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Drug Evaluation

Vildagliptin, a DPP-4 inhibitor for the twice-daily treatment of type 2 diabetes mellitus with or without metformin

1.

Introduction

2.

Vildagliptin

3.

Clinical efficacy

Thomas Forst† & Peter Bramlage

4.

Safety and tolerability



5.

Regulatory affairs

6.

Conclusion

7.

Expert opinion

Profil Institut Mainz, Mainz, Germany

Introduction: Dipeptidyl peptidase-4 inhibitors increase circulating levels of glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide regulating glucose-dependent insulin secretion. In addition, GLP-1 suppresses glucagon secretion, delays gastric emptying and increases satiety. The combination of vildagliptin with the biguanide metformin is of particular interest because of its complementary mode of action, addressing insulin resistance, alpha- and beta cell function in the islet of the pancreas. Areas covered: Because of the abundance of data supporting the use of vildagliptin alone and in combination with metformin, the present paper aims at giving an overview on the current evidence for its use in patients with type 2 diabetes mellitus. Expert opinion: The data suggest that vildagliptin offers similar glycemic control compared to sulfonylureas and thiazolidinediones, while having the benefit of being associated with fewer cases of hypoglycemia and less body weight gain. There is increasing evidence that compared with sulfonylureas, vildagliptin has favorable effects on pancreatic alpha- and beta-cell function. Vildagliptin in combination with metformin, improve glycemic control with a favorable safety and tolerability profile, making it an attractive therapeutic option in patients where metformin monotherapy alone is not sufficient. Keywords: dipeptidyl peptidase-4 inhibitors, metformin, type-2 diabetes, vildagliptin Expert Opin. Pharmacother. (2014) 15(9):1299-1313

1.

Introduction

Estimates from the World Health Organization suggest that 347 million individuals worldwide have diabetes mellitus, and 90% of these cases are type 2 diabetes mellitus (T2DM). In 2004, hyperglycemia-related mortality occurred in ~ 3.4 million individuals, and projections indicate that diabetes will be the seventh leading cause of death in 2030 [1]. The high incidence of T2DM is linked to lifestyle factors, particularly a lack of exercise and high-fat, high-sugar diets. Therefore, guidelines for the treatment of T2DM recommend that exercise and diet modification should be considered as an initial measure for disease control [2,3]. If life interventions alone do not result in attainment of blood glucose targets, the addition of pharmacological treatment is advocated. Standard-of-care first-line drug therapy for T2DM is metformin, but for individuals in whom metformin is contraindicated or intolerable, other oral antidiabetic agents may be prescribed. Currently available oral antidiabetic drugs include sulfonylureas, thiazolidinediones, a-glucosidase inhibitors, sodium-dependent glucose transporter 2 and dipeptidyl peptidase (DPP)-4 inhibitors. In the case that first-line therapy fails, treatment intensification is recommended, with the addition of second- and third-line agents. Dual therapy comprises the use of two oral antidiabetic agents, whereas triple therapy may 10.1517/14656566.2014.920009 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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T. Forst & P. Bramlage

Box 1. Drug summary.

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Drug name Phase Indication Pharmacology description Route of administration Chemical structure Pivotal trial(s)

Vildagliptin Approved in Europe, Japan and countries in Africa, Latin America and the Asia-Pacific region Type 2 diabetes mellitus Peptidomimetic dipeptidyl peptidase 4 inhibitor Oral See Table 1 Vildagliptin monotherapy in treatment-naive patients with type 2 diabetes mellitus (T2DM). Efficacy, safety and tolerability of vildagliptin (50 mg once a day [q.d.], 50 md two-times a day [b.i.d.], 100 mg q.d.) versus placebo over 24 weeks Vildagliptin as an add-on to glimepiride in patients with inadequately controlled T2DM. Efficacy, safety and tolerability of vildagliptin (50 mg po, q.d. or b.i.d.) plus glimepiride (4 mg po, q.d.) over 24 weeks Vildagliptin as an add-on to pioglitazone in patients with inadequately controlled T2DM. Efficacy, safety and tolerability of vildagliptin (50 mg po, q.d. or b.i.d.) plus pioglitazone (45 mg po, q.d.) over 24 weeks Vildagliptin as an add-on to metformin versus vildagliptin or metformin alone in treatment-naı¨ve patients with T2DM. Efficacy, safety and tolerability of vildagliptin (50 mg po, b.i.d.) plus metformin (1000 mg po, b.i.d.) compared with vildagliptin or metformin alone over 24 weeks Vildagliptin compared with glimepiride as an add-on to metformin in patients with inadequately controlled T2DM. Efficacy, safety and tolerability of vildagliptin (50 mg po, b.i.d.) plus metformin versus glimepiride (up to 6 mg/day) plus metformin over 2 years

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include different combinations of oral antidiabetic agents, insulin and the subcutaneously administered glucagon-like peptide (GLP)-1 analogs. Because cardiovascular disease is estimated to be the cause of ~ 60% of deaths in patients with T2DM, treatment strategies should also help to prevent microvascular and macrovascular complications [4]. Both DPP-4 inhibitors and GLP-1 analogs target the incretin system, and these two classes of drug represent some new additions to the therapeutic armamentarium for T2DM [5]. The principle that underlies the development of incretin-based drugs is the importance of the incretin hormone GLP-1 in regulating glucose-dependent stimulation of insulin secretion. In addition, GLP-1 suppresses glucagon secretion, delays gastric emptying and increases satiety [6]. A recent study revealed that the combination of either glimepiride or a DPP-4 inhibitor with metformin improved postprandial glucose control; however, in contrast to glimepiride, the DPP-4 inhibitor reduced postprandial secretion of glucagon and improved b-cell function as indicated by a decrease in the proinsulin/insulin ratio [7]. Proof of concept for targeting GLP-1 was demonstrated by continuous subcutaneous infusion of recombinant GLP-1 to patients with T2DM [8]. However, GLP-1 is a labile peptide and it is rapidly degraded in plasma because of cleavage by the serine protease DPP-4. Current approaches for incretin-based therapies consist of DPP-4-resistant GLP-1 receptor agonists and DPP-4 inhibitors, both of which circumvent the problem of rapid in vivo GLP-1 degradation, leading to increased plasma concentrations of GLP-1 [6,9]. The first DPP-4 inhibitor to be approved by regulatory authorities was sitagliptin, which became available for 1300

