O R I G I N A L P A P E R
`One year of liraglutide treatment offers sustained and
`more effective glycaemic control and weight reduction
`compared with sitagliptin, both in combination with
`metformin, in patients with type 2 diabetes: a
`randomised, parallel-group, open-label trial
`
`R. Pratley,1 M. Nauck,2 T. Bailey,3 E. Montanya,4 R. Cuddihy,5 S. Filetti,6 A. Garber,7 A. B. Thomsen,8
`H. Hartvig,9 M. Davies,10 for the 1860-LIRA-DPP-4 Study Group
`
`S U M M A R Y
`
`Aim: The aim of this study was to compare the efficacy and safety of once-daily
`human glucagon-like peptide-1 analogue liraglutide with dipeptidyl peptidase-4
`inhibitor sitagliptin, each added to metformin, over 52 weeks in individuals with
`type 2 diabetes. Methods: In an open-label, parallel-group trial, metformin-trea-
`ted participants were randomised to liraglutide 1.2 mg ⁄ day (n = 225), liraglutide
`1.8 mg ⁄ day (n = 221) or sitagliptin 100 mg ⁄ day (n = 219) for 26 weeks (main
`phase). Participants continued the same treatment
`in a 26-week extension.
`Results: Liraglutide (1.2 or 1.8 mg) was superior to sitagliptin for reducing HbA1c
`from baseline (8.4–8.5%) to 52 weeks: )1.29% and )1.51% vs. )0.88% respec-
`tively. Estimated mean treatment differences between liraglutide and sitagliptin
`were as follows: )0.40% (95% confidence interval )0.59 to )0.22) for 1.2 mg
`and )0.63% ()0.81 to )0.44) for 1.8 mg (both p < 0.0001). Weight loss was
`greater with liraglutide 1.2 mg ()2.78 kg) and 1.8 mg ()3.68 kg) than sitagliptin
`()1.16 kg)
`(both p < 0.0001). Diabetes Treatment Satisfaction Questionnaire
`scores increased significantly more with liraglutide 1.8 mg than with sitagliptin
`(p = 0.03). Proportions of participants reporting adverse events were generally
`comparable; minor hypoglycaemia was 8.1%, 8.3% and 6.4% for
`liraglutide
`1.2 mg, 1.8 mg and sitagliptin respectively. Gastrointestinal side effects, mainly
`nausea, initially occurred more frequently with liraglutide, but declined after several
`weeks. Conclusion: Liraglutide provides greater sustained glycaemic control and
`body weight
`reduction over 52 weeks. Treatment satisfaction was significantly
`greater with 1.8 mg liraglutide, similar to 26-week results. The safety profiles of
`liraglutide and sitagliptin are consistent with previous reports.
`
`What’s known
`Results of independent trials and several 26-week
`head-to-head trials suggest that GLP-1 receptor
`agonists produce greater glycaemic and weight
`reductions compared with DPP-4 inhibitors. Our
`26-week trial showed that the human once-daily
`GLP-1 analogue liraglutide effected greater
`glycaemic control and weight loss than the DPP-4
`inhibitor sitagliptin.
`
`What’s new
`Longer-term sustainability of the 26-week efficacy
`and safety results with liraglutide and sitagliptin, as
`well as the maintenance of the greater comparative
`efficacy with liraglutide, was not known. This report
`shows that 26-week improvements were sustained
`after 52 weeks of treatment, with liraglutide
`producing significantly greater glycaemic and
`weight reductions than sitagliptin.
`
`Introduction
`
`Metformin is now standard first-line treatment (in
`addition to lifestyle modifications) for type 2 diabe-
`tes
`(T2D)
`(1). The progressive nature of T2D,
`including declining beta-cell function, usually neces-
`sitates addition of other antihyperglycaemic agents to
`metformin, as blood glucose levels rise. However,
`current guidelines vary with respect to second-line
`therapy (1,2). A meta-analysis of currently available
`non-insulin antihyperglycaemic agents added to met-
`formin revealed that, while reductions in glycosylated
`
`haemoglobin (HbA1c) were similar across
`several
`drug classes (including sulphonylureas, thiazolinedi-
`ones
`and alpha-glucosidase
`inhibitors;
`reduction
`range: 0.64–0.97%), treatment side effects (such as
`weight gain and ⁄ or hypoglycaemia) varied consider-
`ably (3). Therefore, head-to-head studies of glucose-
`lowering agents are needed to compare overall
`clinical efficacy and safety when added to metformin.
