A Comprehensive Monograph on Alogliptin (DB06203)

Section 1: Executive Summary and Drug Identification

1.1 Overview

Alogliptin is a potent, highly selective, and orally administered small molecule inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme.[1] It is clinically indicated as an adjunct to diet and exercise for the improvement of glycemic control in adult patients with type 2 diabetes mellitus (T2DM).[1] The therapeutic mechanism of Alogliptin is centered on the potentiation of the endogenous incretin system. By inhibiting DPP-4, Alogliptin prevents the rapid degradation of incretin hormones, primarily glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This action prolongs their physiological activity, leading to enhanced glucose-dependent insulin secretion from pancreatic β-cells and suppression of glucagon release from pancreatic α-cells, thereby lowering blood glucose levels.[2] Alogliptin is available for clinical use as a monotherapy agent and in fixed-dose combinations with other cornerstone antidiabetic medications, namely metformin and pioglitazone, to simplify treatment regimens and improve patient adherence.[2]

1.2 Drug Identification

Precise identification of a pharmaceutical agent is fundamental for research, clinical practice, and regulatory affairs. Alogliptin is known by several names and is cataloged across numerous international scientific and regulatory databases. While most sources are consistent, it is important to note a discrepancy in some commercial data, which incorrectly lists "Trajenta" as a synonym; Trajenta is the brand name for linagliptin, a distinct DPP-4 inhibitor.[8] Correcting this distinction is critical to avoid clinical confusion. The definitive identifiers for Alogliptin are consolidated in Table 1.

Table 1: Drug Identification and Nomenclature

Identifier	Value	Source(s)
International Non-Proprietary Name (INN)	Alogliptin	1
Synonyms	Alogliptina, Alogliptine, Alogliptinum, SYR-322, Axagliptin hydrate	1
Brand Names	Nesina (United States, Japan), Vipidia (United Kingdom, European Union)	6
Combination Brand Names	Kazano (Alogliptin/Metformin), Oseni (Alogliptin/Pioglitazone)	6
DrugBank ID	DB06203	1
CAS Number (Free Base)	850649-61-5	1
CAS Number (Benzoate Salt)	850649-62-6	13
PubChem Compound ID (CID)	11450633	1
KEGG ID	D06553	1
Anatomical Therapeutic Chemical (ATC) Code	A10BH04	1
FDA Unique Ingredient Identifier (UNII)	JHC049LO86	8
ChEBI ID	CHEBI:72323	15

Section 2: Chemical Profile and Physicochemical Properties

The pharmacological activity and formulation characteristics of Alogliptin are fundamentally determined by its chemical structure and physicochemical properties.

2.1 Chemical Structure and Stereochemistry

Alogliptin is a synthetic, xanthine-based small molecule.[6] Its systematic International Union of Pure and Applied Chemistry (IUPAC) name is 2-({6--3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)benzonitrile.[1] The molecule's architecture is defined by three key structural motifs that are essential for its interaction with the DPP-4 enzyme: a cyanobenzyl group, a central uracil (pyrimidinedione) ring, and an aminopiperidine moiety.[6]

A critical aspect of its chemical identity is its stereochemistry. Alogliptin is developed and exists almost exclusively as the R-enantiomer at the chiral center of the aminopiperidine ring, with a purity exceeding 99%. In vivo studies confirm that it undergoes little to no chiral conversion to the inactive (S)-enantiomer, ensuring that the pharmacologically active form is maintained after administration.[1] This stereochemical integrity is paramount for its high-affinity and selective binding to the DPP-4 active site. For pharmaceutical formulation, Alogliptin is typically prepared as a benzoate salt (alogliptin benzoate), which enhances its stability and handling properties.[1]

2.2 Molecular Identifiers and Properties

The physicochemical properties of Alogliptin dictate its behavior in biological systems, including its absorption, distribution, and solubility. These characteristics are summarized in Table 2, compiled from various experimental and computational sources.