commercial use in 2006 [10]. Subsequently, other DPP-4 inhibitors have been successfully developed, including the focus of this review, vildagliptin (Box 1) (LAF-237, DPP-278, Galvus; Novartis Pharma AG, Basel, Switzerland), which is an orally available, small-molecule, competitive reversible DPP-4 inhibitor for the treatment of T2DM [11,12]. Vildagliptin is available as a 50 mg tablet either alone or in fixed-dose combination with two different doses of metformin. This review aims to give a comprehensive overview about the available preparations of vildagliptin to date. For that purpose, a PubMed search was performed on 4 March 2014 using the search term ‘vildagliptin’ and 529 articles were found. Of these, 115 articles were on preclinical experimental studies, 167 were reviews and 99 reported results from randomized controlled trials. Although reviews have been published on the topic in 2011 [13] and 2012 [14], this review appears timely because of the abundance of data published since then. 2.

Vildagliptin

Chemistry Vildagliptin, 1-[[(3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano(S)-pyrrolidine, is an N-substituted-glycyl-2-cyanopyrrolidine (Table 1) [11]. Similar to saxagliptin, vildagliptin is a nitrilecontaining compound that was designed to mimic the dipeptide structure of physiological DPP-4 substrates [11,15]. X-ray crystallography demonstrated that vildagliptin interacts with the core S1 and S2 subsites of DPP-4 and forms a covalent bond with the serine residue at position 630 [15]. This 2.1

Expert Opin. Pharmacother. (2014) 15(9)

Vildagliptin

Table 1. Chemical structures of vildagliptin and metformin.

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Vildagliptin

Trade name Bioavailability Protein binding Metabolism Half-life Excretion

Galvus 85% 9.3% Mainly hydrolysis, no CYP 2 -- 3 h Renal

Metformin

Glucophage 50 -- 60% Minimal No CYP 4 -- 8.7 h Renal 90%

mode of binding was shared by saxagliptin, whereas alogliptin, sitagliptin, linagliptin and teneligliptin interacted with the core subsites of the protease, as well as with the S1¢, S2¢ or S2 extensive subsites. These additional interactions are more effective than the covalent bond formed by vildagliptin and saxagliptin, and are expected to result in greater inhibition of DPP-4 activity [15]. In accordance with the binding study, vildagliptin has been demonstrated to inhibit DPP-4 activity with an IC50 value of 62 nM compared with IC50 values of 50, 24, 19 and 1 nM for saxagliptin, alogliptin, sitagliptin and linagliptin, respectively; however, the maximum effect on suppression of DPP-4 activity was similar for all five compounds [16]. With regard to selectivity for DPP-4, vildagliptin exhibits a Ki value of 3 nM for DPP-4 relative to 810 nM for DPP-8 and 95 nM for DPP-9 [17].

Pharmacodynamics In vivo studies in fat-fed Sprague--Dawley rats and Zucker fatty rats indicated that vildagliptin (3 mg/kg po, maximum effect dose) produced > 90% inhibition of DPP-4 activity within 15 min postdose [17]. In patients with T2DM, vildagliptin (10 -- 100 mg po, single dose or two-times a day (b.i.d.) for 28 days) inhibited DPP-4 activity by > 90% at 45 min postdose for all dose levels tested, but the mean residence time of DPP-4 inhibition over a 24 h period varied in a dose-dependent manner (10 -- 12 h across the dose range tested) [18]. An assessment of the effects of vildagliptin (100 mg po, once a day (q.d.) for 28 days) following administration to patients with T2DM in either the morning or the evening indicated that regardless of the time of dosing, vildagliptin inhibited DPP-4 activity by ‡ 90% during the first 5.5 h postdose, by ‡ 80% at up to 15.5 h postdose and by ‡ 45% at up to 24 h postdose [19]. A recently published, open-label, crossover clinical trial demonstrated that in patients with T2DM, trough levels of DPP-4 inhibition were significantly greater with either twice-daily vildagliptin 2.2

(50 mg) or once-daily sitagliptin (100 mg) compared with once-daily saxagliptin (5 mg) [20]. Pharmacokinetics and metabolism Pharmacokinetic evaluation in healthy individuals and patients with T2DM demonstrated that vildagliptin is rapidly absorbed, with plasma drug concentrations increasing in an approximately dose-proportional manner [18,21,22]. In patients with T2DM, twice-daily administration of vildagliptin at doses of 10, 25 and 100 mg for 28 days yielded a Cmax of 58, 152 and 515 ng/ml, respectively, an area under the plasma concentration--time curve for the dosage interval (AUC0 -- tau) of 119, 529 and 1868 ng.h/ml, respectively, a Tmax of approximately 1 h for all three doses levels and a t1/2 of 1.32, 2.26 and 2.43 h, respectively [18]. The estimated oral bioavailability of vildagliptin is 85% [23], and coadministration with food does not have a clinically relevant impact on the drug’s pharmacokinetic profile [21]. Vildagliptin is metabolized in a CYP-independent manner in humans, which limits the potential for drug--drug interactions. Metabolism of the drug occurs via at least four pathways and leads to the formation of a major metabolite (M20.7) and four minor metabolites (M15.3, M20.2, M20.9 and M21.6). In plasma, the parent molecule and the major metabolite, which is a pharmacologically inactive carboxylic compound, comprise 26 and 55%, respectively, of the total plasma exposure. Vildagliptin is primarily excreted via the kidneys, with 23 and 50% of the total dose of vildagliptin being recovered in the urine as unchanged drug and the major metabolite, respectively. Elimination of vildagliptin and the major metabolite requires the combination of active transport and glomerular filtration [22]. 2.3

