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Sitagliptin
Clinical data
Pronunciation/sɪtəˈɡlɪptɪn/ ⓘ
Trade namesJanuvia, Zituvio, others
AHFS/Drugs.comMonograph
MedlinePlusa606023
License data
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability87%
Protein binding38%
MetabolismLiver (CYP3A4- and CYP2C8-mediated)
Elimination half-life8 to 14 h[7]
ExcretionKidney (80%)[7]
Identifiers
  • (R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.217.948 Edit this at Wikidata
Chemical and physical data
FormulaC16H15F6N5O
Molar mass407.320 g·mol−1
3D model (JSmol)
  • Fc1cc(c(F)cc1F)C[C@@H](N)CC(=O)N3Cc2nnc(n2CC3)C(F)(F)F
  • InChI=1S/C16H15F6N5O/c17-10-6-12(19)11(18)4-8(10)3-9(23)5-14(28)26-1-2-27-13(7-26)24-25-15(27)16(20,21)22/h4,6,9H,1-3,5,7,23H2/t9-/m1/s1 checkY
  • Key:MFFMDFFZMYYVKS-SECBINFHSA-N checkY
  (verify)

Sitagliptin, sold under the brand name Januvia among others, is an anti-diabetic medication used to treat type 2 diabetes.[8] It is in the dipeptidyl peptidase-4 (DPP-4) inhibitor class and works by increasing the production of insulin and decreasing the production of glucagon by the pancreas.[8] In the United Kingdom it is listed as less preferred than metformin or a sulfonylurea.[9] It is taken by mouth.[8] It is also available in the fixed-dose combination medication sitagliptin/metformin (Janumet, Janumet XR).[8]

Common side effects include headaches, swelling of the legs, and upper respiratory tract infections.[8] Serious side effects may include angioedema, low blood sugar, kidney problems, pancreatitis, and joint pain.[8] Whether use in pregnancy or breastfeeding is safe is unclear.[10]

Sitagliptin was developed by Merck & Co. and approved for medical use in the United States in 2006.[8] In 2023, it was the 123rd most commonly prescribed medication in the United States, with more than 5 million prescriptions.[11][12] It is available as a generic medication, but not in the United States.[13][14][15]

Medical uses

[edit]

Sitagliptin is used to treat type 2 diabetes.[8] It is generally less preferred than metformin or sulfonylureas.[9] It is taken by mouth.[8] It is also available as the fixed-dose combinations of sitagliptin/metformin (Janumet, Janumet XR)[8] and sitagliptin/simvastatin (Juvisync).[16]

Sitagliptin should not be used to treat type 1 diabetes. In December 2020, the US Food and Drug Administration (FDA) approved labeling changes stating that Januvia (sitagliptin), Janumet (sitagliptin and metformin hydrochloride), and Janumet XR (sitagliptin and metformin hydrochloride extended-release) are not proven to improve glycemic (blood sugar) control in children aged 10 to 17 with type 2 diabetes.[17] The drugs are approved to improve blood sugar control in adults aged 18 and older with type 2 diabetes.[17]

Adverse effects

[edit]

Adverse effects from sitagliptin are similar to placebo, except for rare nausea, common cold-like symptoms, and photosensitivity.[18] It does not increase the risk of diarrhea.[19] No significant difference exists in the occurrence of hypoglycemia between placebo and sitagliptin.[18][20][21] In those taking sulphonylureas, the risk of low blood sugar is increased.[22]

The existence of rare case reports of kidney failure and hypersensitivity reactions is noted in the United States prescribing information, but a causative role for sitagliptin has not been established.[2]

Several postmarketing reports of pancreatitis (some fatal) have been made in people treated with sitagliptin and other DPP-4 inhibitors,[23][24] and the US FDA package insert carries a warning to this effect,[2] although the causal link between sitagliptin and pancreatitis has not yet been fully substantiated.[25] One study with lab rats published in 2009 concluded that some of the possible risks of pancreatitis or pancreatic cancer may be reduced when it is used with metformin. However, while DPP-4 inhibitors showed an increase in such risk factors, as of 2009, no increase in pancreatic cancer has been reported in individuals taking DPP-4 inhibitors.[26]

