Gliptin

Aka: Gliptin, DPP-4 Inhibitor, Dipeptidyl Peptidase-4 Inhibitor, Dipeptidyl-Peptidase IV Inhibitor, DPP-4, Sitagliptin, Januvia, Saxagliptin, Onglyza, Linagliptin, Tradjenta, Alogliptin, Nesina

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II. Indications

  1. Type II Diabetes Mellitus
  2. Insulin deficiency and Insulin Resistance
    1. Adjunct to Glucophage, Sulfonylureas, Glitazones

III. Mechanism

  1. Dipeptidyl Peptidase-4 (DPP-4) is an enzyme that degrades the Incretins GLP-1 and GLP-2
    1. Incretins (GIP and GLP1) are normally released from GI Tract (enteroendocrine cells) following meals
    2. Incretins increase Glucose dependent Insulin secretion, and inhibit Glucagon secretion
  2. DPP4 Inhibitor Activity
    1. DPP-4 Inhibitors block Incretin degradation
      1. Allows accumulation of GLP-1 by 2-3 fold
    2. Activate Glucose-Dependent Insulinotropic Polypeptides
      1. Stimulates beta cells to secrete Insulin
      2. Lowers Blood Sugar, but low risk of Hypoglycemia
  3. Differs from GLP1 Agonists
    1. Weight neutral
    2. No Nausea

IV. Precautions

  1. Gliptins are less than half as effective as lower cost medications (e.g. Metformin, Sulfonylureas)
  2. No longterm evidence of improved outcomes
  3. Expensive (>$400/month)
  4. Decrease dose in renal Impairment
  5. May consider for those close to goal AND
    1. Already either on other Oral Hypoglycemics or in whom they are contraindicated (e.g. Chronic Kidney Disease)

V. Contraindications

  1. Type I Diabetes Mellitus
  2. Prior history of malignancy
    1. Due to increased risk of cancer invasion and metastases
  3. Women of child bearing age (relative contraindication)
    1. Teratogenicity risk
  4. Congestive Heart Failure

VI. Adverse Effects

  1. Acute Pancreatitis
    1. Incidence may be as high as 1 in 50 for two years
    2. Singh (2013) JAMA Intern Med 173(7):534-9 [PubMed]
  2. Serious Allergic Reaction (Sitagliptin)
    1. Anaphylaxis
    2. Angioedema
  3. Hepatotoxicity (Alogliptin, Vlidagliptin)
  4. Headache
  5. Bullous Pemphigoid
  6. Congestive Heart Failure exacerbation
    1. Risk of hospitalized CHF exacerbation: 1 in 150 patients/2 years using Saxigliptin or Alogliptin
    2. Sitagliptin (Januvia) is less associated with CHF exacerbation
    3. Scirica (2013) N Engl J Med 369(14):1317-26 [PubMed]
  7. Severe, persistent Joint Pain (rare)
    1. Stop agent if suspect Gliptin-induced pain (and avoid other Gliptins)
    2. Consider other possible causes (e.g. Statin induced Myopathy)
    3. FDA Alert
      1. http://www.fda.gov/drugs/drugsafety/ucm459579.htm

VII. Medications

  1. Sitagliptin (Januvia)
    1. Dose: 50 to 100 mg/day
    2. May be dosed with or without food
    3. Fewer Drug Interactions than Saxagliptin (Onglyza) and Linagliptin (Tradjenta)
    4. Standard dosing
      1. Creatinine Clearance >50 ml/min: 100 mg once daily
    5. Renal Insufficiency
      1. Consider Tradjenta instead, as does not require Renal Dosing adjustment
      2. Creatinine Clearance 30-49 ml/min: 50 mg once daily
      3. Creatinine Clearance <30 ml/min: 25 mg once daily
  2. Saxagliptin (Onglyza)
    1. Dose: 2.5 to 5 mg/day
    2. Significant CYP3A4 Drug Interactions
    3. Adjust for renal Impairment
    4. Congestive Heart Failure risk (black box warning)
      1. Higher risk with pre-existing CHF and renal Impairment
  3. Linagliptin (Tradjenta)
    1. Dose: 5 mg/day
    2. Significant CYP3A4 inducer and P-Glycoprotein Inducer
    3. No Renal Dosing required
  4. Alogliptin (Nesina)
    1. Dose: 25 mg/day
    2. First Gliptin to be generic (as of 2016)
    3. Fewer Drug Interactions than Saxagliptin (Onglyza) and Linagliptin (Tradjenta)
    4. Adjust for renal Impairment
    5. Congestive Heart Failure risk (black box warning)
      1. Higher risk with pre-existing CHF and renal Impairment

