Sitagliptin, an dipeptidyl peptidase-4 inhibitor, does not alter the pharmacokinetics of the sulphonylurea, glyburide, in healthy subjects

Transcription

1 British Journal of Clinical Pharmacology DOI: /j x Sitagliptin, an dipeptidyl peptidase-4 inhibitor, does not alter the pharmacokinetics of the sulphonylurea, glyburide, in healthy subjects Goutam C. Mistry, Arthur J. Bergman, Wei Zheng, David Hreniuk, Miguel A. Zinny, 1 Keith M. Gottesdiener, John A. Wagner, Gary A. Herman & Marcella Ruddy Correspondence Dr Marcella Ruddy, MD, Merck Research Laboratories, Mail Code: BMB-3425, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Tel: Fax: marcella_ruddy@merck.com Keywords DPP-4, glyburide, MK-0431, pharmacokinetics, sitagliptin Received 13 February 2007 Accepted 21 January 2008 Published OnlineEarly 22 May 2008 Merck & Co., Inc., Whitehouse Station, NJ and 1 ProMedica Clinical Research Center, Boston, MA, USA WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT No data are available on the potential drug interaction of sitagliptin and glyburide. Sitagliptin belongs to a new class of drugs called DPP-4 inhibitors recently approved for the treatment of Type 2 diabetes. WHAT THIS STUDY ADDS Glyburide is a commonly used sulphonylurea medication to treat Type 2 diabetes. Combination therapy is often required to achieve adequate glucose control in Type 2 diabetes. Sitagliptin does not appear to interfere with glyburide pharmacokinetics and therefore may be potentially co-administered with glyburide for the treatment of Type 2 diabetes. AIMS Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is an incretin enhancer that is approved for the treatment of Type 2 diabetes. Sitagliptin is mainly renally eliminated and not an inhibitor of CYP450 enzymes in vitro. Glyburide, a sulphonylurea, is an insulin sensitizer and mainly metabolized by CYP2C9. Since both agents may potentially be co-administered, the purpose of this study was to examine the effects of sitagliptin on glyburide pharmacokinetics. METHODS In this open-label, randomized, two-period crossover study, eight healthy normoglycaemic subjects, years old, received single 1.25-mg doses of glyburide alone in one period and co-administered with sitagliptin on day 5 following a multiple-dose regimen for sitagliptin (200-mg q.d. 6 days) in the other period. RESULTS The geometric mean ratios and 90% confidence intervals [(glyburide + sitagliptin)/glyburide] for AUC 0 and C max were 1.09 (0.96, 1.24) and 1.01 (0.84, 1.23), respectively. CONCLUSION Sitagliptin does not alter the pharmacokinetics of glyburide in healthy subjects. 36 / Br J Clin Pharmacol / 66:1 / The Authors Journal compilation 2008 Blackwell Publishing Ltd

2 Lack of PK interaction between sitagliptin and glyburide Introduction Type 2 diabetes mellitus (T2DM) afflicts an estimated 6% of the adult population in Western society and over 2% worldwide. The worldwide prevalence of T2DM is increasing and expected to grow from 171 million cases in 2000 to 336 million cases worldwide by 2030 [1]. Shortcomings of current therapies include inadequate efficacy in glucose lowering and limited durability of glycaemic response with monotherapy [2]. For these reasons, not only are new medications needed for the treatment of T2DM, but combination therapy with two or more antihyperglycaemic agents is likely to be required to achieve adequate glucose control [3]. Sitagliptin is a oral, potent and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor, a new class of drug developed for the treatment of T2DM [4]. As is commonly seen with other antihyperglycaemic agents, it is anticipated that a subset of patients that have inadequate glycaemic control will benefit from combination therapy with DPP-4 inhibitors and sulphonylurea (SFU) class of oral antihyperglycaemic agents. Understanding potential drug drug interactions of this combination in healthy volunteers was explored in this present study prior to undertaking combination therapy studies in diabetics. The clinical dose of sitagliptin used to treat T2DM is 100 mg once daily [4]. DPP-4 inhibitors, such as sitagliptin, work by enhancing incretin function. Incretins such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are gut hormones that stimulate insulin production and release and suppress glucagon release in a glucose-dependent manner [5 7]. DPP-4 inhibitors enhance duration of incretin action, inhibiting the enzymatic degradation of these incretins. Sitagliptin