| DPP-IV InhibitorsNadeen Hosein, M.D.; Brian Pinto, Pharm.D. INDICATIONSMECHANISM![[Top]](images/m/top.gif) - 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.
FORMSbrand name | preparation | manufacturer | route | form | dosage^ | cost* | Januvia | sitagliptin phosphate | Merck | oral | tablet | 25 mg | $214 for 30 tabs | | | | oral | tablet | 50 mg | $214 for 30 tabs | | | | oral | tablet | 100 mg | $214 for 30 tabs | Onglyza | saxagliptin | Bristol-Myers Squibb | oral | tablet | 2.5 mg | $190 for 30 tabs | | | | oral | tablet | 5 mg | $190 for 30 tabs | Janumet | sitagliptin phosphate + metformin hydrochloride | Merck Sharp & Dohme Corp. | oral | tablet | 50/500 mg | $197 for 60 tabs | | | | oral | tablet | 50/1000 mg | $196 for 60 tabs |
*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 50-100 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.
- 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, or thiazolidinediones.
- If adding DPP-IV inhibitors to sulfonylurea therapy, consider decreasing the sulfonylurea dose, to reduce hypoglycemia risk.
- Sitagliptin has also been studied for use in combination with insulin, however, insulin dose reductions may be necessary.
DOSING IN SPECIAL POPULATIONSRENAL- 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
- Janumet
- CONTRAINDICATED if GFR ≤ 60 mL/min, or if serum creatinine ≥ 1.4 mg/dL (women) or ≥ 1.5 mg/dL (men)
HEPATIC- No dose adjustments needed, except for Janumet: avoid use if liver disease is present, due to increased risk of lactic acidosis.
BREASTFEEDING- Thomson Lactation Ratings: infant risk cannot be ruled out.
ADVERSE DRUG REACTIONSDRUG INTERACTIONS- Digoxin: Oral sitagliption 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.
PHARMACOKINETICAbsorption- Sitagliptin: 87% bioavailability; time to peak concentration 1-4 hours.
- Saxagliptin: time to peak concentration 2 hours.
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
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%) (Raz). HbA1c reductions with other DPP-IV inhibitors are similar. This and the high cost have led many endocrinologists to use DPP-IV inhibitors as second or third line drugs.
- DPP-IV inhibitors are weight-neutral which may be an attractive option for some patients.
- Long-term safety data is not known for DPP-IV inhibitors. The first drug in this class, sitagliptin (Januvia), was only released in October 2006.
- In July 2009, FDA approved another DPP-IV inhibitor, saxagliptin (Onglyza), for T2DM[Rosenstock, 2009].
- In May 2011, FDA approved a third drug in this class, linagliptin (Trajenta). In contrast to other DPP-IV inhibitors, linagliptin is given once-daily and does not require renal adjustment. This drug is also approved for use as monotherapy or as an add-on therapy to other oral agents.
- In Europe, vildagliptin is widely approved
References- 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.
- 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.
- 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.
- 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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