Dipeptidyl Peptidase-IV Inhibitors: Pharmacological Profile and Clinical Use

Home , Biguanide, Meglitinide, Vildagliptin

F e a t u r e A r t i c l e

John R. White, Jr., PA, PharmD

decade and a half ago, the on insulin biosynthesis and its inhibition creation of molecules that circumvent or choice of an oral antihypergly- of glucagon release.2 reduce the rate degradation by DPP-IV Acemic agent for any particu- Because GLP-1 stimulates insulin while maintaining the agonist effects of lar patient was in some ways a debate secretion only under hyperglycemic GLP-1 has been pursued aggressively. of nuance. Sulfonylureas (SUs) were conditions, there is minimal risk of One GLP-1 analog (exenatide) is avail- the only class available, and provid- hypoglycemia, making this molecule and able in the United States, and another ers were left to sift though pharmacoki- its congeners likely candidates for use as (liraglutide) is in phase III trials. netic, small efficacy, and sometimes sig- antihyperglycemic agents. GLP-1 is also In addition to GLP-1 analogs, mol- nificant side effect differences among associated with increased satiety, possi- ecules that inhibit the activity of DPP-IV the various choices within this class. The bly because it reduces the rate of gastric and thereby prolong the activity of situation today demands a more robust emptying. People with type 2 diabetes endogenous GLP-1 are of great interest. evaluation of multiple categories of med- have reduced circulating levels of GLP-1 Because GLP-1 analogs are proteina- ications with different mechanisms of but retain their ability to respond to this cious in structure, they will most likely action. Providers must consider the pos- hormone. Thus, it is possible to improve all require administration via injection, sible choices of an SU, a biguanide, an glycemic control through administration as exenatide does already. In contrast, DPP-IV inhibitors may be smaller α-glucosidase inhibitor, a meglitinide, of exogenous GLP-1. molecules that can be absorbed intact a thiazolidinedione (TZD), a bile acid Unfortunately, under normal physi- from the gastrointestinal tract, making resin (BAR), or a dipeptidyl peptidase- ological conditions, GLP-1 and GIP are their oral administration possible. One IV (DPP-IV) inhibitor. In addition, sev- rapidly degraded by the enzyme system DPP-IV agent (sitagliptin) is available; eral injectable compounds are available DPP-IV and therefore are not themselves the Food and Drug Administration for the treatment of hyperglycemia. This viable as pharmacological agents. The (FDA) approval of another (vildagliptin) article provides an overview of the func- is probably imminent; and several others tion of the endogenous DPP-IV enzyme I n B r i e f (saxagliptin, alogliptin, and denagliptin) system and the pharmacology and clini- are in development. DPP-IV inhibitors cal use of DPP-IV inhibitors. Sitagliptin is the first agent in a new category of medications, the are an important addition to the list of Incretin Hormones and DPP-IV dipeptidyl peptidase-IV (DPP-IV) pharmacological options for the treatment of hyperglycemia. Any discussion of DPP-IV and its inhibitors. It was recently approved in the United States for the manage- inhibitors would be incomplete without Effects of DPP-IV Inhibitors ment of hyperglycemia in patients mention of the endogenous incretin Based on the effects of the DPP-IV with type 2 diabetes; vildagliptin, a hormones glucagon-like peptide-1(GLP enzyme system, inhibition presumably second agent in this class, is likely 1) and glucose-dependent insulinotopic would result in increased serum levels of to join it on the U.S. market soon. hormone (GIP). These hormones are GLP-1, leading to a net antihyperglyce- These compounds accentuate the released from the L and K cells of the activity of endogenously produced mic effect. This effect has been demon- gastrointestinal tract, respectively, when antihyperglyemic incretin hormones strated in both animal and human mod- those cells are stimulated by intraluminal and are generally well tolerated. els. Animal trials evaluating the impact 1 glucose. Both GLP-1 and GIP cause a This article provides an overview of of DPP-IV inhibition have demonstrated glucose-dependent increase in insulin the pharmacology and clinical use improvement in glucose tolerance, secretion. GLP-1 also contributes to of the DPP-IV inhibitors. enhancement of insulin secretion, and glucose homeostasis through its effects even delay in the onset of overt diabetes

