Omarigliptin (MK-3102): A Comprehensive Pharmacological and Clinical Monograph

Executive Summary

Omarigliptin, known by its developmental code MK-3102, is a potent and highly selective small molecule inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. Developed by Merck & Co., it was engineered as a long-acting oral agent for the management of Type 2 Diabetes Mellitus (T2DM), distinguished within its class by a pharmacokinetic profile amenable to a once-weekly dosing regimen. This feature was designed to enhance patient convenience and medication adherence, addressing a significant challenge in the management of chronic diseases.

The mechanism of action of omarigliptin is consistent with other DPP-4 inhibitors, or "gliptins." By competitively and reversibly inhibiting the DPP-4 enzyme, it prevents the rapid degradation of endogenous incretin hormones, primarily glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The resulting increase 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.

An extensive global clinical development program, O-QWEST, involving approximately 8,000 patients, demonstrated the robust efficacy and favorable safety profile of omarigliptin. In pivotal Phase 3 trials, once-weekly omarigliptin (25 mg) was proven to be non-inferior to the once-daily market leader, sitagliptin, in reducing glycosylated hemoglobin (HbA1c) levels. The drug was generally well-tolerated, with a safety profile comparable to both placebo and active comparators, and exhibited a weight-neutral effect.

This clinical success culminated in the regulatory approval of omarigliptin in Japan in September 2015, where it is marketed as Marizev®. Subsequently, it has been approved in several other Asian markets. However, the trajectory of omarigliptin is defined by a significant strategic divergence. In April 2016, Merck & Co. announced its decision to halt regulatory submissions in the United States and Europe. This was not due to safety or efficacy concerns but was a business decision driven by the evolving diabetes treatment landscape, including the saturation of the DPP-4 inhibitor market and the emergence of newer drug classes, such as SGLT-2 inhibitors, which offered demonstrated cardiovascular benefits.

Consequently, omarigliptin represents a compelling paradox in pharmaceutical development: a molecule that achieved its scientific and clinical objectives but was commercially constrained by external market forces. It stands as a scientifically successful innovation in drug delivery and pharmacology, yet its global impact has been confined to specific regional markets, serving as an important case study in lifecycle management, competitive positioning, and the complex interplay between clinical data and commercial strategy.

Chemical Profile and Physicochemical Characteristics

A comprehensive understanding of omarigliptin's pharmacological behavior begins with a detailed examination of its chemical identity, structure, and inherent physical properties. These characteristics are the foundation upon which its unique pharmacokinetic profile and therapeutic action are built.

Nomenclature and Identifiers

To ensure unambiguous identification across scientific literature, regulatory filings, and chemical databases, omarigliptin is cataloged under a variety of names and unique identifiers.

• Generic Name: Omarigliptin [1]
• Developmental Code Name: MK-3102 [2]
• Brand Names: The primary brand name is Marizev®, under which it was approved and is marketed in Japan.[3] In other markets, such as Bangladesh, it is available under various brand names including Makario, Omaglip, Omaglo, Omari, Omariglip, Omarol, and Wikitin.[5]
• Systematic (IUPAC) Name: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)oxan-3-amine.[6] An alternate, though structurally equivalent, name is also cited: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2,6-dihydro-2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine.[8]
• Key Database Identifiers:
• CAS Number: 1226781-44-7 [2]
• DrugBank ID: DB11992 [1]
• PubChem CID: 46209133 [3]
• ChEMBL ID: CHEMBL2105762 [3]
• UNII: CVP59Q4JE1 [3]
• KEGG ID: D10317 [3]

Molecular Structure and Properties

The molecular architecture and physicochemical attributes of omarigliptin are critical determinants of its absorption, distribution, metabolism, and excretion (ADME) profile, as well as its interaction with the DPP-4 enzyme.

• Chemical Formula: C17​H20​F2​N4​O3​S [2]
• Molecular Weight / Molar Mass: 398.43 g/mol [2]
• Structural Representations:
• InChI: InChI=1S/C17H20F2N4O3S/c1-27(24,25)23-7-10-6-22(8-16(10)21-23)12-5-15(20)17(26-9-12)13-4-11(18)2-3-14(13)19/h2-4,7,12,15,17H,5-6,8-9,20H2,1H3/t12-,15+,17-/m1/s1 [3]
• InChIKey: MKMPWKUAHLTIBJ-ISTRZQFTSA-N [2]
• SMILES: CS(=O)(=O)N1C=C2CN(CC2=N1)[C@@H]3C[C@@H]([C@H](OC3)C4=C(C=CC(=C4)F)F)N [6]
• Chemical Class: Omarigliptin is classified as a pyrrolopyrazole and a synthetic organic compound.[6] It belongs to the therapeutic class of dipeptidyl peptidase-4 (DPP-4) inhibitors and is also categorized as a fluoro-pharmaceutical due to the presence of fluorine atoms.[6]
• Physical Appearance: It is described as a white to off-white solid powder.[2]
• Solubility: The compound exhibits good solubility in organic solvents such as dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) (e.g., 30 mg/mL), with more limited solubility in ethanol (EtOH) (e.g., 1 mg/mL).[2]
• Storage and Stability: Omarigliptin is stable enough for shipment under ambient temperatures. For short-term storage (days to weeks), conditions of 0 - 4 °C are recommended, while long-term storage (months to years) is best at -20 °C in a dry, dark environment. Stock solutions in solvent are stable for up to a year at -80 °C.[2]