inhibits plasma DPP-4 activity, elevates active GLP-1 and GIP levels, and reduces glucagon and glycaemic excursion following an oral glucose tolerance test [8]. Previous clinical studies have demonstrated that steady-state trough concentrations are generally attained within 3 days after initiation of drug administration. The apparent terminal half-life upon multiple dosing ranges from 11.8 to 14.4 h [9]. Sitagliptin is renally excreted, with metabolism of the drug playing a minor role in its excretion. Approximately 80% of drug is eliminated as unchanged compound in the urine [10]. The CYP3A4 isozyme is responsible for limited oxidative metabolism of sitagliptin with some minor contribution also from CYP2C8 [10]. Glyburide (glibenclamide) is a second-generation oral SFU drug that is commonly used in the treatment of T2DM (reviewed by Rendell [11]).The starting dose of glyburide is 1.25 mg,which is titrated to achieve optimal glycaemic control.it has been demonstrated to stimulate insulin secretion by b-cells (reviewed by Krentz and Bailey [12]). Glyburide, like other SFU drugs,however,is extensively metabolized by the liver via mainly CYP2C9 [13] with metabolites excreted in both the urine and bile. In vitro studies suggest that metabolism may also occur to a lesser extent via CYP2C19 and/or CYP3A4 [14]. The two major metabolites of glyburide, a 3-cis-hydroxy and a 4-trans-hydroxy derivative, have minimal pharmacodynamic activity. Since glyburide and sitagliptin have different and potentially complementary mechanisms of actions, and their major elimination pathways differ, use of these drugs in combination therapy could be considered in the treatment of patients with T2DM.The purpose of this study was to investigate whether sitagliptin would meaningfully affect the pharmacokinetics of glyburide as an initial assessment of whether this combination would be potentially possible. Although in vitro, sitagliptin does not appear to be a potent inhibitor of CYP enzymes (IC 50 >100 mm for CYP 3A4, 2C8, 2C9, 2D6, 2C19 or 2B6) [15], this study was conducted to ensure that there would be no clinically meaningful effect on glyburide pharmacokinetics given that glyburide s elimination is dependent upon metabolism via CYP 2C9. This open-label, two-period, crossover study was designed to measure the effect of steady-state concentrations of sitagliptin (achieved by 5 days of once-daily dosing) on the single-dose pharmacokinetics of glyburide in healthy subjects. No effect of glyburide on sitagliptin pharmacokinetics was expected, since glyburide is not expected to alter the renal clearance of sitagliptin and therefore the effect of glyburide on sitagliptin was not assessed in this study. Glyburide is a probe CYP2C9 substrate, therefore this study also assessed the potential inhibitory effects of sitagliptin on CYP2C9-mediated elimination. Furthermore, an additional objective was to assess the safety and tolerability of the co-administration of glyburide and sitagliptin. Methods Subjects The study was conducted in nine healthy normoglycaemic (nondiabetic) male and female subjects of nonreproductive potential, years of age, weighing approximately kg. Prior to the start of dosing, the subjects had normoglycaemic levels, an estimated creatinine clearance of 80 ml min -1, did not have history of Type 2 diabetes, and were considered generally in good health, assessed on the basis of medical history, physical examination including vital signs, 12-lead electrocardiogram (ECG) and routine laboratory tests (haematology/blood chemistry/ urinalysis). Furthermore, unless allowed by the investigator for minor ailments, the subjects were not permitted to take any prescription or nonprescription medications within 14 days of the start of dosing and throughout the study. In particular, the subjects were explicitly instructed not to take herbal remedies such as St John s Wort, oral hypoglycaemic agents, oral or parenteral contraceptives, and drugs with inhibitory or inductive potential on CYP3A4, CYP2C9 or CYP2C19. Br J Clin Pharmacol / 66:1 / 37