`Treatment intensification with incretin-based ther-
`apies is appealing given that they provide good gly-
`caemic control with a low risk of hypoglycaemia,
`because of
`the glucose-dependent
`stimulation of
`
`ª 2011 Blackwell Publishing Ltd Int J Clin Pract, April 2011, 65, 4, 397–407
`doi: 10.1111/j.1742-1241.2011.02656.x
`
`1Diabetes and Metabolism
`Translational Medicine Unit,
`University of Vermont College
`of Medicine, Burlington, VT,
`USA
`2Diabetes Center,
`Diabeteszentrum Bad
`Lauterberg, Bad Lauterberg im
`Harz, Germany
`3Director, AMCR Institute,
`Escondido, CA, USA
`4Endocrine Unit, IDIBELL-
`Hospital Universitari Bellvitge,
`Barcelona, Spain
`5Medical Director, International
`Diabetes Center, Minneapolis,
`MN, USA
`6Department of Clinical
`Sciences, Sapienza University of
`Rome, Rome, Italy
`7Departments of Medicine,
`Biochemistry, and Molecular and
`Cellular Biology, Baylor College
`of Medicine, Houston, TX, USA
`8Medical & Science Department,
`Novo Nordisk A ⁄ S, Soeborg,
`Denmark
`9Biostatistical Department, Novo
`Nordisk A ⁄ S, Soeborg, Denmark
`10Department of Cardiovascular
`Sciences, University of Leicester,
`Leicester, UK
`
`Correspondence to:
`Dr Richard Pratley, Diabetes and
`Metabolism Translational
`Medicine Unit, Colchester
`Research Facility 110C,
`University of Vermont College of
`Medicine, Burlington, VT 04556,
`USA
`Tel.: + 1 802 656 5811
`Fax: + 1 802 656 8031
`Email: richard.pratley@uvm.edu
`
`Disclosures
`RP has attended advisory panels
`for GlaxoSmithKline; has
`received research
`
`397
`
`MPI EXHIBIT 1126 PAGE 1
`
`

`

`398
`
`Liraglutide vs. sitagliptin 1-year results
`
`grants ⁄ participated in clinical
`trials for Merck & Co., Novartis
`Pharmaceuticals, Novo Nordisk
`Inc., Roche, Takeda Global
`Research Development Center
`Inc., Eli Lilly & Co., Merck & Co.,
`Novartis Pharmaceuticals
`Corporation, Novo Nordisk A ⁄ S,
`Pfizer Inc., sanofi-aventis; has
`acted as consultant for
`GlaxoSmithKline; has received
`honoraria from Novartis
`Pharmaceuticals Corp, Novo
`Nordisk Inc., Roche and Takeda
`Global Research Development
`Center and has attended
`speakers’ bureaux for Merck &
`Co. MN has received research
`grants from Bayer Vital Pharma,
`Eli Lilly & Co., Menarini ⁄ Berlin-
`Chemie, Merck Sharp & Dohme,
`Novartis Pharma and Novo
`Nordisk A ⁄ S; has accepted
`honoraria for membership in
`advisory boards and consulting,
`and has received honoraria for
`speaking on incretin-based
`antidiabetic medications from
`Amylin Pharmaceuticals,
`AstraZeneca, Bayer Vital
`Pharma, Berlin-
`Chemie ⁄ Menarini, Biovitrum,
`Boehringer Ingelheim, Eli Lilly &
`Co., GlaxoSmithKline, Hoffman
`La Roche, Novartis Pharma,
`Novo Nordisk A ⁄ S, sanofi-
`aventis Pharma and Takeda. TB
`has attended advisory panels for
`Amylin Pharmaceuticals; has
`received research support from
`Animas Corporation, Becton
`Dickinson, CPEX
`Pharmaceuticals, Dexcom, Eli
`Lilly & Co., GlaxoSmithKline,
`Medtronic MiniMed, Merck,
`Novo Nordisk Inc., Resmed and
`sanofi-aventis; and has attended
`speakers’ bureaux for Amylin
`Pharmaceuticals Inc., Dexcom,
`Eli Lilly & Co., Medtronic
`MiniMed, Novo Nordisk Inc.,
`Roche Diagnostics and sanofi-
`aventis. EM has attended
`advisory panels for Merck Sharp
`& Dohme, Novartis, Novo
`Nordisk and sanofi-aventis.
`RC has attended advisory boards
`for Novo Nordisk, Bayer, Roche,
`CeQur, Eli Lilly and Abbott; has
`received support for educational
`activities from Lifescan, Eli Lilly,
`Merck, Novartis and sanofi-
`aventis; has or is principal or co-
`investigator for sponsored
`clinical trials research for
`Amylin, Abbott, Bayer, Daiichi
`Sankyo, Dexcom, Edwards
`Lifesciences, Eli Lilly, Hygeia,
`Intarcia, Johnson &
`Johnson ⁄ Lifescan, Mannkind,
`Medtronic, Merck, Novo
`Nordisk, Quotient Diagnostics,
`ResMed, Roche, sanofi-aventis,
`
`insulin secretion and inhibition of glucagon release,
`and do not produce weight gain (3–6). Glucagon-like
`peptide-1 (GLP-1) receptor agonists and dipeptidyl
`peptidase-4 (DPP-4) inhibitors are two distinct clas-
`ses of incretin-based therapies. While 26-week, head-
`to-head studies suggest that GLP-1 receptor agonists
`have greater glycaemic and weight reduction efficacy
`than DPP-4 inhibitors (7–9),
`longer-term results
`have not been reported.