The molecular structure of omarigliptin is the product of rational drug design aimed at optimizing both potency and pharmacokinetics. The presence of two fluorine atoms on the phenyl ring is a deliberate medicinal chemistry strategy. Fluorination at these positions can block sites susceptible to metabolic oxidation by cytochrome P450 enzymes, thereby increasing the molecule's metabolic stability. This resistance to breakdown is a key factor contributing to its prolonged half-life. Furthermore, the overall structure, including the tetrahydropyran ring and the methylsulfonyl group on the pyrrolopyrazole core, was engineered to achieve a balance of properties conducive to good oral bioavailability and low clearance, which are prerequisites for a long-acting, once-weekly oral drug.

Table 1: Chemical and Physical Properties of Omarigliptin

Property	Value	Source(s)
Molecular Weight	398.43 g/mol	2
Chemical Formula	C17​H20​F2​N4​O3​S	2
logP	0.63 - 0.93	1
Water Solubility (predicted)	0.543 mg/mL	1
pKa (Strongest Basic)	8.81	1
Polar Surface Area	90.45 - 98.83 Ų	1
Hydrogen Bond Donors	1	1
Hydrogen Bond Acceptors	6	1
Rotatable Bond Count	2 - 3	1
Rule of Five Compliance	Yes	1

The data in Table 1 provide a quantitative basis for the drug's favorable "drug-like" characteristics. Compliance with Lipinski's Rule of Five suggests good potential for oral absorption and membrane permeability. The low rotatable bond count indicates a degree of conformational rigidity that can be favorable for target binding. The pKa value of 8.81 indicates that the primary amine group will be protonated and positively charged at physiological pH, a feature common to many DPP-4 inhibitors that influences their interaction with the enzyme's active site.

Preclinical and Clinical Pharmacology

The therapeutic utility of omarigliptin is rooted in its precise pharmacological actions, which encompass its molecular mechanism, its physiological effects (pharmacodynamics), and its movement through and disposition by the body (pharmacokinetics).

Mechanism of Action

Omarigliptin's therapeutic effect is achieved through the targeted modulation of the incretin system, a key pathway in glucose homeostasis.

• Target and Class: Omarigliptin is a member of the gliptin class of oral antihyperglycemic agents and functions as a Dipeptidyl Peptidase-4 (DPP-4) inhibitor.[2] Its molecular target is the human DPP-4 enzyme, a serine protease also known as CD26 (EC 3.4.14.5).[1]
• The Incretin Effect: In response to food intake, endocrine cells in the gut release incretin hormones, principally glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These hormones are crucial for postprandial glucose control. They act on pancreatic islet cells to stimulate the secretion of insulin from β-cells and suppress the release of glucagon from α-cells. Critically, this action is glucose-dependent, meaning the effects are amplified in hyperglycemic conditions and attenuated as blood glucose normalizes, which inherently minimizes the risk of hypoglycemia.[3]
• DPP-4 Inhibition: The physiological action of GLP-1 and GIP is short-lived, as they are rapidly inactivated and cleaved by the DPP-4 enzyme. Omarigliptin functions by inhibiting this enzyme, thereby prolonging the circulating half-life and increasing the bioavailability of active GLP-1 and GIP. This amplification of the natural incretin effect leads to improved glycemic control.[3]
• Nature of Inhibition: The interaction between omarigliptin and the DPP-4 enzyme is both competitive and reversible.[10] This means omarigliptin binds non-covalently to the active site of the enzyme, competing with endogenous substrates like GLP-1, and can subsequently dissociate, allowing the enzyme to regain function over time.
• Potency and Selectivity: Omarigliptin is a highly potent inhibitor of human DPP-4, with a half-maximal inhibitory concentration (IC50​) of 1.6 nM and an inhibition constant (Ki​) of 0.8 nM.[2] This potency is notably greater than that of the first-in-class DPP-4 inhibitor, sitagliptin ( IC50​ = 18 nM).[16] Equally important is its high selectivity. Omarigliptin shows very weak activity against other related proteases, including quiescent proline peptidase (QPP), fibroblast activation protein (FAP), prolyl endopeptidase (PEP), DPP-7, DPP-8, and DPP-9, with IC50​ values for these enzymes exceeding 67 µM.[9] This selectivity is a critical safety feature, as non-selective inhibition, particularly of DPP-8 and DPP-9, has been associated with toxicity in preclinical models.[14]

Pharmacodynamics

Pharmacodynamic studies confirm that the potent in vitro activity of omarigliptin translates into a sustained physiological effect in humans.