Combination therapy As expected from metabolic studies, vildagliptin does not display relevant pharmacokinetic interactions with other medications that are commonly co-prescribed to patients with T2DM. Vildagliptin can be administered, without the need for dose adjustment, in combination with the antihyperglycemic agents metformin [22], glyburide and pioglitazone [24], the statin simvastatin [25], the antihypertensive agents amlodipine, valsartan and ramipril [26], the anticoagulant warfarin [27] and the cardiac glycoside digoxin [28]. The potential for pharmacokinetic interactions between vildagliptin and glimepiride does not appear to have been evaluated [29]. Using a combination of vildagliptin with metformin that is of particular interest in this respect, patients benefit from a complementary mechanism of action [30]. Both drugs share the same time schedule of administration and a similar time to peak effect (Tmax » 2.5 h) [22,31]. Metformin is able to increase plasma active GLP-1 in obese nondiabetic subjects [32]. The mechanism of action is however largely unknown, and an acute DPP-4 inhibitor action and enhanced L-cell hormone secretion has been suggested [33,34]. In addition, an increase in plasma GLP-1 levels is more pronounced in patients receiving vildagliptin in combination with metformin 2.4

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T. Forst & P. Bramlage

than in patients receiving vildagliptin alone [22,31,35]. In addition, vildagliptin, which has been shown to have a positive impact on pancreatic beta cell mass and function in experimental [36] and clinical studies [37], in combination with metformin had a beneficial effect on b-cell function in patients (n = 171) with T2DM [38,39]. As assessed using homeostatic model assessment indices, vildagliptin plus metformin reduced insulin resistance and enhanced b-cell function (p < 0.05 compared with placebo plus metformin for both indices) [38,39]. The vildagliptin--metformin combination also reduced levels of the adipocytokines resistin, retinalbinding protein 4 and chemerin [40]. Compared with glimepiride, vildagliptin in combination with metformin increased the rate of postprandial conversion of intact proinsulin, thereby indicating the stimulation of a physiological pathway in insulin release from the b-cell [41]. 3.

Clinical efficacy

To date, the clinical trials program for vildagliptin has included over 15,000 patients with T2DM [42]. The ClinicalTrials.gov website indicates that over 70 Phase III clinical trials of vildagliptin have been conducted, and, at the time of publication, several Phase IV clinical trials were ongoing. The following section provides an overview of data from some of the Phase III clinical trials that led to the approval of vildagliptin (Tables 2 and 3) and those currently ongoing (Table 4). Phase III evaluation of vildagliptin included several doubleblind, randomized, multicenter, 24-week clinical trials. Vildagliptin was assessed as a monotherapy in placebo- and active-controlled trials, as dual therapy in combination with other antihyperglycemic agents, including metformin, insulin, the sulfonylureas glimepiride and gliclazide, and the thiazolidinedione pioglitazone, and as initial dual therapy in combination with agents such as pioglitazone [43-49]. Unless stated otherwise, the data discussed below on changes in HbA1c and glucose levels are taken from the 24-week time point for each trial. Vildagliptin alone There are a total of three randomized, controlled, doubleblind trials comparing vildagliptin with placebo and a sample size of ‡ 100 patients (Table 2) [43,50,51]. The largest clinical trial evaluated vildagliptin monotherapy (50 mg q.d., 50 mg b.i.d. or 100 mg q.d.) in treatment-naive patients (n = 632) with T2DM [43]. The 50-mg once-daily, 50-mg twice-daily and 100-mg once-daily dose levels of vildagliptin yielded placebo-corrected mean decreases in HbA1c levels of 0.5, 0.5 and 0.6%, respectively (p = 0.006, 0.006 and 0.001, respectively, compared with placebo). Reductions from baseline in fasting plasma glucose levels were 1.0, 0.8 and 0.8 mmol/l for the three respective dose levels (p = 0.021, 0.093 and 0.058, respectively, compared with placebo). With regard to fasting lipid parameters, the only significant change was observed in the 50-mg twice-daily dose group, 3.1

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with a 4.5% reduction in total cholesterol levels (p = 0.048 compared with placebo) [43]. Vildagliptin in combination with sulfonylureas and thiazolidinediones

3.2

The efficacy of two different dosages of vildagliptin (50 mg po, q.d. or b.i.d.) as an add-on to glimepiride (4 mg po, q.d.) was evaluated in a placebo-controlled clinical trial in patients (n = 515) with T2DM and inadequate glycemic control. Both dose levels of vildagliptin produced a significant placebo-corrected reduction in HbA1C levels (0.6 and 0.7% for the two respective dose levels; p < 0.001 compared with placebo). No significant differences in fasting plasma glucose levels were observed for the two vildagliptin doses relative to placebo [52]. The effects of the same two dosages of vildagliptin (50 mg po, q.d. or b.i.d.) were investigated as an add-on to pioglitazone (45 mg po, q.d.) in patients (n = 463) with T2DM and inadequate glycemic control. In both vildagliptin groups, the placebo-corrected mean decrease from baseline in HbA1C was 0.7% (p < 0.001 vs placebo). The effect of the two dose levels of vildagliptin on fasting plasma glucose levels was not significantly different from that of placebo [53]. Vildagliptin in combination with metformin There are a total of ten randomized, controlled, double-blind trials comparing vildagliptin with placebo or any other antihyperglycemic agent on top of metformin and a sample size ‡ 100 patients (Table 3) [44-47,54-59]. Dual therapy comprising vildagliptin (50 mg po, b.i.d.) plus metformin (1000 mg po, b.i.d.) was compared with vildagliptin or metformin alone in treatment-naive patients (n = 1179) with T2DM [44]. The mean decrease from baseline in HbA1C levels was 1.8% for vildagliptin plus metformin compared with 1.1 and 1.4% for vildagliptin and metformin alone, respectively (p < 0.001 for vildagliptin plus metformin vs either monotherapy). Fasting plasma glucose levels were also significantly reduced from baseline by vildagliptin plus metformin (2.63 mmol/l) compared with either agent alone (1.26 and 1.92 mmol/l for vildagliptin and metformin, respectively; p < 0.001) [44]. Vildagliptin (50 mg po, b.i.d.) has also been compared with either glimepiride (up to 6 mg/day) or pioglitazone (30 mg po, q.d.) as an add-on to metformin in patients with T2DM insufficiently controlled by metformin alone. Reductions from baseline in HbA1c levels were 0.1% for both vildagliptin and glimepiride over 2 years [45], and 0.6% for both vildagliptin and pioglitazone over 24 weeks [46]. Fasting plasma glucose levels were reduced to a similar extent by vildagliptin and glimepiride (0.5 and 0.7 mmol/l for the two respective agents), whereas pioglitazone produced a slightly greater reduction than vildagliptin (1.6 vs 1.0 mmol/l) [45,46]. Another placebo-controlled clinical trial assessed vildagliptin (50 mg po, q.d.) as an add-on to stable insulin therapy, 3.3

