Efficacy and safety of once-weekly semaglutide versus
`once-daily insulin glargine as add-on to metformin (with or
`without sulfonylureas) in insulin-naive patients with type 2
`diabetes (SUSTAIN 4): a randomised, open-label,
`parallel-group, multicentre, multinational, phase 3a trial
`
`Vanita R Aroda, Stephen C Bain, Bertrand Cariou, Milivoj Piletič, Ludger Rose, Mads Axelsen, Everton Rowe, J Hans DeVries
`
`Summary
`Background Several pharmacological treatment options are available for type 2 diabetes; however, many patients do not
`achieve optimum glycaemic control and therefore new therapies are necessary. We assessed the efficacy and safety of
`semaglutide, a glucagon-like peptide-1 (GLP-1) analogue in clinical development, compared with insulin glargine in
`patients with type 2 diabetes who were inadequately controlled with metformin (with or without sulfonylureas).
`
`Methods We did a randomised, open-label, non-inferiority, parallel-group, multicentre, multinational, phase 3a trial
`(SUSTAIN 4) at 196 sites in 14 countries. Eligible participants were insulin-naive patients with type 2 diabetes, aged
`18 years and older, who had insufficient glycaemic control with metformin either alone or in combination with a
`sulfonylurea. We randomly assigned participants (1:1:1) to either subcutaneous once-weekly 0·5 mg or 1·0 mg semaglutide
`(doses reached after following a fixed dose-escalation regimen) or once-daily insulin glargine (starting dose 10 IU per day,
`then titrated weekly to a pre-breakfast self-measured plasma glucose target of 4·0–5·5 mmol/L [72–99 mg/dL]) for
`30 weeks. In all treatment groups, previous background metformin and sulfonylurea treatment was continued throughout
`the trial. We did the randomisation using an interactive voice or web response system. The primary endpoint was change
`in mean HbA1c from baseline to week 30 and the confirmatory secondary endpoint was the change in mean bodyweight
`from baseline to week 30. We assessed efficacy and safety in the modified intention-to-treat population (mITT; all
`randomly assigned participants who were exposed to at least one dose of study drug) and used a margin of 0·3% to
`establish non-inferiority in HbA1c reduction. This trial is registered with ClinicalTrials.gov, number NCT02128932.
`
`Findings Between Aug 4, 2014, and Sept 3, 2015, we randomly assigned 1089 participants to treatment; the mITT
`population consisted of 362 participants assigned to 0·5 mg semaglutide, 360 to 1·0 mg semaglutide, and 360 to insulin
`glargine. 49 (14%) participants assigned to 0·5 mg semaglutide discontinued treatment prematurely, compared with
`55 (15%) assigned to 1·0 mg semaglutide, and 26 (7%) assigned to insulin glargine. Most discontinuations were due to
`adverse events—mostly gastrointestinal with semaglutide, and others such as skin and subcutaneous tissue disorders
`(eg, rash, pruritus, and urticaria) with insulin glargine. From a mean baseline HbA1c of 8·17% (SD 0·89), at week 30,
`0·5 and 1·0 mg semaglutide achieved reductions of 1·21% (95% CI 1·10–1·31) and 1·64% (1·54–1·74), respectively,
`versus 0·83% (0·73–0·93) with insulin glargine; estimated treatment difference versus insulin glargine –0·38%
`(95% CI –0·52 to –0·24) with 0·5 mg semaglutide and –0·81% (–0·96 to –0·67) with 1·0 mg semaglutide (both
`p<0·0001). Mean bodyweight at baseline was 93·45 kg (SD 21·79); at week 30, 0·5 and 1·0 mg semaglutide achieved
`weight losses of 3·47 kg (95% CI 3·00–3·93) and 5·17 kg (4·71–5·66), respectively, versus a weight gain of 1·15 kg
`(0·70–1·61) with insulin glargine; estimated treatment difference versus insulin glargine –4·62 kg (95% CI
`–5·27 to –3·96) with 0·5 mg semaglutide and –6·33 kg (–6·99 to –5·67) with 1·0 mg semaglutide (both p<0·0001).
`Severe or blood glucose-confirmed hypoglycaemia was reported by 16 (4%) participants with 0·5 mg semaglutide and
`20 (6%) with 1·0 mg semaglutide versus 38 (11%) with insulin glargine (p=0·0021 and p=0·0202 for 0·5 mg and 1·0 mg
`semaglutide vs insulin glargine, respectively). Severe hypoglycaemia was reported by two (<1%) participants with 0·5 mg
`semaglutide, five (1%) with 1·0 mg semaglutide, and five (1%) with insulin glargine. Six deaths were reported: four (1%)
`in the 0·5 mg semaglutide group (three cardiovascular deaths, one pancreatic carcinoma, which was assessed as being
`possibly related to study medication) and two (<1%) in the insulin glargine group (both cardiovascular death). The most
`frequently reported adverse events were nausea with semaglutide, reported in 77 (21%) patients with 0·5 mg and in
`80 (22%) with 1·0 mg, and nasopharyngitis reported in 44 (12%) patients with insulin glargine.