In 2015, the US Food and Drug Administration (FDA) added a new warning and precaution about the risk of "severe and disabling" joint pain to the labels of all DPP-4 inhibitor medicines.[27]

Mechanism of action

[edit]
See also: Dipeptidyl peptidase-4 inhibitors

Sitagliptin works to competitively inhibit the enzyme dipeptidyl peptidase 4 (DPP-4). This enzyme breaks down the incretins GLP-1 and GIP, gastrointestinal hormones released in response to a meal.[28] By preventing breakdown of GLP-1 and GIP, they are able to increase the secretion of insulin and suppress the release of glucagon by the alpha cells of the pancreas.[medical citation needed] This drives blood glucose levels towards normal.[medical citation needed] As the blood glucose level approaches normal, the amounts of insulin released and glucagon suppressed diminishes, thus tending to prevent an "overshoot" and subsequent low blood sugar (hypoglycemia), which is seen with some other oral hypoglycemic agents.[medical citation needed]

Sitagliptin has been shown to lower HbA1c level by about 0.7% points versus placebo. It is slightly less effective than metformin when used as a monotherapy. It does not cause weight gain and has less hypoglycemia compared to sulfonylureas. Sitagliptin is recommended as a second-line drug (in combination with other drugs) after the combination of diet/exercise and metformin fails.[29]

History

[edit]
See also: Development of dipeptidyl peptidase-4 inhibitors

Sitagliptin was approved by the US Food and Drug Administration (FDA) in October 2006,[30] and is sold under the brand name Januvia.[31] In April 2007, the FDA approved an oral combination of sitagliptin/metformin sold under the brand name Janumet.[32] In October 2011, the FDA approved an oral combination of sitagliptin/simvastatin sold under the brand name Juvisync.[33][16] The extended release version of sitagliptin/metformin was approved in February 2012.[34]

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Sitagliptin

View on Grokipedia
from Grokipedia
Sitagliptin is an oral antidiabetic medication classified as a dipeptidyl peptidase-4 (DPP-4) inhibitor, primarily used to improve glycemic control in adults with type 2 diabetes mellitus when combined with diet and exercise. Marketed under the brand name Januvia by Merck & Co., it was the first drug in its class to receive approval from the U.S. Food and Drug Administration (FDA) on October 16, 2006, as an adjunct therapy for patients not adequately managed by lifestyle modifications alone. Sitagliptin is available in tablet form (typically 100 mg doses) or as an oral solution and is often prescribed as monotherapy or in fixed-dose combinations with other agents like metformin (e.g., Janumet). The of sitagliptin involves selective inhibition of the DPP-4 enzyme, which prevents the rapid degradation of endogenous hormones such as (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This prolongation enhances glucose-dependent insulin secretion from pancreatic beta cells and suppresses release from alpha cells, thereby reducing fasting and postprandial blood glucose levels without significantly increasing the risk of . Unlike some other antidiabetic drugs, sitagliptin is weight-neutral and does not cause , making it suitable for a broad range of patients with , including those with renal impairment when dose-adjusted. Clinical trials have demonstrated that sitagliptin effectively lowers HbA1c by approximately 0.5–1.0% as monotherapy and provides additive benefits when combined with metformin, , or thiazolidinediones, with sustained efficacy over long-term use. It is generally well-tolerated, with the most common adverse effects being mild, such as nasopharyngitis, , and ; serious risks include , reactions, and severe , though these are infrequent. Ongoing research explores its potential cardiovascular and renoprotective effects, but it is not indicated for or .