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Vildagliptin

Table 2. Randomized clinical trials on vildagliptin monotherapy (at least 100 pts, at least 24 weeks, double-blind) as of PubMed on March 4, 2014.

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Study

Patients

Intervention/control

Dejager et al. [43]

632 pts, 24 weeks, db

50 or 100 mg V versus placebo

Pi-Sunyer et al. [50]

354 pts, 24 weeks, db

50 or 100 mg V versus placebo

Scherbaum et al. [51]

306 pts, 52 weeks, db

50 mg V versus placebo

Schweizer et al. [105]

780 pts, 52 weeks, db

100 mg V versus 2000 mg metformin

Schweizer et al. [106]

335 pts, 24 weeks, db

100 mg V versus 1500 mg metformin

Foley and Sreenan [48]

1092 pts, 104 weeks, db

100 mg V versus 320 mg gliclazide

Pan et al. [107]

661 pts, 24 weeks, db

100 mg V versus 300 mg acarbose

Rosenstock et al. [108]

786 pts, 24 weeks, db

100 mg V versus 8 mg rosiglitazone

Objectives/outcomes HbA1c placebo -0.3 ± 0.1%, 50 mg V -0.8 ± 0.1%, 2  50 mg V -0.8 ± 0.1%, or 100 mg V -0.9 ± 0.1% (p < 0.01 for all groups vs placebo) Body weight decreased modestly in all groups (by 0.3 to 1.8 kg) The incidence of adverse events was similar across all groups and £ 1.2% of patients in any treatment group reported mild hypoglycemia HbA1c 50 mg V -0.5 ± 0.2% (p = 0.011), 2  50 mg V -0.7 ± 0.2% (p < 0.001), 100 mg V -0.9 ± 0.2% (p < 0.001) Relative to baseline, body weight did not change significantly in any of the three V groups and decreased by 1.4 ± 0.4 kg in the placebo group. AEs 50 mg V 55.8%, 2  50 mg V 59.3%, 100 mg V 59.3%, and placebo 57.6% HbA1c V -0.2 ± 0.1%, placebo 0.1 ± 0.1%, difference between groups -0.3 ± 0.1% (p < 0.001) FPG between-group difference -0.4 ± 0.2 mmol/l in favor of V, p = 0.032 Body weight V -0.5 ± 0.3 kg, placebo -0.2 ± 0.3 kg HbA1c V -1.0 ± 0.1%, p < 0.001, metformin -1.4 ± 0.1%, p < 0.001 (statistical non-inferiority not established) Body weight V +0.3 ± 0.2 kg, p = 0.17, metformin -1.9 ± 0.3 kg, p < 0.001 AE V 70.1% versus metformin 75.4% The incidence of hypoglycemia was similarly low in both groups (< 1%) HbA1c V -0.64 ± 0.07%, metformin -0.75 ± 0.07%; non-inferior (UL 95% CI £ 0.3%) Body weight V -0.45 ± 0.20 kg (p = 0.02), metformin 1.25 ± 0.19 kg (p < 0.001; p = 0.004 vs V) AEs V 44.3% versus metformin 50.3% Hypoglycemia V 0%, metformin 1.2% HbA1c V -0.5%, gliclazide -0.6%; between group difference 0.13% (95%CI -0.06 -- 0.33%); non-inferiority based on an UL of the 95%CI of 0.3% not met Body weight V +0.8 ± 0.2 kg, gliclazide +1.6 ± 0.2 kg (p < 0.01) Mild hypoglycemia V 0.7%, gliclazide 1.7% HbA1c V -1.4 ± 0.1%, acarbose -1.3 ± 0.1%; noninferiority based on an UL of the 95%CI of £ 0.4% FPG V -1.2 ± 0.1, acarbose -1.5 ± 0.2 Body weight V -0.4 ± 0.1 kg, acarbose -1.7 ± 0.2 kg, p < 0.001 versus V AE V 35% versus acarbose 51% No hypoglycemia was reported for either group HbA1c V -1.1 ± 0.1% (p < 0.001) and rosiglitazone -1.3 ± 0.1% (p < 0.001); non-inferior (UL 95% CI £ 0.4%) FPG V -1.3 mmol/l, rosiglitazone -2.3 mmol/l Body weight V -0.3 ± 0.2 kg, rosiglitazone +1.6 ± 0.3 kg, p < 0.001 versus V Incidence of edema V (2.1%), rosiglitazone (4.1%)

db: Double-blind; pts: Patients; V: Vildagliptin.

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Table 3. Randomized clinical trials on vildagliptin/metformin (at least 100 pts, at least 24 weeks, double-blind) as of PubMed on March 4, 2014.

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Study

Patients

Intervention/control

Bolli et al. [54]

576 pts, T2D, 24 weeks, db

100 mg vildagliptin versus 30 mg pioglitazone on top of metformin ‡ 1500 mg

Bolli et al. [46]

576 pts, T2D, 52 weeks, db

100 mg vildagliptin versus 30 mg pioglitazone on top of metformin ‡ 1500 mg

Bosi et al. [55]

544 pts, T2D, 24 weeks, db

50 mg vildagliptin versus 100 mg vildagliptin versus placebo on top of metformin ‡ 1500 mg

Bosi et al. [44]

1179 pts, T2D, 24 weeks, db

Ferrannini et al. [56]

2789 pts, T2D, 52 weeks, db

50 mg vildagliptin + metformin 2000 mg (VM high) versus 50 mg vildagliptin + metformin 1000 mg (VM low) versus 100 mg vildagliptin (V) versus 1000 mg metformin (M) 100 mg vildagliptin versus 6 mg glimepiride on top of a stable dose of metformin

Filozof and Gautier [57]

1007 pts, T2D, 52 weeks, db

100 mg vildagliptin versus 320 mg gliclazide on top of ‡ 1500 mg metformin

Goodman et al. [58].