• DPP-4 Inhibition in Humans: Clinical studies in healthy subjects demonstrated that omarigliptin administration leads to profound and sustained inhibition of plasma DPP-4 activity. Following three once-weekly doses of omarigliptin across a range of 10 mg to 100 mg, DPP-4 inhibition at trough (i.e., 168 hours after the last dose) remained substantial, ranging from approximately 77% to 89%.[17] This sustained target engagement throughout the entire weekly dosing interval is the pharmacodynamic basis for its efficacy.
• Effect on Active GLP-1: The direct physiological consequence of this sustained DPP-4 inhibition is the stabilization of active incretin hormones. Studies showed that omarigliptin administration resulted in approximately 2-fold increases in the weighted average of postprandial active GLP-1 concentrations.[17] This provides clear evidence that the drug functions in vivo as intended, amplifying the natural incretin pathway to exert its glucose-lowering effects.

Pharmacokinetics

The pharmacokinetic profile of omarigliptin is its most distinguishing feature, meticulously optimized through chemical design to enable the once-weekly dosing schedule. The absorption, distribution, metabolism, and excretion (ADME) properties collectively result in a long duration of action.

• Absorption: Following oral administration, omarigliptin is rapidly absorbed, with maximum plasma concentrations (Tmax​) achieved within a short window of 0.5 to 2 hours post-dose.[10] The oral bioavailability is high, estimated to be at least 74% in humans and nearly complete in preclinical species.[10] A pivotal clinical pharmacology study demonstrated that co-administration with a high-fat meal had no significant effect on its single-dose pharmacokinetics, allowing for dosing flexibility without regard to meals.[17]
• Distribution: Preclinical data from rats and dogs indicated a volume of distribution at steady state of 0.8 to 1.3 L/kg, suggesting distribution into tissues beyond the plasma volume.[17] In humans, a population pharmacokinetic analysis best described the drug's disposition using a two-compartment model, consistent with distribution into both a central (plasma) and a peripheral (tissue) compartment.[22] Furthermore, a study using radiolabeled omarigliptin found that the blood-to-plasma concentration ratio was less than 1 (ranging from 0.57 to 0.85), indicating that the drug does not preferentially accumulate in red blood cells.[20]
• Metabolism: Omarigliptin is characterized by its high metabolic stability, undergoing minimal biotransformation in the body. In human plasma, unchanged omarigliptin accounted for almost all of the circulating drug-related radioactivity, with no major metabolites detected.[20] This low level of metabolism is a direct result of its chemical structure, which was designed to be resistant to degradation, and is a primary contributor to its long duration of action.
• Excretion: The primary pathway for the elimination of omarigliptin from the body is renal excretion of the parent drug.[20] A human mass balance study utilizing a single oral dose of [¹⁴C]-labeled omarigliptin provided definitive evidence for this clearance mechanism. Approximately 74.4% of the administered radioactive dose was recovered in the urine, while only a minor fraction (3.4%) was found in the feces. Within the urine, unchanged omarigliptin was the major component, accounting for about 89% of the urinary radioactivity.[20] The average renal clearance in healthy subjects was determined to be approximately 2 L/h.[17]
• Half-life and Accumulation: Omarigliptin exhibits a complex, biphasic elimination profile. It is characterized by a very long terminal half-life, reported to be greater than 100 hours.[20] This prolonged terminal phase is a manifestation of target-mediated drug disposition (TMDD). At therapeutic concentrations, a significant fraction of the drug is tightly but reversibly bound to the DPP-4 enzyme throughout the body. This drug-target complex acts as a reservoir, with the slow dissociation of omarigliptin from the enzyme governing the long terminal phase of elimination. However, the clearance of the unbound drug from plasma occurs more rapidly. This unique kinetic behavior means that despite the long terminal half-life, drug accumulation upon repeated weekly dosing is minimal, and a pharmacokinetic steady state is achieved within 2 to 3 weeks of initiating therapy.[17]

Table 2: Summary of Key Human Pharmacokinetic Parameters for Omarigliptin

Parameter	Value / Description	Source(s)
Time to Peak Concentration (Tmax​)	0.5 - 2 hours	10
Oral Bioavailability	≥74%	10
Food Effect	No significant effect on single-dose PK	17
Metabolism	Minimal; no major metabolites detected in plasma	20
Primary Elimination Route	Renal excretion of unchanged drug	20
Terminal Half-life (t1/2​)	>100 hours (governed by target-mediated disposition)	20
Time to Steady State	2 - 3 weeks with once-weekly dosing	17

The combination of these pharmacokinetic properties provides a strong scientific rationale for the once-weekly dosing regimen. Rapid absorption ensures a quick onset of DPP-4 inhibition, while the long effective duration of action, driven by high metabolic stability, renal clearance, and target-mediated disposition, ensures that target inhibition is maintained above a therapeutic threshold for the entire seven-day interval. The lack of a food effect further simplifies the regimen for patients, enhancing the potential for improved long-term adherence.

Clinical Development Program and Therapeutic Efficacy

The clinical utility of omarigliptin was evaluated in a comprehensive and large-scale global development program designed to establish its efficacy and safety in patients with Type 2 Diabetes Mellitus across various stages of the disease and in diverse populations.

Overview of Clinical Trials

The clinical investigation of omarigliptin was extensive, culminating in a robust dataset from multiple Phase 3 studies.