3 G. C. Mistry et al. Study design This was a randomized, open-label, two-period, crossover study. Subjects received single 1.25-mg doses of glyburide alone in one period and, in the other period, sitagliptin 200 mg once daily for 6 days with the glyburide dose also co-administered with sitagliptin on day 5. Administration of study drug was witnessed by the medical staff at the clinical research unit, and glyburide was administered at the same clock time in both periods. During both treatment regimens on days when glyburide was administered, the subjects remained in the clinical research unit until completion of the 24-h postdose study procedures. Since glyburide should be taken with food, a standardized breakfast, which was the same for each subject, was provided in both periods when glyburide was administered to control for potential effects on pharmacokinetics. Food has been demonstrated not to have a meaningful effect on sitagliptin pharmacokinetics [16]. Both periods were separated by a wash-out interval of at least 7 days before the subjects crossed over to the other treatment regimen. Safety assessments included a physical examination, 12-lead ECG, vital signs at rest (systolic/diastolic blood pressure, pulse rate, respiratory rate, body temperature) and routine laboratory tests (haematology/blood chemistry/urinalysis), which were performed at prestudy (screening), predose of the first dose (day 1) in the first period only (12-lead ECG and laboratory safety tests only), 4 h postdose (vital signs only in the glyburide alone period; vital signs and 12-lead ECG on day 5 of the co-administration period), 24 h postdose in glyburide alone period and day 5 of the co-administration period (except 12-lead ECG), and vital signs were only collected at 48 h postdose in the glyburide alone period and day 5 of the co-administration period. These safety evaluations were also repeated at the poststudy visit, which occurred approximately 14 days after administration of the last dose of study drug. Glucometer measurements were conducted to monitor for signs and symptoms of hypoglycaemia at predose and at specified time points up to 24 h postdose in the glyburide alone period and on day 5 of the co-administration period. Clinical adverse experiences were also monitored throughout the study from the prestudy (screening) to poststudy visit. This study was conducted at ProMedica Clinical Research Center according to the provisions of the Declaration of Helsinki, and written informed consent was obtained from each subject prior to conducting any protocol-related procedure. The study was approved by the independent institutional review committee Western Institutional Review Board. Pharmacokinetic assessments Blood samples for glyburide assay were collected at the following time points over a 48-h period after glyburide was administered alone and on day 5 of the co-administration period: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 15, 18, 24 and 48 h. At each collection, 7 ml of blood were drawn into one ethylenediamine tetraaceticacid (spray-dried) lavender top Vacutainer tube.the tubes were placed on ice or refrigerated immediately after collection and then centrifuged at 3000 r.p.m. for 15 min at 4 C. The plasma was than transferred to 4.5-ml polypropylene NUNC tubes and stored in a freezer at -20 C until analysis. The NUNC tubes were sent to PPD Development (Morrisville, NC, USA) on dry ice for drug assay. Plasma samples were assayed for glyburide using high-performance liquid chromatography (90 : 10 methanol : 10 nm ammonium acetate mobile phase and hypersil BDS C mm 3 mm particle size analytical column) with tandem mass spectroscopy (MS/MS) detection (glyburide-d11 internal standard). Liquid-liquid extraction was performed with 30 : 70 ethyl acetate:hexane. The lower limit of quantification for glyburide was ng ml -1 with a coefficient of variation (CV) of 7.47% and an assay linear calibration range of ng ml -1. The CV ranged from 2.48 to 8.09% during the conduct of the assays. The software used to integrate the chromatograms was Sciex Analyst 1.2 (PPD Development). Plasma concentrations and actual sampling times relative to dose were used to determine pharmacokinetic parameters (with the exception of T max) for each subject. The onset of the apparent terminal log-linear portions of the individual plasma concentration time profiles was determined by inspection.the apparent terminal rate constant (l) was estimated by regression of the terminal loglinear portion of the plasma concentration time profile;t 1/2 was calculated as the quotient of ln2 and l. AUC to the last time point was calculated using the linear trapezoidal method for ascending concentrations and the log trapezoidal method for descending concentrations. AUC 0 was estimated as the sum of AUC to the last measured concentration and the extrapolated area