A Comprehensive Pharmacological and Clinical Monograph on Teneligliptin

1.0 Executive Summary

Teneligliptin is a third-generation, orally administered dipeptidyl peptidase-4 (DPP-4) inhibitor developed for the management of type 2 diabetes mellitus (T2DM). It is distinguished by a unique, rigid, "J-shaped" molecular structure that confers high potency and a prolonged duration of action, with a terminal half-life of approximately 24 hours, permitting a convenient once-daily dosing regimen.[1]

The primary mechanism of action involves the selective and competitive inhibition of the DPP-4 enzyme. This action prevents the degradation of endogenous incretin hormones, principally glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The resulting elevation in active incretin levels enhances glucose-dependent insulin secretion from pancreatic β-cells and suppresses glucagon release from α-cells, leading to improved glycemic control with a low intrinsic risk of hypoglycemia.[3]

A defining characteristic of Teneligliptin is its unique pharmacokinetic profile, featuring balanced, dual elimination pathways. The drug is metabolized by hepatic enzymes (cytochrome P450 3A4 and flavin-containing monooxygenase 3) and is also excreted unchanged via the kidneys.[1] This dual route of clearance is a significant clinical advantage, as it obviates the need for dose adjustments in patients with any degree of renal impairment, including those with end-stage renal disease (ESRD) requiring dialysis.[7]

Clinical trials have consistently demonstrated the efficacy of Teneligliptin in reducing key glycemic markers, including glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), and postprandial plasma glucose (PPG), both as a monotherapy and as an add-on to other oral antidiabetic agents and insulin.[10] Comparative studies suggest its efficacy is non-inferior to other widely used DPP-4 inhibitors such as sitagliptin.[13]

The safety profile of Teneligliptin is generally favorable and comparable to other agents in its class. The most commonly reported adverse events are hypoglycemia, particularly when used in combination with sulfonylureas or insulin, and constipation.[7] Prescribing information includes a precaution for potential QT interval prolongation, although this has not been observed at clinically relevant doses in dedicated studies.[15]

Despite its established efficacy and unique benefits for patients with renal comorbidities, Teneligliptin's regulatory approval is geographically limited. It is marketed in several countries in Asia (Japan, Korea, India, Thailand, China) and South America (Argentina) but is not approved for use in the United States or the European Union, likely reflecting differing regulatory assessments of its overall risk-benefit profile.[16]

2.0 Introduction and Background

2.1 Drug Identity and Development History

2.1.1 Chemical Identity and Classification

Teneligliptin, identified by DrugBank ID DB11950 and CAS Number 760937-92-6, is a small molecule drug belonging to the dipeptidyl peptidase-4 (DPP-4) inhibitor class of antihyperglycemic agents.[19] Its chemical structure is complex, incorporating multiple heterocyclic rings, and is classified as a prolylthiazolidine-based ketone, piperazine, pyrazole, and thiazolidine.[15] The full chemical name is {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H- pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-yl} (1,3-thiazolidin-3-yl) methanone hemipentahydrobromide hydrate.[15] This unique configuration results in a rigid, "J-shaped" conformation that is fundamental to its pharmacological activity.[1]

2.1.2 Development and Regulatory Status

Teneligliptin was originally synthesized and developed by Mitsubishi Tanabe Pharma Corporation in Japan, representing the first DPP-4 inhibitor to originate from that country.[3] Following its initial development, it was co-marketed in Japan with Daiichi Sankyo Co., Ltd. under the brand name TENELIA®.[15] Handok Inc. is also a key developer, having sponsored numerous clinical trials, particularly in South Korea.[19]

The regulatory history of Teneligliptin reveals a distinct, Asia-centric commercialization strategy. It first received marketing approval in Japan in June 2012.[14] This was followed by approvals in South Korea (2014), India (2015), Argentina, Thailand (2020), and China (2021).[10] In these markets, it is available under various trade names, including Tenelia®, Teneria®, Teneglucon®, Tenepure, and Teneza.[10] Its availability in countries like India at a significantly lower cost compared to other gliptins has contributed to its widespread adoption.[12]