• Program Scope: The global clinical development program, codenamed O-QWEST (Omarigliptin Q Weekly Efficacy and Safety in Type 2 Diabetes), was a major undertaking by Merck & Co. It comprised 10 Phase 3 clinical trials that collectively enrolled approximately 8,000 patients with T2DM.[4]
• Investigated Indications: The primary indication studied was Type 2 Diabetes Mellitus.[1] Additionally, specific trials were conducted to evaluate the drug's use in patients with comorbid Chronic Renal Insufficiency, a common complication of diabetes.[1]

Table 3: Overview of Select Pivotal Clinical Trials for Omarigliptin

Trial Identifier	Brief Title / Objective	Patient Population	Comparators
NCT01841697	Efficacy and safety of omarigliptin vs. sitagliptin add-on to metformin 27	T2DM with inadequate control on metformin	Sitagliptin
NCT01698775	Omarigliptin in T2DM with chronic kidney disease or on dialysis 27	T2DM with moderate/severe CKD or ESRD	Glipizide, Insulin
NCT01717313	Safety and efficacy of omarigliptin in T2DM with inadequate glycemic control 27	T2DM with inadequate control on metformin +/- glimepiride	Metformin, Glimepiride
NCT01703221	Monotherapy study in Japanese patients with T2DM 27	Japanese patients with T2DM	Placebo, Sitagliptin
NCT01682759	Omarigliptin vs. glimepiride in T2DM on metformin 27	T2DM with inadequate control on metformin	Glimepiride
NCT01814748	Safety and efficacy in young adults (18-45 years) with T2DM 25	Young adults (18-<45 years) with T2DM	Placebo

This selection of trials highlights the breadth of the O-QWEST program, which assessed omarigliptin as monotherapy, as an add-on to standard oral agents like metformin and sulfonylureas, and in direct comparison to both placebo and active comparators, including the class standard, sitagliptin.

Efficacy in Type 2 Diabetes Mellitus

The clinical trials consistently demonstrated the significant glucose-lowering efficacy of omarigliptin.

• Dose-Ranging Studies: An initial 12-week, multicenter, double-blind Phase 2b study involving 685 patients was crucial for dose selection. The study evaluated five once-weekly doses of omarigliptin (0.25 mg, 1 mg, 3 mg, 10 mg, and 25 mg) against placebo. The results showed dose-dependent reductions in HbA1c, 2-hour post-meal glucose (PMG), and fasting plasma glucose (FPG). The 25 mg once-weekly dose provided the greatest glycemic efficacy, with a placebo-adjusted least-squares mean reduction in HbA1c of -0.72%. This dose was subsequently selected for the Phase 3 development program.[19]
• Superiority vs. Placebo: The efficacy of the 25 mg dose was unequivocally established against placebo. A comprehensive meta-analysis of 16 randomized controlled trials (RCTs) involving 8,804 subjects confirmed omarigliptin's superiority. The analysis calculated a statistically significant mean difference in HbA1c reduction of -0.58% in favor of omarigliptin.[31] Omarigliptin also demonstrated significant superiority over placebo in lowering FPG and 2-hour PMG, and substantially increased the proportion of patients achieving the therapeutic targets of HbA1c <7.0% and <6.5%.[31]
• Non-Inferiority vs. Active Comparators: A key strategic objective of the development program was to demonstrate that the convenience of once-weekly dosing did not come at the cost of efficacy compared to established daily therapies. The meta-analysis of 16 RCTs concluded that the glycemic efficacy of omarigliptin was similar to that of the active control groups (which included other DPP-4 inhibitors and sulfonylureas) across all key glycemic parameters.[31] This established omarigliptin as an effective therapeutic alternative, with its primary advantage being the simplified dosing regimen.

Efficacy in Special Populations

The development program included dedicated studies to ensure the drug's utility in specific and often hard-to-treat patient populations.

• Patients with Renal Impairment: Recognizing that T2DM is a leading cause of chronic kidney disease (CKD), the trial NCT01698775 specifically evaluated omarigliptin in patients with moderate to severe CKD or end-stage renal disease (ESRD) requiring dialysis.[27] Given that omarigliptin is primarily cleared by the kidneys, this population requires careful dose adjustment. The availability of a lower-strength 12.5 mg tablet was intended to facilitate this dose reduction, ensuring safe and effective use in patients with compromised renal function.[3]
• Japanese Patient Population: A deliberate and focused development effort was undertaken in Japan. Several pivotal trials were conducted exclusively in Japanese patients, and the very first Phase 3 data to be publicly presented came from one such study (NCT01703221).[24] This study demonstrated that omarigliptin 25 mg once-weekly provided a significant reduction in HbA1c compared to placebo and showed comparable efficacy and tolerability to the standard starting dose of sitagliptin used in Japan (50 mg once-daily).[24] This region-specific strategy was instrumental in securing the world's first regulatory approval for omarigliptin from Japan's PMDA.