`In a 26-week, head-to-head trial of the once-daily
`human GLP-1 analogue liraglutide and the DPP-4
`inhibitor sitagliptin, both in combination with met-
`liraglutide (1.2 or 1.8 mg ⁄ day) was signifi-
`formin,
`cantly more effective than sitagliptin (100 mg ⁄ day)
`for reducing HbA1c ()1.24% and )1.50% vs. )0.90%
`respectively),
`fasting
`plasma
`glucose
`(FPG)
`()1.87 mmol ⁄ l [)33.66 mg ⁄ dl] and )2.14 mmol ⁄ l
`[)38.52 mg ⁄ dl] vs. )0.83 mmol ⁄ l [)14.94 mg ⁄ dl],
`respectively) and body weight ()2.86 and )3.38 kg
`vs. )0.96 kg respectively) (8). Incidence of minor
`hypoglycaemia was low (around 5%) and compara-
`ble across treatment groups. Nausea incidence was
`greater with liraglutide than with sitagliptin during
`therapy initiation, but generally declined after several
`weeks of treatment.
`Trial participants could continue treatment in a
`26-week extension phase designed to evaluate the
`sustainability of efficacy and safety effects of liraglu-
`tide and sitagliptin. This report shows that 26-week
`improvements were sustained after 52 weeks of treat-
`ment, with liraglutide producing greater glycaemic
`and weight reductions than sitagliptin.
`
`Methods
`
`Study design
`inclu-
`Details of
`study design and participant
`sion ⁄ exclusion criteria have been reported previously
`(8). Briefly, in a multinational, randomised, parallel-
`group, open-label, active-comparator trial, participants
`with T2D previously treated with metformin mono-
`therapy (‡ 1500 mg ⁄ day) for a minimum of 3 months,
`but with suboptimal glycaemic control (HbA1c 7.5–
`10%), were randomised (1 : 1 : 1) to treatment with
`either liraglutide 1.2 or 1.8 mg ⁄ day (subcutaneous
`injection) or sitagliptin 100 mg ⁄ day (orally) while
`continuing on existing metformin therapy.
`After completing the 26-week main phase, partici-
`pants choosing to enrol
`in the extension provided
`written informed consent and continued for another
`26 weeks
`in their originally
`assigned treatment
`groups. The protocol, including the extension, was
`institutional review board-approved, followed Good
`Clinical Practice guidelines and conformed to the
`Declaration of Helsinki. The 52-week trial was
`
`initiated on 16 June 2008 and completed on 10
`December 2009.
`Additional withdrawal criteria during the exten-
`sion were: elevated FPG > 11.1 mmol ⁄ l (200 mg ⁄ dl)
`with no treatable intercurrent cause or acute pancre-
`atitis (defined as a minimum two out of three of the
`following: characteristic abdominal pain, amylase
`and ⁄ or lipase > 3 · upper normal range or charac-
`teristic findings on computed tomography ⁄ magnetic
`resonance imaging).
`
`Outcomes
`included
`Efficacy outcomes assessed at 52 weeks
`change in HbA1c, FPG, body weight, proportion of
`participants achieving HbA1c < 7% or £ 6.5%, pro-
`portion of participants reaching the composite end-
`point of HbA1c < 7.0% with no weight gain and no
`confirmed major
`(participant unable
`to
`treat
`him ⁄ herself) or minor (plasma glucose < 3.1 mmol ⁄ l
`[56 mg ⁄ dl]) hypoglycaemia. Other measures included
`fasting C-peptide, fasting pro-insulin : insulin ratio,
`and homeostasis model assessment analyses of beta-
`cell
`function (HOMA-B) and insulin resistance
`(HOMA-IR). Change in Diabetes Treatment Satisfac-
`tion Questionnaire (DTSQ) scores from baseline was
`not assessed in participants from Slovakia, Serbia or
`Slovenia (118 ⁄ 665 [17.7%]) because of the lack of
`validated questionnaires in their native languages.
`Safety and tolerability assessments at 52 weeks
`included incidence of adverse events (AEs) and hyp-
`oglycaemia, as well as various clinical and laboratory
`variables. AEs of special
`interest
`included nausea,
`thyroid AEs and pancreatitis.
`
`Statistical analysis
`Methods for statistical analyses were similar to those
`reported for the first 26 weeks (8). Glycaemic effi-
`cacy, as measured by change in HbA1c from baseline
`to week 52 of
`liraglutide vs. sitagliptin treatment,
`was assessed by a non-inferiority comparison with a
`margin of 0.4%, followed by a superiority compari-
`son. Both tests used two-sided hypotheses, with a
`p-value of < 0.05 considered significant. Analysis of
`covariance, with treatment and country as fixed
`effects and baseline measure as a covariate, was used
`for continuous efficacy end-points. Logistic regres-
`sion was used to analyse categorical variables, includ-
`ing the participant proportions achieving HbA1c
`targets and composite end-point (HbA1c < 7.0% with
`no weight gain and no confirmed major or minor
`hypoglycaemia), with treatment and country as fixed
`effects, and baseline HbA1c (and body weight for
`composite) as covariates. Efficacy assessments were
`performed on the full analysis set: all randomised
`participants exposed to at least one dose of the drug.
`
`ª 2011 Blackwell Publishing Ltd Int J Clin Pract, April 2011, 65, 4, 397–407
`
`MPI EXHIBIT 1126 PAGE 2
`
`

`

`Liraglutide vs. sitagliptin 1-year results
`
`399
`
`Takeda and Valeritas; and is an
`employee of the International
`Diabetes Center at Park Nicollet.