given by the quotient of the last measured concentration and l. C max and T max were obtained by inspection of the plasma concentration data. Provided that the actual observed time of T max did not differ in a meaningful way from the nominal plasma sampling time, nominal plasma sampling times were used to determine T max. Statistical analysis Since efficacy and safety are related to integrated glycaemic control over 24 h (including fasting glucose), overall drug exposure (i.e. AUC) was considered to be the most relevant pharmacokinetic parameter for this study. The single dose glyburide pharmacokinetic parameters (AUC 0, C max, T max and apparent t 1/2) following co-administration of glyburide + sitagliptin relative to glyburide alone were compared. The AUC 0 and C max following a single 1.25-mg dose of glyburide alone or when co-administrated with 200 mg of sitagliptin were analysed using an analysis of variance (ANOVA) model appropriate for a two-period crossover design with the terms sequence, 38 / 66:1 / Br J Clin Pharmacol

4 Lack of PK interaction between sitagliptin and glyburide subject within sequence, period, and treatment. A 90% confidence interval (CI) for the AUC 0 geometric mean ratio (GMR) (glyburide + sitagliptin/glyburide) of glyburide was calculated and then compared against the prespecified comparability bounds of (0.70, 1.43). For evaluation of sitagliptin s effect on glyburide pharmacokinetics, a wider 90% CI of (0.70, 1.43) was chosen for this study, instead of (0.80, 1.25), which is sometimes used in drug interaction studies. The reasoning for the wider 90% CI is as follows. Given the potential for dose-related hypoglycaemia with glyburide, a GMR for AUC 0 (with vs. without sitagliptin) of >1.43 would be considered potentially clinically meaningful, and might warrant dose adjustment, when higher doses of glyburide are used in the clinic for the treatment of T2DM. Similarly, a reduction in plasma glyburide exposure of >30% might warrant a dose increase to maintain an optimal glycaemic lowering effect. The pharmacokinetic parameters T max and apparent t 1/2 following a single 1.25-mg dose of glyburide alone or when co-administered with 200 mg of sitagliptin were also analysed using the same ANOVA model as described above. Prior to statistical analysis, a log transformation was applied to the AUC 0 and C max data; a rank transformation was applied to the T max data and an inverse transformation was applied to the apparent t 1/2 data. The Shapiro Wilk and Levene s test statistics were used to check normality and homogeneous variance for the ANOVA model. For the power calculation, if the true AUC 0 geometric means of glyburide alone vs. that co-administered with sitagliptin were the same (i.e. the true GMR is 1.00), then a sample size of n = 8 subjects in each treatment group provided >99% probability of yielding a 90% CI for the AUC 0 GMR within the interval of (0.70, 1.43). If the true AUC 0 GMR were within the interval of (0.80, 1.26), then this study provided at least 80% power of getting the 90% CI within (0.70, 1.43). Results Demographics Eight of nine healthy normoglycaemic subjects (four male and four female) completed the study. One female subject withdrew consent and discontinued in the first period after receiving a single 200-mg dose of sitagliptin.the subjects in this study had a mean age of 36.5 years (range years), mean weight of 74.5 kg (range kg) and mean height of cm (range cm). Effect of sitagliptin on glyburide pharmacokinetics The mean glyburide plasma concentration time profiles with and without sitagliptin are shown in Figure 1 and the mean pharmacokinetic parameters in Table 1. The Mean glyburide plasma concentration (ng/ml) Figure Time (hrs) Mean plasma concentration time profiles following single oral 1.25-mg doses of glyburide with and without co-administration of multiple 200-mg doses of sitagliptin. Glyburide + Sitagliptin, ( ); Glyburide, ( ) glyburide AUC 0 GMR (glyburide + sitagliptin/glyburide) was 1.09 (Table 1) and the corresponding 90% CI of (0.96, 1.24) was within the prespecified bounds of (0.70, 1.43), indicating that sitagliptin did not alter the plasma pharmacokinetic profile of glyburide. Single-dose administration of glyburide with sitagliptin at steady state did not alter glyburide C max, as indicated by a C max GMR of 1.01 (CI 0.84, 1.23). In addition, co-administration of glyburide with sitagliptin did not cause changes to the T max (P = 0.093) or