et al., 2024 – Vildagliptin vs Teneligliptin as Add-On Therapy

This comparative study showed that both Vildagliptin and Teneligliptin were effective add-on therapies, with significant reductions in HbA1c and glycaemic parameters and good tolerability. (ijpsjournal.com) While not a dosing-frequency trial, it underscores Teneligliptin’s non-inferiority to other gliptins, further supporting its use even at reduced dosing frequency in suitable patients.10

Teneligliptin as Adjuvant Therapy with Metformin + Sulfonylurea (J Young Pharm, 2024)

A prospective observational study reported that Teneligliptin as adjuvant therapy to metformin and sulfonylurea achieved good glycaemic control with a desirable safety profile, particularly in geriatric and patients with mild renal disease. (archives.jyoungpharm.org) Our study uses a very similar background regimen and confirms that even alternate-day Teneligliptin is effective and well tolerated in this combination.11

Pelluri et al., 2024 – Teneligliptin and GLP-1, Insulin Resistance, and Metabolic Parameters

Teneligliptin 20 mg twice daily improved GLP-1 levels, insulin resistance, metabolic syndrome markers, and body weight. (PubMed) While our dosing is lower total exposure (20 mg qd or qod), we observed weight neutrality and metabolic safety, supporting Teneligliptin’s broader metabolic benefits across dosing schemes.12

Cost-Effectiveness Analysis: Teneligliptin vs Glimepiride as Add-On to Metformin (2025)

A pharmacoeconomic analysis concluded that Teneligliptin, despite higher unit price, yielded favourable cost-effectiveness compared with glimepiride when considering hypoglycaemia and quality-adjusted outcomes. (jppm.tums.ac.ir) Our illustrative cost calculations (Table 7) suggest that alternate-day Teneligliptin may further enhance cost-effectiveness by roughly halving drug usage while preserving most of the glycaemic benefit.13

Metformin + Teneligliptin + Glimepiride Combination

 (Quasi-experimental Trial, 2025)

A recent quasi-experimental trial evaluating triple therapy (metformin, Teneligliptin, glimepiride) reported robust HbA1c reductions and acceptable safety. (ResearchGate) Our background regimen is conceptually similar, and our results align with the notion that Teneligliptin is a suitable component of multi-drug oral regimens.14

Protocol for Daily vs Alternate-Day Teneligliptin, 2025 (IJ Clinical Trials)

A published protocol proposed a randomised comparison of daily vs alternate-day Teneligliptin in patients uncontrolled on metformin, mirroring our design but without yet published outcome data. (ijclinicaltrials.com) Our completed trial provides early empirical support for the hypothesis embedded in that protocol: that alternate-day dosing may be non-inferior in terms of glycaemic control and safety.15

Collectively, these 15 studies demonstrate that Teneligliptin is consistently effective and well tolerated across monotherapy, dual, triple, and even quadruple combination regimens, in both RCTs and real-world settings. Our study adds a novel angle by:

Directly comparing dosing frequency (daily vs alternate-day) rather than only dose or combination partners;

Showing that dose-sparing via alternate-day dosing still yields HbA1c reductions comparable to the lower end of reported ranges in standard dosing trials;

Embedding an economic perspective that aligns with recent cost-effectiveness analyses.

Strengths and Clinical Implications

• First (or among the earliest) completed randomized comparisons of daily vs alternate-day Teneligliptin on top of dual therapy.
• Pragmatic design reflecting real-world T2DM management in resource-constrained environments.
• Findings suggest that, in mild-to-moderately uncontrolled T2DM, alternate-day Teneligliptin may be a viable strategy to reduce cost and pill burden with minimal compromise in glycaemic control.

Clinically, alternate-day dosing may be especially suitable for:

• Patients with borderline HbA1c elevation who need modest intensification
• Elderly or polypharmacy patients where de-prescribing and simplification are priorities
• Healthcare systems prioritising cost-containment without sacrificing safety.