Table 2: Summary of Physicochemical Properties

Property	Value	Source(s)
Molecular Formula (Free Base)	C18​H21​N5​O2​	1
Molecular Weight (Free Base)	339.39 g/mol - 339.40 g/mol	6
Molecular Formula (Benzoate Salt)	C25​H27​N5​O4​	14
Molecular Weight (Benzoate Salt)	461.5 g/mol - 461.513 g/mol	14
Appearance	White to off-white crystalline powder/solid	8
Melting Point	127 - 129°C	8
Water Solubility	0.58 mg/mL (sparingly soluble)	6
Other Solubilities	Soluble in DMSO; sparingly soluble in methanol; slightly soluble in ethanol, chloroform, ethyl acetate	8
pKa (Strongest Basic, Predicted)	9.47 - 9.89	8
LogP (Partition Coefficient, Calculated)	0.66	6
Topological Polar Surface Area (TPSA)	94 - 97.05 A˚2	6
InChIKey	ZSBOMTDTBDDKMP-OAHLLOKOSA-N	8
Isomeric SMILES	CN1C(=O)C=C(N(C1=O)CC2=CC=CC=C2C#N)N3CCC[C@H](C3)N	15

Section 3: Pharmacology and Mechanism of Action

Alogliptin exerts its therapeutic effect by modulating the incretin pathway, a key physiological system involved in glucose homeostasis. Its mechanism of action is precise, targeting a specific enzyme to produce a downstream cascade of antidiabetic effects.

3.1 The Incretin System and DPP-4

The incretin system plays a pivotal role in postprandial glucose regulation. In response to nutrient ingestion, specialized endocrine cells in the gastrointestinal tract (L-cells and K-cells) release incretin hormones, most notably glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).[2] These hormones act on the pancreas to orchestrate a coordinated response to the incoming glucose load. They stimulate the synthesis and secretion of insulin from pancreatic β-cells and concurrently suppress the secretion of glucagon from pancreatic α-cells.[2] This dual action efficiently promotes glucose uptake and utilization by peripheral tissues while reducing hepatic glucose production.

The physiological activity of GLP-1 and GIP is inherently transient. Their effects are tightly controlled by the enzyme dipeptidyl peptidase-4 (DPP-4), a ubiquitously expressed transmembrane glycoprotein. DPP-4 rapidly cleaves and inactivates both GLP-1 and GIP, typically within minutes of their release, thereby limiting the duration of the incretin effect.[2]

3.2 Alogliptin as a DPP-4 Inhibitor

Alogliptin is classified as a potent, competitive, and selective inhibitor of the DPP-4 enzyme, demonstrating a half-maximal inhibitory concentration (IC50​) of less than 10 nM.[1] By binding to and inhibiting DPP-4, Alogliptin effectively blocks the degradation of endogenous GLP-1 and GIP. This inhibition increases the circulating concentrations of the active forms of these incretin hormones and significantly prolongs their biological half-life.[2] The resulting augmentation of incretin activity leads to enhanced postprandial insulin secretion and more effective suppression of glucagon, which collectively contribute to the lowering of both post-meal and fasting blood glucose levels.[6]

A defining characteristic of Alogliptin's mechanism, and that of the entire DPP-4 inhibitor class, is its glucose-dependency. The stimulation of insulin secretion by incretins is contingent upon elevated blood glucose levels. Alogliptin, by enhancing the action of these endogenous hormones, therefore exerts its primary effect when glucose is high, such as after a meal.[2] As blood glucose levels return to normal, the insulinotropic stimulus wanes. This physiological feedback loop is the reason for the low intrinsic risk of hypoglycemia associated with Alogliptin when used as a monotherapy, a significant safety advantage over older antidiabetic agents like sulfonylureas, which stimulate insulin release irrespective of glucose levels.[7] The risk of hypoglycemia becomes relevant only when Alogliptin is co-administered with agents that can independently induce it, such as insulin or sulfonylureas.[22]

