Diabetes & Metabolism 46 (2020) 100–109
`
`Available online at
`
`ScienceDirect
`www.sciencedirect.com
`
`Original article
`
`Efficacy and safety of once-weekly semaglutide 1.0 mg vs once-daily
`liraglutide 1.2 mg as add-on to 1–3 oral antidiabetic drugs in subjects
`with type 2 diabetes (SUSTAIN 10)
`
`M.S. Capehorn a,*, A.-M. Catarig b, J.K. Furberg b, A. Janez c, H.C. Price d, S. Tadayon b,
`B. Verge` s e, M. Marre f
`a Rotherham Institute for Obesity, Clifton Medical Centre, S65 1DA Rotherham, South Yorkshire, UK
`b Novo Nordisk A/S, DK-2860 Søborg, Denmark
`c Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
`d West Hampshire Community Diabetes Service, SO43 7NG Lyndhurst, UK
`e CHU, 21000 Dijon, France
`f Clinique Ambroise Pare´, 27, boulevard Victor-Hugo, 92200 Neuilly-sur-Seine, France
`
`A R T I C L E
`
`I N F O
`
`A B S T R A C T
`
`Article history:
`Received 14 June 2019
`Received in revised form 28 August 2019
`Accepted 1st September 2019
`Available online 17 September 2019
`
`Keywords:
`Glycaemic control
`Glucagon-like peptide-1 receptor agonist
`Liraglutide
`Semaglutide
`Type 2 diabetes
`SUSTAIN
`
`Aims. – SUSTAIN 10 compared the efficacy and safety of the anticipated most frequent semaglutide dose
`(1.0 mg) with the current most frequently prescribed liraglutide dose in Europe (1.2 mg), reflecting
`clinical practice.
`Methods. – In this phase 3b, open-label trial, 577 adults with type 2 diabetes (HbA1c 7.0–11.0%) on 1–3
`oral antidiabetic drugs were randomized 1:1 to subcutaneous once-weekly semaglutide 1.0 mg or
`subcutaneous once-daily liraglutide 1.2 mg. Primary and confirmatory secondary endpoints were
`changes in HbA1c and body weight from baseline to week 30, respectively.
`Results. – Mean HbA1c (baseline 8.2%) decreased by 1.7% with semaglutide and 1.0% with liraglutide
`(estimated treatment difference [ETD] –0.69%; 95% confidence interval [CI] 0.82 to 0.56, P < 0.0001).
`Mean body weight (baseline 96.9 kg) decreased by 5.8 kg with semaglutide and 1.9 kg with liraglutide (ETD
`3.83 kg; 95% CI 4.57 to 3.09, P < 0.0001). The proportions of subjects achieving glycaemic targets
`of < 7.0% and  6.5%, weight loss of  5% and  10%, and a composite endpoint of HbA1c < 7.0% without
`severe or blood glucose-confirmed symptomatic hypoglycaemia and no weight gain were greater with
`semaglutide vs liraglutide (all P < 0.0001). Both treatments had similar safety profiles, except for more
`frequent gastrointestinal disorders (the most common adverse events [AEs]) and AEs leading to premature
`treatment discontinuation with semaglutide vs liraglutide (43.9% vs 38.3% and 11.4% vs 6.6%, respectively).
`Conclusion. – Semaglutide was superior to liraglutide in reducing HbA1c and body weight. Safety profiles
`were generally similar, except for higher rates of gastrointestinal AEs with semaglutide vs liraglutide.
` C 2019 Elsevier Masson SAS. All rights reserved.