Clinical Diabetes • Volume 26, Number 2, 2008 53 F e a t u r e A r t i c l e

in Zucker diabetic fatty rats.3 Further 1 compares the action of endogenous 2 diabetes. One phase III trial demon- animal studies have suggested that GLP-1 with that of DPP-IV inhibitors. strated that sitagliptin administered in inhibition of DPP-IV improves insulin 100-mg and 200-mg daily doses reduced Sitagliptin sensitivity and may reverse glucose tox- hemoglobin A1c (A1C) levels by 0.79 icity.4 It has been suggested that DPP-IV In October 2006, sitagliptin became and 0.94%, respectively, at 24 weeks. inhibition and its resultant preservation the first DPP-IV inhibitor to gain FDA These differences were statistically of endogenous GLP-1 activity may lead approval for the treatment of type 2 significant when compared to placebo to β-cell preservation via augmentation diabetes. Sitagliptin tablets are com- (P < 0.001).6 Patients with A1C levels of GLP-1’s antiapopotic effects. mercially available as 100-mg (beige), > 9.0% showed greater reductions in Although DPP-IV inhibition has 50-mg (light beige), and 25-mg (pink) A1C. Improvements in fasting plasma been associated with an enhancement tablets.5 Sitagliptin is also available in glucose and postprandial glucose levels of β-cell survival and neogenesis in a combination product with metformin were also reported in those treated with streptozotocin-treated diabetic rats,4 this in doses of 50 mg sitagliptin/500 mg sitagliptin. effect has not yet been demonstrated metformin and 50 mg sitagliptin/1,000 In another report, daily doses of in humans. This exciting possibility mg metformin. 100 mg sitagliptin were associated undoubtedly will be evaluated in humans The usual recommended dose of with statistically significant(P < 0.001) as a potential agent or class of agents for sitagliptin is 100 mg per day. However, 0.65% reductions in A1C in patients the prevention of type 2 diabetes. the agent is available in three strengths with an initial mean A1C of 8%.7 DPP-IV inhibitors probably exert to allow for lower dosing in patients with Sitagliptin also has been evaluated most, if not all, of their pharmacological moderate to severe renal impairment. in combination with other antihyper- effects in humans by inhibiting the deg- The sitagliptin-metformin combination glycemic medications. In one trial, 701 radation of GLP-1. Through this func- should be taken twice daily with meals patients with a mean baseline A1C of tion, they cause some of the same effects and titrated slowly to minimize potential 8% (range: 7–10%) who were previously of GLP-1, including stimulation of gastrointestinal side effects associated treated with metformin continued ther- insulin secretion, inhibition of glucagon with metformin. apy with metformin and were random- secretion, and enhancement of β-cell ized to receive either 100 mg sitagliptin Clinical trials mass.1 Conversely, they seem to have or placebo daily for 24 weeks.8 Patients Clinical trials have demonstrated that only a marginal slowing effect on the in the placebo group experienced no sitagliptin is safe and efficacious for the rate of gastric emptying and no obvious changes in A1C, whereas those treated management of hyperglycemia in type effect on satiety or weight loss.1 Table with sitagliptin plus metformin realized a 0.65% reduction in A1C at 24 weeks. Table 1. Effects of Endogenous GLP-I Versus DPP-IV Inhibition In the combination therapy group, 47% of the patients concluded the trial with Feature of Type 2 Diabetes Action of Endogenous Mimicked by DPP-IV GLP-1 Inhibitors? A1C levels < 7%, and 17% reached an A1C of < 6.5%. Only 18% of patients in the placebo group reached an A1C Impaired insulin secretion Glucose-dependent stimula- Yes tion of