DPP-IV Inhibitors

Régine Béliard Veillard, Pharm.D., Brian Pinto, Pharm.D.



  • Type 2 diabetes mellitus


  • Inhibits dipeptidyl peptidase IV (DPP-IV) enzyme, which prolongs the action of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These incretin hormones increase insulin secretion and decrease glucagon secretion, which also decreases hepatic glucose production.


Brand Name

Generic Name










25 mg, 50mg, 100mg



Bristol-Myers Squibb



2.5 mg, 5mg



Eli Lilly



5 mg






6.25 mg, 12.5 mg, 25 mg


sitagliptin + metformin

Merck Sharp & Dohme Corp.



50/500 mg, 50/1000 mg

Kombiglyze XR

saxagliptin + metformin XR




2.5/1000 mg, 5/500 mg, 5/1000 mg


linagliptin + metformin

Boehringer Ingelheim



2.5/500 mg, 2.5/850 mg, 2.5/1000 mg

Jentadueto XR

linagliptin + metformin XR

Boehringer Ingelheim



2.5/1000 mg, 5/1000 mg


alogliptin + metformin hydrochloride




12.5/500 mg, 12.5/1000 mg


alogliptin + pioglitazone




25/15 mg, 25/30 mg, 25/45 mg, 12.5/15 mg, 12.5/30 mg, 12.5/45 mg


dapagliflozin + saxagliptin






empagliflozin + linagliptin

Boehringer Ingelheim



10/5 mg, 25/5 mg


ertugliflozin + sitagliptin




5/100 mg, 15/100 mg

There are no generic DPP-IV inhibitors availabile on the martket at this time.

Patient Assistant Programs:







  • Sitagliptin: 100 mg once a day. Can be taken with or without food.
  • Saxagliptin: 2.5 or 5 mg once a day. Can be taken with or without food.
  • Linagliptin: 5 mg once a day. Can be taken with or without food.
  • Alogliptin:25 mg once daily. Can be taken with or without food.
  • 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.



  • Sitagliptin
    • GFR ≥ 45 mL/min, no dosage adjustment needed
    • GFR ≥ 30 to < 45 mL/min, 50 mg daily
    • GFR < 30 mL/min, 25 mg daily
    • For patients on hemodialysis or peritoneal dialysis, 25 mg daily without regard to timing of hemodialysis
  • Saxagliptin
    • GFR ≥ 45 mL/min, no dosage adjustment needed
    • GFR < 45 mL/min, 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


  • None


  • Limited human data - animal data suggest low risk


  • No human data - probably compatible



  • Contraindicated in patients with hypersensitivity reaction to sitagliptin, saxagliptin, linagliptin, or alogliptin.
  • Do not use in diabetic ketoacidosis.
  • Do not use as therapy for type 1 diabetes mellitus.


  • 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


  • Acute pancreatitis
  • 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
  • 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.


  • 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.



  • 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.


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


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


  • Overall A1C reduction for maximum dose sitagliptin (100 mg daily) as monotherapy is only about 0.6% after 18 weeks (range 0.5-0.8%)[10]. When added on to 1.5 grams per day of metformin, A1C reduction was 0.9% with sitagliptin 100 mg daily[6]. A1C reductions with other DPP-IV inhibitors are similar. This modest A1C reduction of DPP-IV inhibitors (overall 0.5-1%), 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[2]. Sitagliptin did not increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events in a subsequent trial..[1]
  • 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[3].
  • A previous analysis found a 2-fold increased odds of hospitalization for acute pancreatitis in patients using sitagliptin or exenatide[4]. However, subsequent studies have not necessarily reported similar findings and the association of DPP-IV inhibitors with pancreatitis remains unclear. 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[12]; patients with these symptoms may need to discontinue the medication if appropriate.


  1. Green JB, Bethel MA, Armstrong PW, et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015;373(3):232-42.  [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.

  2. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317-26.  [PMID:23992601]
  3. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327-35.  [PMID:23992602]
  4. Singh S, Chang HY, Richards TM, 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. 2013.  [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.

  5. Scirica BM, Bhatt DL, Braunwald E, 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. 2011;162(5):818-825.e6.  [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.

  6. Dicker D. DPP-4 inhibitors: impact on glycemic control and cardiovascular risk factors. Diabetes Care. 2011;34 Suppl 2:S276-8.  [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.

  7. Rosenstock J, Aguilar-Salinas C, Klein E, et al. Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes. Curr Med Res Opin. 2009;25(10):2401-11.  [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.

  8. Chia CW, Egan JM. Incretin-based therapies in type 2 diabetes mellitus. J Clin Endocrinol Metab. 2008;93(10):3703-16.  [PMID:18628530]

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

  9. Nauck MA, Meininger G, Sheng D, 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. 2007;9(2):194-205.  [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.

  10. Raz I, Hanefeld M, Xu L, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia. 2006;49(11):2564-71.  [PMID:17001471]

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

  11. http://clinicaltrials.gov/ct2/show/NCT01107886, 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.

  12. 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/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm460238.htmComments

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Last updated: December 3, 2018