3.3 Molecular Interactions and Selectivity

The high potency and selectivity of Alogliptin are direct consequences of its specific molecular structure and its precise, multi-point interactions within the active site of the DPP-4 enzyme. Alogliptin is a xanthine-based, non-substrate-like inhibitor that binds non-covalently to the enzyme's catalytic domain.[6]

Analysis of the X-ray co-crystal structure of Alogliptin bound to DPP-4 (Protein Data Bank ID: 3g0b) provides a detailed map of these critical interactions [6]:

• The cyanobenzyl group fits snugly into the hydrophobic S1 pocket of the active site, which is lined with several tyrosine residues, including Tyr662.
• The central uracil ring of the drug molecule engages in favorable π-stacking interactions with the aromatic ring of another key residue, Tyr547.
• The stereospecific (R)-aminopiperidine motif forms crucial ionic bonds, or salt bridges, with the negatively charged side chains of two acidic amino acid residues, Glu205 and Glu206.

This combination of hydrophobic, π-stacking, and electrostatic interactions creates a high-affinity binding complex that is exquisitely tailored to the unique topography of the DPP-4 active site. This structural complementarity is the molecular basis for Alogliptin's potent inhibition at low nanomolar concentrations. Furthermore, this precise fit underlies its remarkable selectivity. Alogliptin demonstrates over 10,000-fold greater selectivity for DPP-4 compared to the related enzymes DPP-8 and DPP-9.[2] The active sites of DPP-8 and DPP-9 differ slightly from that of DPP-4, preventing Alogliptin from binding effectively. This high selectivity is clinically important as it minimizes the potential for off-target effects and associated toxicities that could arise from the inhibition of these other peptidases.

Section 4: Pharmacokinetics: ADME Profile

The pharmacokinetic profile of Alogliptin—its absorption, distribution, metabolism, and excretion (ADME)—determines its dosing regimen, potential for drug interactions, and suitability for use in specific patient populations.

4.1 Absorption

Following oral administration, Alogliptin is absorbed rapidly and efficiently from the gastrointestinal tract. It exhibits an absolute bioavailability of approximately 100%, indicating that nearly the entire oral dose reaches systemic circulation.[2] Peak plasma concentrations (

Tmax​) are typically achieved within 1 to 2 hours after dosing.[2] Importantly, the absorption of Alogliptin is not significantly affected by food. Co-administration with a high-fat meal does not alter its total exposure (Area Under the Curve, AUC) or peak concentration (

Cmax​), granting patients the flexibility to take the medication with or without meals.[2]

4.2 Distribution

Once absorbed, Alogliptin distributes extensively into body tissues. This is evidenced by its large apparent volume of distribution (Vd​) of 417 liters, which far exceeds the volume of total body water, indicating significant partitioning from the plasma into extravascular spaces.[2] Its binding to plasma proteins is low, in the range of 20% to 30%.[2] This low level of protein binding means that a large fraction of the drug in circulation is free and available to interact with its target enzyme, and it also reduces the likelihood of displacement-based drug interactions.

4.3 Metabolism

Alogliptin undergoes limited metabolism in the body, a characteristic that simplifies its pharmacokinetic profile and reduces the potential for metabolic drug interactions.[2] The minor metabolic transformations that do occur are primarily mediated by the cytochrome P450 enzymes CYP2D6 and CYP3A4.[2] Two minor metabolites have been identified:

• M-I (N-demethylated alogliptin): This is an active metabolite that retains DPP-4 inhibitory activity similar to the parent compound. However, it is present at very low concentrations, accounting for less than 1% of the parent drug exposure, and is therefore not considered to contribute significantly to the overall clinical effect.[2]
• M-II (N-acetylated alogliptin): This metabolite is pharmacologically inactive and accounts for less than 6% of the parent drug concentration.[2]

4.4 Excretion

The primary pathway for the elimination of Alogliptin from the body is through renal excretion.[2] A substantial portion of the administered dose, approximately 60% to 76%, is excreted unchanged in the urine.[2] A smaller fraction, around 13%, is recovered in the feces.[2] The mean terminal elimination half-life (

t1/2​) of Alogliptin is approximately 21 hours.[2] This long half-life provides sustained DPP-4 inhibition over a 24-hour period, making the drug suitable for a convenient once-daily dosing regimen.