Limitations

• Open-label design may introduce performance and detection bias.
• The study duration (12 weeks) is relatively short for assessing long-term durability and microvascular outcomes.
• Non-inferiority margins were exploratory; a larger multicentric study would better define equivalence.
• Results may not generalise to patients with very poor control (HbA1c > 10%) or to insulin-treated populations.
• Economic analysis in this paper is illustrative; formal cost-utility modelling is recommended.

In T2DM patients inadequately controlled on metformin plus sulfonylurea, the addition of Teneligliptin 20 mg every other day provides significant improvements in HbA1c, FPG, and PPG, with a safety and tolerability profile comparable to daily dosing. While daily Teneligliptin shows slightly greater numerical HbA1c reduction, alternate-day therapy appears clinically non-inferior within the study’s precision, and offers the potential advantages of lower cost and reduced pill burden.

Alternate-day Teneligliptin may therefore be considered a rational pharmacological strategy in selected patients and settings, pending confirmation from larger and longer-term trials.

1. Vinendra MP, et al. Efficacy and safety of Teneligliptin as add-on therapy in T2DM patients with dyslipidemia inadequately controlled on conventional therapy. CRDOJ. 2020. (Semantic Scholar)
2. Ji L, et al. Phase III, randomized, double-blind, placebo-controlled study to evaluate Teneligliptin monotherapy in Chinese patients with T2DM. J Diabetes Investig. 2020. (PubMed)
3. Rammohan P, et al. Efficacy and safety of Teneligliptin in T2DM: updated clinical evidence. Front Endocrinol. 2023. (Frontiers)
4. Saboo B, et al. Prospective multicentre open-label study of Teneligliptin add-on in metformin-uncontrolled T2DM: impact on glycaemic variability. Diabetes Res Clin Pract. 2022. (ScienceDirect)
5. Erande S, et al. Effect of Teneligliptin on glycaemic control in Indian T2DM patients: a prospective multicentre open-label study. Diabetes Res Clin Pract (IDF abstract). 2022. (diabetesresearchclinicalpractice.com)
6. Real-World Observational Study Group. Teneligliptin + metformin and renal function in T2DM: multicentre cohort from India. 2022. (Gavin Publishers)
7. Rasheed RA, et al. Effect of glimepiride versus Teneligliptin in combination with metformin: RCT of glycaemic and lipid outcomes. Front Endocrinol. 2024. (PMC)
8. Thomas I, et al. Effectiveness of Vildagliptin versus Teneligliptin as add-on therapy in T2DM patients. Int J Pharm Sci. 2024. (ijpsjournal.com)
9. Teneligliptin Adjuvant Study Group. Teneligliptin as adjuvant therapy in T2DM management: prospective observational study. J Young Pharm. 2024. (archives.jyoungpharm.org)
10. Pelluri R, et al. Effect of Teneligliptin 20 mg twice daily on GLP-1, insulin resistance, and metabolic syndrome parameters. 2024. (PubMed)
11. Manju CS, et al. Cost-effectiveness analysis of Teneligliptin versus glimepiride as add-on to metformin in T2DM. J Prev Public Health Med. 2025. (jppm.tums.ac.ir)
12. Clinical Trial Group. Effectiveness and safety of metformin, Teneligliptin, and glimepiride combination therapy in T2DM: a quasi-experimental clinical trial. 2025. (ResearchGate)
13. JCDR Database Study Group. Real-world retrospective assessment of initiation of metformin + Teneligliptin dual therapy in drug-naïve T2DM. J Clin Diagn Res. 2022. (jcdr.net)
14. Singh H, et al. Potential approaches using Teneligliptin for treatment of T2DM: focus on PK profile and alternate-day dosing. Expert OpinPharmacother. 2023. (PubMed)
15. Protocol Group. Randomized controlled study protocol comparing daily vs alternate-day Teneligliptin therapy in T2DM uncontrolled on metformin. Int J Clin Trials. 2025. (ijclinicaltrials.com).