Sitagliptin

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Sitagliptin quick reference

Sitagliptin
Sitagliptin general drug information
 Pronunciation sit a GLIP tin (.wav file)
 Trade Name(s) Januvia
 How Supplied Tablets: 25 mg, 50 mg, 100 mg
 Generic Availability No generics available
 Patent Expiry Date July 26, 2022
 Classification Antidiabetic Agent, Dipeptidyl-peptidase-IV (DPP-IV) inhibitor
 Schedule Rx
 Pregnancy Category B
 Breast-feeding It is not known whether sitagliptin is excreted in human milk. Caution should be used.
Sitagliptin chemical information
 IUPAC Name 7-[(3 R )- 3-amino - 1 - oxo - 4 - (2,4,5 - trifluorophenyl)butyl] - 5,6,7,8 - tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3- a ]pyrazine phosphate (1:1) monohydrate
 Empirical Formula C16H15F6 N5O•H3PO4•H2O
 Molecular Weight 523.32 g/mol
pharmacokinetic information  |  pharmacogenomic information
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Description

Sitagliptin, a highly selective dipeptidyl peptidase-IV (DPP-IV) inhibitor, is approved for the treatment of type 2 diabetes along with diet and exercise as monotherapy or as combination therapy with either metformin or a thiazolidinedione (e.g., pioglitazone or rosiglitazone) to lower blood sugar.[1][2][3][4][5]

The efficacy and safety of 100 or 200 mg of sitagliptin daily as monotherapy in patients with type 2 diabetes was evaluated in a randomized, double-blind, placebo-controlled study for 24 weeks. The results from the study showed that sitagliptin significantly (P < 0.001) reduced HbA1c, FPG, and 2-h PPG compared with placebo. Additionally, sitagliptin significantly (P < 0.05) improved beta-cell function. Sitagliptin was generally well tolerated in the study, with no hypoglycemia or weight gain.[2]

The efficacy and safety of 100 mg of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes who had inadequate glycemic control (mean HbA1c of 8%) with at least 1500 mg metformin alone was evaluated in a randomized, placebo-controlled, double-blind study for 24 weeks. Sitagliptin treatment led to a significant (P < 0.001) reduction in HbA1c (0.65%), FPG, and 2-h PPG compared with placebo. Approximately 47% of patients achieved an HbA1c <7%. Insulin secretion and beta-cell function were also significantly improved with sitagliptin therapy. Sitagliptin was well tolerated with no significant hypoglycemia or gastrointestinal adverse events.[4]

The efficacy and safety of 100 mg sitagliptin added to ongoing pioglitazone (30 or 45 mg/day) therapy in patients with type 2 diabetes who were not adequately controlled (HbA1c between 7% and 10%) was evaluated in a multicenter, randomized, double-blind, placebo-controlled, parallel-group study for 24 weeks. Sitagliptin led to a significant (P < 0.001) reduction in HbA1c (0.7%) and FPG (17.7 mg/dl). 45.4% of patients achieved target HbA1c of <7%. Sitagliptin was well tolerated with no increased risk of hypoglycemia or body weight. Abdominal pain, upper respiratory tract infection, and headache were generally mild to moderate.[5]

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Mechanism of Action

Sitagliptin is a highly selective dipeptidyl peptidase-IV (DPP-IV) inhibitor; it works by inhibiting the breakdown of incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). When blood glucose levels are elevated, GLP-1 and GIP increase insulin secretion from pancreatic beta-cells. GLP-1 also decreases glucagon secretion. Both peptides, however, are rapidly degraded or inactivated by the DPP-IV enzyme. Sitagliptin works by inhibiting the inactivation of incretin hormones by DPP-IV enzymes, thus enhancing and prolonging the incretin effects and, consequently, causing increased insulin levels in a glucose-dependent manner.[1][6]

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Time Required for Therapeutic Response

  • Following oral administration of sitagliptin, peak plasma concentrations are reached in one to four hours.[1]
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Pharmacokinetics

