Johns Hopkins Diabetes GuideBrand Names

DPP-IV Inhibitors

Nadeen Hosein, M.D., Brian Pinto, Pharm.D.

INDICATIONS

FDA

  • Type 2 diabetes mellitus

MECHANISM

  • Inhibits the degradation of incretins such as GLP-1 by inhibiting the enzyme dipeptidyl peptidase IV (DPP-IV). The incretin effect is prolonged, enhancing glycemic control through various mechanisms, primarily by stimulating insulin synthesis and secretion in a glucose-dependant manner and by reducing glucagon secretion.

FORMS

brand name

preparation

manufacturer

route

form

dosage^

cost*

Januvia

sitagliptin phosphate

Merck

oral

tablet

25 mg

$885 for 90 tabs

oral

tablet

50 mg

$885 for 90 tabs

oral

tablet

100 mg

$295 for 30 tabs

Onglyza

saxagliptin

Bristol-Myers Squibb

oral

tablet

2.5 mg

$295 for 30 tabs

oral

tablet

5 mg

$885 for 90 tabs

Tradjenta

linagliptin

Eli Lilly

oral

tablet

5 mg

$870 for 90 tabs

Janumet

sitagliptin phosphate + metformin hydrochloride

Merck Sharp & Dohme Corp.

oral

tablet

50/500 mg

$885 for 180 tabs

oral

tablet

50/1000 mg

$885 for 180 tabs

Nesina

alogliptin

Takeda

oral

tablet

6.25 mg

$374 for 30 tabs

oral

tablet

12.5 mg

$374 for 30 tabs

oral

tablet

25 mg

$374 for 30 tabs

**Patient Assistant Programs:

http://www.januvia.com…

https://www.rxhope.com…

https://www.tradjenta.com…

https://www.rxhope.com…

http://www.nesina.com…

** Information gathered by Heather Tran and Gladimir Elysee

*Prices represent cost per unit specified, are representative of "Average Wholesale Price" (AWP).
^Dosage is indicated in mg unless otherwise noted.

USUAL ADULT DOSING

  • Sitagliptin: recommended dose is 25-100 mg once a day. Can be taken with or without food.
  • Saxagliptin: recommended dose is 2.5 or 5 mg once a day. Can be taken with or without food.
  • Linagliptin: recommended dose is 5 mg once a day. Can be taken with or without food.
  • Sitagliptin + metformin: co-formulated as Janumet 50/500 mg twice a day, with meals. Can increase to 50/1000 mg twice a day, with meals (maximum dose).
  • Saxagliptin + metformin XR: co-formulated as Kombiglyze. 2.5/1000 mg, 5/1000 mg, or 5/2000 mg once daily with evening meal.
  • Alogliptin: recommended dose is 25 mg once daily.
  • DPP-IV inhibitors are FDA approved for use as monotherapy in type 2 diabetes (T2DM).
  • DPP-IV inhibitors can also be added to patients already on metformin, sulfonylureas, thiazolidinediones, or insulin.
  • If adding DPP-IV inhibitors to sulfonylurea/insulin therapy, consider decreasing the sulfonylurea/insulin dose, to reduce hypoglycemia risk.

DOSING IN SPECIAL POPULATIONS

RENAL

  • Sitagliptin
    • GFR ≥ 50 mL/min, no dosage adjustment needed
    • GFR 30-50 mL/min, do not exceed 50 mg daily
    • GFR < 30 mL/min, do not exceed 25 mg daily
    • For patients on hemodialysis or peritoneal dialysis, do not exceed 25 mg daily
  • Saxagliptin
    • GFR > 50 mL/min, no dosage adjustment needed
    • GFR ≤ 50 mL/min, do not exceed 2.5 mg once daily
    • For patients on hemodialysis, administer 2.5 mg once daily, following hemodialysis
  • Linagliptin
    • No dosage adjustment needed
  • Alogliptin
  • GFR ≥ 60 mL/min, no dosage adjustment needed
  • GFR ≥30 to < 60 mL/minute: 12.5 mg once daily
  • GFR ≥15 to < 30 mL/minute: 6.25 mg once daily
  • ESRD (GFR < 15 mL/minute or requiring hemodialysis): 6.25 mg once daily; administered without regard to timing of hemodialysis
  • Janumet
    • CONTRAINDICATED if GFR ≤ 60 mL/min, or if serum creatinine ≥ 1.4 mg/dL (women) or ≥ 1.5 mg/dL (men)

HEPATIC

  • Janumet: avoid use if liver disease is present, due to increased risk of lactic acidosis from metformin component.
  • Sitagliptin: no dosage adjustment necessary for mild-moderate hepatic impairment. Use in severe hepatic impairment not studied.
  • Saxagliptin: no dosage adjustment necessary for mild-severe hepatic impairment, though Canadian labeling recommends against use in moderate-severe hepatic impairment.
  • Linagliptin: no dosage adjustment necessary, though Canadian labeling recommends against use in severe hepatic impairment.