`All honoraria, speaking fees,
`consulting fees and research and
`educational support are paid
`directly to the non-profit
`International Diabetes Center of
`which RP is a salaried employee;
`he receives no personal
`payments for any of these
`activities. SF has acted as
`consultant and attended
`speakers’ bureaux for Novo
`Nordisk A ⁄ S. AG is an advisor
`and speaker for Novo Nordisk,
`Merck, GlaxoSmithKline and
`Sankyo. ABT is an employee of
`Novo Nordisk and was directly
`involved in study conduct. HH is
`an employee of Novo Nordisk
`and was directly involved in
`study conduct. MD has attended
`advisory panels for Eli Lilly &
`Co., Merck Sharp & Dohme Ltd.,
`Novartis Pharmaceuticals, Novo
`Nordisk Pharma Ltd., Schering-
`Plough, Roche and Bristol-Myers
`Squibb; has received research
`support from Eli Lilly & Co.,
`Merck Sharp & Dohme Ltd.,
`Novartis Pharmaceuticals, Novo
`Nordisk Pharma UK and
`GlaxoSmithKline; and has
`received honoraria for lectures
`from Eli Lilly & Co., Merck Sharp
`& Dohme Ltd., Novartis
`Pharmaceuticals and Novo
`Nordisk Pharma Ltd.
`
`Clinical trial registration
`number: clinicaltrials.gov,
`NCT00700817
`
`Re-use of this article is
`permitted in accordance with
`the Terms and Conditions set
`out at http://wileyonlinelibrary.
`com/onlineopen#OnlineOpen_
`Terms
`
`Missing data were imputed using the last observation
`carried forward (LOCF) method.
`The safety analysis set
`included all participants
`exposed to at least one dose of the drug they were
`randomised to. Serum calcitonin values were analy-
`sed using a repeated measures model, with time,
`gender, treatment and treatment-by-time interaction
`as fixed effects and participant as a random effect.
`Hypoglycaemia was analysed using a general
`linear
`model with treatment as a fixed effect. For each
`week of the extension, the proportions of partici-
`pants experiencing nausea were analysed using Fish-
`er’s exact test. Only summary statistics are reported
`for other safety parameters. Data are reported as
`least square means with 95% confidence interval
`(CI), unless otherwise noted. The significance level
`is p < 0.05.
`
`Results
`
`Participant disposition and baseline
`characteristics
`After screening, 665 participants were randomised
`into three treatment arms: liraglutide 1.2 mg, 1.8 mg
`and sitagliptin (Figure 1). As previously reported, the
`groups were well matched for baseline characteristics
`(8). Of participants completing 26 weeks, 497 ⁄ 554
`(90%) entered into the extension, with 436 ⁄ 497
`(88%) completing 52 weeks. A lower proportion of
`randomised participants withdrew from the exten-
`sion compared with the main phase, and withdrawal
`because of AEs was also lower in the extension.
`Patient withdrawal because of AEs in the main phase
`was higher for both liraglutide groups than for sitag-
`liptin, whereas only the liraglutide 1.8 mg group had
`a slightly higher AE withdrawal rate in the extension.
`
`Efficacy outcomes
`Mean HbA1c decreased more substantially with either
`dose of liraglutide compared with sitagliptin during
`the first 12 weeks, and these reductions were gener-
`ally maintained up to week 52 (Figure 2A). Mean
`reductions in HbA1c from baseline to week 52 with
`liraglutide 1.2 mg ()1.29% [95% CI: )1.43 to
`)1.15]) and 1.8 mg ()1.51% [)1.65 to )1.37]) were
`significantly
`greater
`compared with
`sitagliptin
`()0.88% [)1.02 to )0.74]). Estimated mean treat-
`ment differences were )0.40% (95% CI )0.59 to
`)0.22)
`for
`liraglutide 1.2 mg vs.
`sitagliptin and
`)0.63% ()0.81 to )0.44) for liraglutide 1.8 mg vs.
`sitagliptin (p < 0.0001 for both doses.)
`As with HbA1c, liraglutide was more effective for
`reducing FPG compared with sitagliptin (Figure 2B).
`FPG declined rapidly from baseline during weeks 0–4
`in all treatment groups and the reductions were gen-
`
`erally sustained up to 52 weeks. FPG reductions from
`baseline at week 52 were )1.71 mmol ⁄ l (95% CI
`)2.04 to )1.38) ()30.78 mg ⁄ dl [)36.78 to )24.78])
`for 1.2 mg liraglutide and )2.04 mmol ⁄ l ()2.37 to
`)1.71)
`()36.72 mg ⁄ dl
`[)42.72 to )30.72])
`for
`1.8 mg liraglutide vs. )0.59 mmol ⁄ l ()0.92 to )0.26)
`()10.62 mg ⁄ dl [)16.62 to )4.62]) for sitagliptin.
`Estimated mean treatment differences between lira-
`glutide and sitagliptin were )1.13 mmol ⁄ l (95% CI
`)1.57 to )0.68) ()20.34 mg ⁄ dl [)28.26 to )12.24])
`for 1.2 mg and )1.45 mmol ⁄ l
`()1.89 to )1.01)
`()26.1 mg ⁄ dl
`[)34.02
`to )18.18])
`for
`1.8 mg
`(p < 0.0001 vs. sitagliptin for both doses).
