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DPP-4 Inhibitors Charts & Dosing Information for Special Populations

Forms, dosages and dosing considerations for pregnancy, breastfeeding, hepatic and renal.

brand name preparation manufacturer route form dosage^
Januvia sitagliptin phosphate (Plus Metformin) Merck oral tablet 25 mg
oral tablet 50 mg
oral tablet 100 mg
Onglyza Saxagliptin (Plus with metformin) Bristol-Myers Squibb oral tablet 2.5 mgD
oral tablet 5 mg
Tradjenta Linagliptin (Plus with metformin) Eli Lilly oral tablet 5 mg
Janumet sitagliptin phosphate + metformin hydrochloride Merck Sharp & Dohme Corp. oral tablet 50/500 mg
oral tablet 50/1000 mg
Nesina alogliptin Takeda oral tablet 6.25 mg
oral tablet 12.5 mg
oral tablet 25 mg

Dosing (Oral Tablet)

  • 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-4 inhibitors are FDA approved for use as monotherapy in type 2 diabetes (T2DM).
  • DPP-4 inhibitors can also be added to patients already on metformin, sulfonylureas, thiazolidinediones, or insulin.
  • If adding DPP-4 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
  • 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%

T1/2

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

Notes

  • 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%). When added on to 1.5 grams per day of metformin, HbA1c reduction was 0.9% with sitagliptin 100 mg daily. HbA1c reductions with other DPP-4 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-4 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. Sitagliptin did not increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events in a subsequent trial.
  • 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.
  • A previous analysis found a 2-fold increased odds of hospitalization for acute pancreatitis in patients using sitagliptin or exenatide. 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-4 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-4 inhibitors can cause severe and disabling joint pain; patients with these symptoms may need to discontinue the medication if appropriate.

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

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.

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.

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-4 inhibitors and GLP-1 agonists in treating type 2 diabetes mellitus.

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.