The design of the liraglutide clinical trial programme

review article Diabetes, Obesity and Metabolism 14 (Suppl. 2): 4 12, 2012. 2012 Blackwell Publishing Ltd The design of the liraglutide clinical trial programme M. A. Nauck Diabeteszentrum Bad Lauterberg, Bad Lauterberg im Harz, Germany Liraglutide is a once-daily human glucagon-like peptide-1 analogue used in the treatment of type 2 diabetes (T2D). It has been prospectively investigated in a series of multinational, randomised, controlled phase 3 trials (the Liraglutide Effect and Action in Diabetes programme), as well as in an additional direct head-to-head study with sitagliptin. These trials were designed to clarify the use and safety of liraglutide in clinical practice across the treatment continuum of T2D, and consequently involved a large number and diverse range of patients. These studies also included active comparisons against antidiabetic agents including metformin, rosiglitazone, glimepiride, insulin glargine, exenatide and sitagliptin, and therefore have helped to examine clinical differences and similarities between liraglutide and these commonly used agents. Keywords: efficacy, GLP-1, liraglutide, safety, treatment guidelines Date submitted 30 November 2011; date of final acceptance 11 January 2012 Introduction Liraglutide is a human glucagon-like peptide-1 (GLP-1) analogue, to be administered once daily, independently of meals, in patients with type 2 diabetes (T2D). Substantial and significant reductions in haemoglobin A1c (HbA1c) and weight, often superior to results with comparator drugs, have been reported with liraglutide compared with other commonly used therapies in the liraglutide phase 2 clinical development programme [1 3]. In these trials, which ranged in duration from 5 to 14 weeks of treatment, liraglutide also showed a good tolerability profile with very few hypoglycaemic episodes and mostly mild and transient gastrointestinal adverse events. These encouraging findings supported the initiation of a comprehensive phase 3 clinical trial programme designed to determine liraglutide s efficacy and safety versus placebo in combination with other agents and across the treatment continuum, as well as direct head-to-head comparisons with relevant competitor drugs. Most of the trials in the phase 3 clinical trial plan were part of the Liraglutide Effect and Action in Diabetes (LEAD) programme. This review will focus on the rationale and design of the large, prospective phase 3 trials in the liraglutide clinical development programme, including the LEAD and direct head-to-head studies. How the Phase 3 Trial Programme was Designed and how it Fits with T2D Treatment Guidelines The initial aim of the clinical trial programme was to elucidate the efficacy and safety of liraglutide in relation to other Correspondence to: Prof. Dr. Michael A. Nauck, Diabeteszentrum Bad Lauterberg, Kirchberg 21, Bad Lauterberg im Harz 37431, Germany. E-mail: nauck@diabeteszentrum.de Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://wileyonlinelibrary.com/onlineopen#onlineopen_terms therapies, mainly in combination, but also as a direct comparative agent. The programme also considered patients duration of diabetes and previous antidiabetic treatment, and sought to clarify at what point during the course of T2D liraglutide could be initiated and have benefit, so the trials were designed to complement treatment decisions as suggested by T2D treatment guidelines. The current American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) consensus statement [4] categorises the therapeutic interventions recommended for T2D, if metformin monotherapy does not ensure adequate glycaemic control, into two tiers: tier 1 (well-validated core therapies with a long-term safety record) and tier 2 (less well-validated therapies that have been available for a relatively short time). More details are described in the article by Stephen Gough [5] in this supplement. Alternatively, the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) panel recommends treatment based on the initial HbA1c of the patient [6]. In patients with HbA1c 6.5 7.5%, metformin monotherapy is recommended (provided the patient has no contraindication to metformin and tolerates this drug). Metformin is also the cornerstone of dual therapy in patients with HbA1c 7.6 9.0%, the preferred second agent being exenatide (a GLP-1 receptor agonist), followed by dipeptidyl peptidase- 4 (DPP-4) inhibitors, glinides, or sulphonylureas (SUs). The panel recognised the lower risk of hypoglycaemia associated with exenatide twice daily (BID) and DPP-4 inhibitors compared with glinides and SUs. Moreover, exenatide BID (the only approved GLP-1 receptor agonist at the time) was favoured over DPP-4 inhibitors as it showed greater postprandial glucose lowering and substantial weight loss [6]. For patients requiring triple therapy, metformin + exenatide BID/DPP-4 inhibitor + thiazolidinedione (TZD)/glinide/SU is indicated. Both treatment guidelines acknowledge the need for individualised therapy, aiming for glycaemic targets of 6.5% (AACE) or <7.0% (ADA/EASD) but with a minimal risk of hypoglycaemia and weight gain. In addition, both guidelines