`
`Abbreviations: AACE, American Association of Clinical Endocrinologists; ADA, American Diabetes Association; AE, adverse event; BG, blood glucose; BMI, body mass index;
`bpm, beats per minute; CI, confidence interval; CKD-EPI, The Chronic Kidney Disease Epidemiology Collaboration; CoV, coefficient of variation; CV, cardiovascular; DPP-4i,
`dipeptidyl peptidase-4 inhibitor; DTSQs, Diabetes Treatment Satisfaction Questionnaire status version; E, number of events; EASD, European Association for the Study of
`Diabetes; eGFR, estimated glomerular filtration rate; exenatide ER, exenatide extended release; ETD, estimated treatment difference; ETR, estimated treatment ratio; FAS, full
`analysis set; FPG, fasting plasma glucose; GI, gastrointestinal; GLP-1, glucagon-like peptide-1; GLP-1RA, glucagon-like peptide-1 receptor agonist; KDIGO, Kidney Disease
`Improving Global Outcomes; max., maximum; MedDRA, Medical Dictionary for Regulatory Activities; MET, metformin; min., minimum; MTD, maximum tolerated dose; n,
`number of subjects; N, total number of subjects; OAD, oral antidiabetic drug; OD, once daily; OR, odds ratio; OW, once weekly; PRO, patient-reported outcome; R, event rate
`per 100 exposure-years; SAS, safety analysis set; s.c., subcutaneous; SD, standard deviation; SE, standard error; SGLT-2i, sodium–glucose cotransporter-2 inhibitor; SF-36v21,
`Short-Form 36 Health Survey version 21; SMBG, self-measured blood glucose; SU, sulfonylurea; SUSTAIN, Semaglutide Unabated Sustainability in Treatment of Type
`2 Diabetes; TEAE, treatment-emergent adverse event; T2D, type 2 diabetes.
`* Corresponding author. Rotherham Institute for Obesity (RIO), Clifton Medical Centre, The Health Village, Doncaster Gate, Rotherham S65 1DA, UK.
`E-mail address: mcapehorn@yahoo.co.uk (M.S. Capehorn).
`
`https://doi.org/10.1016/j.diabet.2019.101117
`1262-3636/ C 2019 Elsevier Masson SAS. All rights reserved.
`
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`M.S. Capehorn et al. / Diabetes & Metabolism 46 (2020) 100–109
`
`101
`
`Introduction
`
`There are currently a variety of treatment options for type
`2 diabetes (T2D); despite this, a large proportion of subjects do not
`treatment
`targets
`[1]. Furthermore, optimal
`achieve HbA1c
`treatment of T2D should involve patient-oriented treatment goals
`include minimizing
`extending beyond glycaemic control, to
`like weight gain and hypoglycaemia, and
`unwanted effects
`reducing the risk of complications such as cardiovascular (CV)
`events [2,3].
`Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have
`emerged as effective treatments for T2D and are incorporated into
`the clinical guidelines [2,3]. The 2018 American Diabetes Associa-
`tion (ADA)/European Association for the Study of Diabetes (EASD)
`consensus report and the 2019 ADA Standards of Care treatment
`guidelines recommend preferred treatments, following metformin
`(MET), as either GLP-1RAs or sodium–glucose cotransporter-2
`(SGLT-2is), particularly
`in adults with T2D and
`inhibitors
`additional CV
`risk
`factors
`(e.g. GLP-1RAs or SGLT-2is
`for
`established atherosclerotic disease or SGLT-2is for chronic kidney
`disease or heart failure) [2,3]. In addition to improving glycaemic
`control, some drugs in the GLP-1RA class also provide weight loss,
`have CV benefits, improve renal outcomes, and minimize hypo-
`glycaemic risk [2–7]. Several GLP-1RAs are currently available,
`both short- and long-acting, as once-daily (OD) or once-weekly
`(OW) injections [8], with different molecular sizes and structures
`that result in varying efficacy and safety profiles [9,10].
`Semaglutide (Novo Nordisk A/S) is a long-acting glucagon-like
`peptide-1 (GLP-1) analog, approved for the treatment of T2D in a
`subcutaneous (s.c.), OW formulation [11,12]. The efficacy and
`safety of semaglutide OW has been investigated in the Semaglutide
`Unabated Sustainability in Treatment of Type 2 Diabetes (SUS-
`TAIN) phase 3 clinical trial program across the continuum of care in
`subjects with T2D. In the SUSTAIN trials semaglutide consistently
`demonstrated superior reductions in HbA1c and body weight vs
`placebo and a range of active comparators, including other GLP-
`1RAs (exenatide extended release [ER] and dulaglutide) and basal
`insulin glargine, with a safety profile similar to that of other GLP-
`1RAs [4,13–18]. Furthermore, and in line with findings with the
`GLP-1 analog liraglutide in the LEADER trial [5], the SUSTAIN 6 trial
`demonstrated that semaglutide significantly reduced the risk of
`major adverse CV events, compared with placebo, in subjects with
`T2D and high CV risk [4].
`The aim of the SUSTAIN 10 trial (NCT03191396) was to compare
`the efficacy and safety of OW semaglutide 1.0 mg with OD
`liraglutide 1.2 mg in adults with T2D. These doses were chosen to
`reflect clinical practice regarding use of GLP-1RAs in Europe: OW
`is expected to be the most
`frequently
`semaglutide 1.0 mg
`prescribed dose, whereas OD liraglutide 1.2 mg is currently the
`most frequently prescribed dose [19].