`
`Interpretation Compared with insulin glargine, semaglutide resulted in greater reductions in HbA1c and weight, with
`fewer hypoglycaemic episodes, and was well tolerated, with a safety profile similar to that of other GLP-1 receptor agonists.
`
`Funding Novo Nordisk A/S.
`
`Lancet Diabetes Endocrinol 2017;
`5: 355–66
`Published Online
`March 23, 2017
`http://dx.doi.org/10.1016/
`S2213-8587(17)30085-2
`See Comment page 315
`See Articles page 341
`MedStar Health Research
`Institute, Hyattsville, MD, USA
`(V R Aroda MD); School of
`Medicine, Swansea University,
`Swansea, UK
`(Prof S C Bain FRCP); CHU de
`Nantes, l’Institut du Thorax,
`Nantes, France (B Cariou MD);
`General Hospital, Novo Mesto,
`Slovenia (M Piletič MD);
`Münster Institute for Diabetes
`Research, Münster, Germany
`(L Rose MD); Novo Nordisk,
`Søborg, Denmark
`(M Axelsen MD); Novo Nordisk,
`Princeton, NJ, USA
`(E Rowe PhD); and Academic
`Medical Center, University of
`Amsterdam, Amsterdam,
`Netherlands
`(Prof J H DeVries MD)
`Correspondence to:
`Prof J Hans DeVries, Department
`of Endocrinology, Academic
`Medical Center, 1100 DD,
`Amsterdam, Netherlands
`j.h.devries@amc.uva.nl
`
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`
`355
`
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`

`Research in context
`
`Evidence before this study
`The design of this phase 3a trial of the novel glucagon-like
`peptide-1 (GLP-1) analogue semaglutide was based on findings
`from preclinical safety and pharmacology studies and clinical
`phase 1 and 2 trials. Results from a phase 2 dose-finding trial
`and one of the phase 1 trials suggested that an adjusted
`dose-escalation regimen was likely to offer a more acceptable
`gastrointestinal tolerability profile, while maintaining efficacy,
`than starting at the final dose.
`
`Added value of this study
`The findings from this study show that semaglutide given once
`weekly leads to substantial lowering of HbA1c with substantial
`weight loss compared with basal insulin glargine as a reference
`active comparator. The safety profile of gradually titrated
`
`semaglutide appears to be similar to currently available GLP-1
`receptor agonists, with adverse events consisting mainly of
`gastrointestinal events such as nausea and diarrhoea, with a
`lower risk of hypoglycaemia than insulin glargine.
`
`Implications of all the available evidence
`Semaglutide given once weekly seems to be a beneficial
`treatment for patients with type 2 diabetes who are
`inadequately controlled on metformin, with or without
`sulfonylureas. It both significantly improves glycaemic control
`and leads to weight loss that seems potentially greater than has
`been reported for other GLP-1 receptor agonists, although
`indirect comparisons should be treated with caution.
`Semaglutide has a safety profile that is similar to those of other
`GLP-1 receptor agonists.
`
`Introduction
`Type 2 diabetes is a complex disorder that requires
`individualised
`treatment strategies. Because of
`its
`progressive nature, most patients with type 2 diabetes will
`require treatment intensification, which can be in the form
`of additional antihyperglycaemic agents either as oral or
`injectable therapies.1 Currently, the most commonly used
`injectable treatments for patients who do not meet
`glycaemic targets on oral therapy are basal insulins or
`glucagon-like peptide-1 (GLP-1) receptor agonists.1 Basal
`insulin, although effective in controlling hyperglycaemia
`for many patients,2,3 is associated with adverse effects such
`as hypoglycaemia and weight gain.4 By contrast, GLP-1
`receptor agonists stimulate insulin secretion and inhibit
`the release of glucagon from pancreatic islets in a glucose-
`dependent manner,5 resulting in effective glucose lowering
`that is similar to that achieved with basal insulin therapy
`but without the increased risk of hypoglycaemia.6 These
`drugs have also been shown to reduce bodyweight.6
`Although GLP-1 receptor agonists were initially used once
`or twice per day, more recent efforts have focused on the
`development of once-weekly GLP-1 receptor agonists
`(including exenatide extended release, albiglutide, and
`dulaglutide), with the potential to improve treatment
`adherence and quality of life for patients.6,7
`Semaglutide, a GLP-1 analogue currently in develop-
`ment, is structurally similar to liraglutide, an approved
`once-daily GLP-1 analogue. Structural modifications of the
`semaglutide molecule include aminoacid substitutions
`at position 8 (alanine to α-aminoisobutyric acid) and
`position 34 (lysine to arginine), and acylation of the lysine
`at position 26 with a spacer and C-18 fatty diacid chain.8
`The substitution at position 8 renders semaglutide less
`susceptible to degradation by dipeptidyl peptidase-4
`(DPP-4), and the lysine acylation improves binding to
`albumin.8 These modifications extend the half-life of
`semaglutide to roughly 1 week,8 enabling its once-weekly
`administration.9,10
`
`The findings from the phase 3a SUSTAIN 1 trial11
`showed that 0·5 mg and 1·0 mg semaglutide significantly
`improved HbA1c and bodyweight in treatment-naive
`patients with type 2 diabetes compared with placebo and
`showed a similar safety profile to that of other GLP-1
`receptor agonists. Here, we report the findings from the
`SUSTAIN 4 phase 3a trial, which assessed the efficacy,
`safety, and tolerability of 0·5 mg and 1·0 mg semaglutide
`compared with insulin glargine in insulin-naive patients
`with type 2 diabetes who had inadequate glycaemic
`control with metformin alone or in combination with a
`sulfonylurea.