247 pts, 24 weeks, db

100 mg vildagliptin in the morning versus 100 mg vildagliptin in the evening versus placebo on top of metformin

Kothny et al. [47]

449 pts, 24 weeks, db

100 mg vildagliptin versus placebo on top of insulin with or without metformin

Matthews et al. [45]

3118 pts, 104 weeks, db

100 mg vildagliptin versus 6 mg glimepiride on top of metformin

Objectives/ outcomes HbA1c at 24 weeks HbA1c +0.9 ± 0.1% VM and -1.0 ± 0.1% PM group; non-inferiority of VM on 0.4 and 0.3% margins for UL 95%CI FPG PM -2.1 ± 0.1, VM -1.4 ± 0.1 mmol/l Body weight between-group difference = -1.6 ± 0.3 kg, p < 0.001 AE VM 60%, PM 56.4%; SAE 2.0 and 4.6% Comparable decreases in HbA1c during the additional FU. AE rates and peripheral edema similar, SAE rates increased with pioglitazone. Increase of weight by 2.6 kg in the pioglitazone group only HbA1c -0.7 ± 0.1% for 50 mg VM and -1.1 ± 0.1% for 100 mg VM (both p < 0.001) FPG -0.8 ± 0.3% for 50 mg VM (p = 0.003) and -1.7 ± 0.3% for 100 mg VM (p < 0.001) AEs 50 mg VM 63.3, 100 mg VM 65.0, and PM 63.5% Gastrointestinal AEs 50 mg VM 9.6 (p = 0.022 vs placebo), 100 mg VM 14.8, and PM 18.2% HbA1c change at 24 weeks: -1.8 ± 0.06% VM high, -1.6 ± 0.06% VM low, -1.1 ± 0.06% V and -1.4 ± 0.06% M VM high versus V or M: p < 0.001 VM low versus V or M: p < 0.001/p = 0.004 At 52 weeks Vildagliptin -0.44% (SE 0.02%) and glimepiride -0.53% (SE 0.02%). Vildagliptin non-inferior to glimepiride Vildagliptin significantly reduced body weight relative to glimepiride (between-group difference -1.79 kg; p < 0.001) 10-fold lower incidence of hypoglycemia than glimepiride (1.7 vildagliptin vs 16.2% glimepiride of patients presenting at least one hypoglycemic event p < 0.01) Non-inferiority of vildagliptin (95% CI -0.11, 0.20%); mean change from baseline HbA1c -0.81 vildagliptin and -0.85 gliclazide at 52 weeks Total number of hypoglycemic events was lower in the vildagliptin group (6 vs 11 events) The number of SAE was higher in the gliclazide group (8.7 vs 6.7%) HbA1c improved significantly with vildagliptin AM dosing (-0.66 [0.11] versus 0.17% [0.11] with placebo; p < 0.001) Comparable efficacy between AM and PM dosing BW remained stable in the combined vildagliptin group (+0.06 kg) and decreased with placebo (-0.69 kg); incidence of AEs was similar with vildagliptin AM dosing and placebo (30.4 and 34.4%) HbA1c difference between vildagliptin and placebo was -0.7 ± 0.1% (p < 0.001) overall, -0.6 ± 0.1% (p < 0.001) in pts also receiving metformin and -0.8 ± 0.2% (p < 0.001) in pts without metformin Hypoglycemia: vildagliptin 8.4%, placebo 7.2%; p = 0.66 HbA1c VM -0.1% (0.0%) and GM -0.1% (0.0%); vildagliptin non-inferior Hypoglycemia: VM 2.3% versus GM 18.2% Body weight: between-group difference -1.5 kg; p < 0.001

db: Double-blind; pts: Patients; VM: Vildagliptin-metformin.

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Vildagliptin

Table 3. Randomized clinical trials on vildagliptin/metformin (at least 100 pts, at least 24 weeks, double-blind) as of PubMed on March 4, 2014 (continued).

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Study

Patients

Intervention/control

Pan et al. [59]

438 pts, 24 weeks, db

100 mg vildagliptin versus 50 mg vildagliptin versus placebo on top of metformin

Lukashevich et al. [60]

318 pts, 24 weeks, db

2  50 mg vildagliptin versus placebo on top of metformin

Objectives/ outcomes HbA1c 100 mg VM -1.05 ± 0.08%, 50 mg VM -0.92 ± 0.08% and PM -0.54 ± 0.08% FPG 100 mg VM -0.95 mmol/l (-17.1 mg/dl), 50 mg VM -0.84 mmol/l (-15.1 mg/dl) and PM -0.26 mmol/l (-4.68 mg/dl) (p £ 0.001) AEs 100 mg VM 34.2%, 50 mg VM 36.5% and PM 37.5% HbA1c vildagliptin -1.01%, placebo -0.25%, between-treatment difference -0.76% (p < 0.001) Hypoglycemia 5.1% with vildagliptin, 1.9% with placebo

db: Double-blind; pts: Patients; VM: Vildagliptin-metformin.