`Weight loss was considerably greater with liraglu-
`tide compared with sitagliptin (Figure 2C). Most
`weight loss occurred during the first 26 weeks and
`was
`sustained in the extension in all
`treatment
`groups (Figure 2C). At week 52, weight loss with
`liraglutide 1.2 mg was )2.78 kg (95% CI )3.39 to
`)2.17) compared with )3.68 kg ()4.29 to )3.07) for
`1.8 mg and )1.16 kg ()1.77 to )0.55) for sitagliptin.
`Estimated mean treatment differences were )1.62 kg
`(95% CI )2.43 to )0.82) for liraglutide 1.2 mg and
`)2.53 kg ()3.33 to )1.72) for liraglutide 1.8 mg vs.
`sitagliptin (p < 0.0001 for both doses). Weight loss
`with liraglutide 1.8 mg was significantly greater than
`that with liraglutide 1.2 mg (p = 0.03). The 26-week-
`reductions
`in waist circumference were generally
`maintained at week 52 in all groups and were signifi-
`cantly larger with liraglutide (both doses) than sitag-
`liptin (Table 1).
`As with the main study results (8), postprandial
`plasma glucose data were highly variable and difficult
`to interpret, and are excluded from this report. As
`this was a multinational study, data variability may
`have resulted from the varying meal content, time of
`meals and timing of postprandial glucose measure-
`ments across different countries.
`Overall, the magnitude of HbA1c reduction from
`baseline increased with the higher baseline HbA1c
`categories in all groups (Figure 3A). After 52 weeks,
`mean reductions in HbA1c were significantly greater
`with liraglutide 1.8 mg than with sitagliptin across all
`baseline HbA1c categories. The reductions were sig-
`nificantly larger with liraglutide 1.2 mg than with
`sitagliptin for two baseline HbA1c categories: > 8%
`to £ 8.5% and > 9%.
`Proportions of participants achieving target HbA1c
`< 7% (American Diabetes Association [ADA] target)
`or £ 6.5% (American Association of Clinical Endo-
`crinologists
`[AACE]
`target)
`increased during the
`extension in all treatment groups (Figure 3B). Over-
`all,
`liraglutide (both doses) was significantly more
`effective than sitagliptin in allowing patients to reach
`target HbA1c after 52 weeks.
`
`ª 2011 Blackwell Publishing Ltd Int J Clin Pract, April 2011, 65, 4, 397–407
`
`MPI EXHIBIT 1126 PAGE 3
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`

`400
`
`Liraglutide vs. sitagliptin 1-year results
`
`Figure 1 Trial flow chart with participant demographics at baseline. Demographic data are mean ± SD, unless otherwise
`noted. *Participants were withdrawn if they fulfilled withdrawal criteria, decided that they no longer wanted to participate,
`or did not attend any visit after randomisation. BMI, body mass index; FAS, full analysis set; FPG, fasting plasma glucose
`
`The estimated proportion of participants reaching
`the composite end-point of HbA1c < 7.0%, with
`no weight gain and no confirmed major or minor
`hypoglycaemia, increased during the extension in all
`treatment groups (Figure 3C). After 52 weeks, a sig-
`nificantly greater percentage of participants achieved
`the
`composite
`end-point with liraglutide
`(both
`groups) than with sitagliptin, with an odds ratio
`(OR) vs. sitagliptin of 2.80 (95% CI 1.74 to 4.48)
`and 4.37 (2.74 to 6.98) for 1.2 and 1.8 mg liraglutide
`respectively (both doses p < 0.0001). Liraglutide
`
`1.8 mg was more effective than liraglutide 1.2 mg
`(OR: 1.56 [1.04 to 2.35], p = 0.03).
`Overall, the improved status of several indicators
`of beta-cell function (fasting C-peptide, fasting pro-
`insulin:insulin ratio and HOMA-B) at week 26 was
`maintained at week 52, with liraglutide effecting
`significantly greater improvements than sitagliptin
`(Table 1). The reduction in HOMA-IR became sig-
`nificantly greater with liraglutide 1.8 mg than sitag-
`liptin during the extension. As observed at week 26,
`mean heart rate continued to be slightly but signifi-
`
`ª 2011 Blackwell Publishing Ltd Int J Clin Pract, April 2011, 65, 4, 397–407
`
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`

`Liraglutide vs. sitagliptin 1-year results
`
`401
`
`and sitagliptin respectively) with no consistent
`pattern with respect to system organ class (Table 2).
`Three deaths occurred during the 52-week period.
`Two deaths during the first 26 weeks, one in a
`participant with pancreatic carcinoma (liraglutide
`1.8 mg) and one because of cardiac arrest (sitaglip-
`tin), were reported previously and considered unli-
`kely to be related to the trial drugs (8). One sudden
`cardiac death during the extension occurred in a 66-
`year-old man randomised to sitagliptin and was
`judged as unlikely to be related to the trial drug by
`the investigator.
`Gastrointestinal disorders, as well as infections and
`infestations, were the most commonly reported mild-
`to-moderate AEs with liraglutide. The incidence
`of nausea,
`the most prevalent gastrointestinal AE
`with liraglutide, declined after the first 3 weeks of
`treatment and remained low during the extension
`(Figure 4). For each week of the extension, the pro-
`portions of participants experiencing nausea did not
`differ significantly between liraglutide (1.2 or 1.8 mg)
`and sitagliptin treatment groups.