Analysis of a Confounded Trial (NCT01814748)

One trial within the development program (NCT01814748) yielded unexpected results that provide a valuable lesson in clinical trial conduct. This study was designed to assess the efficacy of omarigliptin monotherapy in a younger adult population (≥18 to <45 years of age).[25]

• Unexpected Outcome: After 24 weeks, the trial failed to demonstrate the superiority of omarigliptin over placebo. The least squares mean change in HbA1c from baseline was -0.33% in the omarigliptin group, which was unexpectedly worse than the -0.45% reduction observed in the placebo group.[29]
• Post-Hoc Investigation: This counterintuitive result prompted an extensive investigation. No issues were found with drug allocation, dispensing, patient compliance with the study medication, or sample analysis. The explanation was discovered through the analysis of stored blood samples, which revealed widespread, undisclosed use of a prohibited antihyperglycemic agent—metformin—by a substantial portion of the trial participants (42.4%).[29]
• Confounding Factor: Crucially, the use of prohibited metformin was not evenly distributed. It was significantly more prevalent in the placebo group (57% of patients) compared to the omarigliptin group (29% of patients). This differential use of an effective background therapy artificially inflated the apparent efficacy of the placebo arm, completely masking the true effect of omarigliptin and invalidating the trial's primary efficacy results.[29] It was hypothesized that the protocol-specified requirement for patients to self-monitor their blood glucose levels may have contributed to this behavior; patients in the placebo arm, observing no improvement in their readings, may have been more motivated to seek effective treatment outside of the trial protocol.[29] This "failed" trial serves as a powerful case study on the potential for patient-driven confounding factors in clinical research and the importance of monitoring for non-adherence to the protocol as a whole, not just to the investigational drug.

Safety, Tolerability, and Risk Profile

The safety and tolerability of omarigliptin were thoroughly assessed throughout its extensive clinical development program. The findings indicate a safety profile consistent with the DPP-4 inhibitor class, characterized by good general tolerability and a low risk of hypoglycemia when used as monotherapy.

Adverse Event Profile

• General Tolerability: Across multiple studies, including a long-term extension study lasting up to 78 weeks, omarigliptin was found to be generally well-tolerated.[17] The overall incidence of adverse events (AEs) was similar in patients treated with omarigliptin compared to those receiving placebo or active comparators like sitagliptin.[12]
• Common Adverse Events: The most frequently reported adverse event in clinical trials was nasopharyngitis (the common cold).[24] Other commonly reported side effects included upper respiratory tract infections, headache, and mild gastrointestinal issues such as constipation and diarrhea.[23]
• Serious Adverse Events (SAEs): The rate of serious adverse events was low and comparable between the omarigliptin and control groups in clinical trials.[12]
• Class-Specific Risks and Warnings: As a member of the DPP-4 inhibitor class, omarigliptin is associated with certain known risks that require monitoring.
• Pancreatitis: Acute pancreatitis is a rare but serious risk associated with DPP-4 inhibitors. While cases were very infrequent in the omarigliptin clinical program and were not deemed drug-related, pancreatitis is listed as a potential serious side effect. It is recommended that omarigliptin be discontinued promptly if pancreatitis is suspected.[19]
• Angioedema: Hypersensitivity reactions, including angioedema, have been reported with the DPP-4 inhibitor class. One case of non-serious tongue edema was reported in an omarigliptin trial.[12] The risk of angioedema may be elevated when omarigliptin is co-administered with angiotensin-converting enzyme (ACE) inhibitors.[1]
• Severe Joint Pain: Severe and disabling arthralgia has been reported in postmarketing surveillance for the DPP-4 inhibitor class and is considered a potential risk.[36]
• Bullous Pemphigoid: Following its approval in Japan, the Pharmaceuticals and Medical Devices Agency (PMDA) mandated a revision to the package insert for Marizev® (omarigliptin) to include pemphigoid, a rare autoimmune blistering skin condition, as a clinically significant adverse reaction.[37]
• GHS Hazard Classification: According to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS), omarigliptin carries the hazard statement H373, indicating it "May cause damage to organs through prolonged or repeated exposure".[6]

Hypoglycemia and Body Weight

Two key considerations for any antihyperglycemic agent are its effect on hypoglycemia risk and body weight.

• Hypoglycemia: Consistent with its glucose-dependent mechanism of action, omarigliptin has a low intrinsic risk of causing hypoglycemia.[17] When used as monotherapy or in combination with metformin, the incidence of symptomatic hypoglycemia was low and similar to that observed with placebo and sitagliptin.[12] However, as with all non-insulin secretagogues, the risk of hypoglycemia is significantly increased when omarigliptin is used in combination with agents that can independently cause hypoglycemia, such as sulfonylureas (e.g., glimepiride, chlorpropamide) or insulin. In such combination therapy, a dose reduction of the sulfonylurea or insulin may be necessary to mitigate this risk.[1]
• Body Weight: Omarigliptin is considered to be weight-neutral. Clinical trials consistently demonstrated no clinically meaningful changes in body weight in patients treated with omarigliptin compared to those receiving placebo or sitagliptin.[12]

Contraindications and Precautions

The use of omarigliptin is contraindicated in certain patient populations and requires caution in others.