DIABETES, OBESITY AND METABOLISM Figure 1. How the clinical trial programme was designed to fit into the treatment pathway for type 2 diabetes. consider the need for treatments to reduce cardiovascular risk, in part by modifying respective risk factors. It is generally believed that durable therapies must also address the question of how to improve and maintain insulin secretory capacity. This is based on the observation that over time, β-cell function is reduced by approximately 4% per year [7,8], and that this decline in insulin secretory capacity is associated with a slow deterioration of glycaemic control, evident from a gradual rise in HbA1c over time. Consequently, the LEAD programme consisted of six randomised, controlled, parallel-group trials investigating liraglutide as a monotherapy (liraglutide is not licensed for use as monotherapy in the European Union) [9], as a combination with an SU [10], as a combination with metformin [11], as a combination with a TZD and metformin [12], as a combination with an SU and metformin versus insulin glargine [13] and as a combination with metformin, SU or both in a head-to-head comparison versus exenatide [14]. Another head-to-head trial, separate from the LEAD programme, investigated liraglutide versus sitagliptin, both in combination with metformin [15] (figure 1). All were designed to cover the continuum of T2D with the primary efficacy endpoint being change in HbA1c; other efficacy endpoints included the percentage of patients reaching HbA1c <7.0% and 6.5%, changes in fasting plasma glucose (FPG), and plasma glucose profiles. Titration of liraglutide towards blood glucose targets was unnecessary because there is a uniform dosage range recommended for all patients, who can be treated with one of two doses (1.2 or 1.8 mg) after an initial dose escalation. Body weight and cardiovascular endpoints such as blood pressure and lipid profiles were also measured, along with safety endpoints including hypoglycaemia; a minor episode was defined as a subject with plasma glucose <3.1 mmol/l, and any episode requiring third-party medical assistance was classed as major. Other safety endpoints were adverse events including pancreatitis, and electrocardiogram (ECG), antibodies and biochemical and haematological measures including calcitonin (due to the observation that GLP-1 and GLP-1 analogues stimulate calcitonin release in rodents [16]). Some studies also measured β-cell function based on fasting insulin, fasting C-peptide, and fasting proinsulin:insulin ratio and homeostasis model assessment (HOMA-β) indices [17]. The general programme rationale was to show whether the addition to or substitution of liraglutide provided greater, or at least non-inferior, levels of glycaemic control compared with commonly used therapies, as well as overall safety and tolerability. All the trials included standardised background therapy with a run-in phase (for trials less than 52 weeks), and six of seven trials included an active comparator. The trials also encompassed the broad spectrum of T2D, from early disease (i.e. short duration of diabetes or treatment naïve) to subjects previously failing with two oral antidiabetic drugs (OADs). Consequently, the trials contained two pre-specified sub-cohorts of subjects: (i) subjects who were treatment naïve or taking one OAD as a background therapy where liraglutide was a true add-on treatment or (ii) subjects failing on two OADs where liraglutide was substituted for one of the agents. Liraglutide has been approved by the European Medicines Agency, Food and Drug Administration, the Japanese Ministry of Health, Labour and Welfare and the Chinese Food and Drug Administration, and is currently indicated as a second- and third-line treatment option for T2D [18,19]. In Europe, liraglutide in combination with metformin or SU, as a second-line treatment option, is indicated in patients with sub-optimal glycaemic control despite therapy with maximal tolerated doses of metformin or SU [18]. Liraglutide in combination with metformin and SU or metformin and TZD is indicated as a third-line treatment option when unsatisfactory glycaemic control is achieved during dual therapy [18]. The addition of insulin detemir to liraglutide has recently been approved in Europe, but the addition of liraglutide in patients already treated with insulin has not been evaluated and is therefore not recommended [18,20]. Exenatide BID in combination with metformin, SU, TZD, metformin and SU, or metformin and TZD is indicated as a third-line option when unsatisfactory glycaemic control is achieved with dual therapy [21]. In the Volume 14 No. (Suppl. 2) April 2012 doi:10.1111/j.1463-1326.2012.01573.x 5