`
`Methods
`
`Trial design
`
`SUSTAIN 10 was a 30-week, randomized, multicentre, multi-
`national, active-controlled, parallel-group, open-label, two-armed
`phase 3b trial conducted in 11 European countries (Bulgaria, Czech
`Republic, Finland, France, Hungary, Italy, Poland, Slovenia, Spain,
`Sweden, United Kingdom). The trial design is shown in Figure S1
`(see supplementary materials associated with this article on line)
`and a full list of trial investigators is shown in Table S1 (see
`supplementary materials associated with this article on line). The
`trial was conducted in compliance with the International Council
`on Harmonisation of Technical Requirements for Registration of
`
`Pharmaceuticals for Human Use Good Clinical Practice guidelines
`[20], and the Declaration of Helsinki [21]. Subjects provided
`consent before the commencement of any trial-related activities.
`The protocol is available in the Appendix (see supplementary
`materials associated with this article on line).
`
`Participants
`
`Key inclusion criteria were age  18 years; T2D with HbA1c 7.0–
`11.0%; and stable daily doses of any of the following antidiabetic
`drug(s) or combination regimens 90 days prior to screening:
`biguanides (MET  1500 mg or maximum tolerated dose [MTD]),
`(SU) or SGLT-2i
`(for both SU and SGLT-2i:
`sulfonylurea
` 0.5 maximum approved dose according to local label or MTD
`as documented in subject medical record). Key exclusion criteria
`were renal impairment, measured as estimated glomerular filtration
`rate (eGFR) < 30 mL/min/1.73 m2; presence of New York Heart
`Association Class IV heart failure; proliferative retinopathy or
`maculopathy requiring acute treatment, verified by fundus photog-
`raphy or dilated fundoscopy within the 90 days prior to randomiza-
`tion; impaired liver function (alanine aminotransferase  2.5 times
`upper limit of normal at screening); and presence or history of
`malignant neoplasms within the past 5 years prior to screening. Full
`trial eligibility criteria are listed in Table S2 (see supplementary
`materials associated with this article on line).
`
`Randomization
`
`Subjects with T2D inadequately controlled on 1–3 oral antidiabetic
`drug(s) (OADs) were randomized 1:1 to treatment with either s.c. OW
`semaglutide 1.0 mg or s.c. OD liraglutide 1.2 mg (both supplied by
`Novo Nordisk A/S, Bagsværd, Denmark). Subjects were stratified
`based on background medication of SU and SGLT2-i (SU  MET; SGLT-
`2i  MET; SU and SGLT-2i  MET; MET monotherapy).
`
`Treatments
`
`Following a 2-week screening period, the treatment period was
`30 weeks, with a 5-week safety data collection follow-up to
`accommodate for the long half-life of semaglutide. After randomi-
`followed a dose-escalation regimen. The
`zation, all subjects
`semaglutide maintenance dose was reached after an 8-week
`escalation period consisting of 4 weeks of 0.25 mg OW, followed by
`4 weeks of 0.5 mg OW. The liraglutide maintenance dose was
`reached after 1 week of 0.6 mg OD. In the event of unacceptable
`gastrointestinal (GI) adverse events (AEs) with liraglutide, escala-
`tion from 0.6 mg to 1.2 mg could be extended over 2 weeks at the
`discretion of the investigator. Both medications were administered
`by injections to the thigh, abdomen, or upper arm, at any time of
`irrespective of meals. Semaglutide
`injections were
`day and
`administered OW preferably on the same day, while liraglutide
`injections were administered OD at the same time every day.
`Subjects were intended to continue on stable, pre-trial background
`medication dose(s) throughout treatment, unless rescue criteria
`were met or a safety concern relating to the background
`medication arose.
`Rescue medication (intensification of antidiabetic background
`medication and/or initiation of new antidiabetic medication) was
`if subjects experienced persistent and unacceptable
`offered
`hyperglycaemia (fasting plasma glucose [FPG] levels  13.3 m-
`mmol/L from week 8 to the end of week 15, or  11.1 mmol/L from
`week 16 to the end of treatment). Rescue medication was
`prescribed at the investigators’ discretion according to ADA/EASD
`2012 and 2015 guidelines [22,23]; GLP-1RAs, dipeptidyl pepti-
`inhibitors
`(DPP-4is), and amylin analogs were not
`dase-4
`permitted.