A critical aspect of Teneligliptin's development history is its stalled progress in Western markets. Although the drug was registered for Phase 1 clinical development with the U.S. Food and Drug Administration (FDA) in 2007 and for Phase 2 trials with the European Medicines Agency (EMA) in 2009, it has not been approved for use in either the United States or the European Union.[16] This halt in development, despite a clear clinical advantage in patients with renal impairment, strongly suggests that regulatory bodies in the US and EU identified a risk that was perceived to outweigh the drug's benefits within their specific market and population contexts. The most probable factor contributing to this decision is the observed signal for QT interval prolongation, a cardiovascular safety concern that is a high-priority area of scrutiny for Western regulators.[8] This has resulted in a bifurcated global profile for Teneligliptin: it is a successful and often cost-effective therapeutic option in several Asian and South American nations, while remaining an unapproved agent in the West, likely due to differing regulatory risk-benefit assessments concerning cardiovascular safety.

Property	Description	Source(s)
Generic Name	Teneligliptin	26
DrugBank ID	DB11950	28
CAS Number	760937-92-6	26
Drug Class	Dipeptidyl peptidase-4 (DPP-4) inhibitor; Antihyperglycemic	19
Chemical Class	Prolylthiazolidine; Ketone; Piperazine; Pyrazole; Thiazolidine	15
Molecular Formula	C22H30N6OS	26
Molecular Weight	426.58 g·mol−1	26
Key Structural Feature	"J-shaped" structure with five consecutive rings	1
Originator	Mitsubishi Tanabe Pharma Corporation	15
Table 1: Key Pharmacological and Chemical Properties of Teneligliptin

2.2 Therapeutic Context: The Role of DPP-4 Inhibition in Type 2 Diabetes Mellitus

Type 2 Diabetes Mellitus is a chronic metabolic disorder characterized by hyperglycemia resulting from a combination of insulin resistance and relative insulin deficiency. A key physiological system involved in glucose homeostasis is the incretin system.[3] In response to food intake, enteroendocrine cells in the gastrointestinal tract release incretin hormones, primarily glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).[3] These hormones play a crucial role in postprandial glucose regulation by stimulating the pancreatic β-cells to secrete insulin in a glucose-dependent manner. They also suppress the secretion of glucagon from pancreatic α-cells, thereby reducing hepatic glucose production.[5]

The physiological action of incretins is short-lived, as they are rapidly inactivated and degraded by the enzyme dipeptidyl peptidase-4 (DPP-4).[3] DPP-4 inhibitors, also known as gliptins, are a class of oral antidiabetic agents that function by blocking this enzymatic degradation. By inhibiting DPP-4, these drugs increase the circulating concentrations and prolong the half-life of active GLP-1 and GIP. This enhancement of the natural incretin system leads to improved glycemic control. A key therapeutic advantage of this mechanism is its glucose-dependency; the stimulation of insulin secretion is more pronounced when blood glucose levels are elevated, which confers a low intrinsic risk of causing hypoglycemia.[3]

3.0 Pharmacology and Mechanism of Action

3.1 Inhibition of Dipeptidyl Peptidase-4 (DPP-4)

The primary pharmacological action of Teneligliptin is the potent, selective, and competitive inhibition of the DPP-4 enzyme.[1] This inhibition prevents the cleavage and inactivation of the endogenous incretin hormones GLP-1 and GIP. Consequently, the plasma concentrations of the active forms of these hormones are increased, and their biological activity is prolonged.[3] In vitro studies have quantified the high potency of Teneligliptin, demonstrating half-maximal inhibitory concentrations (IC50) of 0.889 nmol/L against recombinant human DPP-4 and 1.75 nmol/L against DPP-4 in human plasma.[1] Clinical studies confirm this potent activity, showing that a 20 mg once-daily dose effectively inhibits plasma DPP-4 activity over a 24-hour period.[20]

3.2 Unique Molecular Interactions

The potent and sustained activity of Teneligliptin is attributed to its unique chemical structure and binding mode to the DPP-4 enzyme. Teneligliptin is categorized as a Class 3 DPP-4 inhibitor, interacting with the S1, S2, and S2 extensive subsites of the enzyme's active site, a characteristic it shares with sitagliptin.[1]