insulin level < 7%, and only 5% reached an A1C < 6.5%. Similar results have been Hyperglucagonemia Suppression of glucagon Yes published from other clinical trials secretion evaluating the efficacy of combination Reduced pancreatic β-cell Increased synthesis of Yes metformin and sitagliptin therapy.9,10 mass proinsulin One study evauated 353 patients Abnormally high rate of Inhibition of β-cell apop- Probably previously treated with pioglitazone.11 β-cell apoptosis tosis Patients received either 100 mg sita- Gastric emptying ac- Deceleration of gastric Marginally gliptin or placebo daily in addition to 30 celerated, decelerated, or emptying or 45 mg/day pioglitazone for 24 weeks. normal Mean baseline A1C values reported in Hypercaloric energy in- Suppression of appetite/ Not obvious this trial were 8% (range: 7–10%) at take/obesity induction of satiety the completion of a short run-in period Weight loss No pioglitazone. A mean reduction in A1C of 0.7% was reported in patients treated Adapted from Ref. 1 with combination therapy, compared

54 Volume 26, Number 2, 2008 • Clinical Diabetes F e a t u r e A r t i c l e

to no significant change in A1C in the whether sitagliptin is secreted in human Sitagliptin is primarily excreted in an placebo group. breast milk, and the effects on nursing unchanged form in the urine (79%) via In summary, evidence suggests that babies are also unknown. active tubular secretion. The terminal sitagliptin is an efficacious antihypergly- Safety and efficacy in patients < 18 t1/2 of sitagliptin was 12.4 hours after cemic agent when used as monotherapy years of age have not been studied, but a single 100-mg dose in healthy vol- or in combination with metformin nothing thus far suggests that problems unteers.5 A relatively small fraction of or pioglitazone for the treatment of would result from using the agent in sitagliptin undergoes hepatic metabolism type 2 diabetes. In addition to favor- younger patients with type 2 diabetes. primarily via cytochromes P450 3A4 able changes in A1C, clinical trials of Sitagliptin is contraindicated in and 2C8.18 However, when sitagliptin sitagliptin have shown improvement in patients with type 1 diabetes and is not pharmacokinetics were studied in fasting and postprandial glucose levels. intended for use in the treatment of dia- patients with moderate hepatic impair- betic ketoacidosis.5 Patients with moder- ment (Child-Pugh score 7–9), significant Side effects, contraindications, and ate renal insufficiency receiving 50 differences in pharmacokinetic param- precautions mg/day sitagliptin had a slightly greater eters were not found.19 Patients treated with sitagliptin mono- increase in serum creatinine (0.05 mg/dl) Because of limited hepatic metabo- therapy or combination sitagliptin-met- than matched control subjects with the formin or sitagliptin-pioglitzone therapy same degree of renal impairment receiv- lism of sitagliptin by cytochrome P450 had an incidence of adverse events ing placebo.14 enzymes 3A4 and 2C8, it is not consid- and rates of discontinuation of therapy ered likely that any clinically relevant similar to those of control subjects. Pharmacokinetics and drug interactions exist with other drugs that Three side effects have been reported to interactions use the cytochrome P450 system or occur with more frequency in sitagliptin- Sitagliptin is an interesting compound p-glycoprotein transport system. This treated patients than in control subjects: from a pharmacokinetic standpoint, statement is supported by the fact that nasopharyngitis (5.2% in the sitagliptin in part because it is an enzyme inhibi- no clinically important pharmacokinetic group vs. 3.3% in the placebo group), tor. Its inhibition of DPP-IV results in interactions requiring dosage adjustment upper respiratory tract infection (6.3% prolonged incretin activity, which in turn were identified during clinical trials.5 in the sitagliptin-pioglitazone group vs. results in enhanced glucose-dependent Because sitagliptin is primarily 15 3.4% in the pioglitazone-only group), insulin release. Dipeptidyl peptidase eliminated unchanged via renal excre- and headache (5.1% in the sitagliptin- encompasses a large family of enzymes. tion, dosage adjustments are required for pioglitazone group vs. 3.9% in the Full-scale inhibition of an enzyme patients with moderate to severe renal pioglitazone-only group). system such as this could cause myriad impairment. A dose of 50 mg/day is rec- The sitagliptin package insert reports deleterious effects, and, because of ommended in patients with a creatinine that a slight increase in white blood cell this, the selectivity of an inhibitor is of clearance (CrCl) ≥ 30 to < 50 ml/min. count (~ 200 cells/µl) was observed in prime importance. Sitagliptin exhibits a patients treated witih sitagliptin com- > 2,600-fold higher affinity for DPP-IV A dose of 25 mg/day is recommended pared to those receiving placebo. This than for structurally related DPP-VIII for patients with a CrCl < 30 ml/min or small increase primarily results from an and DPP-IX enzymes.16 Sitagliptin has in patients with end-stage renal disease 5 increase in the number of neutrophils. not been associated with toxicity as requiring dialysis. This observation was deemed clinically a result of inhibition of these related Dosage and indications insignificant by investigators.5 enzyme systems.17 Sitagliptin is available commercially in The reported incidence of hypogly- Sitagliptin is rapidly absorbed (peak 25-mg, 50-mg, and 100-mg tablets. It cemia in subjects receiving sitagliptin concentration at 1–4 hours) after oral is similar to that in control subjects (1.2 administration and has a high oral is indicated for mono- or combination vs. 0.9%). Additionally, the occurrence bioavailability (F = 0.87). Clinical trials therapeutic management of hyperglyce- of hypoglycemia with sitagliptin treat- to date have reported no correlation mia in patients with type 2 diabetes. In ment is not enhanced by the addition of between changes in the pharmacokinetic patients with normal renal function, it is metformin or pioglitazone.5,12,13 parameters of sitagliptin and age, sex, dosed at 100 mg daily; in patients with Sitagliptin is a pregnancy risk Cat- race, or BMI. The average volume of CrCl ≥ 30 to < 50 ml/min, the dose is 50 egory B agent and should only be used distribution (Vd) at steady state is 198 l mg/day; and in patients with CrCl < 30 during pregnancy if deemed necessary. after a single dose of sitagliptin. Sita- ml/min, the dose is 25 mg daily. It can Caution is also advised in women who gliptin is moderately bound to plasma be taken with or without food. are nursing. It is currently unknown proteins (bound fraction = 38%).5

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Vildagliptin 0.5% versus a reduction of 0.2% in the volume of distribution at steady state is a FDA approval for vildagliptin, a second placebo-plus-insulin group (P = 0.022) mean of 70.5 l.29 DPP-IV inhibitor, is being sought. The after 24 weeks of therapy. Vildagliptin is hydrolyzed to a FDA has asked the manufacturer to In summary, studies have suggested pharmacologically inactive metabolite. provide additional safety data for review that vildagliptin is useful in the manage- Excretion of this metabolite is carried before approval. ment of hyperglycemia in patients with out mainly through the urine (85%), type 2 diabetes as a monotherapeutic with 15% excreted within the feces. The Clinical trials agent and when used in conjunction with mean terminal t1/2 of vildagliptin has Vildagliptin has been evaluated for the metformin, pioglitazone, or insulin. been reported to be between 1.68 and management of hyperglycemia in type 2 2.54 hours.31 The disparity between the diabetes as monotherapy and in com- Side effects, contraindications, and long duration of action of vildagliptin bination with metformin, pioglitazone, precautions and the short plasma half-life is thought or insulin and has demonstrated ability Vildagliptin was generally well tolerated to be the result of the slow-binding inhi- to improve glycemic control in type in phase III trials. One case of signifi- bition kinetics seen with this agent.32 20–22 2 diabetes. Patients treated with cant peripheral edema was reported and