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`102
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`Endpoints
`
`M.S. Capehorn et al. / Diabetes & Metabolism 46 (2020) 100–109
`
`The primary endpoint was change in HbA1c (%-point, hereafter
`referred to as ‘%’) from baseline to week 30. The confirmatory
`secondary endpoint was change in body weight (kg) from baseline
`to week 30. Other pre-specified supportive secondary efficacy
`endpoints included changes from baseline to week 30 in: FPG;
`mean postprandial increment across all meals and mean 7-point
`profile based on self-measured blood glucose (SMBG); fasting
`blood lipids (total cholesterol, low-density lipoprotein-cholesterol,
`lipoprotein-cholesterol, and
`triglycerides); body
`high-density
`mass index (BMI); waist circumference; and systolic and diastolic
`blood pressure.
`included subjects
`Pre-specified clinical treatment targets
`who, after 30 weeks of treatment, achieved HbA1c < 7.0% (ADA)
`[24] or  6.5% (American Association of Clinical Endocrinolo-
`gists) [25]. In addition, the proportions of subjects achieving
`reduction  1%; weight
`loss  3%,  5%, or  10%; a
`HbA1c
`composite endpoint of HbA1c < 7.0% without severe
`(ADA
`classification) [26] or blood glucose (BG)-confirmed symptom-
`atic hypoglycaemic episodes and no weight gain; and composite
`reduction of  1% and weight
`loss
`endpoints of HbA1c
`of  3%,  5%, or  10%. Supportive secondary endpoints
`for
`(PROs)
`included changes
`from
`patient-reported outcomes
`baseline to week 30 in Short-Form 36 Health Survey version
`21 (SF-36v21) and Diabetes Treatment Satisfaction Question-
`naire status version (DTSQs) scores [27,28].
`Safety endpoints included the number of treatment-emergent
`adverse events (TEAEs, classified as events that had an onset date,
`‘on-treatment’ observation
`or increase in severity, during the
`period) and the number of treatment-emergent severe or BG-
`confirmed symptomatic hypoglycaemic episodes. Other safety
`endpoints included change from baseline to week 30 in haema-
`tology, biochemistry, calcitonin, pulse rate, electrocardiogram
`category, physical examination category, and eye examination
`category. All AEs were coded using the most recent version of the
`Medical Dictionary for Regulatory Activities (MedDRA).
`
`Statistical analysis
`
`The primary estimand was defined as the treatment difference
`between semaglutide and liraglutide at week 30 for all randomized
`subjects if all subjects completed treatment and did not initiate
`rescue medication. This estimand was considered clinically
`relevant as it assessed the glycaemic benefit a subject with T2D
`was expected to achieve if they initiated and continued treatment
`with semaglutide vs liraglutide.
`Efficacy endpoints were evaluated based on the full analysis set
`included all randomized subjects)
`from the
`‘on-
`(FAS, which
`treatment without rescue medication’ observation period; safety
`endpoints were analyzed using the safety analysis set (SAS, which
`included data from all subjects exposed to at least one dose of trial
`product) from the ‘on-treatment’ or ‘in-trial’ observation periods. See
`Table S3 and protocol (see supplementary materials associated with
`this article on line) for the definitions of the observation periods.
`Three confirmatory hypotheses were tested using the following
`hierarchical testing procedure [29]:
`
`1 HbA1c non-inferiority of semaglutide 1.0 mg vs
`1.2 mg (non-inferiority margin of 0.3);
`2 Body weight superiority of semaglutide 1.0 mg vs liraglutide
`1.2 mg;
`3 HbA1c superiority of semaglutide 1.0 mg vs liraglutide 1.2 mg
`[Figure S2 (see supplementary materials associated with this
`article on line)].
`
`liraglutide
`
`The Type-I error rate for testing the three confirmatory
`hypotheses relating to HbA1c and body weight was preserved at
`an overall one-sided alpha (a) level of 2.5%. A sample size of
`in each of the semaglutide and
`288 subjects was needed
`liraglutide groups (total planned randomized: 576 subjects), to
`provide at least 90% power to reject all three confirmatory
`hypotheses and, thus, confirm HbA1c superiority and body weight
`superiority of semaglutide vs liraglutide across efficacy and in-
`trial assumptions.