`One episode of major hypoglycaemia (blood glu-
`cose 3.6 mmol ⁄ l [64.8 mg ⁄ dl]) occurred during the
`first 26 weeks in a participant on liraglutide 1.2 mg
`(8). Third-party assistance was required, but no sei-
`zures or coma occurred. The participant recovered
`and the episode was categorised as possibly related to
`the trial product by the investigator. No major hypo-
`glycaemic episodes occurred during the extension.
`Minor hypoglycaemia rates were low and comparable
`between treatment
`groups over 52 weeks,
`after
`excluding an outlier in the 1.8 mg liraglutide group
`with 21 minor events during the first 26 weeks and
`two events in the extension (leading to participant
`withdrawal
`from the trial). Adjusted minor hypo-
`glycaemia rates were 0.143, 0.154 and 0.137 hypogly-
`caemic episodes per patient per year for liraglutide
`1.2 mg, 1.8 mg and sitagliptin respectively.
`One case of ‘non-acute’ pancreatitis was reported
`during the extension in a 54-year-old man, with a
`medical history of hepatitis and hyperlipidaemia,
`treated with liraglutide 1.8 mg for 227 days. Initially,
`the participant experienced abdominal pain, nausea,
`vomiting for 1 day and black stools for 3 days. The
`participant was instructed to stop aspirin and initiate
`omeprazole treatment. Upon later hospitalisation for
`a different condition, laboratory tests showed slightly
`increased levels of amylase (2.6 lkat ⁄ l, normal range:
`0–1.67 lkat ⁄ l) and lipase (1.44 lkat ⁄ l, normal range:
`0–1 lkat ⁄ l). The investigator decided to withdraw
`the participant, although the specific withdrawal cri-
`teria for acute pancreatitis were not met. The event
`was rated as mild and possibly related to the trial
`drug by the investigator.
`
`Figure 2 Effect of 1.2 mg liraglutide, 1.8 mg liraglutide or
`100 mg sitagliptin on glycaemic control and body weight
`from baseline to 52 weeks. (A) Mean HbA1c values. (B)
`Mean fasting plasma glucose (FPG) values. (C) Mean
`change in body weight. Error bars are 1.96 · SE,
`corresponding to the 95% CI
`
`cantly elevated with liraglutide compared with sitag-
`liptin at week 52 (Table 1).
`The increase in DTSQ scores at week 26 was gen-
`erally sustained at week 52 in all treatment groups.
`The improvement in overall treatment satisfaction,
`measured as the increase in DTSQ scores between
`weeks 0 and 52, was significantly higher with liraglu-
`tide 1.8 mg (baseline: 28.0) than with sitagliptin
`(baseline: 27.1): 4.3 (95% CI 3.3 to 5.3) vs. 3.0 (2.0
`to 4.0) (p = 0.03). By contrast, the increase from
`baseline (27.8) with liraglutide 1.2 mg (3.3 [2.3 to
`4.3]) was not statistically different from sitagliptin.
`
`Safety outcomes
`The majority (‡ 97%) of treatment-emergent AEs in
`all groups over 52 weeks were mild or moderate. The
`proportion of participants reporting serious AEs was
`low and comparable between treatment groups
`(4.5%, 6.0% and 5.5% for liraglutide 1.2 mg, 1.8 mg
`
`ª 2011 Blackwell Publishing Ltd Int J Clin Pract, April 2011, 65, 4, 397–407
`
`MPI EXHIBIT 1126 PAGE 5
`
`

`

`402
`
`Liraglutide vs. sitagliptin 1-year results
`
`1.63 ()7.74 to 11.00)
`0.09 (0.03 to 0.15)
`)0.09 ()0.13 to )0.05)
`25.76 (19.39 to 32.13)
`)1.36 ()2.05 to )0.67)
`
`)2.27 ()11.76 to 7.22)
`0.01 ()0.05 to 0.07)
`)0.01 ()0.05 to 0.03)
`3.98 ()2.45 to 10.45)
`)0.41 ()1.1 to 0.28)
`
`1.67 ()11.2 to 14.51); 0.80
`0.04 ()0.05 to 0.12); 0.38
`)0.06 ()0.11 to )0.02); 0.005
`18.60 (9.82 to 27.38); < 0.001
`)0.85 ()1.79 to 0.08); 0.07
`
`3.90 ()8.76 to 16.57); 0.55
`0.08 (0.00 to 0.16); 0Æ06
`)0.08 ()0.13 to )0.04); < 0.001
`21.77 (13.12 to 30.42); < 0.001
`)0.94 ()1.86 to )0.02); 0.04
`
`)2.55 ()4.37 to )0.72)
`)0.87 ()1.99 to 0.25)
`3.09 (1.91 to 4.27)
`
`)1.03 ()2.85 to 0.79)
`)1.47 ()2.59 to )0.35)
`0.09 ()1.09 to 1.27)
`
`0.66 ()1.79 to 3.10); 0.60
`0.94 ()0.57 to 2.45); 0.22
`1.63 (0.03 to 3.22); 0.05
`
`)1.53 ()3.97 to 0.92); 0.22
`0.60 ()0.90 to 2.11); 0.43
`3.00 (1.40 to 4.59); < 0.001
`
`)0.09 ()0.21 to 0.03)
`0.09 ()0.01 to 0.19)
`)0.19 ()0.27 to )0.11)