Vildagliptin does not appear to 100 mg/day vildagliptin for 24 weeks attributed to the study drug in clini- induce or inhibit the cytochrome P450 showed mean reductions in A1C of 1.1% cal trials of vildagliptin. In this case, enzyme system.30 The t1/2 was not from a mean baseline A1C of 8.7% in peripheral edema was reported in a affected by the presence of hepatic 1,301 subjects (P < 0.01 vs. baseline patient treated with vildagliptin plus impairment when studied.33 Additional values).23 metformin in a 40-week extension of the clinical trials are underway to evaluate The addition of vildagliptin to vildagliptin-plus-metformin combination the potential effects of renal impairment metformin therapy resulted in improved therapy study.24 on the pharmacokinetic disposition and glycemic control compared to metfor- Withdrawal rates from clinical trials clinical activity of vildagliptin. min plus placebo.24 After ~ 1 year of because of adverse events were low Drug interaction data for vilda- combination vildagliptin-metformin in monotherapeutic and combination gliptin are limited. However, clinically therapy, 41.7% of subjects achieved a significant drug interactions have not A1C level of 7% (from a baseline level therapy studies (3.2–7.8% and 1.4%, respectively), and no deaths resulted in been reported in clinical trials involving of 7.6–7.8%). Conversely, only 10.7% 34 24,27 the coadministration of pioglitazone, of patients on metformin plus placebo either study. metformin,35 or glyburide.31 reached an A1C < 7%. The most common adverse events reported with vildagliptin were mild and Vildagliptin has also been shown Dosage and indications to be effective when used with piogli- included nasopharyngitis, headache, and Because of the pending FDA review of tazone.25 Patients treated with either 50 dizziness. Vildagliptin has been associ- vildagliptin, the adult daily dosage for mg/day vildagliptin plus 15 mg/day ated with very few episodes of hypogly- which the manufacturer will receive pioglitazone or 100 mg/day vildagliptin cemia when used as monotherapy or in approval is not known, although one plus 30 mg/day pioglitazone for 24 combination with other antihyperglyce- could assume that the dose in an adult weeks achieved greater improvements mic medications. No significant labora- with normal renal function will probably in A1C values from baseline compared tory abnormalities have been observed be 100 mg/day. to subjects receiving 30 mg/day pio- during or resulting from trials involving glitazone as monotherapy. Mean A1C vildagliptin.28 Summary changes from baseline were −1.7, −1.9, One DPP-IV inhibitor is available and −1.4%, respectively (P < 0.05). Pharmacokinetics and drug for use in the United States, and the Another trial evaluated 256 patients interactions approval of a second agent is imminent. whose diabetes was inadequately As has been observed with sitagliptin, DPP-IV inhibitors offer a safe and effi- controlled on insulin therapy. This the pharmacokinetic parameters of cacious method for modestly reducing study demonstrated that the addition of vildagliptin appear unaffected by age, hyperglycemia alone or in combina- vildagliptin resulted in improvement in sex, and BMI.29 Vildagliptin is rapidly tion with other agents in patients with glycemic control endpoints for these absorbed with maximal concentrations type 2 diabetes without causing weight patients.26 Patients receiving 50 mg being reached within 1–2 hours after an gain, significant hypoglycemia, or other vildagliptin twice daily in addition to oral dose of the drug.30 The oral bioavail- major side effects. These agents can be their insulin therapy experienced a sta- ability of vildagliptin appears to be simi- taken orally and are given in a single tistically significant reduction in A1C of lar to sitagliptin (F = 0.85). The reported daily dose. They represent a significant