`The primary analysis addressed the primary estimand, which
`was based on the FAS using measurements up to and including
`‘on-treatment without rescue medication’
`week 30 from the
`observation period.
`In the primary analysis, imputation of missing data was
`handled using multiple imputation assuming that missing data
`imputed as
`were missing at random. Missing data were
`intermittent values using a Markov Chain Monte Carlo method
`to obtain a monotone missing data pattern. This imputation was
`done for each treatment group separately and 500 copies of the
`dataset were generated. A sequential regression approach for
`imputing monotonely missing values at planned visits was
`implemented starting with the first visit after baseline and
`sequentially continued to the last planned visit (week 30). A
`linear model was applied to each treatment group. This model
`used the background medication stratification factor (SU  MET,
`SGLT-2i  MET, SU and SGLT-2i  MET, and MET monotherapy) as a
`categorical effect, and baseline and post-baseline HbA1c values
`(observed and imputed) prior to the visit in question as covariates.
`An analysis of covariance with treatment and background medica-
`tion stratification factor as categorical effects and baseline HbA1c as
`a covariate were used to analyze HbA1c at week 30 for each of the
`500 data sets generated as part of the imputation of missing values.
`Rubin’s rule was used to combine the analysis results in order to
`draw inference. Sensitivity analyses (tipping-point, retrieved drop-
`out [superiority only], and per-protocol [non-inferiority only]
`analyses) were conducted on the primary analysis, see Table S3 (see
`supplementary materials associated with this article on line) for
`details.
`The secondary confirmatory endpoint of change from baseline
`to week 30 in body weight was analyzed in the same way as the
`primary endpoint, but using baseline and post-baseline body
`weight measurements as covariates (instead of HbA1c). Sensitivity
`analyses (tipping-point and retrieved drop-out analyses) were also
`conducted on the secondary confirmatory endpoint, see Table S3
`(see supplementary materials associated with this article on line)
`for details.
`Continuous endpoints were analyzed separately using a similar
`model approach as for the primary endpoint, with associated
`baseline values as covariates (instead of HbA1c). The binary
`endpoints were analyzed using a logistic regression model with
`treatment and stratification factor as fixed factors and baseline
`values as covariates. Before analysis, missing data for individual
`components were imputed separately using the same approach as
`for continuous endpoints and subsequently dichotomized. The
`PRO questionnaires (SF-36v21 and DTSQs) were used to evaluate
`life and treatment satisfaction; see Table S3 (see
`quality of
`supplementary materials associated with this article on line) for
`further details on the PRO questionnaires.
`Safety outcomes were summarized descriptively based on
`the SAS using data the from ‘on-treatment’ observation period,
`retinopathy, which were
`except neoplasms and diabetic
`from the
`‘in-trial’ observation period.
`reported using data
`Summaries of treatment-emergent hypoglycaemic episodes
`were presented as an overview, including all episodes and
`episodes by severity.
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`103
`
`Results
`
`Between June and November 2017, 767 subjects were screened,
`of whom 577 were randomized and 576 were exposed to
`treatment (Fig. 1). Of the FAS, a total of 287 (99.0%) subjects in
`the OW semaglutide 1.0 mg arm and 282 (98.3%) subjects in the OD
`liraglutide 1.2 mg arm completed the trial; 249 (85.9%) and 261
`(90.9%) completed treatment, respectively.
`Baseline characteristics and background medications were
`generally similar in each treatment group. The overall mean age
`was 59.5 years, HbA1c 8.2%, body weight 96.9 kg, and diabetes
`duration 9.3 years. Most subjects (94.8%) received biguanides;
`46.8% of subjects received SU and 24.6% received SGLT-2i. Few
`subjects in either treatment arm required rescue medication
`(4 subjects with semaglutide vs 12 subjects with liraglutide; all
`in the
`liraglutide group were treatment
`subjects except one
`completers; Table 1; Fig. 1). Diabetes complications at screening
`are shown in Table S4 (see supplementary materials associated
`with this article on line).
`Mean HbA1c (baseline 8.2%) decreased over time for both
`treatment arms (Fig. 2a), and from baseline to week 30 (Fig. 2b) by
`liraglutide (estimated
`1.7% with semaglutide and 1.0% with
`treatment difference (ETD) at week 30 0.69% [95% confidence
`interval (CI) 0.82 to 0.56], P < 0.0001 for superiority). The
`results of the primary analysis were supported by the sensitivity
`analyses.