USA, exenatide is recommended as add-on to insulin glargine with or without metformin and/or TZDs [22]. Sitagliptin is indicated as monotherapy in combination with metformin or TZD, SU, metformin and SU/TZD or in combination with insulin with/without metformin [23]. Vildagliptin and saxagliptin are indicated as dual therapy in combination with metformin, SU or TZD [24,25]. The LEAD Studies and Separate Head-to-Head Study The LEAD programme plus the separate head-to-head study involved more than 5000 patients recruited from over 600 sites in 40 countries [9 15]. The main trial periods designed for evaluation of the primary endpoint ranged in duration from 26 to 52 weeks. All trials included a dose-escalation period for liraglutide in which the initial dose of 0.6 mg was increased weekly by 0.6 mg to either 1.2 or 1.8 mg (depending on the treatment group or trial). Liraglutide in Combination with Oral Antidiabetic Drugs Over time, the majority of patients with T2D will eventually require more than one therapeutic intervention as β-cell function deteriorates and subjects fail to achieve adequate glycaemic control [26,27]. The LEAD-1 and LEAD-2 trials examined the use of liraglutide as second-line therapy when added to existing glimepiride or metformin monotherapy, respectively [10,11]. Both trials were double-blind and doubledummy-controlled, so patients in the placebo group received placebo doses of liraglutide as well as the active comparator. Subjects included in each 26-week trial were previously treated with one or two OADs for at least 3 months. In LEAD-1, subjects were randomised to receive one of three doses of liraglutide, 0.6, 1.2 or 1.8 mg in combination with glimepiride (2 4 mg/day), or glimepiride + placebo (placebo control), or combination therapy of glimepiride + rosiglitazone (4 mg/day; active comparator) [10]. At the time of randomisation, subjects were stratified according to their previous OAD therapy (monotherapy or combination therapy) in order to ensure an equal distribution of subjects to both subgroups. The trial was designed to establish whether liraglutide in combination with glimepiride would provide superior glycaemic control than achieved with glimepiride monotherapy (placebo) and non-inferior results to glimepiride and rosiglitazone (active comparator) treatment. More study details are included in Table 1. Similarly, in LEAD-2, subjects were randomised to receive one of three doses of liraglutide (0.6, 1.2 or 1.8 mg) in combination with metformin (1 g twice daily), or metformin + placebo, or combination therapy of metformin with glimepiride (4 mg/day; active comparator) [11]. The trial examined whether liraglutide added to metformin was superior to metformin monotherapy (+ placebo) or non-inferior to glimepiride as an add-on to metformin [11]. Further study details are listed in Table 1. When the effectiveness of dual therapy also deteriorates, it may be necessary to initiate triple therapy in subjects with DIABETES, OBESITY AND METABOLISM T2D. To assess liraglutide as a third-line treatment option, the LEAD-4 study explored the addition of liraglutide in patients already being treated with two anti-hyperglycaemic agents [12]. LEAD-4 was double-blind and placebo-controlled as it did not include an active comparator group. It was designed to assess whether liraglutide was a safe and effective option when used in combination with metformin (1 g twice daily) and rosiglitazone (4 mg twice daily), and whether it provided superior glycaemic control compared to metformin and rosiglitazone combination therapy (+ placebo) [12]. Patients entered a 6-9 week run-in period for titrating doses of metformin and rosiglitazone. Study details are summarised in Table 1, and the results from the LEAD-1, -2 and -4 trials are described in more detail in the article by Alan Garber [28] in this supplement. Liraglutide versus Insulin or Other Incretin Therapies Basal insulin analogues are frequently added to OADs in clinical practice when OADs alone are no longer effective