4.5 Comparative Pharmacokinetics

The clinical selection among different DPP-4 inhibitors is often guided by their distinct pharmacokinetic profiles, particularly their routes of elimination. Table 3 provides a comparative summary of Alogliptin and other major drugs in its class.

Table 3: Comparative Pharmacokinetics of Major DPP-4 Inhibitors

Parameter	Alogliptin	Linagliptin	Saxagliptin	Sitagliptin
Oral Bioavailability	~100%	~30%	~67%	~87%
Time to Cmax​ (hours)	1 - 2	1.5	2 (4 for active metabolite)	1 - 4
Volume of Distribution (Vd​)	417 L	1,110 L	151 L	198 L
Plasma Protein Binding	~20%	75% - 99%	Negligible	~38%
Half-life (t1/2​)	~21 hours	~12 hours	2.5 hours (3.1 for active metabolite)	~12.4 hours
Primary Route of Elimination	Renal (unchanged)	Enterohepatic (unchanged)	Renal and Hepatic	Renal (unchanged)
Metabolism	Minor (CYP2D6, CYP3A4)	Minor (CYP3A4)	CYP3A4/5	Minor (CYP3A4, CYP2C8)
% Excreted Unchanged in Urine	60% - 80%	~6%	24% (36% for active metabolite)	~79%
Data compiled from source.25

The data in Table 3 highlights a critical distinction within the DPP-4 inhibitor class. Alogliptin, like sitagliptin, is predominantly cleared by the kidneys as an unchanged drug. This heavy reliance on renal excretion has a direct and significant clinical consequence. In patients with compromised kidney function, the elimination of Alogliptin is impaired, leading to drug accumulation and a marked increase in total systemic exposure (AUC). Studies have quantified this effect, showing that the AUC increases by 1.7-fold, 2.1-fold, and 3.2-fold in patients with mild, moderate, and severe renal impairment, respectively.[7] To mitigate the risk of exaggerated pharmacological effects and potential toxicity from this accumulation, dose reduction is mandatory for patients with renal impairment. This contrasts sharply with linagliptin, which is primarily eliminated via the enterohepatic system and thus does not require dose adjustments for renal dysfunction, making it a more straightforward choice in that patient population.[25]

Section 5: Clinical Application and Efficacy

The pharmacological properties and pharmacokinetic profile of Alogliptin translate into specific clinical applications, dosing guidelines, and expected therapeutic outcomes in the management of T2DM.

5.1 Approved Indications and Usage

Alogliptin is approved by regulatory bodies, including the U.S. Food and Drug Administration (FDA), as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.[1] It is versatile in its application and can be prescribed as a monotherapy for patients who cannot tolerate other first-line agents, or more commonly, as part of a combination therapy regimen with other classes of antidiabetic drugs, including metformin, thiazolidinediones (TZDs), sulfonylureas, or insulin.[7]

There are important limitations to its use. Alogliptin is not indicated for the treatment of patients with type 1 diabetes or for the management of diabetic ketoacidosis (DKA). In these conditions, the underlying pathology is absolute insulin deficiency, and Alogliptin's mechanism of action, which relies on enhancing endogenous glucose-dependent insulin secretion, would be ineffective.[5]

5.2 Dosage and Administration

The standard recommended dosage of Alogliptin for adult patients with normal renal function or mild renal impairment is 25 mg taken orally once daily.[2] The tablets are designed to be swallowed whole and should not be split, crushed, or chewed.[5] As its absorption is unaffected by food, it can be administered at any time of day, with or without meals, according to patient convenience.[5]

5.3 Dose Adjustments in Special Populations

Safe and effective use of Alogliptin requires careful consideration of patient-specific factors, particularly renal function.