Table 4. Ongoing randomized clinical trials on vildagliptin (at least 100 pts, at least 24 weeks, double-blind; unknown status excluded) as of clinicaltrials.gov on March 4, 2014. NCT

Patients

Intervention/control

Objectives/ outcomes

NCT01099137

230 pts, T2D, 24 weeks, db

2  50 mg vildagliptin versus sulfonylurea in pts uncontrolled with SU and metformin

NCT01528254

2000 pts, T2D, 26 weeks and 5 years, db

50 mg vildagliptin versus placebo on top of metformin

NCT01018602

140 pts, gestational diabetes, 3 years, db

100 mg vildagliptin versus placebo

Investigate the change in HbA1C and fasting glucose of 24 weeks treatment with vildagliptin (DPP-IV inhibitor) in combination with a sulfonylurea agent and metformin in type 2 diabetic patients Determine whether the initiation of a vildagliptin plus metformin combination regimen would result in more durable glycemic control than metformin monotherapy in treatment-naı¨ve patients with T2DM To determine the effects of vildagliptin on the development of diabetes in women with a recent history of insulin-requiring gestational diabetes

DPP: Dipeptidyl peptidase; T2DM: Type 2 diabetes mellitus.

with or without metformin, in patients (n = 449) with T2DM and inadequate glycemic control. Placebo-corrected mean reductions from baseline in HbA1C were 0.7% in the vildagliptin plus placebo group, 0.6% in the vildagliptin with metformin group and 0.8% in the vildagliptin without metformin group (all p < 0.001 vs placebo) [47]. Vildagliptin was evaluated as part of triple-agent therapy in a placebo-controlled clinical trial in which vildagliptin (50 mg po, b.i.d.) was added to stable treatment with metformin (‡ 1500 mg) and glimepiride (‡ 4 mg) in patients (n = 318) with T2DM and inadequate glycemic control. The mean placebo-corrected decrease from baseline in HbA1C levels was 0.8% (p < 0.001 compared with placebo). Fasting plasma glucose levels were also significantly lowered, with a placebocorrected reduction of 1.13 mmol/l (p < 0.001) [60]. Filozof and Gautier aimed to demonstrate noninferiority of vildagliptin compared with gliclazide, as an add-on therapy, in patients with type 2 diabetes inadequately controlled with metformin. Patients receiving a stable dose of metformin (‡ 1500 mg) were randomized to receive 2  50 mg vildagliptin or up to 320 mg gliclazide. It was shown that vildagliptin

was noninferior to gliclazide (95% CI -0.11 -- 0.20%) with a mean change from baseline HbA1c to a 52-week end point of -0.81% with vildagliptin and -0.85% with gliclazide. Vildagliptin was noninferior (margin 0.6 mmol/l) to gliclazide in reducing fasting plasma glucose (1.31 vs 1.52 mmol/l, p = 0.257) [57]. The fixed-dose combination of vildagliptin has been shown to be bioequivalent to administration of individual components at different dose levels (50/500, 50/850 and 50/1000 mg) [61]. 4.

Safety and tolerability

Hypoglycemia Vildagliptin is associated with a low incidence of hypoglycemic events, with data from the clinical trials discussed above suggesting that rates of hypoglycemia in the vildagliptin groups were not significantly different from those observed in the placebo groups. In the clinical trials of vildagliptin as an add-on to insulin, and as an add-on to metformin plus glimepiride, hypoglycemic events were reported by 8.4 and 5.1% of patients in the vildagliptin groups in the two 4.1

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respective trials, compared with 7.2 and 1.9% in the placebo groups in the two respective trials [47,60]. Evaluation of vildagliptin versus placebo in elderly patients indicated that the rate of hypoglycemia was 2.2% in the vildagliptin group and 0.7% in the placebo group [62]. All hypoglycemic events occurred in patients using concomitant sulphonylureas and no severe hypoglycemic events were reported in either group. In the clinical trial of vildagliptin monotherapy in treatmentnaive patients with T2DM, no cases of hypoglycemia were recorded [43]. Body weight Similar to other members of the DPP-4 inhibitor drug class, vildagliptin is considered to be weight-neutral. Changes from baseline in body weight appear to range between a reduction of 0.3 kg, which was observed in treatment-naive patients, to an increase of 0.5 kg [43,47,53,60,62]. 4.2

three hepatic impairment groups, the AUC0 -- ¥ and Cmax values for the inactive metabolite were increased by 29 to 84%, respectively, and 24 to 63%, respectively. The differences in vildagliptin plasma exposure were not significant between each of the hepatic impairment groups and the healthy group, and it was concluded that no dose adjustment was necessary for patients with hepatic dysfunction [68]. Subsequent clinical trials have revealed a trend toward mild increases in hepatic transaminase levels following vildagliptin treatment [69]. Although a meta-analysis using data from 38 clinical trials indicated that relative to comparator drugs, vildagliptin was not associated with an increased risk of hepatic adverse events [70], the drug is not approved for patients with hepatic dysfunction. In addition, liver function testing is recommended during the first 3 months of vildagliptin treatment [63]. Pancreatitis and pancreatic cancer The use of DPP-4 inhibitors has been tenuously linked to an increased risk of developing pancreatitis or pancreatic cancer [71]. An analysis of few cases recorded in the French Pharmacovigilance Database from 2008 to 2013 suggested that pancreatitis occurred more frequently in patients who received incretin-based therapies as opposed to other antihyperglycemic agents. Because of the potential seriousness of this observation, several studies have analyzed the effect of DPP-4 inhibitors on the pancreas as well as the incidence of pancreatitis in clinical trials of DPP-4 inhibitors. In 2-year rodent toxicity studies of vildagliptin, in which the drug was administered at dose levels up to 240-fold higher than those used in humans, there was no evidence of pancreatitis, pancreatic islet cell, acinar cell or ductal neoplasia [71]. Two safety meta-analyses of clinical trials also indicate that relative to comparator drugs, treatment with DPP-4 inhibitors is not correlated with an increased risk of pancreatitis or pancreatic cancer [70,72]. Although we should remain vigilant, the balance of all available evidence dwarfs the pancreatic risk with benefits of DPP-IV inhibitors far overweighing potential risks [73]. 4.5

4.3

Renal impairment

Because the predominant route of excretion of vildagliptin is via the kidneys, it may be expected that the drug is not suitable for patients with renal insufficiency. However, vildagliptin is approved for patients with mild renal impairment (creatinine clearance ‡ 50 ml/min) and may be administered without dose adjustment. For patients with moderate or severe renal impairment, a reduced dose of 50 mg once-daily is recommended [63]. A 24-week and a 52-week clinical trial of vildagliptin (50 mg po, q.d.) added to ongoing stable antidiabetic therapy in patients (n = 515 and 369 in the two respective trials) with T2DM and either moderate or severe renal insufficiency indicated that vildagliptin had a similar safety profile to placebo [64-66]. With regard to other kidney disorders, a recently published clinical trial highlighted the potential of vildagliptin as a safe and efficacious treatment option for patients with new-onset diabetes following kidney transplantation [67]. Treatment with metformin is contraindicated in patients with renal impairment and a creatinine clearance < 60 ml/min. Therefore, a combination of vildagliptin with metformin should be avoided in these patients.