`FPG was reduced with both semaglutide and liraglutide from
`baseline to week 30, but changes were significantly greater with
`(ETD 1.24 mmol/L
`[95% CI 1.54
`to 0.93],
`semaglutide
`P < 0.0001, Fig. 2c). Observed SMBG 7-point profile (at baseline
`and week 30) and change in mean 7-point SMBG profile from
`baseline to week 30 are shown in Fig. 2d and e, respectively;
`reductions in the mean profile were greater with semaglutide vs
`(ETD 0.89 mmol/L
`[95% CI 1.15
`to 0.64],
`liraglutide
`
`P < 0.0001). Reductions in the SMBG increment from baseline to
`week 30 were also greater with semaglutide vs liraglutide (ETD
`0.53 mmol/L [95% CI 0.77 to 0.28], P < 0.0001; data not
`shown).
`The proportions of subjects achieving HbA1c < 7.0% and  6.5%
`at week 30 were 80% vs 46% and 58% vs 25%, respectively, with
`semaglutide vs liraglutide (estimated odds ratio [OR] 5.98 [95% CI
`3.83 to 9.32] and 4.84 [95% CI 3.21 to 7.30], respectively,
`P < 0.0001; Fig. 2f and g). A greater proportion of subjects achieved
`HbA1c reduction  1% with semaglutide vs liraglutide (83% vs 48%
`respectively, estimated OR 7.24 [95% CI 4.55 to 11.50], P < 0.0001;
`Figure S3a [see supplementary materials associated with this
`article on line]).
`Mean body weight (baseline 96.9 kg) decreased over time for
`both treatment arms (Fig. 3a), and from baseline to week 30
`(Fig. 3b) by 5.8 kg vs 1.9 kg with semaglutide vs liraglutide (ETD
`3.83 kg [95% CI 4.57 to 3.09], P < 0.0001). The results of the
`confirmatory analysis were supported by the sensitivity analyses.
`The proportions of subjects achieving weight loss of  5%
`and  10% at week 30 were 56% vs 18% and 19% vs 4%, respectively,
`with semaglutide vs liraglutide (estimated OR 5.89 [95% CI 3.93 to
`8.81] and 4.99 [95% CI 2.57 to 9.68], respectively, both P < 0.0001;
`Fig. 3c and d). Similarly, a greater proportion of subjects also
`achieved weight loss  3% with semaglutide vs liraglutide (73% vs
`34% respectively, estimated OR 5.22 [95% CI 3.57 to 7.62],
`P < 0.0001); Figure S3b (see supplementary materials associated
`with this article on line).
`Changes in BMI and waist circumference from baseline to week
`30 were also significantly greater with semaglutide than with
`liraglutide [Table S5 (see supplementary materials associated with
`this article on line)].
`The composite endpoint of HbA1c < 7.0% without severe or BG-
`confirmed symptomatic hypoglycaemia and without weight gain
`was achieved by a greater proportion of subjects treated with
`
`Fig. 1. Subject disposition. One subject receiving liraglutide 1.2 mg discontinued treatment prematurely, the primary reason for which was a non-treatment-emergent
`adverse event. *Screened subjects who withdrew consent before randomization; yincludes only exposed subjects; zsubjects who completed the trial according to the end-of-
`trial form; §subjects who completed treatment according to the end-of-treatment form; ôone extra subject in the liraglutide group received rescue medication but did not
`complete treatment.
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`
`Table 1
`Baseline characteristics – full analysis set.