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additional option in ongoing efforts to 12Rosenstock J, Brazg R, Andryuk PJ, Lu K, 23Nathwani A: The use of vildagliptin for treat- Stein P: Addition of sitagliptin to pioglitazone im- ment of patients with type 2 diabetes mellitus. control hyperglycemia in patients with proved glycemic control with neutral weight ef- Diabetes;55(Suppl. 1):Abstract 474-P, 2006 fect over 24 weeks in inadequately controlled type type 2 diabetes. 24Ahren B, Gomis R, Standl E, Mills D, 2 diabetes (T2DM). Poster 556-P presented at Schweizer A: Twelve- and 52-week efficacy of the American Diabetes Association 66th Annual References the dipeptidyl peptidase IV inhibitor LAF237 in Meeting and Scientific Sessions in Washington metformin-treated patients with type 2 diabetes. 1Drucker DJ, Nauck MA: The incretin D.C., June 2006 Diabetes Care 27:2874–2880, 2004 system: glucagon-like peptide-1 receptor agonists 13 Karasik A, Charbonnel B, Liu J, Wu M, 25Baron MA, Rosenstock J, Bassiri B, and dipeptidyl peptidase-IV inhibitors in type 2 Meininger G: Sitagliptin added to ongoing met- diabetes. Lancet 368:1696–1705, 2006 Rochotte E, Cressien Y: Efficacy of vildagliptin formin therapy enhanced glycemic control and be- combined with pioglitazone in patients with type 2Gonzalez C, Beruto V, Keller G, Santoro S, Di ta-cell function in patients with type 2diabetes. 2 diabetes [Abstract]. Diabetologia 49 (Suppl. 1): Girolamo G: Investigational treatments for type 2 Poster 501-P presented at the American Diabetes A111, 2006 Association 66th Annual Meeting and Scientific diabetes mellitus: exenatide and liraglutide. Expert 26 Opin Invest Drugs 15:887–895, 2006 Sessions in Washington D.C., June 2006 Fonseca V, DeJager S, Albrecht D, Shirt L, Schweizer A: Vildagliptin as add-on to insulin in 3Sudre B, Broqua P, White RB: Chronic in- 14Scott R, Wu M, Sanchez M, Stein P : patients with type 2 diabetes (T2DM) [Abstract]. hibition of circulating dipeptidyl peptidase IV by Efficacy and tolerability of the dipeptidyl pepti- Diabetes 55 (Suppl. 1):A111, 2006 dase-4 inhibitor sitagliptin as monotherapy over 12 FE 999001 delays the occurrence of diabetes in 27 male Zucker diabetic fatty rats. Diabetes 51:1461– weeks in patients with type 2 diabetes. Int J Clin Ristic S, Byiers S, Foley J, et al. Improved 1469, 2002 Pract 61:171–180, 2007 glycaemic control with dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes: vildagliptin 4Pospisilik JA, Stafford SG, Demuth HU, 15Deacon CF, Holst JJ: Dipeptidyl peptidase (LAF237) dose response. Diabetes Obes Metab McIntosh CH, Pederson RA: Long-term treatment IV inhibitors: a promising new therapeutic ap- 7:423–428, 2005 proach for the management of type 2 diabetes. Int with dipeptidyl peptidase IV inhibitor improves 28 J Biochem Cell Biol 38:831–844, 2006 Henness S, Keam SJ: Vildagliptin. Drugs hepatic and peripheral insulin sensitivity in the 66:1989–2001, 2006 VDH Zucker rat: a euglycemic-hyperinsulinemic 16 Kim D, Wang L, Beconi M, Eirman G, Fisher 29 clamp study. Diabetes 51:2677–2683, 2003 MH, Huaibing H, Hickey G, Kowalchick JE, He YL, Sabo R, Balez S, Wang J, Campestrini A, Marion M, Ligueros-Saylan M: 5 Leiting B, Lyons K, Marsilio F, Mccann ME, Patel Januvia (sitagliptin) Tablets package insert. Absolute bioavailability of vildagliptin in healthy Whitehouse Station, N.J., Merck & Co., 2007 R, Petrov A, Scapin G, Patel S, Ranabir A, Singa R, Wu J, Wyvratt MJ, Zhang BB, Zhu L, Thornberry subjects. Clin Pharmacol Ther 79:38, 2006 6 Aschner P, Kipnes M, Lunceford M, Sanchez NA, Weber AE: (2R)4-oxo-4-[3-(trifluoromethyl)- 30He YL, Balch A, Campestrini J, Rivere M, Mickel C, Williams-Herman DE: Effect of 5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]- G, Serra D, Prasad P, Ligueros-Saylan M: the dipeptidyl peptidase-4 inhibitor sitagliptin as 1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, Pharmacokinetics and pharmacodynamics of the monotherapy on glycemic control in patients with orally active dipeptidyl peptidase IV inhibitor for DPP-4 inhibitor, LAF237, in patients with type 2 type 2 diabetes. Diabetes Care 29:2632–2637, the treatment of type 2 diabetes. J Clin Endocrinol diabetes. Clin Pharmacol Ther 77:56, 2005 2006 Metab 91:4612–4619, 2006 31Barilla D, He Y, Balez S, Bullock J, Ho Y, 7 Aschner P, Kipnes M, Lunceford J, Sanchez 17Lankas GR, Leiting B, Roy RS, Beconi M, Gutierrez M, Ligueros-Saylan M: No pharma- M, Mickel C, Williams-Herman D: Sitagliptin Biftu E: Dipeptidyl peptidase IV inhibition for the cokinetic interactions or acute clinical safety is- monotherapy improved glycemic control in the treatment of type 2 diabetes: potential importance sues preclude combination of the DPP-4 inhibi- fasting and postprandial states and beta-cell func- of selectivity over dipeptidyl peptidases 8 and 9. tor LAF237 with glyburide [Abtsract]. Diabetes 53 tion after 24 weeks in patients with type 2 diabe- Diabetes 54:2988–2994, 2005 (Suppl. 