However, its structure is distinct, characterized by a rigid, "J-shaped" conformation created by five consecutive rings.[1] This pre-organized conformation is thought to minimize the entropy loss upon binding to the enzyme, a thermodynamic factor that contributes to its high binding affinity and potency.[1]

A key differentiating feature is the interaction with the S2 extensive subsite, which is mediated by a portion of the molecule referred to as an "anchor lock domain." This domain forms strong hydrophobic interactions with the enzyme, which are believed to be responsible for both the potency of inhibition and the long duration of action observed in vivo.[1] X-ray co-crystal structure analysis has confirmed that the key interaction involves the phenyl ring on the pyrazole moiety of Teneligliptin binding to this S2 extensive subsite.[31] The molecular structure directly underpins the clinical pharmacology, enabling potent, 24-hour DPP-4 inhibition with a single daily dose.

Furthermore, Teneligliptin exhibits high selectivity for DPP-4. It has an affinity for DPP-4 that is approximately 700- to 1500-fold greater than its affinity for related enzymes like DPP-8 and DPP-9.[1] This selectivity is important, as off-target inhibition of other dipeptidyl peptidases has been linked to certain adverse effects, and high selectivity may therefore contribute to a more favorable safety profile.[7]

3.3 Pharmacodynamic Effects

The inhibition of DPP-4 and subsequent enhancement of the incretin system translate into several key pharmacodynamic effects that contribute to improved glycemic control:

• Glucose-Dependent Insulin Secretion: By increasing active GLP-1 and GIP levels, Teneligliptin potentiates insulin secretion from pancreatic β-cells in direct response to elevated blood glucose levels, such as after a meal.[4] This glucose-dependent action is central to the low risk of hypoglycemia associated with the drug class.
• Glucagon Suppression: Teneligliptin suppresses the postprandial release of glucagon from pancreatic α-cells, another effect mediated by elevated GLP-1 levels. This reduction in glucagon leads to decreased hepatic glucose production, contributing to lower overall blood glucose.[4]
• β-Cell Function: Chronic treatment with Teneligliptin has been associated with improvements in pancreatic β-cell function, as measured by the Homeostasis Model Assessment of β-cell function (HOMA-β).[4] This suggests a potential for preserving the function of insulin-producing cells, which is crucial for the long-term management of T2DM.

3.4 Pleiotropic Effects

In addition to its primary glycemic effects, preclinical and clinical studies have suggested that Teneligliptin may possess pleiotropic, or secondary, beneficial effects. These include antioxidative properties, such as the ability to scavenge hydroxyl radicals and induce the body's antioxidant cascade.[1] Furthermore, some evidence points toward protective effects on the vascular endothelium and improvements in left ventricular (LV) function, potentially mediated by increased levels of the cardioprotective hormone adiponectin.[2]

While these findings are promising and provide a basis for further investigation, their clinical significance remains to be definitively established. The data primarily originate from smaller-scale clinical studies or non-clinical models. Crucially, the provided research does not indicate the completion of large-scale, dedicated cardiovascular outcome trials (CVOTs) for Teneligliptin. In the modern landscape of diabetes therapeutics, where cardiovascular risk reduction is a paramount consideration and has been demonstrated for other drug classes like SGLT2 inhibitors and GLP-1 receptor agonists, the absence of such data is a notable limitation. Therefore, these pleiotropic effects should be considered investigational rather than established clinical benefits of Teneligliptin therapy.

4.0 Pharmacokinetic Profile (ADME)

The pharmacokinetic (PK) profile of Teneligliptin is characterized by rapid absorption, moderate protein binding, and a unique dual pathway of elimination that confers a significant clinical advantage in specific patient populations.

4.1 Absorption

Following oral administration, Teneligliptin is rapidly absorbed, with the time to reach maximum plasma concentration (tmax) occurring at approximately 1.1 to 1.33 hours in the fasting state.[20] The presence of food affects the rate but not the extent of absorption; co-administration with a meal decreases the peak concentration (Cmax) by approximately 20% and delays tmax to 2.6 hours, but the total drug exposure, as measured by the area under the concentration-time curve (AUC), remains unaffected.[20] This lack of a clinically significant food effect offers flexibility in dosing and can contribute to better patient adherence, as the drug can be taken without regard to meals.