Clinical Applications

Indications and Efficacy

Sitagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with mellitus, either as monotherapy when metformin is inappropriate due to intolerance or contraindications, or in combination with other antidiabetic agents such as metformin, , or insulin. Clinical trials and meta-analyses have demonstrated sitagliptin's efficacy in reducing HbA1c by 0.5% to 0.8% compared to , alongside significant decreases in plasma glucose (by approximately 15-20 mg/dL) and postprandial glucose excursions. These improvements in glycemic control occur without associated or an increased risk of , distinguishing sitagliptin from agents like . In specific populations, sitagliptin provides comparable HbA1c reductions (around 0.6-0.7%) in elderly patients aged 65 years or older, with good tolerability and no need for routine dose adjustment unless renal function is impaired. For patients with renal impairment, dose adjustments (50 mg daily for moderate impairment or 25 mg for severe) maintain in glycemic control, as shown in studies of those with mild . However, sitagliptin is not indicated for or , as it does not address insulin deficiency or ketosis. Fixed-dose combinations, such as (Janumet), enhance adherence by simplifying regimens while providing additive HbA1c reductions of about 1.0-1.5% over baseline in treatment-naive patients, supporting its role in initial or add-on therapy.

Dosage and Administration

Sitagliptin is administered orally in tablet or oral solution form. Tablets are available in strengths of 25 mg, 50 mg, and 100 mg; the oral solution is 25 mg/mL (e.g., 4 mL for a 100 mg dose). The recommended dose for adults with is 100 mg once daily, which can be taken with or without food and does not require dose . Consistent daily timing is advised to maintain steady-state levels, though flexibility in scheduling is permitted. Dose adjustments are necessary based on renal function, assessed using estimated glomerular filtration rate (eGFR). For patients with mild renal impairment (eGFR ≥45 mL/min/1.73 m²), no adjustment is required. In moderate renal impairment (eGFR 30 to <45 mL/min/1.73 m²), the dose is reduced to 50 mg once daily. For severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose is 25 mg once daily; in dialysis patients, the dose should be administered after the dialysis session. Renal function should be evaluated prior to initiation and periodically thereafter. No dosage adjustment is needed for mild or moderate hepatic impairment, though caution is advised in severe hepatic impairment due to limited clinical data. Age does not require dose modification, as are similar across elderly and younger adults. Sitagliptin is typically integrated with lifestyle modifications, such as diet and exercise, and may be used in combination with other antidiabetic agents, including insulin, metformin, , or thiazolidinediones, with dosing coordinated to avoid .

Safety and Tolerability

Adverse Effects

Sitagliptin is generally well tolerated, with adverse effects similar in incidence to in clinical trials. Common side effects include , affecting approximately 5.6% of patients compared to 5.3% on , in about 5.2% versus 4.0%, and nasopharyngitis in 5.4% versus 5.1%. Gastrointestinal disturbances such as (3.0% versus 2.3%) and (2.3% versus 2.1%) also occur at low rates. Serious adverse effects are rare. Post-marketing reports have documented , with an estimated incidence of 1-2 cases per 1000 patient-years, though clinical trials showed low rates with no significant increase compared to (e.g., ~0.1% incidence in sitagliptin vs. ~0.04% in ). reactions, including and , have been reported in post-marketing surveillance, occurring in less than 1% of patients. , potentially linked to dipeptidyl peptidase-4 inhibitors, was observed in 2.1% of sitagliptin-treated patients versus 1.4% on in pooled analyses. , a severe blistering reaction, has been reported post-marketing. In pivotal trials, the overall incidence of adverse events leading to discontinuation was low, at less than 2% for sitagliptin versus 1.7% for . Long-term data from the TECOS trial, involving over 14,000 patients with and established , confirmed no increased risk of hospitalization (hazard ratio 1.01; 95% CI, 0.90-1.12) or compared to . Management of adverse effects involves monitoring for symptoms of , such as persistent severe that may radiate to the back and be accompanied by , with immediate discontinuation if suspected. For reactions, sitagliptin should be stopped promptly, and appropriate supportive care initiated. Drug interactions, such as with , may increase the risk of , which presents as common but mild in .