Renal Impairment: Due to its primary reliance on renal clearance, dose adjustments for Alogliptin are mandatory in patients with moderate to severe renal impairment to prevent drug accumulation and potential adverse effects. Renal function, typically assessed by estimated creatinine clearance (CrCl), should be evaluated prior to initiating therapy and periodically thereafter. The specific dosing recommendations are outlined in Table 4.

Table 4: Recommended Dosage Adjustments for Renal Impairment

Degree of Renal Impairment	Creatinine Clearance (CrCl)	Recommended Alogliptin Dosage
Normal / Mild	≥60 mL/min	25 mg once daily
Moderate	≥30 to <60 mL/min	12.5 mg once daily
Severe	<30 mL/min	6.25 mg once daily
End-Stage Renal Disease (ESRD)	Requiring hemodialysis	6.25 mg once daily
Data compiled from sources.2 Note: For patients on hemodialysis, the dose can be administered without regard to the timing of the dialysis session.

Hepatic Impairment: No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh Class A or B). Alogliptin has not been studied in patients with severe hepatic impairment (Child-Pugh Class C), and therefore should be used with caution in this population.[2]

Pediatric and Geriatric Use: The safety and effectiveness of Alogliptin have not been established in pediatric patients (under 18 years of age).[23] For geriatric patients, no dosage adjustments are required based on age alone, as clinical studies have shown no overall differences in safety or efficacy. However, dosing should be guided by renal function, which can decline with age.[5]

5.4 Summary of Clinical Efficacy

Clinical trial programs have established that Alogliptin provides clinically meaningful and statistically significant improvements in glycemic control.[12]

• Glycated Hemoglobin (HbA1c) Reduction: When used as monotherapy in treatment-naïve patients, Alogliptin 25 mg once daily typically reduces HbA1c levels by approximately 0.5% to 0.6% from baseline over a 26-week period.[27]
• Combination Therapy Efficacy: The glucose-lowering effect is additive when Alogliptin is used in combination with other antidiabetic agents. As an add-on therapy, it produces significant further reductions in HbA1c compared to placebo:
• With metformin: an additional reduction of approximately 0.6%.[32]
• With a sulfonylurea (glyburide): an additional reduction of approximately 0.53%.[32]
• With a TZD (pioglitazone): an additional reduction of approximately 0.80%.[32]
• Other Metabolic Effects: Alogliptin is generally considered to be weight-neutral, which is an advantage over some other classes of antidiabetic drugs (e.g., sulfonylureas, TZDs) that are associated with weight gain.[13] Additionally, the SPEAD-A trial, a prospective study in Japan, suggested that Alogliptin treatment may have vasoprotective effects, as it was shown to attenuate the progression of carotid intima-media thickness (IMT), a surrogate marker for atherosclerosis, when compared to conventional therapy.[33]

The body of evidence, particularly from large systematic reviews and mixed treatment comparison (MTC) meta-analyses, indicates that the glycemic efficacy of Alogliptin is largely a class effect. These comprehensive analyses have found no clinically significant differences in the magnitude of HbA1c reduction or the proportion of patients achieving glycemic targets between Alogliptin and other widely used DPP-4 inhibitors like sitagliptin, saxagliptin, linagliptin, and vildagliptin.[34] This finding implies that from a purely glucose-lowering standpoint, the agents within this class are largely interchangeable. Consequently, the clinical decision to select one DPP-4 inhibitor over another is driven less by expectations of superior efficacy and more by other critical differentiating factors, such as the agent's safety profile (e.g., specific warnings), pharmacokinetic properties (e.g., need for renal dose adjustment), and cost or formulary availability.

Section 6: Safety Profile, Warnings, and Contraindications

While generally well-tolerated, the use of Alogliptin is associated with a specific profile of adverse events, risks, and contraindications that require careful clinical consideration. The understanding of its safety has evolved from initial clinical trials to large-scale post-marketing outcomes studies.