`0.02 (0.00 to 0.04)
`)0.32 ()0.52 to )0.12)
`)0.10 ()0.14 to )0.06)
`–0.03 ()0.05 to )0.01)
`
`0.03 ()0.15 to 0.09)
`0.17 (0.07 to 0.27)
`)0.15 ()0.23 to )0.07)
`0.01 ()0.01 to 0.03)
`)0.23 ()0.43 to )0.03)
`)0.06 ()0.10 to )0.02)
`–0.03 ()0.05 to )0.01)
`
`)0.04 ()0.20 to 0.12); 0.61
`)0.08 ()0.20 to 0.05); 0.25
`0.04 ()0.06 to 0.13); 0.47
`0.00 ()0.03 to 0.04); 0.92
`0.12 ()0.13 to 0.38); 0.34
`)0.01 ()0.06 to 0.04); 0.67
`0.00 ()0.03 to 0.04); 0.83
`
`)0.12 ()0.28 to 0.03); 0.12
`)0.08 ()0.21 to 0.05); 0.23
`)0.04 ()0.14 to 0.06); 0.43
`0.01 ()0.02 to 0.05); 0.53
`)0.09 ()0.34 to 0.16); 0.49
`)0.05 ()0.09 to 0.00); 0.05
`)0.00 ()0.04 to 0.03); 0.93
`
`)3.02 ()3.76 to )2.28)
`
`)1.23 ()1.97 to )0.49)
`
`)1.13 ()2.12 to )0.13); 0Æ03
`
`)1.79 ()2.78 to )0.79); < 0.001
`
`Table 1 Changes in secondary end-points from baseline to week 52
`
`Mean change from baseline [95% CI]
`
`Estimated treatment difference; p-value
`
`Liraglutide 1.2 mg
`
`Liraglutide 1.8 mg
`
`Sitagliptin 100 mg
`
`Liraglutide 1.2 mg–sitagliptin
`
`Liraglutide 1.8 mg–sitagliptin
`
`Beta-cell function and insulin resistance
`)0.60 ()10.11 to 8.91)
`Fasting insulin (pmol ⁄ l)
`0.05 ()0.01 to 0.11)
`Fasting C-peptide (nmol ⁄ l)
`)0.07 ()0.11 to )0.03)
`Fasting pro-insulin:insulin ratio
`HOMA-B (%)
`22.58 (16.09 to 29.07)
`)1.27 ()1.96 to )0.58)
`HOMA-IR (%)
`Blood pressure
`Systolic blood pressure (mmHg)
`Diastolic blood pressure (mmHg)
`Heart rate (beats ⁄ min)
`Lipid profiles
`Total cholesterol (mmol ⁄ l)
`LDL cholesterol (mmol ⁄ l)
`VLDL cholesterol (mmol ⁄ l)
`HDL cholesterol (mmol ⁄ l)
`Triglycerides (mmol ⁄ l)
`Free fatty acids (mmol ⁄ l)
`Apolipoprotein B (g ⁄ l)
`Physical measure(s)
`Waist circumference (cm)
`
`)0.01 ()0.13 to 0.11)
`0.09 ()0.01 to 0.19)
`)0.11 ()0.19 to )0.03)
`0.01 ()0.01 to 0.03)
`)0.10 ()0.30 to 0.10)
`)0.07 ()0.11 to )0.03)
`)0.03 ()0.05 to )0.01)
`
`)2.36 ()3.10 to )1.62)
`
`)0.37 ()2.19 to 1.45)
`–0.53 ()1.65 to 0.59)
`1.72 (0.54 to 2.90)
`
`Data are least square means (95% CI); p-values (for treatment differences). CI, confidence interval; HDL, high-density lipoprotein; HOMA-B, homeostasis model assessment of beta-cell function; HOMA IR, HOMA
`insulin resistance; LDL, low-density lipoprotein; VLDL, very low-density lipoprotein.
`
`ª 2011 Blackwell Publishing Ltd Int J Clin Pract, April 2011, 65, 4, 397–407
`
`MPI EXHIBIT 1126 PAGE 6
`
`

`

`Liraglutide vs. sitagliptin 1-year results
`
`403
`
`Figure 3 Mean reductions in HbA1c by baseline category and proportions of participants reaching target end-points with
`1.2 mg liraglutide, 1.8 mg liraglutide and 100 mg sitagliptin from weeks 0–52. (A) Mean reductions in HbA1c from
`baseline to week 52 by baseline HbA1c category. (B) Percentage of participants achieving target HbA1c < 7% (ADA) or
`£ 6.5% (AACE). (C) Percentage of participants reaching the composite end-point of HbA1c < 7.0%, with no weight gain
`and no confirmed major or minor hypoglycaemia. In (B) and (C), solid bar portions represent percentages from weeks
`0–26, while shaded portions represent percentages from weeks 27–52. *p < 0.05 vs. sitagliptin; **p £ 0.01 vs. sitagliptin;
`***p < 0.001 vs. sitagliptin. p-values are derived from a logistic regression model with treatment and country as fixed
`effects and baseline HbA1c and body weight (for composite) as covariate(s). AACE, American Association of Clinical
`Endocrinologists; ADA, American Diabetes Association
`
`Mean changes in serum calcitonin, an indicator
`of C-cell hyperplasia, were small and there were no
`statistically significant differences between treatment
`groups. Mean calcitonin levels remained below the
`upper normal limit for both genders from baseline
`to 52 weeks. The proportions of subjects reporting
`thyroid-related treatment-emergent AEs were compa-
`rable across treatment groups (5.0%, 5.5% and 4.6%
`for liraglutide 1.2 mg, 1.8 mg and sitagliptin respec-
`
`tively) (Table S1). No cases of thyroid malignancy
`were found during the trial period (Table S2).