• Contraindications:
• Patients with a known history of a serious hypersensitivity reaction to omarigliptin or any of its components.[23]
• Patients with Type 1 diabetes, severe ketosis, or diabetic coma or pre-coma, as insulin is required for these conditions.[23]
• Patients with severe infections, major surgery, or severe trauma, where glycemic control is best managed with insulin.[23]
• Precautions:
• Renal Impairment: Since omarigliptin is primarily eliminated by the kidneys, dose adjustment is required for patients with severe renal impairment (e.g., eGFR <30 mL/min/1.73 m²) or end-stage renal disease (ESRD) requiring dialysis.[23]
• Increased Hypoglycemia Risk: Caution should be exercised in patients with predisposing factors for hypoglycemia, such as pituitary or adrenal insufficiency, malnutrition, starvation, irregular dietary intake, excessive alcohol consumption, or engagement in intense physical activity.[34]

Drug-Drug Interactions

Omarigliptin has the potential to interact with numerous other medications, primarily through pharmacodynamic mechanisms that either potentiate its glucose-lowering effect or antagonize it.

Table 4: Clinically Significant Drug-Drug Interactions with Omarigliptin

Interacting Drug / Class	Nature of Interaction	Clinical Effect and Management	Example Drugs
Agents Increasing Hypoglycemia Risk
Sulfonylureas, Glinides, Insulin	Pharmacodynamic	Additive hypoglycemic effect. Increased risk of hypoglycemia. May require dose reduction of the concomitant agent.	Acetohexamide, Chlorpropamide, Glimepiride, Albiglutide, Insulin 1
Salicylates, NSAIDs	Pharmacodynamic	May increase hypoglycemic activity. Monitor blood glucose.	Acetylsalicylic acid, Choline salicylate, Balsalazide 1
Beta-Blockers	Pharmacodynamic	Can increase therapeutic efficacy of omarigliptin and may mask symptoms of hypoglycemia. Use with caution.	Atenolol, Carvedilol, Celiprolol 1
Quinolone Antibiotics	Pharmacodynamic	May increase therapeutic efficacy of omarigliptin. Monitor blood glucose.	Cinoxacin, Ciprofloxacin 1
Agents Decreasing Efficacy (Hyperglycemia Risk)
Corticosteroids (systemic/inhaled)	Pharmacodynamic	Antagonize hypoglycemic effect. Increased risk of hyperglycemia. Monitor blood glucose.	Betamethasone, Budesonide, Ciclesonide, Cortisone acetate 1
Thiazide & Loop Diuretics	Pharmacodynamic	May decrease therapeutic efficacy of omarigliptin. Monitor blood glucose.	Chlorothiazide, Chlorthalidone, Bumetanide 1
Atypical Antipsychotics	Pharmacodynamic	May decrease therapeutic efficacy of omarigliptin. Monitor blood glucose.	Aripiprazole, Brexpiprazole, Clozapine 1
Sympathomimetics	Pharmacodynamic	Antagonize hypoglycemic effect. May decrease therapeutic efficacy.	Albuterol, Epinephrine 1
Tricyclic Antidepressants	Pharmacodynamic	May decrease hypoglycemic activities of omarigliptin. Monitor blood glucose.	Amitriptyline, Clomipramine, Amoxapine 1
Estrogens, Thyroid Hormones	Pharmacodynamic	May attenuate hypoglycemic action. Monitor blood glucose.	Conjugated estrogens, Thyroid hormone 1
Agents Increasing Angioedema Risk
ACE Inhibitors	Pharmacodynamic	Additive risk. Increased risk of angioedema. Use with caution.	Benazepril, Captopril, Cilazapril, Azilsartan medoxomil 1
Thrombolytics	Pharmacodynamic	Potential for increased risk of angioedema.	Anistreplase 1

This categorized table transforms an extensive list of potential interactions into a clinically actionable guide, allowing healthcare providers to anticipate and manage risks based on a patient's concomitant medications.

Comparative Assessment within the DPP-4 Inhibitor Class

To fully appreciate the clinical positioning of omarigliptin, it is essential to compare its profile against other prominent members of the DPP-4 inhibitor class, particularly the once-daily market leader sitagliptin and the metabolically distinct linagliptin.

Head-to-Head Efficacy and Safety vs. Sitagliptin (Once-Daily)

A cornerstone of the O-QWEST clinical program was the direct, head-to-head comparison of once-weekly omarigliptin with once-daily sitagliptin to establish non-inferiority.

• Trial Design: Multiple large, randomized, double-blind Phase 3 trials, such as the study identified as NCT01841697, were designed specifically for this purpose. These trials typically enrolled patients with T2DM who had inadequate glycemic control on metformin monotherapy and randomized them to receive either omarigliptin 25 mg once weekly or sitagliptin 100 mg once daily (or 50 mg once daily in studies conducted in Japan).[12]
• Efficacy Outcomes: These trials consistently met their primary efficacy endpoint. The data demonstrated that omarigliptin was non-inferior to sitagliptin in reducing HbA1c levels from baseline after 24 weeks of treatment. The least squares mean difference in HbA1c reduction between the two groups was clinically negligible, typically ranging from -0.02% to -0.03%.[12] Secondary efficacy endpoints, including the reduction in fasting plasma glucose and the proportion of patients achieving glycemic targets (e.g., HbA1c <7.0%), were also similar between the two treatment arms.[12]
• Safety and Tolerability: The safety profiles of the two drugs were found to be highly comparable. There were no notable differences in the incidence of overall adverse events, serious adverse events, or discontinuations due to adverse events. Importantly, the incidence of symptomatic hypoglycemia was low and similar in both the omarigliptin and sitagliptin groups.[12]

These results robustly established that the convenience of a once-weekly dosing schedule with omarigliptin could be achieved without compromising the proven efficacy and safety of the daily standard of care, sitagliptin.