Absorption
After oral administration of a 100 mg dose of sitagliptin, peak plasma concentrations are achieved in 1-4 hours. Absolute bioavailability is 87%. Sitagliptin's pharmacokinetics are not affected by high-fat meals. Therefore, sitagliptin can be given with or without food.[1][7]

Distribution
Following a single 100 mg IV dose, the drug’s mean volume of distribution at steady state in healthy subjects is 198L. Sitagliptin is not highly bound to plasma proteins (38%).[1]

Metabolism
Metabolism is a minor pathway of elimination – approximately 79% of a dose is excreted unchanged in the urine and 16% is excreted as metabolites. The drug’s metabolites do not affect sitagliptin's activity significantly. The primary enzyme responsible for metabolism is CYP 3A4, with some contribution from CYP 2C8.[1][8]

Excretion
Sitagliptin is renally excreted via active tubular secretion. The apparent terminal half-life of 100 mg sitagliptin is 12.4 hours and renal clearance is 350 ml/min (PK study was 388 ml/min [7]) Nearly 100% of an administered dose is excreted in the urine (87%) or feces (13%) within 1 week of dosing.[1][8] Sitagliptin is a substrate for both human organic anion transporter-3 (hOAT-3) and p-glycoprotein, though the clinical relevance of hOAT-3 in sitagliptin transport has not been established. Moreover, p-glycoprotein inhibition does not seem to influence the drug’s renal excretion.[1]

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Special Population Pharmacokinetics

  • Renal insufficiency: In studies, patients with mild renal insufficiency (CrCl 50 ml/min to 80mL/min) failed to show clinically significant increases in sitagliptin serum levels. For patients with moderate renal insufficiency (CrCl 30 ml/min to 50 ml/min) or severe renal insufficiency (CrCl <30 ml/min), serum levels were increased as much as four-fold .[1]
  • Hepatic insufficiency: No dosage adjustment is needed for patients with mild or moderate hepatic insufficiency.[1]
  • Hemodialysis: A three-to-four hour session of hemodialysis has been shown to remove around 13% of the sitagliptin dose. Still, due to reduced renal function in patients requiring hemodialysis or peritoneal dialysis, the recommended sitagliptin dose is 25 mg once daily. The dose may be administered without regard to the timing of dialysis.[1]
  • Geriatric: Sitagliptin's pharmacokinetics in elderly patients are not significantly different when compared with younger patients. Elderly patients, however, are more likely to have decreased renal function. Therefore, caution should be used.[1]
  • Pediatric: Safety and effectiveness of sitagliptin have not been established in this population.[1]
  • Gender: No dosage adjustment is necessary based on gender.[1]
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Indications and Dosages

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FDA Approved Indications

Adjunctive treatment of type 2 diabetes mellitus in combination with diet and exercise as monotherapy or as combination therapy with metformin or a thiazolidinedione (e.g., pioglitazone or rosiglitazone) to improve glycemic control[1][2][3][4][5]

  • Monotherapy
    • Oral dosage:
      • Adults: 100 mg PO once daily.
  • Combination with metformin or a thiazolidinedione (e.g., pioglitazone or rosiglitazone)
    • Oral dosage:
      • Adults: 100 mg PO once daily.
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Dosage Adjustment

Renal insufficiency:[1]

  • CrCl >= 50 ml/min: No dosage adjustment needed.
  • CrCl >= 30—50 ml/min: 50 mg PO once daily.
  • CrCl < 30 ml/min: 25 mg PO once daily.

Hemodialysis:[1]

  • 25 mg PO once daily. The dose may be administered without regards to timing of hemodialysis

Hepatic insufficiency:[1]

  • No dosage adjustments are needed.
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Dosage Limits

  • Adults: 100 mg/day PO.
  • Elderly: 100 mg/day PO.
  • Adolescents and children: Safety and effectiveness have not been established in this population.