4.2 Distribution

In circulation, Teneligliptin exhibits moderate binding to plasma proteins, with reported binding rates ranging from 77.6% to 82.2%.[9]

4.3 Metabolism

Teneligliptin undergoes hepatic metabolism, primarily mediated by two distinct enzyme systems: cytochrome P450 (CYP) 3A4 and flavin-containing monooxygenase 3 (FMO3).[1] CYP2D6 and FMO1 are involved to a minor extent.[38] This metabolism results in several metabolites, with the most abundant in plasma being a thiazolidine-1-oxide derivative known as M1. Other minor metabolites, designated M2 through M5, have also been identified.[20] Studies have shown that genetic polymorphisms in the FMO3 and CYP3A4 genes can influence the pharmacokinetics of Teneligliptin, which may account for some of the observed inter-individual variability in drug response.[37]

4.4 Excretion

A defining feature of Teneligliptin's pharmacokinetic profile is its balanced, dual elimination pathway. The drug and its metabolites are cleared from the body through both renal and hepatic/fecal routes in nearly equal measure. Following administration of a radiolabeled dose, approximately 45.4% of the radioactivity is recovered in the urine and 46.5% in the feces.[34] A significant portion of the drug, about 34%, is excreted unchanged by the kidneys.[33] The primary components found in urine are unchanged Teneligliptin (14.8% of the dose) and the M1 metabolite (17.7% of the dose).[34] The drug has a long terminal elimination half-life (t½) of approximately 24 to 26.9 hours, which provides sustained DPP-4 inhibition over a 24-hour period and supports the convenience of a once-daily dosing schedule.[1]

Parameter	Value	Source(s)
Time to Cmax (tmax), Fasting	~1.1–1.3 hours	20
Time to Cmax (tmax), Fed	~2.6 hours	20
Terminal Half-life (t½)	~24–26.9 hours	1
Plasma Protein Binding	77.6%–82.2%	9
Renal Excretion (% of dose)	~45.4% (total radioactivity)	34
Fecal Excretion (% of dose)	~46.5% (total radioactivity)	34
Major Metabolizing Enzymes	CYP3A4 and FMO3	1
Table 2: Summary of Key Pharmacokinetic Parameters of Teneligliptin

4.5 Pharmacokinetics in Special Populations

4.5.1 Renal Impairment

The dual excretion pathway of Teneligliptin provides a profound clinical advantage in the management of T2DM patients with renal comorbidities, a very common scenario. Clinical pharmacokinetic studies conducted in subjects with varying degrees of renal function—from mild impairment to severe and even end-stage renal disease (ESRD) requiring hemodialysis—have demonstrated that renal dysfunction does not have a clinically significant impact on the drug's exposure.[9] While the total exposure (AUC) shows a slight increase in these populations, the effect is modest and, importantly, is not correlated with the severity of the renal impairment.[9] Consequently, and in contrast to several other DPP-4 inhibitors that require dose reduction in the setting of renal impairment,

no dose adjustment is necessary for Teneligliptin in patients with any degree of renal impairment, including those on dialysis.[7] This simplifies prescribing, reduces the risk of dosing errors, and makes Teneligliptin a particularly suitable option for this vulnerable patient population.

4.5.2 Hepatic Impairment

In patients with mild-to-moderate hepatic impairment, the exposure to Teneligliptin is moderately increased. Studies have shown that Cmax and AUC increase by approximately 25–38% and 46–59%, respectively, compared to subjects with normal hepatic function.[16] While dose adjustment is not explicitly required for mild or moderate impairment, the prescribing information advises careful administration.[16] The safety and pharmacokinetics of Teneligliptin have not been established in patients with severe hepatic impairment.[41]

5.0 Clinical Efficacy

The clinical efficacy of Teneligliptin in improving glycemic control has been established through a robust program of Phase II, III, and IV clinical trials, as well as large-scale, real-world post-marketing surveillance studies. Its effectiveness has been demonstrated both as a monotherapy and as an add-on to a wide range of other antidiabetic agents.