Head-to-Head Efficacy and Safety vs. Linagliptin (Once-Daily)

A comparison with linagliptin is particularly relevant for patients with renal impairment, as linagliptin is unique among DPP-4 inhibitors for its primary non-renal route of elimination, which obviates the need for dose adjustment in CKD.

• Trial Design: A prospective, randomized, open-label, multicenter study was conducted to compare the efficacy and safety of omarigliptin and linagliptin specifically in patients with T2DM on maintenance hemodialysis.[39] Patients previously stable on linagliptin were randomized to either continue linagliptin (5 mg/day) or switch to omarigliptin (at a renally adjusted dose of 12.5 mg/week) for 24 weeks.
• Efficacy Outcomes: The study's primary endpoint was to demonstrate the non-inferiority of omarigliptin to linagliptin. This endpoint was met. Furthermore, the analysis revealed a statistically significant difference in favor of omarigliptin for the change in HbA1c from baseline. The omarigliptin group experienced a mean reduction in HbA1c of -0.2%, whereas the linagliptin group saw a mean increase of +0.4% (p=0.024).[40]
• Safety and Tolerability: The treatment was well-tolerated, and no episodes of hypoglycemia were reported in the omarigliptin group.[40] This study provided evidence that once-weekly omarigliptin is a feasible and effective option for glycemic control even in the complex population of patients with ESRD on hemodialysis.

Positional Analysis and the "Weekly" Advantage

Omarigliptin's defining characteristic is its once-weekly administration, a feature it shares with only a few other DPP-4 inhibitors worldwide, such as trelagliptin (also approved in Japan).[33]

• The Adherence Hypothesis: The primary rationale for developing a weekly formulation is to improve patient convenience and, consequently, medication adherence, which is often suboptimal in chronic diseases like diabetes.[14]
• Clinical Reality: While theoretically appealing, the real-world benefit of a weekly schedule can be debated. Many patients with T2DM are on polypharmacy, often including daily medications like metformin. For these patients, managing a mix of daily and weekly pills might not necessarily simplify their regimen.[43] A meta-analysis that pooled data from trials of weekly (omarigliptin and trelagliptin) versus daily DPP-4 inhibitors found no significant differences in glycemic efficacy or safety outcomes, suggesting that while the dosing frequency is different, the ultimate clinical effects are comparable.[44] The choice between a weekly and a daily agent may therefore depend more on individual patient preference, lifestyle, cost, and specific clinical circumstances (e.g., use in a directly observed therapy setting).

Table 5: Comparative Profile of Omarigliptin vs. Select DPP-4 Inhibitors

Attribute	Omarigliptin	Sitagliptin (Januvia®)	Linagliptin (Tradjenta®)
Dosing Frequency	Once-Weekly	Once-Daily	Once-Daily
Standard Dose	25 mg	100 mg	5 mg
Renal Dose Adjustment	Yes (12.5 mg for severe impairment/ESRD)	Yes (50 mg for moderate, 25 mg for severe)	No
Primary Excretion Route	Renal (unchanged drug)	Renal (unchanged drug)	Biliary/Fecal (unchanged drug)
Key Efficacy Finding	Non-inferior to sitagliptin	Established efficacy vs. placebo and comparators	Established efficacy vs. placebo and comparators
Heart Failure Warning	No specific warning	No specific warning	No specific warning

This comparative table distills the key clinical differentiators among these three agents. Omarigliptin offers the unique convenience of weekly dosing but requires renal dose adjustment, similar to sitagliptin. Linagliptin, while a daily medication, stands apart due to its non-renal clearance, making it a simpler choice for patients with fluctuating or severe kidney disease. This framework highlights the nuanced clinical decision-making involved in selecting a DPP-4 inhibitor, where omarigliptin's primary value proposition is convenience rather than a fundamental difference in efficacy or safety.

Global Regulatory Journey and Commercial Outlook

The story of omarigliptin is a tale of two distinct paths: successful clinical development and regional commercialization, contrasted with a strategic withdrawal from the world's largest pharmaceutical markets. This journey provides a compelling look into the complex factors that determine a drug's ultimate global footprint.

Approval in Japan and Other Markets

Following a clinical development program that was strategically tailored to the Japanese patient population and regulatory environment, omarigliptin achieved its first global approval in Japan.