VIII. Preparations: Combination

  1. Kanzano (Alogliptin and Metformin)
  2. Oseni (Alogliptin and Pioglitazone)
  3. Janumet (Stagliptin and Metformin)
  4. Trijardy XR (Linagliptin, Empagliflozin and Metformin XR)

IX. Efficacy

  1. No longterm cardiovascular benefit
    1. Green (2015) N Engl J Med 373(3): 232-42 [PubMed]
    2. Scirica (2013) N Engl J Med 369(14): 1317-26 [PubMed]
    3. White (2013) N Engl J Med 369(14): 1327-35 [PubMed]
  2. Lowers HBA1C 0.5 to 0.9% (mean 0.6%)
    1. Contrast with Metformin, Sulfonylureas, GLP-1 Agonists, Pioglitazone lower A1C 1.0 to 1.5% at generic costs
    2. When combined with other hypoglycemics, its Glucose lowering effects are not additive

X. References

  1. (2013) Presc Lett 20(8):46
  2. Jones (2007) Am Fam Physician 75:1831-5 [PubMed]
  3. Steinberg (2019) Am Fam Physician 99(4): 237-43 [PubMed]
  4. Vaughan (2024) Am Fam Physician 109(4): 333-42 [PubMed]

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Related Studies

Cost: Medications

januvia (on 1/6/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
JANUVIA 100 MG TABLET $16.68 each
JANUVIA 25 MG TABLET $16.66 each
JANUVIA 50 MG TABLET $16.69 each
saxagliptin (on 10/18/2023 at Medicaid.Gov Survey of pharmacy drug pricing)
SAXAGLIPTIN HCL 5 MG TABLET Generic $1.63 each
onglyza (on 1/1/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
ONGLYZA 2.5 MG TABLET $15.07 each
ONGLYZA 5 MG TABLET $15.07 each
tradjenta (on 1/1/2023 at Medicaid.Gov Survey of pharmacy drug pricing)
TRADJENTA 5 MG TABLET $16.80 each
alogliptin (on 12/21/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
ALOGLIPTIN 12.5 MG TABLET Generic $5.17 each
ALOGLIPTIN 25 MG TABLET Generic $5.30 each
ALOGLIPTIN 6.25 MG TABLET Generic $5.22 each
ALOGLIPTIN-METFORMIN 12.5-1000 Generic $2.55 each
ALOGLIPTIN-METFORMIN 12.5-500 Generic $2.44 each
nesina (on 3/23/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
NESINA 25 MG TABLET Generic $5.30 each
FPNotebook does not benefit financially from showing this medication data or their pharmacy links. This information is provided only to help medical providers and their patients see relative costs. Insurance plans negotiate lower medication prices with suppliers. Prices shown here are out of pocket, non-negotiated rates. See Needy Meds for financial assistance information. GoodRx is another tool for finding lower drug prices.

Ontology: sitagliptin (C1565750)

Definition (NCI) An orally available, competitive, beta-amino acid-derived inhibitor of dipeptidyl peptidase 4 (DDP-4) with hypoglycemic activity. Sitagliptin may cause an increased risk in the development of pancreatitis.
Concepts Organic Chemical (T109) , Pharmacologic Substance (T121)
MSH C496398
SnomedCT 424106006, 423307000
English 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, sitagliptin, Sitagliptin (product), Sitagliptin, Sitagliptin (substance), SITAGLIPTIN, sitagliptin [Chemical/Ingredient], sitaGLIPtin
Spanish sitagliptina (producto), sitagliptina, sitagliptina (sustancia)
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: saxagliptin (C1611934)

Definition (NCI) A potent, selective and competitive, cyanopyrrolidine-based, orally bioavailable inhibitor of dipeptidyl peptidase 4 (DPP-4), with hypoglycemic activity. Saxagliptin is metabolized into an, although less potent, active mono-hydroxy metabolite.
Concepts Pharmacologic Substance (T121) , Amino Acid, Peptide, or Protein (T116)
MSH C502994
SnomedCT 443087004, 443066009
English SAXAGLIPTIN, Saxagliptin (substance), Saxagliptin, Saxagliptin (product), (1S,3S,5S)-2-((2S)-2-Amino-2-(3-hydroxyadamantan-1-yl) acetyl)-2-azabicyclo(3.1.0)hexane-3-carbonitrile hydrate, saxagliptin, 3-hydroxyadamantylglycine-4,5-methanoprolinenitrile hydrate
Spanish saxagliptina (sustancia), saxagliptina (producto), saxagliptina
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Januvia (C1702177)