Contraindications and Precautions

Sitagliptin is contraindicated in patients with a history of serious reactions to the drug, including , , or Stevens-Johnson syndrome. It should not be used in individuals with mellitus or for the treatment of , as it does not address the underlying insulin deficiency in these conditions. Renal impairment requires dosage adjustments to prevent accumulation; the standard 100 mg daily dose is reduced to 50 mg for eGFR 30 to less than 45 mL/min/1.73 m² and 25 mg for eGFR less than 30 mL/min/1.73 m² or end-stage renal disease on dialysis. In patients with a history of or chronic renal disease, sitagliptin should be used cautiously, with immediate discontinuation if is suspected based on symptoms such as persistent severe . Use during is not well-studied in humans (previously classified as Category B), though animal reproduction studies showed no evidence of fetal harm at doses up to 250 mg/kg; pregnant patients should discuss risks with their healthcare provider. For breastfeeding, sitagliptin is excreted in the milk of lactating rats, and its safety in human milk is unknown; a decision to discontinue or the drug should weigh potential benefits against risks. Renal function must be evaluated before starting and monitored periodically during treatment, especially in elderly patients or those with conditions predisposing to renal decline, such as or concurrent nephrotoxic drugs. Caution is warranted in patients with , where monitoring for worsening symptoms is recommended due to potential class-related cardiovascular considerations, though sitagliptin itself has a neutral profile in this regard. Patients should be counseled to seek immediate medical attention for signs of reactions, such as , , or swelling, or for pancreatitis indicators like severe radiating to the back. They should also avoid initiating or continuing sitagliptin during acute illnesses that could impair renal function, such as severe infections or .

Pharmacology

Mechanism of Action

Sitagliptin is a selective inhibitor of (DPP-4), an enzyme responsible for the rapid degradation of hormones such as (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). By competitively binding to the of DPP-4, sitagliptin prevents the cleavage of these incretins at their N-terminal , thereby increasing their circulating levels and prolonging their . The endogenous GLP-1 and GIP have short half-lives—approximately 1-2 minutes for active GLP-1 and about 5-7 minutes for GIP—due to swift enzymatic breakdown by DPP-4 following their release from intestinal L- and K-cells in response to nutrient ingestion. Inhibition by sitagliptin extends the duration of these active forms, elevating intact GLP-1 levels by roughly twofold and enhancing GLP-1 receptor activation in target tissues. This selective blockade does not affect the degradation of other peptides unrelated to incretin pathways. The elevated levels mediated by sitagliptin promote glucose-dependent insulin secretion from pancreatic beta cells while suppressing release from alpha cells, particularly in the presence of elevated blood glucose. Additionally, increased GLP-1 activity contributes to slowed gastric emptying, further aiding postprandial glycemic control. Sitagliptin's high selectivity—exhibiting over 2,600-fold greater potency against DPP-4 compared to related enzymes like DPP-8 and DPP-9—ensures targeted action without off-target effects on immune or other functions, thereby minimizing the risk of through its glucose-dependent mechanism.

Pharmacokinetics

Sitagliptin is rapidly absorbed following , with peak plasma concentrations (Cmax) achieved at a time (Tmax) of 1 to 4 hours post-dose. The absolute is approximately 87%, and administration with food does not significantly affect the . Pharmacokinetics are linear over the therapeutic dose range of 50 to 200 mg, with area under the curve (AUC) increasing proportionally with dose. The volume of distribution at is approximately 198 L following intravenous administration, indicating moderate tissue distribution. Sitagliptin exhibits low , with about 38% reversibly bound to proteins. Sitagliptin undergoes minimal hepatic , with approximately 79% excreted unchanged in the urine; the remaining <20% is metabolized primarily via cytochrome P450 enzymes and CYP2C8. Elimination of sitagliptin occurs predominantly through renal excretion, involving active tubular secretion, with a renal clearance of approximately 350 mL/min and an apparent terminal of about 12.4 hours following a 100 mg oral dose. In patients with renal impairment, exposure to sitagliptin is prolonged, necessitating dose adjustments to avoid accumulation. The of sitagliptin are similar between healthy subjects and patients with mellitus.