`
`Age, years
`Sex, male
`Race, White
`HbA1c, %
`Fasting plasma glucose, mmol/L
`Diabetes duration, years
`Body weight, kg
`Body mass index, kg/m2
`eGFR, mL/min/1.73 m2 geometric mean (CoV)
`Renal function, mL/min/1.73 m2a
`eGFR  90
`eGFR  60– < 90
`eGFR 30– < 60
`Antidiabetes medication at screening
`Biguanides
`Sulfonylurea
`SGLT-2i
`DPP-4ib
`Other blood glucose-lowering drugs, excluding insulinb
`
`Semaglutide
`1.0 mg
`(n = 290)
`
`60.1 (10.5)
`160 (55.2%)
`264 (91.0%)
`8.2 (0.9)
`9.8 (2.3)
`9.6 (6.1)
`96.6 (21.0)
`33.7 (6.6)
`91.3 (20.3)
`
`190 (65.5%)
`86 (29.7%)
`14 (4.8%)
`
`279 (96.2%)
`136 (46.9%)
`73 (25.2%)
`0
`1 (0.3%)
`
`Liraglutide
`1.2 mg
`(n = 287)
`
`58.9 (10.0)
`167 (58.2%)
`268 (93.4%)
`8.3 (1.0)
`9.9 (2.5)
`8.9 (5.7)
`97.2 (21.7)
`33.7 (7.0)
`89.7 (23.1)
`
`185 (64.5%)
`88 (30.7%)
`14 (4.9%)
`
`268 (93.4%)
`134 (46.7%)
`69 (24.0%)
`1 (0.3%)
`0
`
`Total
`(N = 577)
`
`59.5 (10.2)
`327 (56.7%)
`532 (92.2%)
`8.2 (1.0)
`9.9 (2.4)
`9.3 (5.9)
`96.9 (21.3)
`33.7 (6.8)
`90.5 (21.7)
`
`375 (65.0%)
`174 (30.2%)
`28 (4.9%)
`
`547 (94.8%)
`270 (46.8%)
`142 (24.6%)
`1 (0.2%)
`1 (0.2%)
`
`Data are mean (SD) or n (%) for the full analysis set (FAS), unless otherwise stated. Baseline information is defined as the measurement at the latest assessment before dosing.
`Body mass index is calculated based on baseline measurement of body weight and height.
`%: percentage of subjects; CKD-EPI: The Chronic Kidney Disease Epidemiology Collaboration; CoV: coefficient of variation; DPP-4i: dipeptidyl peptidase-4 inhibitor; eGFR:
`estimated glomerular filtration rate; max.: maximum; min.: minimum; n: number of subjects; N: total number of subjects; SD: standard deviation; SGLT-2i: sodium–glucose
`cotransporter-2 inhibitor.
`a The renal function categories are based on the eGFR using CKD-EPI. No subjects had an eGFR < 30 mL/min/1.73 m2.
`b The two subjects on DPP-4is and repaglinide were randomized in error and discontinued treatment.
`
`semaglutide vs liraglutide (76% vs 37% respectively, estimated OR
`6.07 [95% CI 4.02 to 9.15], P < 0.0001; Fig. 4a).
`A greater proportion of subjects treated with semaglutide vs
`also
`achieved
`composite
`endpoints of HbA1c
`liraglutide
`reduction  1% and different weight-loss responses of  3%,
` 5%, and  10% body weight: 62% vs 21%
`(estimated OR
`6.63 [95% CI 4.44 to 9.91], P < 0.0001; Figure S4a [see supplemen-
`tary materials associated with this article on line]), 50% vs 12%
`(estimated OR 7.55 [95% CI 4.80 to 11.88], P < 0.0001; Figure S4b
`[see supplementary materials associated with this article on line]),
`and 17% vs 4% (estimated OR 5.26 [95% CI 2.58 to 10.73],
`P < 0.0001; Fig. 4b), respectively.
`The change from baseline (136.4 mmHg) to week 30 in systolic
`blood pressure was moderate with both semaglutide (4.5 mmHg
`[standard error (SE) 0.7]) and liraglutide (3.5 [0.7]), and the ETD
`between the treatment arms was not significant (1.0 [95% CI 3.0
`to 1.1] Table S5 [see supplementary materials associated with this
`article on line]). Similarly, there was no significant difference in
`diastolic blood pressure between treatments [Table S5 (see
`supplementary materials associated with this article on line)].
`Changes from baseline to week 30 for lipid levels were modest
`for both treatments, but the semaglutide group showed signifi-
`cantly greater improvements vs the liraglutide group for total
`triglycerides
`[Table S6
`(see supplementary
`cholesterol and
`materials associated with this article on line)].
`in PRO scores were
`reported with both
`Improvements
`treatment arms. The DTSQs showed a significant difference
`between treatment groups in ‘Feeling of unacceptably high blood
`favouring
`sugars’, with this aspect of treatment satisfaction
`semaglutide (ETD 0.55 [95% CI 0.83 to 0.27], P = 0.0001;
`Table S7 [see supplementary materials associated with this article
`on line]). The SF-36v21 questionnaire showed significant diffe-
`rences between the two treatment groups in two components of
`health-related quality of life, with the results favouring sema-
`glutide: vitality (ETD 1.68 [95% CI 0.45 to 2.92], P = 0.0076) and
`mental health (ETD 1.30 [95% CI 0.06; 2.53], P = 0.0396; Table S7
`[see supplementary materials associated with this article on
`
`line]). There were no significant differences in any other DTSQs
`scales or SF-36v21 domains
`[Table S7
`(see supplementary
`materials associated with this article on line)].