at maintaining glycaemic control [4,29,30]. The 26-week LEAD-5 trial examined the effectiveness of liraglutide in combination with a background therapy of glimepiride (4 mg once daily) + metformin (1 g twice daily) and compared this with insulin glargine as an add-on to glimepiride + metformin (active comparator), and glimepiride + metformin alone (+ placebo); the liraglutide and placebo arms were blinded but the insulin glargine arm was open-label due to the need to titrate the insulin dose [13]. Other study information is included in Table 1, and the results from the LEAD-5 trial are described in more detail in the article by Garber [28] in this supplement. Head-to-Head Studies The acknowledgement by current guidelines that GLP-1 receptor agonists can be a recommended therapeutic option for T2D was originally based on data from the first available GLP-1 agonist, exenatide BID (a once-weekly preparation of exenatide was recently approved in Europe). Exenatide is a molecule with a 53% amino acid sequence identity to GLP-1. It is administered twice daily and in clinical trials has showed reductions in HbA1c of up to 1.0%, with a low risk of hypoglycaemia and with reductions in body weight [4,31,32]. Exenatide is well tolerated, but with frequent, mostly transient, gastrointestinal adverse events [4]. Exenatide is described in more detail in the article by Lawrence Blonde and Eduard Montanya [33] in this supplement. With respect to important characteristics, there are important differences between exenatide and liraglutide, which are dissimilar in terms of structure, duration of action and dosing [19,21]. Consequently, a direct comparison between exenatide and liraglutide was necessary to clarify any differences in clinical outcomes. The LEAD-6 trial included patients previously inadequately controlled on maximal doses of metformin, SU or both who were then randomised to liraglutide (1.8 mg once daily) or exenatide (10 μg twice daily) as an add-on therapy [14]. Both agents require different administration (i.e. different pen devices, doses and dosing intervals) and the trial had an open-label design to account for this. Not only was LEAD-6 intended to establish the use of liraglutide in triple therapy, it 6 Nauck Volume 14 No.(Suppl.2) April 2012

DIABETES, OBESITY AND METABOLISM Table 1. Study designs. Liraglutide in combination with OADs vs. insulin vs. other incretin therapies Marre (LEAD-1) [10] Nauck (LEAD-2) [11] Zinman (LEAD-4) [12] Russell-Jones (LEAD-5) [13] Liraglutide + SU + Metformin + Metformin + Metformin/SU OR + metformin and SU Comparator SU + rosiglitazone SU + placebo Design Randomised, double-blind, double-dummy, active-comparator, parallel group Metformin + SU Metformin + placebo Randomised, double-blind, double-dummy, active-control, parallel group Metformin + rosiglitazone + placebo Randomised, double-blind, placebo-controlled, parallel group Insulin glargine + metformin +SU Metformin + SU + placebo Randomised, placebo-controlled, parallel group, (with blinded liraglutide and placebo, but open-label insulin glargine) Buse (LEAD-6) [14] Pratley (1860 study) [15] + Metformin + rosiglitazone Exenatide + metformin/su or + metformin and SU Randomised, open-label, active comparator, parallel group Duration 26 weeks 26 weeks 26 weeks 26 weeks 26-week main trial 14-week switch extension No. of sites 116 sites 170 sites 96 sites 107 sites 132 sites 158 sites Countries 21 countries in Europe and Asia 21 countries in Europe, Asia, South America, and including South Africa, Australia and New Zealand USA and Canada South America, Europe, India, Philippines and South Africa + Metformin + SU Sitagliptin + metformin Randomised, open-label, active comparator, parallel group 26 weeks 26-week extension 26-week switch second extension USA and Europe 11 European countries, USA and Canada No of patients 1041 1091 533 581 464 665 Duration of diabetes 6.5 6.7 years (median) 7 8 years (mean) 9 years (mean) 9.2 9.7 years (mean) 7.9 8.5 years (mean) 6.0 6.4 years (mean) Mean BMI (kg/m 2 ) 29.4 30.3 kg/m 2 30.5 31.6 kg/m 2 33.5 kg/m 2 30.3 to 31.3 kg/m 2 32.9 kg/m 2 32.6 33.1 kg/m 2 Previous treatment Approximately 70% of patients were previously treated with combination oral therapy compared with 30% previously treated with oral monotherapy Around two-thirds of patients were previously treated with combination oral therapy, the remainder with oral monotherapy The majority of patients were previously treated with two agents (83%) Almost all patients had been treated with combination OAD therapy (95%) 63% of patients were originally treated with a combination of both metformin and SU, with 27% treated with metformin alone, and 10% with SU alone Patients had previously been treated with metformin ( 1500 mg/day) for 3 months or longer BMI, body mass index; LEAD, liraglutide effect and action in diabetes programme; SU, sulphonylurea; OAD, oral antidiabetic drugs. Volume 14 No. (Suppl. 2) April 2012 doi:10.1111/j.1463-1326.2012.01573.x 7