`
`Discussion
`
`Liraglutide produced sustained and greater reduc-
`tions in HbA1c, FPG and body weight compared
`with sitagliptin after 52 weeks of treatment, similar
`to results previously reported after week 26 (8).
`
`ª 2011 Blackwell Publishing Ltd Int J Clin Pract, April 2011, 65, 4, 397–407
`
`MPI EXHIBIT 1126 PAGE 7
`
`

`

`404
`
`Liraglutide vs. sitagliptin 1-year results
`
`Table 2 Participants with treatment-emergent adverse events during weeks 0–52
`
`Adverse events
`
`Serious adverse events*
`Deaths
`Severe adverse events
`Gastrointestinal disorders
`Musculoskeletal and connective
`tissue disorders
`Infections and infestations
`Neoplasms (benign, malignant
`and unspecified)
`Cardiac disorders
`Investigations
`Nervous system disorders
`Renal and urinary disorders
`Adverse events (of any severity)
`reported by > 5% of participants
`Gastrointestinal disorders
`Nausea
`Vomiting
`Diarrhoea
`Constipation
`Dyspepsia
`Infections and infestations
`Nasopharyngitis
`Influenza
`Nervous system disorders
`Headache
`Musculoskeletal and connective
`tissue disorders
`General disorders and administration-site
`conditions
`Metabolism and nutrition disorders
`Decreased appetite
`Investigations
`Skin and subcutaneous tissue disorders
`Respiratory, thoracic and mediastinal
`disorders
`Injury, poisoning and procedural
`complications
`Vascular disorders
`
`Liraglutide
`1.2 mg/day
`(n = 221)
`
`Liraglutide
`1.8 mg/day
`(n = 218)
`
`Sitagliptin
`100 mg/day
`(n = 219)
`
`10 (4.5)
`0
`12 (5.4)
`4 (1.8)
`3 (1.4)
`
`3 (1.4)
`1 (0.5)
`
`2 (0.9)
`0 (0.0)
`0 (0.0)
`0 (0.0)
`158 (71.5)
`
`80 (36.2)
`48 (21.7)
`18 (8.1)
`20 (9.0)
`10 (4.5)
`8 (3.6)
`74 (33.5)
`27 (12.2)
`13 (5.9)
`40 (18.1)
`21 (9.5)
`39 (17.6)
`
`13 (6.0)
`1 (0.5)
`15 (6.9)
`5 (2.3)
`1 (0.5)
`
`3 (1.4)
`3 (1.4)
`
`1 (0.5)
`1 (0.5)
`0 (0.0)
`0 (0.0)
`167 (76.6)
`
`94 (43.1)
`60 (27.5)
`23 (10.6)
`27 (12.4)
`13 (6.0)
`15 (6.9)
`77 (35.3)
`32 (14.7)
`4 (1.8)
`48 (22.0)
`29 (13.3)
`45 (20.6)
`
`12 (5.5)
`2 (0.9)
`13 (5.9)
`4 (1Æ8)
`1 (0.5)
`
`3 (1.4)
`1 (0.5)
`
`1 (0.5)
`0 (0.0)
`2 (0.9)
`1 (0.5)
`139 (63.5)
`
`52 (23.7)
`12 (5.5)
`11 (5.0)
`14 (6.4)
`8 (3.7)
`5 (2.3)
`75 (34.2)
`31 (14.2)
`8 (3.7)
`44 (20.1)
`27 (12.3)
`45 (20.5)
`
`31 (14.0)
`
`32 (14.7)
`
`13 (5.9)
`
`25 (11.3)
`8 (3.6)
`21 (9.5)
`22 (10.0)
`16 (7.2)
`
`27 (12.4)
`12 (5.5)
`27 (12.4)
`20 (9.2)
`18 (8.3)
`
`19 (8.7)
`3 (1.4)
`16 (7.3)
`22 (10.0)
`21 (9.6)
`
`20 (9.0)
`
`20 (9.2)
`
`21 (9.6)
`
`16 (7.2)
`
`15 (6.9)
`
`10 (4.6)
`
`Data are number (%) of participants. A participant could experience more than one adverse
`event. *Liraglutide 1.2 mg group: acute myocardial infarction, myocardial infarction, epiglottic
`carcinoma, thyroid disorder, hypertensive crisis (relapsing), hypoesthesia, coxarthrosis defor-
`mans, worsening of coxarthrosis, haemorrhagic anaemia, haematochezia, infected seb