Immunological responses Members of the serine protease family to which DPP-4 belongs, including DPP-4, DPP-8 and DPP-9, are known to be expressed on immune cells [74,75]. A study published in 2005 reported that in rats, administration of a compound that exhibited nanomolar inhibition of both DPP-8 and DPP-9, as well as weak inhibition of DPP-4 activity, was associated with multiple toxicities and mortality [76]. In addition, some clinical trials of DPP-4 inhibitors have suggested that this drug class may increase the risk of upper respiratory tract infections [77]. Therefore, the potential for modulation of immune responses by selective DPP-4 inhibitors has been investigated in several studies. In rodents, plasma vildagliptin concentrations that exceeded the Ki value for DPP-8 and DPP-9 did not result in organ toxicities or increased mortality [17]. A study conducted in human blood 4.6

4.4

Hepatic impairment

The suitability of vildagliptin for patients with varying degrees of hepatic dysfunction has been evaluated, and the drug was reported to be well tolerated [68]. However, levels of plasma exposure to vildagliptin (100 mg po, single dose) and its inactive metabolite were altered in individuals with hepatic dysfunction relative to those observed in healthy individuals. An increase in the AUC0 -- ¥ and Cmax values for vildagliptin of 20 and 30%, respectively, was observed in individuals with mild hepatic impairment. Moderate and severe hepatic impairment was associated with a reduction in the AUC0 -- ¥ value of 6 and 8%, respectively, whereas the Cmax value was reduced by 23% in individuals with moderate hepatic impairment, and increased by 22% in individuals with severe hepatic impairment. Across the 1306

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Vildagliptin

mononuclear cells and mice demonstrated that neither innate nor adaptive immune responses were influenced by sitagliptin, saxagliptin or vildagliptin [78]. In patients (n = 16) with T2DM, serum cytokine concentrations and ex vivo cytokine production were measured following 28 days of treatment with either vildagliptin (50 mg po, b.i.d.) or the a-glucosidase inhibitor acarbose (50 mg three-times a daily (t.i.d.) for 7 days followed by 100 mg t.i.d. for 21 days). Cytokine responses were not different in patients treated with vildagliptin compared with acarbose, suggesting that DPP-4 inhibition does not increase the susceptibility to infection by decreasing cytokine release [79]. Cardiovascular The potential impact of vildagliptin (100 or 400 mg po, q.d. for 5 days) on cardiac repolarization and conduction was investigated in healthy individuals (n = 101) [80]. At 1 and 8 h postdose, the 100-mg dose level produced a mean change in the heart rate-corrected QT interval (QTc) that was greater than the predefined limit for QTc prolongation (upper 90% confidence interval > 10 ms). Analysis of vildagliptin plasma exposure indicated that changes in the QTc interval were not related to plasma drug concentrations. No increases in the QTcF interval of > 450 ms were observed, and vildagliptin did not affect PR or QRS intervals [80]. One explanation for the effect of vildagliptin on the QTc interval may be the occurrence of hypoglycemic events [81]. Nevertheless, the effect of vildagliptin on the QTc interval deserves further investigation because QTc prolongation, QTc-prolonging drugs and diabetes mellitus have all been associated with an increased risk of cardiovascular mortality [82,83]. Given the focus of regulatory authorities on the cardiovascular safety of antidiabetic agents as well as the common occurrence of concomitant heart failure and diabetes mellitus, the effect of vildagliptin on left ventricular function was assessed in patients (n = 254) with T2DM and congestive heart failure (New York Heart Association class I to III) [84]. Although, compared with placebo, vildagliptin did not have a negative impact on the left ventricular ejection fraction (p = 0.67), increases in left ventricular end diastolic volume (LVEDV; p = 0.007), end systolic volume (LVESV; p = 0.06) and stroke volume (p = 0.002) were observed. Currently, the clinical implications of these results are unclear; whereas increases in LVEDV and LVESV are considered to reflect a decrease in systolic function, levels of brain natriuretic peptide were also reduced in the vildagliptin group, suggesting that the increased ventricular volume was not associated with greater ventricular wall stress [84]. Of note, recent data from a clinical trial assessing the cardiovascular effects of saxagliptin indicated that the rate of hospitalization for heart failure was increased relative to placebo [85]. This finding has led to the FDA requesting further data related to the potential risk of heart failure in patients receiving saxagliptin [86]. Two meta-analyses of the cardiovascular safety profile of vildagliptin and saxagliptin indicate that neither drug is 4.7

associated with an increased rate of cardiovascular events [87,88]. However, to resolve this matter, further studies are necessary. 5.

Regulatory affairs

Vildagliptin was approved by the European Medicines Agency in 2007, and it is currently available in over 100 countries worldwide, including Japan, and in Africa, Latin America and the Asia-Pacific region [12,89]. In Europe, vildagliptin was initially approved as a dual therapy for T2DM, to be used in combination with metformin, a thiazolidinedione or a sulfonylurea in patients with inadequate glycemic control. The recommended dose level was either 100 mg once-daily or 50 mg twice-daily, with the exception of use in combination with a sulfonylurea, for which the recommended dose level was 50 mg once-daily in the morning [90]. However, during the registration process, pooled analyses of the clinical trial data suggested that the 100 mg once-daily dose level was associated with mild increases in liver transaminases, with the subsequent recommendation that only the 50 mg twice-daily dose level be used [63,90]. In 2011 and 2012, the EMA granted market authorization for the expanded use of vildagliptin, with the approval of three additional indications as follows: i) monotherapy for patients with insufficient glycemic control with diet and exercise, and for whom metformin is inappropriate because of contraindications or intolerance [91]; ii) triple therapy in combination with metformin and a sulfonylurea for patients with inadequate glycemic control on dual therapy plus diet and exercise; and iii) in combination with insulin, either with or without metformin, in patients with inadequate glycemic control on a stable dose of insulin plus diet and exercise [12]. At the time of publication, vildagliptin was not approved in the US; Novartis received an approvable letter from the FDA in 2007, but after the request for additional clinical trials data, it appears that FDA approval of vildagliptin has not been further pursued [92]. 6.