`
`Methods
`Study design and participants
`We did a phase 3a, randomised, open-label, non-
`inferiority, active-controlled, parallel-group, multicentre,
`multinational, three-armed trial (SUSTAIN 4) at 196 sites
`(including hospitals, clinical research units, and private
`offices) in Argentina, Croatia, France, Germany, India,
`Macedonia, Mexico, the Netherlands, Romania, Slovakia,
`Slovenia, South Africa, the UK, and the USA. The study
`protocol was approved by either institutional review
`boards or ethics committees at each site, according to
`local practice.
`Eligible participants were insulin-naive patients with
`type 2 diabetes (HbA1c 7·0%–10·0% [53–86 mmol/mol]),
`aged 18 years or older, on stable treatment with
`metformin alone or in combination with a sulfonylurea
`for at least 90 days before screening. Key exclusion
`criteria included a history of chronic or idiopathic acute
`pancreatitis, a screening calcitonin value of at least
`50 ng/L, any personal or family history of medullary
`thyroid carcinoma or multiple endocrine neoplasia
`syndrome type 2, severely impaired renal function
`(estimated glomerular filtration rate [eGFR] <30 mL/min
`per 1·73 m²), heart failure (New York Heart Association
`class IV) or any acute coronary or cerebrovascular events
`
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`See Online for appendix
`
`within the previous 90 days before screening, and known
`proliferative retinopathy or maculopathy requiring acute
`treatment (any cases of retinopathy identified in the trial
`were likely to be new; however, retinopathy was not
`monitored as a trial procedure). Full eligibility criteria are
`in the appendix. Written informed consent was obtained
`from all participants.
`
`Randomisation and masking
`Participants were randomly assigned (1:1:1) to receive
`0·5 mg semaglutide, 1·0 mg semaglutide, or insulin
`glargine via an interactive, automated voice or web
`response system without human involvement. Patients
`were stratified based on their pretrial medication
`(metformin, or metformin and a sulfonylurea).
`Investigators and participants were unmasked, apart
`from members of an external event adjudication
`committee who validated predefined events in a masked
`manner (appendix). The trial had an open-label design
`because of the different dosing frequencies and titration
`of insulin glargine compared with semaglutide.
`
`Procedures
`After a 2-week screening period, participants received
`once-weekly
`subcutaneously
`injected
`semaglutide
`(0·5 mg or 1·0 mg; Novo Nordisk A/S, Bagsværd,
`Denmark) or once-daily subcutaneously
`injected
`insulin glargine (Lantus U100, Sanofi, Gentilly, France)
`for 30 weeks, followed by a 5-week follow-up.
`Participants who stopped treatment prematurely were
`encouraged to remain in the trial and complete
`follow-up. We selected semaglutide dosing on the basis
`of findings from the phase 2 dose-finding trial,12 and
`participants followed a fixed dose-escalation regimen.
`For those allocated to 0·5 mg semaglutide, this dose
`was reached after 4 weeks of once-weekly 0·25 mg
`semaglutide. The 1·0 mg semaglutide dose was reached
`after 4 weeks of once-weekly 0·25 mg, followed by
`4 weeks of once-weekly 0·5 mg.