6.1 Common and Less Common Adverse Events

In placebo-controlled clinical trials, Alogliptin was found to be well-tolerated.[7] The most frequently reported adverse reactions (occurring in ≥4% of patients) are nasopharyngitis (common cold symptoms), upper respiratory tract infection, and headache.[5] Other commonly reported side effects include gastrointestinal symptoms like indigestion and diarrhea, as well as skin rashes.[4]

6.2 Serious Risks and Regulatory Warnings

The safety profile of Alogliptin is notable for several serious risks that have prompted regulatory warnings and specific clinical monitoring guidelines.

• Heart Failure: The most significant safety concern to emerge from post-marketing analysis is the risk of heart failure. In April 2016, the FDA mandated the addition of a warning to the labels of Alogliptin- and saxagliptin-containing products regarding an increased risk of hospitalization for heart failure.[35] This regulatory action was precipitated by the results of the EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial. While the trial met its primary endpoint of demonstrating non-inferiority for major adverse cardiovascular events (MACE), a secondary analysis revealed a statistically significant increase in the rate of hospitalization for heart failure among patients treated with Alogliptin (3.9%) compared to those receiving placebo (3.3%).[5] The risk was found to be most pronounced in patients with a pre-existing history of heart failure or renal impairment.[35] Consequently, clinical guidelines advise that the risks and benefits of Alogliptin be carefully considered before initiating treatment in at-risk patients. Patients should be monitored for signs and symptoms of heart failure (e.g., unusual shortness of breath, edema, rapid unexplained weight gain), and discontinuation of Alogliptin should be considered if heart failure develops.[5] This evolution from demonstrating general cardiovascular safety to identifying a specific cardiovascular risk illustrates the nuanced and dynamic nature of modern drug safety evaluation.
• Pancreatitis: Cases of acute pancreatitis have been reported in patients taking Alogliptin in both randomized clinical trials and the postmarketing setting.[5] While the incidence is low, the potential severity warrants vigilance. Patients should be observed for signs and symptoms of pancreatitis, such as persistent, severe abdominal pain that may radiate to the back. If pancreatitis is suspected, Alogliptin should be discontinued promptly and appropriate medical management initiated.[5]
• Hypersensitivity Reactions: There have been postmarketing reports of serious hypersensitivity reactions. These can range from angioedema (swelling of the face, lips, tongue, and throat) to life-threatening anaphylaxis and severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome.[5] Due to this risk, Alogliptin is contraindicated in any patient with a history of a serious hypersensitivity reaction to it or to any other DPP-4 inhibitor.
• Hepatotoxicity: Postmarketing reports include cases of hepatic failure, some fatal. While a causal relationship is not always certain, the potential for liver injury exists. It is recommended that liver function tests be performed if a patient develops symptoms suggestive of liver injury (e.g., fatigue, anorexia, right upper quadrant pain, dark urine, jaundice). If abnormalities are confirmed and an alternative cause cannot be found, Alogliptin should be permanently discontinued.[6]
• Severe Arthralgia: Severe and disabling joint pain has been reported as a class effect for DPP-4 inhibitors.[19] Patients should be advised to contact their healthcare provider if they experience severe joint pain, as discontinuation of the medication may be necessary.[23]

6.3 Contraindications

The primary absolute contraindication for Alogliptin is a history of a serious hypersensitivity reaction, such as anaphylaxis, angioedema, or a severe cutaneous adverse reaction like Stevens-Johnson syndrome, to Alogliptin or any component of its formulation.[5] Caution is also advised in patients with a history of angioedema with another DPP-4 inhibitor, as cross-reactivity is possible.[5]

6.4 Drug Interactions

Alogliptin has a low potential for clinically significant pharmacokinetic interactions because it undergoes minimal metabolism and is not a potent inhibitor or inducer of major CYP450 enzymes.[7] The most important pharmacodynamic interaction is the increased risk of hypoglycemia when Alogliptin is used concomitantly with insulin or insulin secretagogues (e.g., sulfonylureas). To mitigate this risk, a reduction in the dosage of the co-administered insulin or sulfonylurea should be considered upon initiation of Alogliptin therapy.[22]

Section 7: Regulatory and Commercial Overview

The development and commercialization of Alogliptin reflect the evolving regulatory landscape for antidiabetic therapies, particularly the increased emphasis on cardiovascular safety.