`In total, 70.6% (n = 204) subjects experienced TEAEs in the
`semaglutide group, and 66.2% (n = 190) in the liraglutide group
`(Table 2). TEAEs were mainly mild to moderate in severity. A
`slightly higher number of subjects experienced serious TEAEs with
`liraglutide (n = 22, 7.7%) than with semaglutide (n = 17, 5.9%).
`in either treatment group. A higher
`There were no deaths
`proportion of subjects reported TEAEs
`leading to premature
`treatment discontinuation with semaglutide (n = 33, 11.4%) vs
`liraglutide (n = 19, 6.6%); this was primarily driven by GI AEs (7.6%
`with semaglutide vs 3.8% with liraglutide).
`The most commonly reported AEs were GI disorders, reported
`in 127 (43.9%) subjects with semaglutide and 110 (38.3%) subjects
`with liraglutide. The onset of GI AEs was typically during the initial
`12 weeks of the trial. GI AEs were most prevalent during the dose-
`escalation period (liraglutide) or within the first 12 weeks of
`treatment (semaglutide); events were generally mild in severity.
`Nausea was the most frequently reported GI AE, reported by 63
`(21.8%) vs 45 (15.7%) subjects with semaglutide vs liraglutide
`(Table 2). Other frequently reported GI AEs with semaglutide and
`liraglutide were: diarrhea (15.6% and 12.2%), vomiting (10.4% and
`8.0%), constipation (5.9% and 3.5%), and abdominal pain (5.2% and
`2.1%). A list of the AEs reported in  5% of subjects in either
`treatment arm is shown in Table S8 (see supplementary materials
`associated with this article on line).
`Severe or BG-confirmed symptomatic hypoglycaemia was
`experienced by 1.7% of subjects (n = 5; 8 events) in the semaglutide
`group and 2.4% of subjects (n = 7; 8 events) in the liraglutide group;
`no subject in either group experienced severe hypoglycaemic
`episodes (ADA definition; data not shown). Of the 16 episodes of
`severe or BG-confirmed symptomatic hypoglycaemia, 15 were in
`subjects receiving background SU.
`Pancreatitis TEAEs (pre-defined MedDRA search) were reported
`in two (0.7%) subjects receiving liraglutide and no subjects receiving
`semaglutide. Neoplasms (benign, malignant, and unspecified) were
`
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`M.S. Capehorn et al. / Diabetes & Metabolism 46 (2020) 100–109
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`105
`
`Fig. 2. Glycaemic endpoints with semaglutide 1.0 mg and liraglutide 1.2 mg. Estimated change in HbA1c by week (a); estimated change in HbA1c from overall baseline mean to
`week 30 (b); estimated change in FPG over time (c); observed mean 7-point SMBG profile at baseline and at week 30 (d); mean 7-point SMBG profile change from baseline to
`week 30 (e); proportion of subjects achieving HbA1c < 7.0% (f) and  6.5% (g) at week 30. *P < 0.0001 vs liraglutide 1.2 mg. All figures based on the full analysis set, using ‘on-
`treatment without rescue medication’ data. Figures a–c and e: mean estimates are from an analysis of covariance, where missing data were accounted for using multiple
`imputation (data from subjects within the same group defined by randomized treatment) using a regression model including stratification factor as categorical effect and data
`from baseline and all previous post-baseline visits as covariates. Error bars are  standard errors of the means. Dashed grey lines indicate the overall mean values at baseline.
`Values in square brackets are 95% CIs. Figure d: dashed lines indicate baseline values; solid lines indicate week 30 data. SMBG assessed with glucose meter as plasma equivalent
`values of capillary whole blood glucose. Figures f, g: missing HbA1c data were accounted for using multiple imputation (data from subjects within the same group defined by
`randomized treatment) using a regression model including stratification factor as categorical effect and data from baseline and all previous post-baseline visits as covariates. After
`imputation, continuous data were dichotomized. AACE: American Association of Clinical Endocrinologists; ADA: American Diabetes Association; CI: confidence interval; ETD:
`estimated treatment difference; FPG: fasting plasma glucos