`Participants assigned to insulin glargine started on
`a dose of 10 IU once daily. Protocol instructions
`were to titrate the insulin dose weekly to a pre-breakfast
`self-measured plasma glucose
`(SMPG)
`target of
`4·0–5·5 mmol/L (72–99 mg/dL; appendix). Titration was
`according to the lowest value of each participant’s fasting
`one-point profile SMPG concentrations 3 days before
`visits or phone contacts. All insulin adjustments were at
`the discretion of the investigators and were not reinforced
`by a titration committee. Patients administered their own
`injections in the thigh, abdomen, or upper arm. For
`semaglutide administration, injections (via prefilled
`PDS290 injectors [Novo Nordisk A/S, Denmark]) could
`be done at any time of the day, but on the same day each
`week. Participants were encouraged to inject in the
`same area throughout the trial for future semaglutide
`pharmacokinetic analyses of equivalence between
`injection sites. For insulin glargine, injection sites had to
`
`be rotated within a given injection area from one
`injection to the next. The time of administration was up
`to the patient but it had to be the same time every day. In
`all treatment groups, previous metformin treatment,
`with or without a sulfonylurea, was continued throughout
`the trial.
`Participants with unacceptable hyperglycaemia
`(defined
`as
`any
`fasting SMPG measurement
`>15·0 mmol/L [270 mg/dL] from randomisation to end
`of week 5, 13·3 mmol/L [240 mg/dL] from week 6 to end
`of week 11, or 11·1 mmol/L [200 mg/dL] after week 12)
`were to be offered rescue treatment (intensification of
`existing background medication or initiation of new
`medication, preferably excluding GLP-1
`receptor
`agonists, DPP-4 inhibitors, or amylin analogues) as an
`add-on to their randomised treatment at the discretion
`of the investigator, in accordance with treatment
`guidelines from the American Diabetes Association
`(ADA) and the European Association for the Study of
`Diabetes (EASD).1
`
`Outcomes
`The primary endpoint was the change in mean HbA1c
`from baseline to week 30 (end of treatment). The
`confirmatory secondary endpoint was change
`in
`bodyweight from baseline to week 30. Other secondary
`efficacy endpoints measured at week 30 were the
`proportion of participants who achieved HbA1c of less
`than 7·0% (53 mmol/mol)13 or HbA1c of 6·5% or less
`(48 mmol/mol)14 by the end of treatment; the proportion
`of participants achieving HbA1c of less than 7·0%
`without severe hypoglycaemia according to the ADA
`classification15 (ie, an event requiring assistance of
`another person to actively administer carbohydrates,
`glucagon, or take other corrective actions) or blood
`glucose-confirmed symptomatic hypoglycaemia (plasma
`glucose ≤3·1 mmol/L [56 mg/dL]) and no weight gain;
`change from baseline to week 30 in mean fasting
`plasma glucose (FPG), mean 8-point SMPG profiles,
`and postprandial increment; proportions of participants
`who achieved a weight loss of at least 5% and at least
`10% by the end of treatment; and the changes from
`baseline in BMI, waist circumference, fasting blood
`lipids
`(total cholesterol, LDL cholesterol, HDL
`cholesterol, VLDL cholesterol, triglycerides, and free
`fatty acids), systolic and diastolic blood pressure,
`plasminogen activator inhibitor-1, C-reactive protein,
`and patient-reported outcomes (Short Form [SF]-36
`version 2 health survey and Diabetes Treatment
`Satisfaction Questionnaire [DTSQ]).
`Safety endpoints were the number of treatment-
`emergent adverse events and the number of treatment-
`emergent severe or blood glucose-confirmed symptomatic
`hypoglycaemic episodes during exposure, and pulse rate.
`Other safety measurements were changes in laboratory
`variables (haematology, biochemistry, calcitonin, urin-
`alysis, and urinary albumin-to-creatinine ratio) and
`
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`1610 patients assessed for eligibility
`
`521 ineligible
`
`429 did not meet inclusion criteria or met exclusion criteria
`
`29 other
`
`1089 enrolled
`
`1089 randomly assigned
`
`362 assigned to 0·5 mg semaglutide
`362 exposed
`
`362 assigned to 1·0 mg semaglutide
`360 exposed
`
`365 assigned to insulin glargine
`360 exposed
`
`49 discontinued treatment
`
`19 adverse events*
`
`12 randomly assigned in
`
`error
`
`18 other
`24 withdrew from trial
` 3 withdrew after treatment
` completion
`
`55 discontinued treatment
` 27 adverse events*
`
`1 pregnancy
`
`13 randomly assigned in
` error
`14 other
`
`19 withdrew from trial
` 1 withdrew after treatment
` completion
`
`26 discontinued treatment
`
`5 adverse events*
`
`1 pregnancy
`
`2 randomly assigned in
`error
`18 other
`
`20 withdrew from trial
` 2 withdrew after treatment
` completion
`
`335 completed trial
`313 completed treatment
`299 completed treatment without
`
`rescue medication
`
`342 completed trial
`305 completed treatment
`296 completed treatment without
`
`rescue medication
`
`343 completed trial
`334 completed treatment
`323 completed treatment without
`
`rescue medication
`
`Figure 1: Trial profile
`Patients who completed the trial were defined as those with at least one follow-up visit. Reasons for patients not being exposed to treatment were withdrawal by the
`patient or loss to follow-up. *Main reason for treatment discontinuation, as judged by the investigator.