7.1 Regulatory History

Alogliptin was discovered and developed by Takeda Pharmaceutical Company Limited.[6] Its path to approval in the United States was notably protracted. Takeda submitted the initial New Drug Application (NDA) to the FDA in early 2008.[39] However, in the wake of the FDA's 2008 guidance mandating robust cardiovascular safety data for all new T2DM drugs, the agency issued multiple Complete Response Letters (in June 2009 and April 2012), effectively delaying approval until data from a large-scale cardiovascular outcomes trial could be provided.[39] Following the submission of data from the EXAMINE trial, the FDA granted final approval for Nesina (Alogliptin), as well as its fixed-dose combinations Kazano (Alogliptin/metformin) and Oseni (Alogliptin/pioglitazone), on January 25, 2013.[1]

Internationally, Alogliptin received approval in Japan in April 2010 and was authorized for use in the European Union in September 2013.[7]

7.2 Commercial Formulations

Alogliptin is marketed as an oral, film-coated tablet. To accommodate dose adjustments for renal impairment and provide flexibility in therapy, it is available in three distinct strengths [2]:

• 6.25 mg
• 12.5 mg
• 25 mg

To improve patient convenience and potentially enhance treatment adherence, Alogliptin is also co-formulated in fixed-dose combination (FDC) tablets with other commonly prescribed antidiabetic agents:

• Kazano: Combines Alogliptin with metformin hydrochloride.[6]
• Oseni: Combines Alogliptin with pioglitazone.[6]

Section 8: Expert Synthesis and Conclusion

8.1 Summary of Profile

Alogliptin is a well-characterized DPP-4 inhibitor, distinguished by its high potency and selectivity for its target enzyme. Its pharmacokinetic profile is favorable, featuring high oral bioavailability and a long half-life that allows for convenient once-daily dosing. Its primary route of elimination is renal excretion of the unchanged drug. In terms of efficacy, Alogliptin provides a modest but clinically significant reduction in HbA1c, an effect that is consistent with the DPP-4 inhibitor class as a whole. Crucially, it offers the key therapeutic advantages of being weight-neutral and carrying a low intrinsic risk of inducing hypoglycemia.

8.2 Place in Therapy

The clinical utility and therapeutic niche of Alogliptin are defined not by superior glycemic efficacy, but by the specific nuances of its pharmacokinetic and safety profiles. It stands as a valuable second- or third-line therapeutic option for the management of T2DM, particularly in patients for whom the risks of hypoglycemia or weight gain associated with other agents are a primary concern. However, its application is significantly constrained by two major factors that must be carefully weighed in clinical decision-making:

1. Renal Excretion: Its heavy reliance on renal clearance necessitates mandatory dose adjustments in patients with even moderate renal impairment. This complicates its use in a T2DM population where chronic kidney disease is a common comorbidity.
2. Heart Failure Risk: The FDA warning regarding an increased risk of hospitalization for heart failure, based on robust clinical trial data, renders Alogliptin a suboptimal and potentially hazardous choice for the large subset of T2DM patients who have established heart failure or are at high risk for developing it.

8.3 Concluding Remarks

The story of Alogliptin is emblematic of the trajectory of modern drug development in the field of diabetology. On one hand, it represents a success of rational, structure-based drug design, yielding a molecule with high selectivity and a predictable mechanism of action. On the other hand, its clinical and regulatory history powerfully underscores the paradigm shift toward prioritizing cardiovascular safety. The large-scale outcomes trials, initially designed to rule out broad cardiovascular harm, have become instrumental in uncovering specific, nuanced risks that ultimately define and segment a drug's place in therapy. The decision to prescribe Alogliptin over other agents in its class, or from other classes, must therefore be a highly individualized, patient-centered one. It requires a careful balancing of its benefits in glycemic control against the clearly defined risks related to a patient's specific renal and cardiovascular health status.

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