Development and History

Discovery and Preclinical Research

Sitagliptin's discovery stemmed from research into the system, which gained momentum in the with the identification of (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) as key hormones enhancing insulin secretion and glucose . Building on this foundation, Merck & Co. initiated a (DPP-4) inhibitor program in 1999 to develop an oral therapy that prolongs activity by blocking their rapid degradation. This effort targeted DPP-4, the primary enzyme responsible for inactivating these hormones, aiming to mimic effects without the limitations of injectable GLP-1 analogs. The structure-activity relationship (SAR) studies at Merck focused on designing small-molecule inhibitors with high potency, selectivity, and oral bioavailability. Researchers developed a β-amino acid scaffold, optimizing substituents to enhance DPP-4 binding affinity while minimizing off-target effects on related proteases like DPP-8 and DPP-9. This scaffold provided the structural basis for sitagliptin's triazolopyrazine moiety, which conferred selectivity and metabolic stability. Early patents covering this class of β-amino acid derivatives, including sitagliptin, were filed by Merck in 2001. Preclinical studies demonstrated sitagliptin's potent and selective DPP-4 inhibition, achieving over 80% enzyme occupancy at low doses in and dogs. In diabetic animal models, such as Zucker diabetic fatty rats and high-fat diet/ mice, sitagliptin improved oral glucose tolerance by elevating active GLP-1 and GIP levels, enhancing insulin secretion, and reducing postprandial without inducing or . Key milestones included proof-of-concept data showing sustained levels and beta-cell protection, with restoration of cell mass and function in models of , supporting its advancement as a therapeutic candidate. In beagle dogs, sitagliptin similarly enhanced glucose tolerance during oral challenges, confirming its efficacy across .

Clinical Trials and Regulatory Approval

Sitagliptin's clinical development included multiple phase III trials that established its glycemic efficacy as monotherapy and in combination with other agents. In three placebo-controlled, randomized, double-blind monotherapy studies (one 12-week with baseline HbA1c 7.5%, one 18-week with 8.1%, and one 24-week with 8.0%) involving patients with , sitagliptin 100 mg once daily achieved placebo-subtracted HbA1c reductions of 1.05%, 0.60%, and 0.79%, respectively. As add-on therapy to metformin in a 24-week phase III trial, sitagliptin provided an additional HbA1c reduction of 0.65% compared to in patients inadequately controlled on metformin alone (baseline HbA1c 7.9%). These trials also demonstrated a low incidence of , with rates comparable to (0.6% vs. 0.5% in monotherapy). Safety profiles across these studies showed good tolerability, with gastrointestinal adverse events similar between sitagliptin and groups. Regulatory approval for sitagliptin, marketed as Januvia, was granted by the U.S. (FDA) on October 17, 2006, as an adjunct to diet and exercise to improve glycemic control in adults with . The (EMA) followed with approval on March 21, 2007, authorizing its use as monotherapy or in combination with metformin, a , or insulin when these alone were insufficient. Subsequent approvals included the fixed-dose combination with metformin, Janumet, by the FDA on March 30, 2007, and by the EMA on July 16, 2008, facilitating simplified dosing for dual therapy. A pivotal post-approval cardiovascular outcomes trial, TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin), enrolled 14,671 patients with and established from 2010 to 2015. This randomized, double-blind, -controlled study added sitagliptin 100 mg daily or matching to existing antidiabetic therapy, demonstrating non-inferiority for the primary composite endpoint of cardiovascular death, nonfatal , or nonfatal (3.8% annual event rate with sitagliptin vs. 3.9% with ; hazard ratio 0.99, 95% CI 0.89-1.10). No significant differences emerged in secondary endpoints, including hospitalization for (hazard ratio 1.00, 95% CI 0.83-1.20), confirming sitagliptin's cardiovascular safety in high-risk patients. Post-approval meta-analyses through the 2020s have affirmed sitagliptin's low risk, with pooled data from randomized trials showing no significant increase compared to ( 1.07, 95% CI 0.78-1.47) when used as monotherapy or add-on therapy. Exploratory analyses from TECOS and subsequent observational studies indicate neutral effects on renal function progression, with no acceleration of estimated decline in patients with . Sitagliptin has been approved in over 130 countries globally, and following expirations beginning in in select markets, generic formulations have become available in regions such as parts of and , enhancing accessibility. In January 2025, the FDA approved an oral solution formulation of sitagliptin (Brynovin, 25 mg/mL) for adults with who have difficulty swallowing tablets.