was the first trial to directly compare the efficacy and safety of liraglutide with exenatide [14]. Following a 26-week main trial, a 14-week extension was carried out in which patients switched from exenatide 10 μg to liraglutide 1.8 mg [34]. Further study information is listed in Table 1; the results of the LEAD-6 trial and its extension are described in more detail in the article by Blonde and Montanya [33] in this supplement. A second head-to-head, 26-week, randomised, parallel group, open-label study (not part of the LEAD trials) has been performed to compare liraglutide 1.2 and 1.8 mg with sitagliptin 100 mg [15]. Published trials comparing currently available GLP-1 receptor agonists and DPP-4 inhibitors are scarce, so this trial was conducted to further explore the differences between these incretin subclasses. The trial was open-label, as sitagliptin is an oral medication; however, data were masked until database release. A 26-week extension was carried out to compare the efficacy and safety of liraglutide 1.2 and 1.8 mg with sitagliptin 100 mg up to 52 weeks [35], and a second 26-week extension was carried out to assess the efficacy and safety of switching from sitagliptin 100 mg to liraglutide after 52 weeks, in order to assess the sustainability of liraglutide treatment over 78 weeks [36]. More study information is given in Table 1. The results of this trial and its extensions are described in more detail in the article by Blonde and Montanya [33] in this supplement. Special Features of the Liraglutide Phase 3 Clinical Trial Programme Few comparative trials exist for incretin-based therapies. The liraglutide clinical trial programme is unusual in that it includes active comparator treatments; the comparators were chosen to represent the therapies commonly used in clinical practice at the time. To justify the use of liraglutide as a new therapy option in diabetes management, the programme not only measured the required efficacy and safety parameters over 26 52 weeks but also considered a number of clinical endpoints currently unsuccessfully addressed by commonly used glucose-lowering therapies; for example, the measurement of β-cell function, body weight and systolic blood pressure. Another intention of the LEAD phase 3 trials was to mimic the spectrum of patients seen in real-life clinical practice. Patients were consequently recruited from across the preinsulin continuum of care, and comparators were dosed at the maximum approved dose in all participating countries. In a typical clinical setting, therapies are usually added on to existing treatments (rather than substituted for one or more existing therapies) in order to help patients achieve or maintain glycaemic control as T2D progresses. These trials evaluated the impact of liraglutide when it was added on to a background diabetes therapy, when it was substituted for another antidiabetes agent, or in direct comparison to another incretin-based therapy. Subjects included in the clinical trials underwent a forced titration period to establish their assigned liraglutide doses. The doses selected for the programme (0.6, 1.2 and 1.8 mg/day) were chosen based on previous results from a clinical trial with liraglutide that investigated 0.65, 1.25 or 1.90 mg/day [3]. DIABETES, OBESITY AND METABOLISM In the LEAD phase 3 trials, subjects specifically randomised to treatment with liraglutide 0.6 mg remained on this dose, whereas subjects requiring 1.2 or 1.8 mg/day were up-titrated, from an initial 0.6-mg dose, across a 2 3 week escalation period. The 0.6-mg dose was not studied in some of the trials, as it was not intended to be a maintenance dose. A similar doseescalation method was adopted for exenatide in the AMIGO (AC2993: Diabetes Management for Improving Glucose Outcomes) trials in order to mitigate nausea, an adverse effect experienced with both liraglutide and exenatide treatment. How do the LEAD Studies and Separate Head-to-Head Study Compare to Other Large Phase 3 Trials with Incretin-Based Therapies? Exenatide BID has also been subject to extensive clinical studies, including the so-called AMIGO trials [31,37,38]. These 30- week, randomised, double-blind trials investigated exenatide use in clinical practice; however, unlike the LEAD/head-tohead study programme, the AMIGO trials compared exenatide against placebo and did not include active comparators. Treatment with exenatide (5 or 10 μg twice daily) was assessed as an add-on to existing therapy with metformin ( 1,500 mg/day) [37], SU (maximum effective dose) [38], or metformin + SU [31]. In the study by DeFronzo et al. [37], 336 patients were included from 82 sites in the USA, with a mean duration of diabetes of 4.9 6.6 years and a mean body mass index (BMI) of 34 kg/m 2.InthestudybyBuseetal.