apparent t 1/2 (P = 0.602) of glyburide. Safety and tolerability Sitagliptin and glyburide were generally well tolerated whether administered alone or co-administered. No serious adverse experiences were reported and no subject discontinued the study due to an adverse experience. Two of the nine subjects reported a total of three nonserious clinical adverse experiences. Of the three adverse experiences, one (anxiety, which was reported after the administration of a single 200-mg dose of sitagliptin) was considered possibly drug related. The other two adverse experiences, upper respiratory infection (diagnosed in the same subject who reported the anxiety) and lightheadedness (in another subject), were considered as probably not drug related by the investigator. The lightheadedness was reported after the subject received sitagliptin 200 mg q.d. for 4 days. All of the adverse experiences were transient and judged to be mild in intensity, and no moderate or severe adverse experience was reported. No laboratory adverse experiences, including hypoglycaemia, or treatment-related clinically meaningful deviations in physical examinations, vital signs or ECG parameters occurred during the study Br J Clin Pharmacol / 66:1 / 39

5 G. C. Mistry et al. Table 1 Mean glyburide pharmacokinetic parameters following single 1.25-mg doses of glyburide with or without co-administration of multiple 200-mg doses of sitagliptin Pharmacokinetic parameter (n = 8) Glyburide + sitagliptin, geometric mean Glyburide, geometric mean Glyburide + sitagliptin/glyburide GMR (90% CI) AUC 0- (ng h -1 ml -1 ) (0.96, 1.24) C max (ng ml -1 ) (0.84, 1.23) T max (h) Apparent t 1/2 (h) Median. Harmonic mean. Between-treatment P-value. GMR, geometric mean ratio (glyburide + sitagliptin/glyburide); CI, confidence interval. Discussion Novel antihyperglycaemic therapies with distinct mechanisms of action may prove beneficial over currently available regimens either as monotherapy or combination. Sitagliptin belongs to a new class of oral antihyperglycaemic agents known as DPP-4 inhibitors. Sitagliptin is in clinical development for the treatment of patients with T2DM and has been demonstrated to be safe, well tolerated and efficacious in a number of clinical trials when administered alone or in combination therapy [17 20]. Since SFU agents are amongst the most commonly prescribed class of medications used to treat T2DM, it is important to understand whether sitagliptin could be combined with these agents for improved glycaemic control. SFUs have the potential to cause hypoglycaemia if not dosed appropriately; therefore, a potential pharmacokinetic effect of sitagliptin on SFU was considered an important question to explore in healthy volunteers, prior to combination treatment in patients. Although both glyburide and sitagliptin target the b-cell to increase insulin secretion, they do so through different pathways, making the combination of these agents potentially valuable to patients. Sitagliptin also has additional glucose-lowering mechanisms which may further synergize with glyburide s glucose-lowering effects. SFU agents increase insulin secretion in a nonglucosedependent fashion, thus, a drug drug interaction that lead to higher glyburide concentrations could result in hypoglycaemia in a patient with previously stable glycaemic control. Although it is known that sitagliptin has no meaningful effect on the cytochromes involved in the clearance pathways of SFU agents (e.g. cytochrome P450 2C9), making a pharmacokinetic interaction unlikely, clinically demonstrating the predicted lack of effect is important given that potential combination therapy may be desired for certain patients. Furthermore, it is also important to demonstrate that the co-administration of both agents is safe and generally well tolerated. This study was therefore designed to explore whether sitagliptin would have any effects on glyburide pharmacokinetics. Glyburide was the SFU chosen because it is a commonly prescribed agent.a dose of 200 mg sitagliptin,twice the clinical dose, was chosen to maximize the sensitivity for detecting an effect on glyburide pharmacokinetics. The starting 1.25-mg dose of glyburide was chosen to lower the risk of hypoglycaemia. In this study, glyburide also served as a probe substrate for CYP2C9 metabolism, since previous studies have demonstrated that inhibition of CYP2C9-mediated metabolism of glyburide alters glyburide pharmacokinetics in vivo [13, 