`
`examinations (electrocardiogram and physical exam-
`ination) at week 30, the occurrence and concentration of
`antisemaglutide antibodies, and semaglutide pharmaco-
`kinetics
`(to be
`included
`in
`future population
`pharmacokinetic analyses).
`
`Statistical analysis
`The trial was powered for the primary endpoint (change
`in HbA1c at 30 weeks) to assess non-inferiority for both
`doses of semaglutide, separately tested against insulin
`glargine, under the following assumptions: no treatment
`difference; a non-inferiority margin of 0·3%; 1:1:1
`randomisation; SD 1·1%; a one-sided significance level
`of 0·025; and 30% dropout. On the basis of these
`assumptions, a sample size of 1047 participants was
`specified, which would ensure at least 90% power for
`each of the HbA1c non-inferiority tests. Furthermore, this
`sample size ensured 99% power to detect a difference
`between 1·0 mg semaglutide versus insulin glargine of
`1·5 kg change in bodyweight (SD 4·0 kg). With a
`conservative assumption of independence between the
`two endpoints, the joint power was 80%.
`To preserve the overall type I error rate, we used a
`prespecified hierarchical testing approach (appendix):
`non-inferiority for the change in HbA1c for 1·0 mg
`
`semaglutide versus insulin glargine; superiority in the
`change in bodyweight for 1·0 mg semaglutide versus
`insulin glargine; non-inferiority in the change in HbA1c for
`0·5 mg semaglutide versus insulin glargine; superiority in
`the change in HbA1c for 1·0 mg semaglutide versus insulin
`glargine; superiority in the change in bodyweight for
`0·5 mg semaglutide versus
`insulin glargine; and
`superiority in the change in HbA1c for 0·5 mg semaglutide
`versus insulin glargine. Superiority for either change in
`HbA1c or bodyweight was considered established if the
`upper limit of the two-sided 95% CI for the estimated
`differences was less than 0% or 0 kg, respectively.
`We assessed efficacy in the modified intention-to-treat
`(mITT) population, which consisted of all randomly
`assigned participants who were exposed to at least one
`dose of study drug, as specified in the trial protocol; the
`assessment used data obtained before the initiation of
`any rescue medication or before premature treatment
`discontinuation. We assessed safety in the same mITT
`population. For safety, we used only data obtained
`before premature treatment discontinuation, with an
`ascertainment window of 42 days to define treatment-
`emergent adverse events. We also did supportive
`sensitivity analyses using all data obtained during the
`trial for both efficacy and safety.
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`Analysis methods for HbA1c, bodyweight, and other
`continuous endpoints assessed over time included a
`mixed model for repeated measurements, with factors
`for treatment, country, stratum (metformin with or
`without a sulfonylurea), and baseline value, all nested
`within visits. An unstructured covariance matrix was
`assumed for measurements within the same participant.
`Outcomes assessing the secondary HbA1c and bodyweight
`targets were analysed with logistic regression. All
`p values are from two-sided tests of the null hypothesis of
`no treatment difference; a value of 0·05 was regarded as
`significant. The robustness of the analyses of HbA1c and
`bodyweight was assessed by handling missing data in
`several ways, including a comparator-based multiple
`imputation model in which missing data points were
`imputed on the basis of observed data in the insulin
`glargine group. Prespecified sensitivity analyses included
`a mixed model for repeated measurements analysis of
`the mITT population using all data, irrespective of
`whether they were obtained while the participants had
`discontinued the study drug or whether the participant
`had been given rescue medication (appendix). We used
`SAS version 9.3 for all statistical analyses. A data safety
`monitoring committee was not involved in this study.
`This trial is registered with ClinicalTrials.gov, number
`NCT02128932.
`
`Role of the funding source
`The funder of the study designed the trial and developed
`the protocol in consultation with VRA and JHDV. The
`funder provided logistical support during the trial and
`obtained the data. The authors interpreted the data and
`wrote the report, with medical writing services provided
`by the funder. The corresponding author had full access
`to all the data in the study and had final responsibility for
`the decision to submit for publication.