Society and Culture

Brand Names and Combinations

Sitagliptin is marketed worldwide under the primary brand name Januvia by Merck & Co., available as film-coated tablets in strengths of 25 mg, 50 mg, and 100 mg for monotherapy in the treatment of type 2 diabetes. Januvia is formulated as an oral tablet containing sitagliptin phosphate monohydrate, with no injectable forms approved or available. Fixed-dose combinations include Janumet, which pairs sitagliptin with immediate-release metformin hydrochloride in tablet strengths such as sitagliptin 50 mg/metformin 500 mg or 1000 mg, and Janumet XR, the extended-release version combining sitagliptin with metformin extended-release in various strengths like sitagliptin 100 mg/metformin 1000 mg. Another combination, Juvisync, combined sitagliptin with simvastatin for patients requiring both glycemic control and management but was discontinued by Merck in 2013 and is no longer available in the United States. Internationally, sitagliptin monotherapy is sold under names such as Xelevia in the , where it is available as 25 mg, 50 mg, and 100 mg film-coated tablets approved by the . In , the brand Istavel is marketed by Sun Pharmaceutical Industries, offered in 100 mg tablets. Zituvio represents a branded generic version approved in the United States in October 2023. Generic versions and combinations, such as Zituvimet (), have entered markets post-patent expiry in regions including the EU and , typically as film-coated oral tablets in standard strengths.

Availability and Economic Aspects

Sitagliptin is approved for the treatment of in the United States, the , and numerous other countries worldwide, with regulatory authorizations spanning regions such as , the , and parts of and . Its availability is widespread in developed markets through established healthcare systems, but in low-income regions, access remains variable due to economic constraints, issues, and limited . In the United States, the branded product Januvia (sitagliptin) costs approximately $500 per month for a 30-day supply without or discounts prior to widespread generic availability. Merck provides assistance programs that offer Januvia free of charge to eligible uninsured or underinsured individuals meeting and residency criteria. Generic sitagliptin has been available internationally since the mid-2010s in markets like and , where monthly costs range from $50 to $100, representing a substantial reduction from branded pricing. In the , authorized generic versions such as Zituvio have been available since October 2023, while full generic entry for additional manufacturers is expected after the key patent expiration in November 2026, with tentative FDA approvals already granted to multiple companies. Economic analyses demonstrate sitagliptin's favorable cost-effectiveness relative to other antidiabetic therapies, with incremental cost-effectiveness ratios (ICERs) typically below €20,000 per (QALY) gained when added to metformin or . For instance, comparisons with yield ICERs around $7,000 per QALY in second-line treatment settings. Additionally, Januvia was selected for the U.S. Medicare Drug Price Negotiation Program in 2023, with negotiated maximum fair prices set to take effect on January 1, 2026, aiming to reduce costs for beneficiaries. In developing countries, however, patent enforcement has created barriers to generic production and importation, leading to ongoing litigation in jurisdictions like and that limits affordable access for patients. As a (DPP-4) inhibitor, sitagliptin is recommended in the American Diabetes Association's 2025 Standards of Care for glycemic management in , particularly for patients requiring oral agents with low risk, alongside metformin or other therapies. Post-patent expiration in various markets is expected to further accelerate generic approvals and enhance global economic accessibility.

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  61. https://diabetesjournals.org/care/article/48/Supplement_1/S181/157569/9-Pharmacologic-Approaches-to-Glycemic-Treatment
  62. https://www.drugpatentwatch.com/p/tradename/JANUVIA
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