PREGNANCY

  • FDA Category B

BREASTFEEDING

  • Thomson Lactation Ratings: infant risk cannot be ruled out. Thus, use with caution in breastfeeding women.

ADVERSE DRUG REACTIONS

GENERAL

  • Contraindicated in patients with hypersensitivity reaction to sitagliptin, saxagliptin, or linagliptin.
  • Do not use in diabetic ketoacidosis.
  • Do not use as therapy for type 1 diabetes mellitus.
  • A recent analysis suggested a 2-fold increased risk for acute pancreatitis in patients using sitagliptin [8]; physicians should monitor patients closely for signs and symptoms of pancreatitis when starting sitagliptin, or increasing dose. Consider avoiding use in patients with other risk factors for pancreatitis.
  • Due to metformin component in Janumet, it is contraindicated in renal disease (see above).

OCCASIONAL

  • Hypoglycemia, more common when used in conjunction with a sulfonylurea or insulin.
  • Nasopharyngitis or upper respiratory tract infections
  • Headache
  • Nausea, diarrhea, abdominal pain
  • Urinary tract infections
  • Peripheral edema
  • Janumet: GI disturbance initially (nausea, vomiting, diarrhea) due to metformin; lessened if taken with meals

RARE

  • Acute pancreatitis with sitagliptin [8]
  • Stevens-Johnson syndrome, urticaria, exfoliative dermatitis, and other hypersensitivity skin reactions
  • Anaphylaxis
  • Angioedema
  • Rhabdomyolysis
  • Acute renal failure
  • Bone fractures with saxagliptin
  • Lactic acidosis with Janumet, due to metformin component

DRUG INTERACTIONS

  • Digoxin: oral sitagliptin caused small (11%) increase in AUC and plasma Cmax (18%) of digoxin at 0.25 mg/day. Dose adjustment of digoxin not recommended, but monitor closely.

PHARMACOKINETIC

Absorption

  • Sitagliptin: 87% bioavailability; time to peak concentration 1-4 hours.
  • Saxagliptin: time to peak concentration 2 hours.
  • Linagliptin: rapid absorption; time to peak concentration 1.5 hours.
  • Alogliptin: 100% regardless of food

Metabolism and Excretion

  • Sitagliptin: hepatic metabolism; 87% renal and 13% fecal excretion; dialyzable, with 13.5% removed.
  • Saxagliptin: hepatic metabolism; 60% renal and 22% fecal excretion; dialyzable, with 23% removed.
  • Linagliptin: not extensively metabolized.
  • Alogliptin: not extensively metabolized.

Protein Binding

  • Sitagliptin: 38%
  • Saxagliptin: negligible
  • Linagliptin: 70-80%; concentration dependent
  • Alogliptin: 20%

Cmax, Cmin, and AUC

  • Sitagliptin: following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 µM*hr; Cmax was 950 nM
  • Saxagliptin: AUC is increased by 27% when saxagliptin is given with a meal compared to fasted conditions.

T1/2

  • Sitagliptin: 12.4 hours
  • Saxagliptin: 2.5 hours
  • Linagliptin: 12 hours
  • Alogliptin: 21 hours

Distribution

  • Sitagliptin: Vd 2.8L/kg
  • Saxagliptin: Vd 2.7L/kg
  • Linagliptin: Vd 1110L
  • Alogliptin: Vd 417 L

COMMENTS

  • Overall HbA1c reduction for maximum dose sitagliptin (100 mg daily) as monotherapy is only about 0.6% after 18 weeks (range 0.5-0.8%) [9]. When added on to 1.5 grams per day of metformin, HbA1c reduction was 0.9% with sitagliptin 100 mg daily [1]. HbA1c reductions with other DPP-IV inhibitors are similar. This modest HbA1c reduction, and the high cost of this class of drugs, must be factored in when considering this class of drugs for use in patients.
  • DPP-IV inhibitors are weight-neutral, thus may be an attractive option for some patients.
  • Cardiovascular long-term safety data for saxagliptin was investigated in the SAVOR TIMI 53 trial which reported no difference compared to placebo in the rate of ischemic events, however, the rate of hospitalization for heart failure was increased [7]. Sitagliptin did not increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events in a subsequent trial.. [2]
  • Among patients with type 2 diabetes with a recent acute coronary syndrome, major adverse cardiovascular events were not increased with alogliptin as compared with placebo [11].
  • A previous analysis found a 2-fold increased odds of hospitalization for acute pancreatitis in patients using sitagliptin or exenatide [8]. Thus, consider alternative therapy in patients with other independent risk factors for pancreatitis (e.g. hypertriglyceridemia, alcohol use, gallstones, tobacco use, certain prescribed drugs, etc.). The FDA continues to investigate other unpublished findings of pancreatitis and pre-cancerous pancreatic duct metaplasia in association with use of incretin mimetics (DPP-IV inhibitors, GLP-1 agonists).
  • In Europe, vildagliptin (Galvus) is widely used, but it is not approved in the U.S.
  • The FDA issued a safety alert in August 2015 warning that DPP-IV inhibitors can cause severe and disabling joint pain [10]; patients with these symptoms may need to discontinue the medication if appropriate.