[38], 377 patients were included from 100 sites in the USA, with a mean duration of diabetes of 5.7 6.6 years and a mean BMI of 33 kg/m 2. Finally, in the study by Kendall et al. [31], 733 patients were included from 91 sites in the USA, with a mean duration of diabetes of 8.7 9.4 years and a mean BMI of 34 kg/m 2. The AMIGO trials have also had long-term follow up with interim analyses of open-label extensions of 52 weeks (totalling 82 weeks) [39,40] and 3 years [41]. Several subsequent trials also compared exenatide with long-acting insulin [32,42] and premixed insulin [43]. All were multinational, randomised controlled trials ranging from 26 to 52 weeks in duration. In the study by Heine et al. [32], 551 patients with T2D inadequately controlled with metformin and an SU from 82 centres in 13 countries were randomised to receive either 10 μg exenatide twice daily, or once-daily insulin glargine titrated to fasting blood glucose (FBG) target <5.6 mmol/l. Patients had a mean duration of diabetes of 9.2 9.9 years and a mean BMI of 31 kg/m 2. In a similar trial, Barnett et al. [42] included 138 patients who were inadequately controlled on either metformin or an SU; however, this crossover trial included two 16-week treatment periods. Patients had a mean duration of diabetes of 7.4 years and a mean BMI of 31 kg/m 2. Twice-daily exenatide (10 μg) has also been compared with twice-daily biphasic insulin aspart in an open-label, non-inferiority trial of 501 patients with T2D inadequately controlled on metformin and an SU [43]. Included patients were from 13 countries, with a mean duration of diabetes of 10.0 years and a mean BMI of 30 kg/m 2. 8 Nauck Volume 14 No.(Suppl.2) April 2012

DIABETES, OBESITY AND METABOLISM Primary clinical endpoints in the AMIGO trials included glycaemic control, as assessed by HbA1c. Secondary endpoints included percentage of patients achieving HbA1c <7%, and the effect of exenatide on meal cohort plasma glucose concentrations, body weight, fasting and postprandial concentrations of blood insulin, fasting proinsulin and lipids. Safety endpoints included adverse events, hypoglycaemia, clinical laboratory tests and antibodies. Consequently, the original exenatide trials differ from the liraglutide trials by representing fewer patients, a less diverse patient population, and no active comparators (although subsequent trials did compare exenatide with long-acting insulin [32,42,44] and premixed insulin [43]). A number of clinical endpoints assessed in the liraglutide and AMIGO trials also differed; for example, systolic blood pressure was measured throughout the liraglutide trials, but not in the AMIGO trials. However, it should be acknowledged that the effect of GLP-receptor analogues on blood pressure was discovered with the initial exenatide trials, so this was included as an endpoint in the subsequent insulin comparator trials. Exenatide once weekly (QW) is a long-acting, extendedrelease formulation of exenatide that has recently been approved (in Europe only) for use as a once-weekly injection. This sustained release formulation consists of injectable microspheres of exenatide and poly(d,l lactic-co-glycolic acid). The polymer breaks down over time, allowing an extended duration of drug delivery [45]. Exenatide QW has been studied in the large-scale, randomised DURATION clinical trials [45 48], which included the head-to-head study with liraglutide, DURATION 6 [49]. In this multicentre, open-label, randomised, 2-arm, parallel group, non-inferiority study, 911 patients [stratified by SU use, baseline HbA1c (<9.0% and 9.0%) and country] received exenatide 2 mg once weekly or liraglutide 1.8 mg once daily, both with OAD treatment. Patients in this trial had a mean HbA1c of 8.5% and mean BMI of 32.3 kg/m 2. Endpoints included non-inferiority [if the upper limit of the confidence interval for the treatment difference of change from baseline HbA1c (exenatide once weekly vs. liraglutide) was <0.25%], HbA1c 7%, body weight, systolic blood pressure, diastolic blood pressure, hypoglycaemia and adverse events. Sitagliptin, a DPP-4 inhibitor, has also been investigated in several phase 3 