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Gliptin

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

  • See Also
  1. Incretin Mimetic
  2. Byetta
  3. Type II Diabetes Medications
  • Indications
  1. Type II Diabetes Mellitus
  2. Insulin deficiency and Insulin Resistance
    1. Adjunct to Glucophage, Sulfonylureas, Glitazones
  • 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
  • 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)
  • 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
  • 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
  • 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
  • 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)
  • 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
  • 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]