Concepts Organic Chemical (T109) , Pharmacologic Substance (T121)
MSH C496398
English Januvia
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Dipeptidyl-Peptidase IV Inhibitors (C1827106)

Definition (MSH) Compounds that suppress the degradation of INCRETINS by blocking the action of DIPEPTIDYL-PEPTIDASE IV. This helps to correct the defective INSULIN and GLUCAGON secretion characteristic of TYPE 2 DIABETES MELLITUS by stimulating insulin secretion and suppressing glucagon release.
Concepts Pharmacologic Substance (T121)
MSH D054873
SnomedCT 423837000, 422403005
English Dipeptidyl peptidase IV inhibitor, Dipeptidyl peptidase IV inhibitor (substance), Dipeptidyl peptidase IV inhibitor (product), Gliptins, Dipeptidyl Peptidase IV Inhibitors, Inhibitors, Dipeptidyl-Peptidase IV, Dipeptidyl-Peptidase IV Inhibitors, Dipeptidyl-Peptidase 4 Inhibitors, Dipeptidyl Peptidase 4 Inhibitors
Spanish inhibidor de dipeptidil peptidasa IV (sustancia), inhibidor de dipeptidil peptidasa IV (producto), inhibidor de dipeptidil peptidasa IV, Inhibidores de Dipeptidil-Peptidasa IV, Gliptinas
Portuguese Gliptinas, Inibidores da Dipeptidil Peptidase IV
Finnish Dipeptidyylipeptidaasi IV:n salpaajat
French Gliptines, Inhibiteurs de la dipeptidyl-peptidase de type 4, Inhibiteurs de la dipeptidyl-peptidase IV
German Gliptine, Dipeptidyl-Peptidase IV-Inhibitoren, DPP IV-Inhibitoren
Italian Gliptine, Inibitori della dipeptidil peptidasi IV
Russian DIPEPTIDIL-PEPTIDAZY IV INGIBITORY, GLIPTINY, ДИПЕПТИДИЛ-ПЕПТИДАЗЫ IV ИНГИБИТОРЫ, ГЛИПТИНЫ
Czech gliptiny, DPP-4 inhibitory, dipeptidylpeptidasa IV - inhibitory, inhibitory DPP-4, inhibitory dipeptidylpeptidázy 4
Swedish Dipeptidylpeptidas IV-hämmare
Polish Inhibitory dipeptydylopeptydazy IV, Gliptyny, Inhibitory peptydazy dipeptydylowej IV
Japanese ジペプチジルペプチダーゼIV阻害剤, DPP-4阻害薬, DPP-IV阻害薬, ジペプチジルペプチダーゼIV阻害薬, DPP-IV阻害剤
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: alogliptin (C1958126)

Definition (NCI) A selective, orally bioavailable, pyrimidinedione-based inhibitor of dipeptidyl peptidase 4 (DPP-4), with hypoglycemic activity. In addition to its effect on glucose levels, alogliptin may inhibit inflammatory responses by preventing the toll-like receptor 4 (TLR-4)-mediated formation of proinflammatory cytokines.
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C520853
SnomedCT 702799001, 703669009
English alogliptin, Benzonitrile, 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)- pyrimidinyl]methyl]-, alogliptin (medication), oral hypoglycemics alogliptin, Alogliptin (substance), Alogliptin, Alogliptin (product), ALOGLIPTIN
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Linagliptin (C2746078)

Definition (NCI) A potent, orally bioavailable dihydropurinedione-based inhibitor of dipeptidyl peptidase 4 (DPP-4), with hypoglycemic activity. The inhibition of DPP-4 by linagliptin appears to be longer lasting than that by some other DPP-4 inhibitors tested.
Concepts Organic Chemical (T109) , Pharmacologic Substance (T121)
MSH C568794
SnomedCT 702798009, 703667006
English 8-((3R)-3-Aminopiperidin-1-yl)-7-(but-2-yn-1-yl)-3-Methyl-1-((4-Methylquinazolin-2-yl)Methyl)-3,7-Dihydro-1H-Purine-2,6-Dione, (R)-8-(3-Amino-Piperidin-1-yl)-7-but-2-ynyl-3-Methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione, linagliptin, LINAGLIPTIN, Linagliptin, Linagliptin (substance), Linagliptin (product)
Derived from the NIH UMLS (Unified Medical Language System)

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