trials. It appears the majority of these trials, which ranged in duration from 18 to 24 weeks, were placebo-controlled only [50 53], with only one using an active comparator [54]. This 52-week, multinational, randomised, parallel group, non-inferiority study with an active-controlled, double-blind treatment period trial involved 1172 metformintreated patients [54]. Patients were randomised to either sitagliptin 100 mg or glipizide up to 20 mg, and had a mean duration of diabetes of 6.4 years and a mean BMI of 31.3 kg/m 2. Endpoints included HbA1c, FPG, insulin, proinsulin, lipid parameters, HOMA-β measurements and adverse events, weight and hypoglycaemia. As with the AMIGO exenatide studies, it appears that the sitagliptin phase 3 trials were mostly limited to a placebo-controlled design. A head-to-head 26- week, randomised, double-blind, double-dummy, superiority study with sitagliptin 100 mg and exenatide QW 2 mg as an adjunct to metformin in 491 patients with T2D. In this trial, patients had a mean HbA1c of 8.5% and a mean body weight of 88.0 kg. Endpoints included change in HbA1c from baseline to week 26, proportion of patients reaching HbA1c target of 6.5% or 7.0%, body weight, fasting lipid profile, fasting insulin profile, systolic blood pressure, diastolic blood pressure, cardiovascular risk markers, patient-reported outcomes, safety and tolerability [46]. In contrast, vildagliptin, another DPP-4 inhibitor, has been investigated in several active comparator trials [55 61], ranging in duration from 24 to 104 weeks and including SUs, metformin, acarbose and pioglitazone as active comparators. These studies, like the liraglutide trials, also included a considerable number of patients, most notably in the randomised, doubleblind, multicentre study by Ferrannini et al. [57] in which 2789 patients with T2D were randomised to either vildagliptin 50 mg twice daily or glimepiride up to 6 mg/day, both as add-on therapy to metformin. These patients had a mean duration of diabetes of approximately 6 years and a mean BMI of 31.8 kg/m 2. Endpoints included change in HbA1c, responder rates, HbA1c reduction by baseline HbA1c category, age group, FPG, body weight and lipid parameters. Adverse events and hypoglycaemia were recorded, as well as cardiovascular and cerebrovascular events plus pre-specified ECG changes. There are few published studies investigating saxagliptin, another DPP-4 inhibitor [62 65], including an active comparator trial [66]. This multicentre, randomised, double-blind, active-controlled phase 3 trial involved 1306 treatment-naïve patients with T2D. Included patients, who had a mean diabetes duration of 1.4 2.0 years and a mean BMI of 40.0 kg/m 2, were randomised to receive saxagliptin 5 mg + metformin 500 mg, saxagliptin 10 mg + metformin 500 mg, saxagliptin 10 mg + placebo or metformin 500 mg + placebo for 24 weeks. Endpoints included HbA1c, FPG, HbA1c 7% and 6.5%, postprandial glucose following an oral glucose tolerance test, fasting and postprandial insulin, C-peptide and glucagon, β-cell function and insulin resistance, body weight, lipid parameters, adverse events and ECG. An 18-week, multicentre, double-blind, non-inferiority trial compared the efficacy and safety of saxagliptin 5 mg and sitagliptin 100 mg, both as add-on to metformin, in 801 patients with T2D inadequately controlled with metformin. Endpoints included a comparison of the change in HbA1c from baseline, assessment of non-inferiority, change in body weight and safety [67]. Finally, the most recent DPP-4 inhibitor to be approved, linagliptin, has been studied in a multicentre, randomised, double-blind, parallel group, phase 3 trial which involved 1058 patients with T2D who were inadequately controlled with metformin and SU combination therapy [68]. Included patients received linagliptin 5 mg and placebo, when added to metformin + SU. Endpoints included HbA1c, HbA1c 7%, FPG, HOMA-β measurements, adverse events, body weight and hypoglycaemia. Conclusion The six LEAD trials and the separate head-to-head study were designed to explore the use of liraglutide in routine clinical Volume 14 No. (Suppl. 2) April 2012 doi:10.1111/j.1463-1326.2012.01573.x 9