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Administration

  • Route: Oral
  • Method:
    • May be taken with or without food.[1]
    • Take your dose at the same time each day.[1]
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Monitoring Parameters

  • Glycosylated hemoglobin A1c (HbA1c)
  • Serum creatinine/BUN
  • Fasting blood glucose
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Contraindications/Precautions

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Contraindications

  • Hypersensitivity to sitagliptin or any of its components
  • Diabetic ketoacidosis (DKA)
  • Type 1 diabetes mellitus
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Precautions

  • Caution in patients with diarrhea, gastroparesis, GI obstruction, ileus, or vomiting.
  • Dosage adjustment is required in patients with moderate or severe renal impairment and in patients with ESRD requiring hemodialysis or peritoneal dialysis.
  • Caution with hypoglycemia-related conditions (e.g., debilitated physical condition, drug interactions, malnutrition, uncontrolled adrenal insufficiency, pituitary insufficiency or hypothyroidism).
  • Caution with hyperglycemia related conditions (e.g., drug interactions, female hormonal changes, high fever, severe psychological stress, and uncontrolled hypercortisolism or hyperthyroidism).
  • Caution when sitagliptin is used in combination with drugs known to cause hypoglycemia (e.g., insulin, exenatide, nateglinide, repaglinide, sulfonylureas).
  • Caution should be exercised when sitagliptin is administered to a woman who is pregnant or breast-feeding.
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Pregnancy indications

Category B

Reproduction studies performed in pregnant rats and rabbits at doses up to 125 mg/kg were not associated with functional or behavioral malformations. Well-controlled studies in pregnant women have not been established. Sitagliptin should be used with caution during pregnancy.[1]

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Breast-feeding indications

It is not known whether sitagliptin is excreted in human milk. Therefore, caution should be exercised.[1]

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Drug-Drug, -Food, -Herb Interactions

Click the link above to go to the drug interactions page.


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Adverse Reactions/Side Effects

Sitagliptin Adverse Reactions Chart
Incidence Body System Adverse Reactions
>10% All None
1-10% CNS Headache 5.1% (sitagliptin/pioglitazone)
Gastrointestinal Abdominal pain (2.3%), nausea/vomiting (1.4%), and diarrhea (3%)
Endocrine & metabolic Hypoglycemia (1.2%)
Respiratory Upper respiratory tract infection 6.3% (sitagliptin/pioglitazone), nasopharyngitis (5.2%)
<1% All For moderate renal insufficiency, a mean increase in serum creatinine of 0.12 mg/dl.

WBC count (increase ~200 cells/mcl)

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Overdosage Measures


  • The effect of a single 800 mg dose of sitagliptin is not considered clinically important. There is no experience with higher doses in humans.[1]
  • In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’s clinical status.[1]
    • Unabsorbed drug should be removed from the patient’s GI tract if possible.
    • The patient should receive ECG monitoring.
    • If necessary, sitagliptin may be removed by hemodialysis. The effects of peritoneal dialysis are unknown.
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Product Information and Distribution

Note: appearance only available for brand-name product
Dose/form Drug color(s) Drug shape Markings or odor/flavor
25 mg tablet pink round 221
50 mg tablet light beige round 112
100 mg tablet beige round 277
  • Inactive ingredients for tablets: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, sodium stearyl fumarate, polyvinyl alcohol, polyethylene glycol (PEG), talc, titanium dioxide, red iron oxide, and yellow iron oxide.
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Patient Information