Conclusion

Vildagliptin, at a dose of 50 mg twice-daily, has been demonstrated to be a safe and efficacious treatment for T2DM. It may be administered as a monotherapy and as part of dualor triple-agent therapeutic regimens. Vildagliptin produces good glycemic control, with a low rate of hypoglycemia and weight-neutrality. Furthermore, vildagliptin appears to preserve b-cell function. However, other issues, in particular its effects on various parameters of cardiovascular function, are less clear. 7.

Expert opinion

Currently available data indicate that as a second-line therapy combined with metformin, vildagliptin may represent a better option than sulfonylureas. Although DPP-4 inhibitors and

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sulfonylureas offer similar levels of glycemic control, the molecular pathways to achieve lower blood glucose levels appear to be largely different. Although vildagliptin improves metabolic control by the restoration of the glucose dependent a- and b-cell signaling pathways, sulfonylureas act as exhausting stimulators of insulin release from the b-cell. In addition, DPP-4 inhibitors have the benefit of being associated with fewer cases of hypoglycemia and less body weight gain. A post hoc comparison of the real-life efficacy and safety of vildagliptin versus sulfonylureas as an add-on to metformin indicated that the frequency of hypoglycemic events was fourfold higher among patients receiving a sulfonylurea. Furthermore, this study indicated that compared with a sulfonylurea, patients treated with vildagliptin were more likely to attain their target HbA1C goal [93]. Similar findings were reported from a meta-analysis of randomized, controlled clinical trials that compared the efficacy and safety of DPP-4 inhibitors with that of other antihyperglycemic drugs in combination with metformin. Interestingly, a meta-analysis of clinical trials involving patients with T2DM demonstrated that for eight different classes of antidiabetic drugs, the only significant predictor of attaining an HbA1c target of < 7% was higher baseline HbA1c levels, whereas in a meta-analysis that was restricted to DPP-4 inhibitors, both higher baseline HbA1c levels and lower fasting plasma glucose levels were identified as significant predictive factors [94,95]. To the author’s knowledge, head-to-head clinical trials to demonstrate the noninferiority of vildagliptin versus other DPP-4 inhibitors have not been conducted to date. One clear differentiating factor between vildagliptin and the other DPP-4 inhibitors is the dose frequency, whereas all the other approved DPP-4 inhibitors are approved for once-daily dosing, the standard dose regimen for vildagliptin is twice-daily. An indirect comparison of randomized clinical trials of vildagliptin and sitagliptin in Japanese patients with T2DM suggested that the 50-mg twice-daily dose level of vildagliptin was associated with a significantly greater reduction in HbA1C levels than either the 50- or the 100-mg dose level of sitagliptin [96]. In accordance with these data, continuous glucose monitoring of patients with T2DM who were receiving either vildagliptin or sitagliptin indicated that better glycemic control was achieved with vildagliptin [97]. At the time publication, a randomized, open-label, crossover trial was comparing vildagliptin with sitagliptin as an add-on to insulin in patients with T2DM. The primary end point of this trial is to assess the hypoglycemic profile of each agent, and completion of the trial is expected in May 2014. Another important factor to be considered in the treatment of T2DM is the cost-effectiveness of the different therapies. A recently published pharmacoeconomic study compared

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the usage, efficacy and cost of vildagliptin, sitagliptin and alogliptin following administration to patients in Japan. This study indicated that vildagliptin was the most costeffective of the three agents -- the proportion of patients who met their treatment target was highest with vildagliptin, but the cost of vildagliptin was the lowest [98]. Because the two types of incretin-based therapies, GLP-1 analogs and DPP-4 inhibitors, are approved for similar indications, it is of relevance to compare the safety and efficacy of these drug classes. Two separate meta-analyses indicate that DPP-4 inhibitors are inferior to GLP-1 analogs with regard to HbA1c and weight reduction [5,99]. A potential disadvantage of GLP-1 analogs is their subcutaneous mode of delivery and the high treatment costs. Oral administration, as for all DPP-4 inhibitors, is often preferred by patients and may be associated with better treatment compliance. However, newer GLP-1 analogs such as dulaglutide (Eli Lilly) have the benefit of being administered once-weekly as opposed to once- or twice-daily administration for other members of this drug class [100]. Indeed, a very recently completed clinical trial demonstrated noninferiority of dulaglutide to the once-daily GLP-1 analog liraglutide (Novo Nordisk) [101]. Furthermore, currently available data suggest that GLP-1 agonists may have a positive impact on cardiovascular function [102]. Liraglutide has been demonstrated to reduce systolic blood pressure [103], whereas infusion of GLP-1 improved left ventricular systolic function in patients with diabetes and NYHA III/IV heart failure [104]. Nevertheless, additional data are necessary before conclusions can be drawn regarding the cardiovascular effects of incretin-based therapies. In summary, the various members of the DPP-4 inhibitor drug class appear to display similar characteristics in terms of safety and efficacy. Head-to-head evaluations of the gliptins, and of gliptins versus GLP-1 agonists, are awaited in order to better differentiate between the advantages and disadvantages of particular agents.

Declaration of interest T Forst has been a consultant for and received research grants from Novartis. Pater Bramlage has acted as a consultant for Novartis. Forst and Bramlage report to have received consultancy fees and/or research funding from Novartis Pharma GmbH, Nu¨rnberg, Germany. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Dipeptidyl peptidase-4 inhibitors increase circulating levels of glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide regu...
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