References

  1. Dicker D: DPP-4 inhibitors: impact on glycemic control and cardiovascular risk factors. Diabetes Care 34 Suppl 2:S276, 2011  [PMID:21525468]

    Comment: In patients already on metformin 1.5 g/day but with inadequate glycemic control, HbA1c reductions were a further 0.9% with the addition of sitagliptin 100 mg/day, versus 1.23% with liraglutide 1.2 mg/day, versus 1.5% with liraglutide 1.8 mg/day.

  2. Green JB et al: Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 373:232, 2015  [PMID:26052984]

    Comment: The TECOS Study was done in patients with type 2 diabetes and known cardiovascular disease, and showed that taking sitagliptin for 3 years did not increase or decrease the risk of major adverse cardiovascular events or hospitalization for heart failure.

  3. Nauck MA et al: Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 9:194, 2007  [PMID:17300595]

    Comment: In this non-inferiority study, 1172 patients on metformin monotherapy and baseline HbA1c of 7.5% were randomly assigned to receive either sitagliptin 100 mg/day or glipizide 5-20 mg/day. After 1 year, both groups showed a 0.67% HbA1c reduction, demonstrating non-inferiority.

  4. Chia CW, Egan JM: Incretin-based therapies in type 2 diabetes mellitus. J Clin Endocrinol Metab 93:3703, 2008  [PMID:18628530]

    Comment: Overview of the role of DPP-IV inhibitors and GLP-1 agonists in treating type 2 diabetes mellitus.

  5. Rosenstock J et al: Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes. Curr Med Res Opin 25:2401, 2009  [PMID:19650754]

    Comment: In this double-blind trial, 401 patients were randomized to 2.5 mg, 5 mg, 10 mg of saxagliptin or placebo for 24 weeks. Patients in the saxagliptin groups taking 2.5 mg, 5 mg and 10 mg achieved hemoglobin A1C reductions of 0.43%, 0.46 % and 0.54%, respectively, compared to a 0.19% reduction in the placebo group.

  6. Scirica BM et al: The design and rationale of the saxagliptin assessment of vascular outcomes recorded in patients with diabetes mellitus-thrombolysis in myocardial infarction (SAVOR-TIMI) 53 study. Am Heart J 162:818, 2011  [PMID:22093196]

    Comment: The SAVOR- TIMI 53 showed that in patients with type 2 diabetessaxagliptin did not increase or decrease the rate of ischemic events, though the rate of hospitalization for heart failure was increased.

  7. Scirica BM et al: Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 369:1317, 2013  [PMID:23992601]
  8. Singh S et al: Glucagonlike Peptide 1-Based Therapies and Risk of Hospitalization for Acute Pancreatitis in Type 2 Diabetes Mellitus: A Population-Based Matched Case-Control Study. JAMA Intern Med Feb 25  [PMID:23440284]

    Comment: In this administrative database study of 1269 hospitalized patients with acute pancreatitis and 1269 control matched subjects, treatment with sitagliptin or exenatide was associated with increased odds of hospitalization for acute pancreatitis, with adjusted odds ratios of approximately 2.

  9. Raz I et al: Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia 49:2564, 2006  [PMID:17001471]

    Comment: Sitagliptin monotherapy reduced HbA1c by 0.6% after 18 weeks at its maximum daily dose of 100 mg.

  10. U.S. Food and Drug Administration: DPP-4 Inhibitors for Type 2 Diabetes: Drug Safety Communication - May Cause Severe Joint Pain http://www.fda.gov…
  11. White WB et al: Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 369:1327, 2013  [PMID:23992602]
  12. http://clinicaltrials.gov…, last accessed 27th July 2015. "Does Saxagliptin Reduce the Risk of Cardiovascular Events When Used Alone or Added to Other Diabetes Medications (SAVOR- TIMI 53)?"

    Comment: This ongoing study is a multicenter, randomised, double-blind, placebo-controlled phase IV trial to evaluate the effect of saxagliptin on the incidence of cardiovascular death, myocardial infarction or ischemic stroke in patients with type 2 diabetes. Study has been completed.

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Last updated: October 3, 2015