5.1 Monotherapy

When used as a standalone therapy for drug-naïve patients with T2DM, Teneligliptin has shown significant efficacy. A 12-week clinical study demonstrated that Teneligliptin 20 mg once daily resulted in mean reductions of 0.60% in HbA1c, 19.4 mg/dL in fasting plasma glucose (FPG), and 49.8 mg/dL in postprandial plasma glucose (PPG).[42] Another 12-week, placebo-controlled trial found that Teneligliptin at doses of 10 mg, 20 mg, and 40 mg produced placebo-adjusted HbA1c reductions of -0.8%, -0.8%, and -0.9%, respectively.[10] These findings are further supported by a large "real-world" observational study conducted in India (the TREAT-INDIA study), which analyzed data from over 4,300 patients and found a mean HbA1c reduction of 0.98% when Teneligliptin was used as monotherapy.[12]

5.2 Combination Therapy

Teneligliptin is indicated for use in combination with other oral hypoglycemic agents (e.g., metformin, sulfonylureas, pioglitazone) and insulin.[38] Clinical trials have consistently shown its efficacy in these settings:

• Add-on to Metformin: In a 16-week, placebo-controlled trial of patients inadequately controlled on metformin, the addition of Teneligliptin 20 mg resulted in a mean HbA1c reduction of -0.87%, compared to -0.06% in the placebo group.[10]
• Add-on to Sulfonylurea (Glimepiride): In patients inadequately controlled on glimepiride, adding Teneligliptin 20 mg for 12 weeks led to a mean HbA1c reduction of -0.7%, whereas the placebo group experienced an increase of 0.3%.[10]
• Add-on to Multiple Agents: The TREAT-INDIA study provided valuable real-world data, showing significant mean HbA1c reductions when Teneligliptin was added to various existing regimens: -1.07% as an add-on to metformin, -1.46% as an add-on to a metformin plus sulfonylurea combination, and -1.55% as an add-on to insulin.[12]
• Fixed-Dose Combination (FDC): A Phase III study evaluating an FDC of Teneligliptin and pioglitazone demonstrated superior glycemic control (reductions in HbA1c, FPG, and PPG) compared to monotherapy with either agent alone, supporting the clinical benefit of combining these complementary mechanisms of action.[30]

Study/Reference	Therapy	Duration	Baseline HbA1c (%)	Mean Change in HbA1c (%)	Mean Change in FPG (mg/dL)	Mean Change in PPG (mg/dL)
Kadowaki and Kondo 10	Teneligliptin 10-40 mg Monotherapy	12 weeks	~8.0	-0.8 to -0.9	N/A	N/A
Kim et al. 10	Add-on to Metformin	16 weeks	~7.9	-0.87	N/A	N/A
Kadowaki and Kondo 10	Add-on to Glimepiride	12 weeks	~8.4	-0.7	N/A	N/A
Ghosh et al. (TREAT-INDIA) 12	Monotherapy or Add-on	3 months	8.8	-1.37	-51.3	-80.9
Dange et al. 42	Monotherapy	12 weeks	~7.8	-0.60	-19.4	-49.8
FDC Study 30	FDC with Pioglitazone	24 weeks	~8.5	Superior to monotherapy	Superior to monotherapy	Superior to monotherapy
Table 3: Summary of Efficacy Outcomes from Key Phase III and Real-World Studies

5.3 Comparative Efficacy Analysis

Direct comparisons with other DPP-4 inhibitors are crucial for positioning Teneligliptin within its therapeutic class. The available evidence, primarily from studies conducted in Asian populations, shows that its efficacy is broadly comparable to that of other widely used gliptins.

5.3.1 Teneligliptin vs. Sitagliptin

Multiple head-to-head studies have compared Teneligliptin with Sitagliptin, with the evidence largely pointing toward non-inferiority.