14]. Therefore, in addition to assessing changes in the pharmacokinetics of glyburide specifically, the study also provided important information on the potential for sitagliptin to alter the pharmacokinetics of other medications cleared through CYP2C9-mediated metabolism. Although not measured in the current study, the steady-state concentration of the 200-mg dose of sitagliptin after multiple dosing has been found to be approximately 8.5 mmol l -1 h -1 [9]. In this study, steady-state concentrations of sitagliptin (obtained after 5 days of administration of once-daily dosing) had no clinically meaningful effect on the pharmacokinetics of a single dose of glyburide.the AUC 0 GMR (glyburide + sitagliptin/ glyburide) was 1.09 with a corresponding 90% CI of (0.96, 1.24), which was contained within the prespecified bounds of (0.70, 1.43) and supported the study s primary hypothesis. The C max GMR (glyburide + sitagliptin/glyburide) was 1.01 with a corresponding 90% CI of (0.84, 1.23). In addition, T max and apparent t 1/2 were generally similar across treatments and there were no statistically significant differences between treatments. These results are in agreement with the finding that sitagliptin was not a potent inhibitor of CYP enzymes in vitro (IC 50 >100 mm for CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6) [15]. Thus, the results of this study confirm that sitagliptin was not a potent inhibitor of CYP2C9 metabolism in vivo. In separate clinical studies, sitagliptin has also been found not to be an inhibitor of CYP3A4 in vivo [21] and not a potent inhibitor of CYP2C8 in vivo [22], which supported the in vitro data [15]. Taken together, the results suggest that sitagliptin does not meaningfully alter the pharmacokinetics of the CYP2C9 substrate, glyburide, and hence no dosage adjustment for glyburide would be necessary. This study was performed in healthy volunteers and was not designed to evaluate the glucose-lowering efficacy of the 40 / 66:1 / Br J Clin Pharmacol

6 Lack of PK interaction between sitagliptin and glyburide combination of sitagliptin and glyburide. Although the utility of such an analysis may be of limited value in healthy subjects, such an analysis in diabetic patients would be more clinically meaningful. No hypoglycaemia was observed in the current study, which included only a small sample size of eight nondiabetic healthy subjects with normal insulin responses. Subsequently, in a large clinical trial, sitagliptin was demonstrated to improve glycaemic control and be generally well-tolerated when added to on-going SFU-based therapy, without evidence of hypoglycaemia [23]. The data from this study demonstrate that sitagliptin had no effect on this CYP2C9-metabolized drug, and therefore it appears that sitagliptin would be unlikely to have an effect on pharmacokinetics of other drugs primarily metabolized by this pathway. For example, glipizide, another SFU agent, is also primarily metabolized by CYP2C9 [11], and thus sitagliptin would not be expected to alter the pharmacokinetic profile of this drug. In addition, data from the current study support the conclusion that drugs that are predominantly metabolized by CYP2C9 such as losartan, irbesartan, tolbutamide, phenytoin and others (reviewed by Brockmoller et al. [24]) could be co-administered with sitagliptin without warranting any dose adjustment. Multiple-dose administration of sitagliptin with a single dose of glyburide was also generally well tolerated in our healthy subjects. There were no serious adverse experiences or laboratory adverse experiences, and all nonserious clinical adverse experiences were transient and mild in intensity and did not require dose interruption or adjustment. In summary, steady-state concentrations of sitagliptin had no clinically meaningful effect on the pharmacokinetics of a single dose of glyburide in healthy adult subjects, suggesting that it would be unlikely to alter glyburide pharmacokinetics in patients treated with this combination therapy and that it would be unlikely that sitagliptin would effect the pharmacokinetics of other medications metabolized primarily by the CYP 2C9 pathway. Competing interests GCM, AJB, WZ, KMG, JAW, GAH, MR are all employees of Merck & Co, Inc., and hold stock in the company. This study was funded by Merck & Co., Inc. REFERENCES 1 Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for Diabetes Care 2004; 27: Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 2002; 287: Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA 1999; 281: Merck & Inc. JANUVIA (Sitagliptin Phosphate) [Product Circular]. Whitehouse Station, NJ: Merck & Co., Inc., Ahren B, Landin-Olsson M, Jansson PA, Svensson M, Holmes D, Schweizer A. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. J Clin Endocrinol Metab 2004; 89: Ahren B, Simonsson E, Larsson H, Landin-Olsson M, Torgeirsson H, Jansson PA, Sandqvist M, Bavenholm P, Efendic S, Eriksson JW, Dickinson S, Holmes D. Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in type 2 diabetes. Diabetes Care 2002; 25: Ahren B, Gomis R, Standl E, Mills D, Schweizer A. Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. Diabetes Care 2004; 27: Herman GA, Bergman A, Stevens C, Kotey P, Yi B, Zhao P, Dietrich B, Golor G, Schrodter A, Keymeulen B, Lasseter KC, Kipnes MS, Snyder K, Hilliard D, Tanen M, Cilissen C, De Smet M, de Lepeleire I, Van Dyck K, Wang AQ, Zeng W, Davies MJ, Tanaka W, Holst JJ, Deacon CF, Gottesdiener KM, Wagner JA. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels following an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab 2006; 91: Bergman AJ, Stevens C, Zhou Y, Yi B, Laethem M, De Smet M, Snyder K, Hilliard D, Tanaka W, Zeng W, Tanen M, Wang AQ, Chen L, Winchell G, Davies MJ, Ramael S, Wagner JA, Herman GA. Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-iv inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers. Clin Ther 2006; 28: Vincent SH, Reed JR, Bergman AJ, Elmore CS, Zhu B, Xu S, Ebel D, Larson P, Zeng W, Chen L, Dilzer S, Lasseter K, Gottesdiener K, Wagner JA, Herman GA. Metabolism and excretion of the dipeptidyl peptidase inhibitor [14C]sitagliptin in humans. Drug Metab Dispos 2007; 35: Rendell M. The role of sulphonylureas in the management of type 2 diabetes mellitus. Drugs 2004; 64: Krentz AJ, Bailey CJ. Oral antidiabetic agents current role in type 2 diabetes mellitus. Drugs 2005; 65: Kirchheiner J, Brockmoller J, Meineke I, Bauer S, Rohde W, Meisel C, Roots I. Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers. Clin Pharmacol Ther 2002; 71: Br J Clin Pharmacol / 66:1 / 41

7 G. C. Mistry et al. 14 van Giersbergen PL, Treiber A, Clozel M, Bodin F, Dingemanse J. In vivo and in vitro studies exploring the pharmacokinetic interaction between bosentan, a dual endothelin receptor antagonist, and glyburide. Clin Pharmacol Ther 2002; 71: Herman G, Bergman A, Wagner JA. Sitagliptin, a DPP-4 Inhibitor: an Overview of the Pharmacokinetic (PK) Profile and the Propensity for Drug Drug Interactions (DDI). Abstract. 42nd Annual Meeting of the European Association for the Study of Diabetes, September 14 17, Herman GA, Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M, Snyder K, Hilliard D, Tanen M, Tanaka W, Wang AQ, Zeng W, Musson D, Winchell G, Davies MJ, Ramael S, Gottesdiener KM, Wagner JA. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther 2005; 78: Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H;Sitagliptin Study 023 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia 2006; 49: Charbonnel B, Karasik A, Liu J, Wu M, Meininger G;Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled on metformin alone. Diabetes Care 2006; 29: Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P;Sitagliptin Study 019 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther 2006; 28: Aschner P, Kipnes M, Lunceford J, Sanchez M, Mickel C, Williams-Herman DE;Sitagliptin 021 Group. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care 2006; 29: Bergman AJ, Cote J, Maes A, Zhao J, Roadcap B, Sun L, Valesky R, Yang A, Keymeulen B, De Smet M, Laethem T, Wagner J, Herman G. Sitagliptin (MK- 0431), a selective dipeptidyl-peptidase-iv (DPP-IV) inhibitor, does not affect the pharmacokinetics of simvastatin in humans. Clin Pharm Ther 2006; 79 (2 Suppl.): S Mistry GC, Bergman AJ, Luo WL, Cilissen C, Haazen W, Davies MJ, Gottesdiener KM, Wagner JA, Herman GA. Multiple-dose administration of sitagliptin, a dipeptidyl peptidase-4 inhibitor, does not alter the single-dose pharmacokinetics of rosiglitazone in healthy subjects. J Clin Pharmacol 2007; 47: Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P; for the Sitagliptin Study 035 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab 2007; 9: Brockmoller J, Kirchheiner J, Meisel C, Roots I. Pharmacogenetic diagnostics of cytochrome P450 polymorphisms in clinical drug development and in drug treatment. Pharmacogenomics 2000; 1: / 66:1 / Br J Clin Pharmacol