  • Sitagliptin, along with diet and exercise, helps control blood sugar in type 2 diabetes
  • Take sitagliptin with a full glass of water, with or without food.
  • Common side effects include stuffy or runny nose, upper respiratory infection, headache, diarrhea, and stomach pain .
  • Monitor your blood sugar as directed by your doctor
  • Symptoms of high blood sugar (hyperglycemia) include: dizziness, dry mouth, flushed dry-skin, fruit-like breath odor, loss of appetite, nausea, stomach ache, unusual thirst, frequent passing of urine.
  • Symptoms of low blood sugar (hypoglycemia) include: anxiety or nervousness, confusion, difficulty concentrating, hunger, pale skin, nausea, fatigue, sweating, headache, palpitations, numbness of the mouth, tingling in the fingers, tremors, muscle weakness, blurred vision, cold sensations, uncontrolled yawning, irritability, rapid heartbeat, shallow breathing, and loss of consciousness.
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References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 Januvia™ (sitagliptin) package insert. Whitehouse Station, NJ: Merck & CO, Inc.; 2006 October.
  2. ↑ 2.0 2.1 2.2 Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE; Sitagliptin Study 021 Group. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006 December; 29(12):2632-7.
  3. ↑ 3.0 3.1 Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H: Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia. 2006 November; 49(11):2564–71.
  4. ↑ 4.0 4.1 4.2 Charbonnel B, Karasik A, Liu J, Wu M, Meininger G; Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006 December; 29(12):2638-43.
  5. ↑ 5.0 5.1 5.2 Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P; Sitagliptin Study 019 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006 October; 28(10):1556-68.
  6. ↑ Gautier JF, Fetita S, Sobngwi E, Salaün-Martin C. Biological actions of the incretins GIP and GLP-1 and therapeutic perspectives in patients with type 2 diabetes. Diabetes Metab. 2005 June; 31(3 Pt 1):233-42.
  7. ↑ 7.0 7.1 Herman GA, Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M, Snyder K, Hilliard D, Tanen M, Tanaka W, Wang AQ, Zeng W, Musson D, Winchell G, Davies MJ, Ramael S, Gottesdiener KM, Wagner JA. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther. 2005 December; 78(6):675-88.
  8. ↑ 8.0 8.1 Vincent SH, Reed JR, Bergman AJ, Elmore CS, Zhu B, Xu S, Ebel D, Larson P, Zeng W, Chen L, Dilzer S, Lasseter K, Gottesdiener K, Wagner JA, Herman GA. Metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [14C]sitagliptin in humans. Drug Metab Dispos. 2007 April; 35(4):533-8.
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PUBMED References

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Efficacy Trial Articles

  1. Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE; Sitagliptin Study 021 Group. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006 December; 29(12):2632-7.
  2. Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H: Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia. 2006 November; 49(11):2564–71.
  3. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G; Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006 December; 29(12):2638-43.
  4. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P; Sitagliptin Study 019 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006 October; 28(10):1556-68.
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Pharmacokinetics Articles

  1. Herman GA, Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M, Snyder K, Hilliard D, Tanen M, Tanaka W, Wang AQ, Zeng W, Musson D, Winchell G, Davies MJ, Ramael S, Gottesdiener KM, Wagner JA. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther. 2005 December; 78(6):675-88.
  2. Vincent SH, Reed JR, Bergman AJ, Elmore CS, Zhu B, Xu S, Ebel D, Larson P, Zeng W, Chen L, Dilzer S, Lasseter K, Gottesdiener K, Wagner JA, Herman GA. Metabolism and excretion of the dipeptidyl peptidase 4 inhibitor (14C) sitagliptin in humans. Drug Metab Dispos. 2007 April; 35(4):533-8.
  3. Herman GA, Bergman A, Stevens C, Kotey P, Yi B, Zhao P, Dietrich B, Golor G, Schrodter A, Keymeulen B, Lasseter KC, Kipnes MS, Snyder K, Hilliard D, Tanen M, Cilissen C, De Smet M, de Lepeleire I, Van Dyck K, Wang AQ, Zeng W, Davies MJ, Tanaka W, Holst JJ, Deacon CF, Gottesdiener KM, Wagner JA. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab. 2006 November; 91(11):4612-9.
  4. Bergman AJ, Stevens C, Zhou Y, Yi B, Laethem M, De Smet M, Snyder K, Hilliard D, Tanaka W, Zeng W, Tanen M, Wang AQ, Chen L, Winchell G, Davies MJ, Ramael S, Wagner JA, Herman GA. Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers. Clin Ther. 2006 January; 28(1):55-72.
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Drug Interaction Articles

  1. Krishna R. Bergman A. Larson P. Cote J. Lasseter K. Dilzer S. Wang A. Zeng W. Chen L. Wagner J. Herman G. Effect of a single cyclosporine dose on the single-dose pharmacokinetics of sitagliptin (MK-0431), a dipeptidyl peptidase-4 inhibitor, in healthy male subjects. Journal of Clinical Pharmacology. 2007 February; 47(2):165-74.


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External Links

Clinical treatment guidelines

Patient information pages

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