• A 24-week, randomized, double-blind, non-inferiority trial in Korean patients on a background of metformin and glimepiride is among the most robust comparisons. It found that Teneligliptin 20 mg was non-inferior to Sitagliptin 100 mg, with the two groups achieving nearly identical mean HbA1c reductions (-1.03% for Teneligliptin vs. -1.02% for Sitagliptin).[13]
• The open-label INSITES study in India also found that the two drugs produced similar and significant reductions in HbA1c, FBG, and PPBG over 12 weeks. A post-hoc analysis noted a trend favoring Teneligliptin in the proportion of patients reaching the target HbA1c of <7% (33.3% vs. 19.4%), though this was not a primary endpoint.[43]
• Other studies have reported some differences; for instance, one trial found a significantly greater reduction in HbA1c and lipid parameters (LDL-C, TC) with Teneligliptin over 12 weeks.[45]

Overall, the highest quality evidence from a double-blind, non-inferiority trial supports the conclusion that Teneligliptin provides comparable glycemic control to Sitagliptin. The choice between these agents in clinical practice is therefore likely to be driven by other factors, such as the patient's renal function status, cost, and local availability, rather than an expectation of superior glycemic efficacy.

5.3.2 Teneligliptin vs. Vildagliptin

Comparative data for Teneligliptin versus Vildagliptin is more varied.

• A Bayesian network meta-analysis that pooled data from multiple trials concluded that Teneligliptin was superior to Vildagliptin for lowering HbA1c, whereas Vildagliptin was more effective at reducing FPG.[46]
• One study suggested a mechanistic difference, finding that Vildagliptin improved markers of insulin sensitivity (HOMA-R) and non-HDL cholesterol, while Teneligliptin did not, despite similar overall effects on HbA1c.[48]
• Conversely, another study found no significant differences in glycemic control or renal safety parameters between the two drugs.[49]

The mixed nature of these findings suggests that while both are effective agents, there may be subtle differences in their pharmacological profiles that could be relevant for specific patient subgroups. However, a clear and consistent superiority of one agent over the other has not been established across all parameters.

Comparison	Study/Reference	Key Efficacy Finding	Key Safety Finding	Conclusion
Teneligliptin vs. Sitagliptin	Hong et al. 13	Non-inferiority in HbA1c reduction (-1.03% vs. -1.02%) at 24 weeks.	Similar rates of AEs and hypoglycemia.	Teneligliptin is a non-inferior alternative to sitagliptin.
Teneligliptin vs. Sitagliptin	Mohan et al. (INSITES) 43	Similar reductions in HbA1c, FBG, PPBG at 12 weeks. Trend favoring teneligliptin for achieving HbA1c <7%.	Both well-tolerated with no difference in AEs.	Similar efficacy and safety profiles.
Teneligliptin vs. Vildagliptin	Li et al. (Meta-analysis) 46	Teneligliptin superior for HbA1c reduction; Vildagliptin superior for FBG reduction.	No significant differences in serious AEs.	Both are effective, with potential differences in their primary glucose-lowering effects.
Teneligliptin vs. Vildagliptin	Sharma et al. 49	Comparable efficacy in glycemic control.	Comparable renal safety profiles and incidence of hypoglycemia.	Both are safe and effective options.
Table 4: Head-to-Head Comparison of Efficacy and Safety: Teneligliptin vs. Other DPP-4 Inhibitors

6.0 Safety and Tolerability

6.1 Overview of Adverse Events

The safety profile of Teneligliptin has been evaluated in numerous clinical trials and extensive post-marketing surveillance. It is generally considered to be well-tolerated, with a safety profile consistent with the DPP-4 inhibitor class.[7] A large-scale, 3-year post-marketing surveillance study in Japan, involving over 10,000 patients, provides robust real-world safety data. In this study, the overall incidence of adverse drug reactions (ADRs) was 3.46%, with serious ADRs occurring in just 0.86% of patients over a median treatment period of two years.[14]

6.2 Specific Adverse Events of Interest

6.2.1 Hypoglycemia

As with all DPP-4 inhibitors, the risk of hypoglycemia is a key safety consideration. The glucose-dependent mechanism of Teneligliptin means that its intrinsic risk of causing hypoglycemia is low.[12] When used as a monotherapy or in combination with agents that do not independently cause hypoglycemia (such as metformin or pioglitazone), the incidence of hypoglycemia is low, typically around 1.1% to 1.5%, and not significantly different from placebo.[38]