`
`Results
`We did the trial from August 4, 2014, to Sept 3, 2015,
`with participant recruitment taking place between
`Aug 4, 2014, and Dec 16, 2014. We randomly assigned
`1089 participants, of whom 1082 (99%) were exposed to
`a study drug (figure 1). 1020 (94%) randomly assigned
`participants completed
`the
`trial and 952
`(88%)
`completed
`their assigned
`treatment. The mITT
`population consisted of 362 participants assigned to
`0·5 mg semaglutide, 360 assigned
`to 1·0 mg
`semaglutide, and 360 assigned to insulin glargine. The
`numbers of participants who completed assigned
`treatment without the need for rescue medication were
`299 (83%) with 0·5 mg semaglutide, 296 (82%) with
`1·0 mg semaglutide, and 323 (91%) with insulin
`glargine. Numerically more participants discontinued
`treatment prematurely in the semaglutide groups
`compared with the insulin glargine group (figure 1);
`most discontinuations were due to adverse events
`(mostly gastrointestinal with semaglutide and from
`
`0·5 mg semaglutide
`(n=362)
`
`1·0 mg semaglutide
`(n=360)
`
`Insulin glargine
`(n=360)
`
`Total
`(n=1082)
`
`Age (years)
`Sex
`Female
`Male
`HbA1c (%)
`HbA1c (mmol/mol)
`Diabetes duration (years)
`Bodyweight (kg)
`BMI (kg/m)
`eGFR (MDRD; mL/min per
`1·73 m)
`Oral antidiabetes treatment†
`Metformin
`monotherapy
`Metformin plus a
`sulfonylurea
`Ethnic origin
`Hispanic or Latino
`Not Hispanic or Latino
`NA‡
`Race
`Native American or
`Alaska Native
`Asian
`Black or African
`American
`White
`Other
`NA‡
`
`56·5 (10·3)
`
`56·7 (10·4)
`
`56·2 (10·6)
`
`56·5 (10·4)
`
`165 (46%)
`197 (54%)
`8·1 (0·8)
`65·4 (9·3)
`7·8 (5·1)
`93·7 (21·4)
`33·1 (6·5)
`97·9 (25·9)
`
`178 (49%)
`182 (51%)
`8·3 (0·9)
`66·6 (10·3)
`9·3 (7·2)
`94·0 (22·5)
`33·0 (6·5)
`98·0 (27·5)
`
`165 (46%)
`195 (54%)
`8·1 (0·9)
`65·4 (9·6)
`8·6 (6·3)
`92·6 (21·5)
`33·0 (6·5)
`99·7 (26·5)
`
`508 (47%)
`574 (53%)
`8·2 (0·9)
`65·8 (9·7)
`8·6 (6·3)
`93·5 (21·8)
`33·0 (6·5)
`98·5 (26·6)
`
`176 (49%)
`
`175 (49%)
`
`172 (48%)
`
`523 (48%)
`
`186 (51%)
`
`185 (51%)
`
`188 (52%)
`
`559 (52%)
`
`61 (17%)
`301 (83%)
`0
`
`1 (<1%)
`
`42 (12%)
`32 (9%)
`
`279 (77%)
`3 (<1%)
`5 (1%)
`
`74 (21%)
`286 (79%)
`0
`
`78 (22%)
`281 (78%)
`1 (<1%)
`
`213 (20%)
`868 (80%)
`1 (<1%)
`
`0
`
`1 (<1%)
`
`2 (<1%)
`
`39 (11%)
`34 (9%)
`
`279 (78%)
`3 (<1%)
`5 (1%)
`
`38 (11%)
`33 (9%)
`
`276 (77%)
`5 (1%)
`7 (2%)
`
`119 (11%)
`99 (9%)
`
`834 (77%)
`11 (1%)
`17 (2%)
`
`Data are mean (SD) or n (%). eGFR=estimated glomerular filtration rate. MDRD=modification of diet in renal disease.
`NA=not applicable. *The modified intention-to-treat population comprised all randomly assigned participants who
`were exposed to at least one dose of study drug. †Metformin doses ≥1500 mg or maximum tolerated dose were
`allowed. Sulfonylurea doses ≥half the maximum dose allowed according to national label. ‡One patient at a US site
`chose not to report their ethnic origin, and data about race were not collected in sites in France (all counted as NA).
`
`Table 1: Baseline characteristics of the modified intention-to-treat population*
`
`other causes with insulin glargine, including skin and
`subcutaneous tissue disorders such as rash, pruritus,
`and urticaria). Baseline characteristics were similar
`between all groups (table 1; appendix).
`Mean HbA1c (baseline 8·17% [SD 0·89]) decreased over
`time in all three groups, with most of the decrease
`occurring by week 12 (figure 2). By week 30, mean HbA1c
`decreased by 1·21% (95% CI 1·10–1·31) with 0·5 mg
`semaglutide and 1·64%
`(1·54–1·74) with 1·0 mg
`semaglutide, versus 0·83% with
`insulin glargine
`(0·73–0·93); estimated treatment differences versus
`insulin glargine –0·38% (95% CI –0·52 to –0·24) with
`0·5 mg semaglutide and –0·81% (–0·96 to –0·67) with
`1·0 mg semaglutide (both p<0·0001; figure 2, table 2).