• PMDA Approval: On September 28, 2015, Japan's Pharmaceuticals and Medical Devices Agency (PMDA) approved Marizev® (omarigliptin) in 25 mg and 12.5 mg tablets for the treatment of adults with Type 2 diabetes.[3] This made Japan the first country in the world to approve the once-weekly DPP-4 inhibitor.[4] The approval was based on the positive results from the Phase 3 trials conducted in Japanese patients.[4]
• Expansion in Asia: Following its successful launch in Japan, omarigliptin has since been approved and made available in several other countries, particularly in Asia. For example, it was introduced to the market in Bangladesh in August 2023.[5]

Strategic Withdrawal from U.S. and European Markets

Despite its success in Japan and initial plans to file for regulatory approval with the U.S. Food and Drug Administration (FDA) by the end of 2015, Merck & Co. made a significant strategic pivot.[4]

• The Announcement: In April 2016, Merck announced that it would no longer pursue marketing authorization for omarigliptin in the United States or in Europe.[3]
• The Rationale: The company was explicit that this decision was not based on any new or concerning findings related to the drug's safety or efficacy profile. Instead, the withdrawal was attributed to "business reasons".[43] This distinction is crucial, as it separates omarigliptin from drugs that are withdrawn due to safety signals or failed efficacy endpoints.
• Inferred Market Dynamics: The business decision was likely a pragmatic response to a rapidly changing and increasingly challenging market for new diabetes therapies in the West. Several key factors are thought to have influenced this choice:

1. Market Saturation and Cannibalization: The DPP-4 inhibitor market was already mature and highly competitive, with Merck's own once-daily blockbuster, Januvia® (sitagliptin), holding a dominant position. Launching a new, similar-acting drug, even with a convenience advantage, risked cannibalizing sales of their existing market leader without necessarily expanding the overall market share for the company.[43]
2. Shifting Treatment Paradigm: A more profound market shift was underway with the emergence of compelling data for newer drug classes. Specifically, SGLT-2 inhibitors and GLP-1 receptor agonists had begun to demonstrate significant cardiovascular and renal benefits in large outcomes trials—a high bar that the DPP-4 inhibitor class as a whole had not met. This shifted the focus of diabetes management beyond mere glucose lowering to include cardio-renal risk reduction, thereby limiting the perceived value and growth potential of new agents in the DPP-4 class.[43]
3. Uncertain Value Proposition: There was significant uncertainty as to whether healthcare payers and providers in the U.S. and Europe would consider the once-weekly dosing schedule a sufficient innovation to warrant preferential formulary placement or a premium price, particularly for the large number of patients who were already taking other daily medications.[43]
4. Competitive Precedent: The decision was not without precedent. Takeda had previously opted not to pursue U.S. and European approval for its own once-weekly DPP-4 inhibitor, trelagliptin, citing the prohibitive costs of entry into these markets.[43]

This strategic choice highlights the reality that by the mid-2010s, the goalposts for commercial success in the Western diabetes market had moved. A drug that demonstrated non-inferior glucose lowering was no longer sufficient; new entrants were increasingly expected to provide additional benefits, such as cardiovascular risk reduction or a truly unique mechanism of action. Omarigliptin, despite being a well-designed and clinically effective molecule, arrived at a moment when the market's definition of value was evolving beyond what it could offer. Its divergent fate—a successful product in Japan but a non-starter in the U.S. and Europe—underscores the profound impact that regional market dynamics, competitive landscapes, and shifting standards of care can have on the global trajectory of a new pharmaceutical agent.

Synthesis and Concluding Remarks

Omarigliptin (MK-3102) stands as a significant achievement in medicinal chemistry and clinical pharmacology. Through rational drug design, a potent, highly selective, and metabolically stable dipeptidyl peptidase-4 (DPP-4) inhibitor was created. Its molecular structure was meticulously optimized to yield a pharmacokinetic profile characterized by rapid absorption, minimal metabolism, and a long effective half-life governed by target-mediated drug disposition. This profile successfully translated into the drug's primary innovation: a well-tolerated and effective oral therapy for Type 2 Diabetes Mellitus that could be administered on a convenient once-weekly schedule.

The comprehensive O-QWEST clinical development program rigorously validated the therapeutic potential of omarigliptin. It was proven to be superior to placebo and, critically, non-inferior to the once-daily standard of care, sitagliptin, in achieving glycemic control. Its safety profile was consistent with the well-established profile of the DPP-4 inhibitor class, demonstrating a low risk of hypoglycemia and a weight-neutral effect. Based on this strong evidence, omarigliptin secured regulatory approval and has become a valuable treatment option in Japan and other Asian markets.

However, the legacy of omarigliptin is ultimately defined by the efficacy-commercialization paradox. Despite its clear scientific and clinical success, its journey was curtailed by the pragmatic realities of a rapidly evolving global pharmaceutical market. The strategic decision by Merck & Co. to forgo regulatory submission in the United States and Europe was not a reflection of the drug's merit but rather a response to a saturated market, a shifting therapeutic paradigm that increasingly demanded cardiovascular outcome benefits, and an uncertain valuation of the convenience it offered.

In conclusion, omarigliptin is a scientifically sound and clinically effective medication that successfully met its development objectives. It serves as a powerful case study in modern pharmaceutical strategy, demonstrating that clinical success alone does not guarantee global market access. Its story illustrates how external forces—including competitive pressure, the emergence of new standards of care, and regional differences in healthcare priorities—can profoundly influence a drug's trajectory, ultimately confining a well-engineered innovation to a more limited, regional role in the therapeutic armamentarium.

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