practice per T2D treatment guidelines. The large number and range of patients included in the LEAD programme have also helped to elucidate the application of liraglutide across the spectrum of diabetes. Active comparisons against common diabetes treatments including metformin, rosiglitazone, glimepiride, insulin glargine, exenatide and sitagliptin have helped to clarify the similarities and differences in clinical outcomes between liraglutide and these agents. Considering the recent focus on cardiovascular and safety issues with diabetes treatments, it is also useful that extraglycaemic outcomes not usually addressed by other agents have been measured in the liraglutide trials. Acknowledgements The assistance of Watermeadow Medical, New York, NY, USA, funded by Novo Nordisk Inc, Princeton, NJ, USA, in preparing this article is gratefully acknowledged. Conflict of Interest Prof. Nauck has received research support from Bayer Vital, Berlin Chemie, Boehringer Ingelheim, Eli Lilly, GSK, MSD, Novartis, NN, Roche and ToleRx. He has been a consultant for AstraZeneca, Berlin Chemie, Eli Lilly, GSK, Roche, MSD, NN, sanofi-aventis, Takeda, Versartis and XOMA, and has participated in speakers bureaus/advisory panels on behalf of AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Roche, Merck Sharp & Dohme, Novartis, Novo Nordisk, Takeda and sanofi-aventis. References 1. Madsbad S, Schmitz O, Ranstam J, Jakobsen G, Matthews DR. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analogue liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial. Diabetes Care 2004; 27: 1335 1342. 2. Nauck MA, Hompesch M, Filipczak R, Le TD, Zdravkovic M, Gumprecht J. 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Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: Volume 14 No. (Suppl. 2) April 2012 doi:10.1111/j.1463-1326.2012.01573.x 11

a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther 2006; 28: 1556 1568. 54. Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP, Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 2007; 9: 194 205. 55. Foley JE, Sreenan S. Efficacy and safety comparison between the DPP-4 inhibitor vildagliptin and the sulfonylurea gliclazide after two years of monotherapy in drug-naïve patients with type 2 diabetes. Horm Metab Res 2009; 41: 905 909. 56. Bosi E, Dotta F, Jia Y, Goodman M. Vildagliptin plus metformin combination therapy provides superior glycaemic control to individual monotherapy in treatment-naive patients with type 2 diabetes mellitus. Diabetes Obes Metab 2009; 11: 506 515. 57. Ferrannini E, Fonseca V, Zinman B et al. Fifty-two-week efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes Obes Metab 2009; 11: 157 166. 58. Göke B, Hershon K, Kerr D et al. Efficacy and safety of vildagliptin monotherapy during 2-year treatment of drug-naïve patients with type 2 diabetes: comparison with metformin. Horm Metab Res 2008; 40: 892 895. 59. Pan C, Yang W, Barona JP et al. Comparison of vildagliptin and acarbose monotherapy in patients with Type 2 diabetes: a 24-week, double-blind, randomized trial. Diabet Med 2008; 25: 435 441. 60. Bolli G, Dotta F, Rochotte E, Cohen SE. Efficacy and tolerability of vildagliptin vs. pioglitazone when added to metformin: a 24-week, randomized, double-blind study. Diabetes Obes Metab 2008; 10: 82 90. 61. Filozof C, Gautier JF. A comparison of efficacy and safety of vildagliptin and gliclazide in combination with metformin in patients with Type 2 diabetes DIABETES, OBESITY AND METABOLISM inadequately controlled with metformin alone: a 52-week, randomized study. Diabet Med 2010; 27: 318 326. 62. Hollander P, Li J, Allen E, Chen R, CV181-013 Investigators. Saxagliptin added to a thiazolidinedione improves glycemic control in patients with type 2 diabetes and inadequate control on thiazolidinedione alone. J Clin Endocrinol Metab 2009; 94: 4810 4819. 63. Chacra AR, Tan GH, Apanovitch A, Ravichandran S, List J, Chen R, CV181-040 Investigators. Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: a randomised controlled trial. Int J Clin Pract 2009; 63: 1395 1406. 64. DeFronzo RA, Hissa MN, Garber AJ, Saxagliptin 014 Study Group et al. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care 2009; 32: 1649 1655. 65. Rosenstock J, Sankoh S, List JF. Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes. Diabetes Obes Metab 2008; 10: 376 386. 66. Jadzinsky M, Pfützner A, Paz-Pacheco E, Xu Z, Allen E, Chen R, CV181-039 Investigators. Saxagliptin given in combination with metformin as initial therapy improves glycaemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial. Diabetes Obes Metab 2009; 11: 611 622. 67. Scheen AJ, Charpentier G, Ostgren CJ, Hellqvist A, Gause-Nilsson I. Efficacy and safety of saxagliptin in combination with metformin compared with sitagliptin in combination with metformin in adult patients with type 2 diabetes mellitus. Diabetes Metab Res Rev 2010; 26: 540 549. 68. Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons with Type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study Diabet Med 2011; 28: 1352 1361. 12 Nauck Volume 14 No.(Suppl.2) April 2012