`The mean insulin glargine dose at the end of treatment
`was 29·2 IU per day (SD 16·0). Results from the
`sensitivity analyses for HbA1c supported the primary
`analysis results (appendix).
`
`www.thelancet.com/diabetes-endocrinology Vol 5 May 2017
`
`359
`
`Articles
`
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`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
`

`

` 0·5 mg
`semaglutide
`
` 1·0 mg
`semaglutide
`
` Insulin
`glargine
`
`–0·83
`
`–1·21
`
`–1·64
`
` ETD: –0·81*
`(–0·96 to –0·67)
` ETD: –0·38*
`(–0·52 to –0·24)
`
`–2·04
`
`–2·12
`
`–2·73
`
` ETD: –0·61*
`(–0·93 to –0·29)
` ETD: 0·08
`(–0·24 to 0·40)
`
`1·15
`
`–3·47
`
`–5·17
`
` ETD: –6·33*
`(–7·00 to –5·68)
` ETD: –4·62*
`(–5·27 to –3·96)
`
`B
`
`0
`
`–0·5
`
`–1·0
`
`–1·5
`
`–2·0
`
`D
`
`0
`
`–0·5
`
`–1·0
`
`–1·5
`
`–2·0
`
`–2·5
`
`–3·0
`
`F
`
`012
`
`–1
`–2
`–3
`–4
`–5
`–6
`
`Change from baseline (%)
`
`Change from baseline (mmol/L)
`
`Change from baseline (kg)
`
`Week 0
`
`Week 30
`
`Overall mean at baseline: 8·17%
`
`0·5 mg semaglutide
`1·0 mg semaglutide
`Insulin glargine
`
`0
`
`4
`
`8
`
`16
`12
`Time since randomisation (weeks)
`
`23
`
`30
`
`Overall mean at baseline: 9·73 mmol/L
`
`0
`
`4
`
`8
`
`16
`12
`Time since randomisation (weeks)
`
`23
`
`30
`
`Overall mean at baseline: 93·45 kg
`
`0
`
`4
`
`8
`
`12
`16
`Time since randomisation (weeks)
`
`23
`
`30
`
`A
`8·5
`
`8·0
`
`7·5
`
`7·0
`
`6·5
`
`6·0
`
`C
`10·0
`
`9·5
`
`9·0
`
`8·5
`
`8·0
`
`7·5
`
`7·0
`
`6·5
`
`6·0
`
`E
`96
`95
`94
`93
`92
`91
`90
`89
`88
`87
`
`G
`15
`14
`13
`12
`11
`10
`
`6789
`
`HbA1c (%)
`
`FPG (mmol/L)
`
`Bodyweight (kg)
`
`SMPG (mmol/L)
`
`Before
`breakfast
`
`90 min after
`breakfast
`
`Before
`lunch
`
`90 min after
`lunch
`
`Before
`dinner
`
`90 min after
`dinner
`
`Bedtime
`
`Breakfast
`day plus 1
`
`Timepoint
`
`www.thelancet.com/diabetes-endocrinology Vol 5 May 2017
`
`Figure 2: Efficacy outcomes
`Semaglutide 0·5 mg and
`1·0 mg once weekly, compared
`with insulin glargine: change in
`mean HbA1c by week (A), mean
`HbA1c after 30 weeks (B),
`overall mean fasting plasma
`glucose over time (C), mean
`fasting plasma glucose (FPG)
`after 30 weeks (D), change in
`mean bodyweight by week (E),
`mean bodyweight after
`30 weeks (F), and mean
`8-point self-monitored plasma
`glucose (SMPG) profile at
`baseline and week 30 (G).
`Panels A–F: *indicates
`significance (p <0·0001); values
`are estimated means (95% CIs)
`from a mixed model for
`repeated measurements
`analysis using on-treatment
`without rescue medication
`data from participants in the
`full analysis set; dotted lines are
`the overall mean value at
`baseline. Panel G: values are
`observed means (95% CIs)
`based on on-treatment
`without rescue medication
`data from participants in the
`full analysis set. ETD=estimated
`treatment difference.