2):A470, 2004 tes (T2DM) [Abstract]. Diabetes 55 (Suppl. 1): A462, 2006 18Vincent SH, Reed JR, Bergman AJ, Elmore 32Hughes TE, Mone MD, Russell ME, Weldon CS, Zhu B, Xu S, Ebel D, Larson P, Zeng W, Chen SC, Villhaur EB : NVP-DPP728 (1-[[[2-[(5-cy- 8 Charbonnel B, Karasik A, Liu J, Wu M, L, Dilzer S, Lasseter K, Gottesdiener K, Wagner anopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cy- Meininger G: Efficacy and safety of the dipeptidyl JA, Herman GA:. Metabolism and excretion of the ano-(S)-pyrrolidine), a slow-binding inhibitor peptidase-4 inhibitor sitagliptin added to ongoing DPP-4 inhibitor [14C] sitagliptin in humans. Drug of dipeptidyl peptidase IV. Biochemistry (Mosc) metformin therapy in patients with type 2 diabe- Metab Dispos Electronically published 12 January 38:11597–11603, 1999 tes inadequately controlled with metformin alone. 2007 33 Diabetes Care 29:2638–2643, 2006 He Y, Sabo R, Campestrini J, Wang Y, 19 Ligueros-Saylan M, Lasseter K, Dilzer S, Howard 9 Stevens C, Bergman AJ, Liu Q, Luo W, Wang Williams-Herman D, Goldstein BJ, Feinglos AQ: Lack of clinically significant effect of mod- D, Dole W: The influence of hepatic impairment MN, Lunceford JK, Johnson J: Initial combination erate hepatic insufficiency on the pharmacokinet- on the pharmacokinetics of vildagliptin. Eur J Clin therapy with sitagliptin, a dipeptidyl peptidase-4 ics of MK-0431 (sitagliptin), a dipeptidyl-pepti- Pharmacol 63677–686, 2007 inhibitor, and metformin provides substantial gly- dase-IV inhibitor [Abstract]. Clin Pharmacol Ther 34Serra DB, He YL, Wang Y, et al. cemic improvements and HgbA1c goal attainment 79:P49, 2006 in patients with type 2 diabetes mellitus (T2DM) Combination of the DPP-4 inhibitor vildagliptin [Abstract]. Diabet Med 23 (Suppl. 4):319, 2006 20Pratley RE, Jauffret-Kamel S, Galbreath (LAF237) with pioglitazone is safe and well tolerated with no pharmacokinetic interaction. Diabetes 10 E, Holmes D: Twelve-week monotherapy with Nauck M, Meininger G, Sheng D, Terranella the DPP-4 inhibitor vildagliptin improves glyce- 54 (Suppl. 1):528–529, 2005 L, Stein P: Efficacy and safety of the dipeptidyl mic control in subjects with type 2 diabetes. Horm 35He YL, Sabo R, Picard F, Wang Y, peptidase-4 inhibitor, sitagliptin, compared to the Metab Res 38:423–428, 2006 Campestini J, Herron J, Ligueros-Saylan M: Lack sulfonylurea, glipizide, in patients with type 2 dia- of pharmacokinetic interaction between vilda- 21Ristic S, Byiers S, Foley J, Holmes D: betes inadequately controlled on metformin alone: gliptin and metformin in patients with type 2 dia- a randomized, double-blind, non-inferiority trial. Improved glycaemic control with dipeptidyl pep- betes. Clin Pharmacol Ther 79:62, 2006 Diabetes Obes Metab 9:194–205, 2007 tidase-4 inhibition in patients with type 2 diabe-

11 tes: vildagliptin (LAF237) dose response. Diabetes Rosenstock J, Brazg R, Andryuk PJ, Lu K, Obes Metab 7:692–698, 2005 Stein P: Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pio- 22Mimori N, Terao S, Holmes D: Vildagliptin John R. White, Jr., PA, PharmD, is a glitazone therapy in patients with type 2 diabetes: improves glucose control as evidenced by HbA1c professor of pharmacotherapy at the a 24 week, multicenter, randomized, double-blind, after 12 weeks therapy in Japanese patients with placebo-controlled, parallel-group study. Clin Ther type 2 diabetes [Abstract]. Diabetes 55 (Suppl. 1): Washington State University College of 28:1556–1568, 2006 Abstract 527-P, 2006 Pharmacy in Spokane.

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