However, this risk profile changes significantly with concomitant use of insulin secretagogues or insulin itself. This is a predictable pharmacodynamic interaction, as sulfonylureas and insulin lower blood glucose irrespective of the ambient glucose level. When Teneligliptin is added to a sulfonylurea, the incidence of hypoglycemia increases substantially, to approximately 8.9%.[38] Similarly, the risk is elevated when used with glinides (3.8%) or insulin.[50] Consequently, a dose reduction of the co-administered sulfonylurea or insulin is strongly recommended when initiating Teneligliptin to mitigate the risk of severe hypoglycemia.[38]

6.2.2 Cardiovascular Safety and QT Prolongation

A specific point of caution noted in prescribing information is the potential for QT interval prolongation.[15] This is a measure of the time it takes for the heart's ventricles to repolarize after a contraction, and prolongation can increase the risk of serious arrhythmias. This potential was observed in studies using a supratherapeutic dose of 160 mg once daily.[8] However, in dedicated studies using the clinically relevant doses of 20 mg and 40 mg, no clinically significant prolongation of the QT/QTc interval was observed.[8] Nevertheless, caution is advised when prescribing Teneligliptin to patients with pre-existing risk factors for QT prolongation or those taking other drugs known to affect the QT interval, such as Class IA or Class III antiarrhythmics.[38]

6.2.3 Gastrointestinal and Other Events

• Gastrointestinal: Constipation is one of the most frequently reported ADRs, with an incidence of 0.27% in the large Japanese surveillance study.[14] Other reported GI events include abdominal distension, discomfort, nausea, and flatulence. Rare but serious events such as intestinal obstruction and acute pancreatitis have also been reported and are listed as important precautions.[20]
• Other: Other reported adverse events include dizziness, headache, and skin reactions such as rash and eczema.[51] Increases in serum uric acid have also been observed.[16] Like other DPP-4 inhibitors, there have been rare reports of bullous pemphigoid, though the reporting odds ratio may be overestimated for drugs not approved by the FDA.[53] Interstitial pneumonia is another rare but serious potential ADR that requires monitoring.[51]

Adverse Event	Incidence Rate (%)	Context / Note	Source(s)
Overall ADRs	3.46	Large Japanese post-marketing surveillance (PMS) study (n>10,000)	14
Serious ADRs	0.86	Large Japanese PMS study	14
Hypoglycemia (all)	0.32	Large Japanese PMS study	14
Hypoglycemia (add-on to SU)	8.9	Clinical trial data	38
Constipation	0.27	Large Japanese PMS study	14
Abnormal Hepatic Function	0.24	Large Japanese PMS study	14
Intestinal Obstruction	0.1	Prescribing information	51
Table 5: Incidence of Common and Serious Adverse Events

6.3 Contraindications and Precautions

Teneligliptin is contraindicated in patients with [38]:

• Known hypersensitivity to Teneligliptin or its excipients.
• Severe ketosis, diabetic coma, or a history of diabetic coma.
• Type 1 diabetes mellitus.
• Severe infections, or in the perioperative period or with severe trauma, where insulin is the preferred method for glycemic control.

Special precautions are warranted for [38]:

• Patients with severe hepatic impairment (safety not established).
• Patients with advanced congestive heart failure (NYHA Class III-IV).
• Patients with a history of bowel obstruction or abdominal surgery.
• Patients with risk factors for QT prolongation.
• Use during pregnancy and lactation should be avoided as safety has not been established.

7.0 Drug-Drug Interactions

The potential for drug-drug interactions with Teneligliptin is considered low, owing to its multiple metabolic and elimination pathways.