`
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`
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`
`

`

`0·5 mg semaglutide (n=362)
`
`1·0 mg semaglutide (n=360)
`
`Overall
`baseline* value
`(mean [SD])
`
`Insulin glargine (n=360);
`change from baseline at
`week 30 (mean [95% CI])
`
`Change from
`baseline at week 30
`(mean [95% CI])
`
`Estimated treatment
`difference vs insulin
`glargine (95% CI)
`
`p value
`
`Change from
`baseline at week 30
`(mean [95% CI])
`
`Estimated treatment
`difference vs insulin
`glargine (95% CI)
`
`p value
`
`Glycaemia endpoints
`HbA1c (%)
`
`8·2 (0·9)
`
`HbA1c (mmol/mol)
`
`65·8 (9·7)
`
`FPG (mmol/L)
`
`9·7 (2·8)
`
`8–point SMPG (mmol/L)
`Mean
`
`Postprandial
`increments
`Bodyweight endpoints†
`Bodyweight (kg)
`
`10·9 (2·5)
`
`2·4 (2·0)
`
`93·5 (21·8)
`
`BMI (kg/m2)
`
`33·0 (6·5)
`
`109·2 (15·2)
`
`Waist circumference
`(cm)
`Blood pressure and pulse rate
`DBP (mm Hg)
`79·9 (8·5)
`
`SBP (mm Hg)
`
`132·1 (15·3)
`
`Pulse rate (beats
`per min)
`
`74·5 (10·2)
`
`–1·21
`(–1·31 to –1·10)
`–13·22
`(–14·32 to –12·08)
`–2·04
`(2·28 to –1·82)
`
`–0·38 (–0·52 to –0·24)
`
`<0·0001
`
`–4·16 (–5·72 to –2·60)
`
`<0·0001
`
`0·08 (–0·24 to 0·40)
`
`0·6243
`
`–1·64
`(–1·74 to –1·54)
`–17·93
`(–19·06 to –16·79)
`–2·73
`(–2·96 to –2·50)
`
`–0·81 (–0·96 to –0·67)
`
`<0·0001
`
`–0·83 (–0·93 to –0·73)
`
`–8·87 (–10·45 to –7·30)
`
`<0·0001
`
`–9·06 (–10·14 to –7·97)
`
`–0·61 (–0·93 to –0·29)
`
`0·0002
`
`–2·12 (–2·34 to –1·90)
`
`–2·40
`(–2·61 to –2·23)
`–0·59
`(–0·78 to –0·41)
`
`–3·47
`(–3·93 to –3·00)
`–1·23
`(–1·40 to –1·07)
`–3·20
`(–3·79 to –2·61)
`
`–1·38
`(–2·22 to –0·52)
`–4·65
`(–6·01 to –3·20)
`2·31
`(1·38 to 3·24)
`
`–0·04 (–0·30 to 0·23)
`
`0·7816
`
`–0·39 (–0·65 to –0·13)
`
`0·0029
`
`–4·62 (–5·27 to –3·96)
`
`<0·0001
`
`–1·66 (–1·89 to –1·43)
`
`<0·0001
`
`–3·42 (–4·24 to –2·59)
`
`<0·0001
`
`0·06 (–1·12 to 1·24)
`
`0·9183
`
`–2·97 (–4·92 to –1·03)
`
`0·0028
`
`2·36 (1·07 to 3·65)
`
`0·0004
`
`–2·94
`(–3·12 to –2·75)
`–0·85
`(–1·04 to –0·66)
`
`–5·17
`(–5·66 to –4·71)
`–1·85
`(–2·02 to –1·69)
`–4·54
`(–5·16 to –3·96)
`
`–0·98
`(–1·85 to –0·12)
`–5·17
`(–6·62 to –3·76)
`3·14
`(2·20 to 4·09)
`
`–0·57 (–0·83 to –0·31)
`
`<0·0001
`
`–2·37 (–2·55 to –2·18)
`
`–0·65 (–0·91 to –0·39)
`
`<0·0001
`
`–0·20 (–0·38 to –0·02)
`
`–6·33 (–6·99 to –5·67)
`
`<0·0001
`
`1·15 (0·70 to 1·61)
`
`–2·27 (–2·51 to –2·04)
`
`<0·0001
`
`0·42 (0·26 to 0·59)
`
`–4·76 (–5·59 to –3·93)
`
`<0·0001
`
`0·22 (–0·35 to 0·79)
`
`0·45 (–0·74 to 1·64)
`
`0·4545
`
`–1·44 (–2·26 to –0·63)
`
`–3·50 (–5·46 to –1·54)
`
`0·0005
`
`–1·68 (–3·02 to –0·33)
`
`3·19 (1·88 to 4·50)
`
`<0·0001
`
`–0·05 (–0·95 to 0·85)
`
`p values are from a two-sided test of the null hypothesis that there is no treatment difference. FPG=fasting plasma glucose. SMPG=self-monitored plasma glucose. DBP=diastolic blood pressure. SBP=systolic
`blood pressure. *Baseline is for the entire trial population. †Missing bodyweight data imputed by a mixed model for repeated measurements.
`
`Table 2: Primary and selected secondary endp