- 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.
*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.
- 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
- 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
- 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
- No dosage adjustment needed
- CONTRAINDICATED if GFR ≤ 60 mL/min, or if serum creatinine ≥ 1.4 mg/dL (women) or ≥ 1.5 mg/dL (men)
- 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.
- Thomson Lactation Ratings: infant risk cannot be ruled out. Thus, use with caution in breastfeeding women.
ADVERSE DRUG REACTIONS
- 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; 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).
- Hypoglycemia, more common when used in conjunction with a sulfonylurea or insulin.
- Nasopharyngitis or upper respiratory tract infections
- Nausea, diarrhea, abdominal pain
- Urinary tract infections
- Peripheral edema
- Janumet: GI disturbance initially (nausea, vomiting, diarrhea) due to metformin; lessened if taken with meals
- Acute pancreatitis with sitagliptin
- Stevens-Johnson syndrome, urticaria, exfoliative dermatitis, and other hypersensitivity skin reactions
- 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.
- 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.
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.
- Saxagliptin: negligible
- Linagliptin: 70-80%; concentration dependent
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.
- Saxagliptin: 2.5 hours.
- Linagliptin: 12 hours.
- Sitagliptin: Vd 2.8L/kg
- Saxagliptin: Vd 2.7L/kg
- Linagliptin: Vd 1110L
- 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%) (Raz). 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-IV inhibitors are similar. This modest HbA1c reduction, and the high cost of this class of drugs, must be considered 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 is being studied for saxagliptin in the ongoing SAVOR TIMI 53 trial, with study completion expected in July 2013. Early data suggests no increased risk of adverse cardiovascular events.
- In January 2013, FDA approved alogliptin (Nesina); anticipated availability is summer 2013.
- In Europe, vildagliptin (Galvus) is widely used, but it is not approved in the U.S.
- A recent logistical regression 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 announced on March 14th, 2013, that it is investigating other unpublished findings of pancreatitis and pre-cancerous pancreatic duct metaplasia in association with use of incretin mimetics (DPP-IV inhibitors, GLP-1 agonists).
- 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.
- 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.
- http://clinicaltrials.gov/ct2/show/NCT01107886, last accessed 20th March 2013. "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 completion is expected in July 2013.
- 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: This trial, being conducted in 25 countries, is designed to evaluate the safety and efficacy of saxagliptin during long-term treatment of approximately 16,500 patients with type 2 diabetes. SAVOR-TIMI 53 is testing the hypothesis that treatment with saxagliptin is safe and reduces cardiovascular events in these patients.
- 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-IV 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.
- 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.
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