7.1 Metabolic Interactions (CYP450 System)

Teneligliptin is primarily metabolized by CYP3A4 and FMO3.[1] While it is a substrate for these enzymes, it is only a weak inhibitor of CYP2D6, CYP3A4, and FMO, and it does not significantly inhibit or induce other major CYP isozymes.[15]

The clinical relevance of its interaction with CYP3A4 inhibitors has been studied. Co-administration with ketoconazole, a potent inhibitor of CYP3A4, resulted in a modest increase in Teneligliptin exposure (Cmax increased 1.37-fold, AUC increased 1.49-fold).[36] This increase was not considered clinically significant, and therefore,

no dose adjustment of Teneligliptin is required when it is co-administered with drugs that inhibit CYP3A4.[38] This low potential for metabolic interactions is a practical advantage, particularly for elderly patients with T2DM who are often on multiple medications (polypharmacy).

7.2 Pharmacodynamic Interactions

The most significant interactions are pharmacodynamic in nature, related to its glucose-lowering effect.

• Other Hypoglycemic Agents: As detailed in the safety section, the risk of hypoglycemia is significantly increased when Teneligliptin is used concomitantly with insulin or insulin secretagogues like sulfonylureas and glinides. Proactive dose reduction of these agents is crucial.[38]
• Other Oral Antidiabetics: No clinically relevant pharmacokinetic interactions have been observed with metformin, pioglitazone, or glimepiride.[38]
• Other Drugs: Caution is advised when Teneligliptin is used with drugs that can potentiate its hypoglycemic effect (e.g., β-blockers, MAO inhibitors) or attenuate it (e.g., corticosteroids, thyroid hormones).[38]

8.0 Dosing and Administration

The prescribing information for Teneligliptin provides clear guidelines for its use in the management of T2DM.

• Indication: Teneligliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It can be used as monotherapy or in combination with other oral hypoglycemic agents (including metformin, sulfonylureas, pioglitazone, and others) and insulin.[38]
• Dosage: The standard recommended adult dose is 20 mg administered orally once daily.[15]
• Dose Escalation: If the therapeutic effect is insufficient, the dose may be increased to 40 mg once daily, with continued close monitoring of the patient's clinical course.[38]
• Method of Administration: The tablet may be taken with or without food, providing flexibility for the patient.[38]
• Dosing in Special Populations: As a result of its dual elimination pathways, no dose adjustment is required for patients with any degree of renal impairment, including those with end-stage renal disease.[7] Caution is advised for patients with severe hepatic impairment.[41]

9.0 Conclusion and Future Perspectives

Teneligliptin has established itself as a potent, effective, and well-tolerated dipeptidyl peptidase-4 (DPP-4) inhibitor in the markets where it is approved. Its pharmacological profile is defined by several key strengths: a unique molecular structure conferring high potency, a long half-life that supports a convenient once-daily dosing regimen, and, most notably, a dual excretion pathway that makes it a uniquely valuable therapeutic option for the large and growing population of T2DM patients with concomitant chronic kidney disease. In these patients, the ability to use Teneligliptin without dose adjustment simplifies treatment and reduces the risk of error. Furthermore, its cost-effectiveness in certain countries has made it an accessible and widely prescribed option.

However, the clinical profile of Teneligliptin is also characterized by notable limitations and challenges. The most significant of these is its lack of regulatory approval in the major Western markets of the United States and the European Union. This geographical restriction appears to stem from a regulatory risk-benefit assessment that differs from that of Asian and South American authorities, likely centered on cardiovascular safety signals, particularly the potential for QT interval prolongation. Although dedicated studies have not shown this to be a risk at clinical doses, the initial signal remains a significant hurdle. Additionally, while Teneligliptin's efficacy is comparable to other leading DPP-4 inhibitors, the evidence does not consistently demonstrate superiority in glycemic control. Its competitive positioning, therefore, relies more on its favorable pharmacokinetic profile and economic advantages rather than on superior efficacy.

In conclusion, Teneligliptin is a valuable tool in the armamentarium against type 2 diabetes, especially in approved regions for patients with renal impairment. Its future global impact will likely depend on the generation of further long-term safety data, particularly from large-scale cardiovascular outcome trials, which could be necessary to address regulatory concerns in Western markets. Further investigation into novel dosing strategies, such as the potential for alternate-day therapy, could also enhance its value proposition by improving patient compliance and further reducing treatment costs.[54]

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