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`258
`
`Diabetes Care Volume 41, February 2018
`
`Andrew J. Ahmann,1 Matthew Capehorn,2
`Guillaume Charpentier,3 Francesco Dotta,4
`Elena Henkel,5 Ildiko Lingvay,6
`Anders G. Holst,7 Miriam P. Annett,8 and
`Vanita R. Aroda9
`
`Efficacy and Safety of Once-
`Weekly Semaglutide Versus
`Exenatide ER in Subjects With
`Type 2 Diabetes (SUSTAIN 3):
`A 56-Week, Open-Label,
`Randomized Clinical Trial
`
`Diabetes Care 2018;41:258–266 | https://doi.org/10.2337/dc17-0417
`
`CLINCARE/EDUCATION/NUTRITION/PSYCHOSOCIAL
`
`OBJECTIVE
`To compare the efficacy and safety of once-weekly semaglutide 1.0 mg s.c. with
`exenatide extended release (ER) 2.0 mg s.c. in subjects with type 2 diabetes.
`
`RESEARCH DESIGN AND METHODS
`In this phase 3a, open-label, parallel-group, randomized controlled trial, 813 subjects
`with type 2 diabetes taking oral antidiabetic drugs were randomized (1:1) to
`semaglutide 1.0 mg or exenatide ER 2.0 mg for 56 weeks. The primary end point
`was change from baseline in HbA1c at week 56.
`
`RESULTS
`Mean HbA1c (8.3% [67.7 mmol/mol] at baseline) was reduced by 1.5% (16.8 mmol/mol)
`with semaglutide and 0.9% (10.0 mmol/mol) with exenatide ER (estimated treatment
`difference vs. exenatide ER [ETD] –0.62% [95% CI –0.80, –0.44] [–6.78 mmol/mol
`(95% CI –8.70, –4.86)]; P < 0.0001 for noninferiority and superiority). Mean body
`weight (95.8 kg at baseline) was reduced by 5.6 kg with semaglutide and 1.9 kg
`with exenatide ER (ETD –3.78 kg [95% CI –4.58, –2.98]; P < 0.0001). Significantly
`more subjects treated with semaglutide (67%) achieved HbA1c <7.0% (<53 mmol/mol)
`versus those taking exenatide ER (40%). Both treatments had similar safety
`profiles, but gastrointestinal adverse events were more common in semaglutide-
`treated subjects (41.8%) than in exenatide ER–treated subjects (33.3%); injection-site
`reactions were more frequent with exenatide ER (22.0%) than with semaglutide
`(1.2%).
`
`CONCLUSIONS
`Semaglutide 1.0 mg was superior to exenatide ER 2.0 mg in improving glycemic
`control and reducing body weight after 56 weeks of treatment; the drugs had com-
`parable safety profiles. These results indicate that semaglutide treatment is highly
`effective for subjects with type 2 diabetes who are inadequately controlled on oral
`antidiabetic drugs.
`
`1Harold Schnitzer Diabetes Health Center, Ore-
`gon Health & Science University, Portland, OR
`2Rotherham Institute for Obesity, Clifton Medical
`Centre, Rotherham, U.K.
`3Centre Hospitalier Sud Francilien, Corbeil-
`Essonnes, France
`4Department of Medicine, Surgery and Neurosci-
`ence, University of Siena, Siena, Italy
`5Center for Clinical Studies, GWT-TU Dresden,
`Dresden, Germany
`6Departments of Internal Medicine and Clinical
`Sciences, University of Texas Southwestern Med-
`ical Center, Dallas, TX
`7Novo Nordisk A/S, Søborg, Denmark
`8Novo Nordisk Inc., Plainsboro, NJ
`9MedStar Health Research Institute, Hyattsville,
`MD
`
`Corresponding author: Andrew Ahmann, ahmanna@
`ohsu.edu.
`
`Received 28 February 2017 and accepted 22
`October 2017.
`
`Clinical trial reg. no. NCT01885208, clinicaltrials
`.gov.
`
`This article contains Supplementary Data online
`at http://care.diabetesjournals.org/lookup/
`suppl/doi:10.2337/dc17-0417/-/DC1.
`
`A full list of trial investigators is available in
`Supplementary Table 6.
`
`This article is featured in a podcast available at
`http://www.diabetesjournals.org/content/
`diabetes-core-update-podcasts.
`
`© 2017 by the American Diabetes Association.
`Readers may use this article as long as the work
`is properly cited, the use is educational and not
`for profit, and the work is not altered. More infor-
`mation is available at http://www.diabetesjournals
`.org/content/license.
`See accompanying article, p. 333.
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`Glucagon-like peptide-1 (GLP-1) receptor
`agonists (RAs) are an established treat-
`ment option for type 2 diabetes (1).
`GLP-1 RAs stimulate insulin secretion
`in a glucose-dependent manner and sup-
`press glucagon production, resulting in
`significant reductions in hemoglobin A1c
`(HbA1c) levels with minimal risk of hypo-
`glycemia (2). GLP-1 RAs also reduce body
`weight by inducing feelings of satiety and
`fullness and reducing feelings of hunger,
`thereby lowering energy intake (3,4).
`These effects are particularly beneficial
`given the role of obesity in the complex
`pathophysiology of type 2 diabetes (5–7).
`Recent advances in GLP-1 RA therapeutics
`include the development of once-weekly
`GLP-1 RAs, which may improve patient
`adherence and health-related quality of
`life compared with daily formulations
`(8), as has been demonstrated for pa-
`tients with other chronic illnesses (9).
`Semaglutide is a GLP-1 analog currently
`in development for the treatment of
`type 2 diabetes. It has 94% structural ho-
`mology to native human GLP-1 and is
`structurally similar to liraglutide (10),
`but important structural modifications
`make it less susceptible to degradation
`by dipeptidyl peptidase-4 and increase
`its specific high-affinity binding to al-
`bumin (10). Its resultant half-life of ap-
`proximately 1 week makes semaglutide
`appropriate for once-weekly subcutane-
`ous administration (10). Exenatide, the
`comparator treatment in this trial, is a
`synthetic form of the GLP-1 RA exendin-
`4, which has 53% homology to native
`human GLP-1 (11). When encapsulated
`in microspheres, exenatide is released
`slowly from the injection site (extended
`release [ER]) and is therefore suitable for
`once-weekly dosing (12).
`The Semaglutide Unabated Sustain-
`ability in Treatment of Type 2 Diabetes
`(SUSTAIN) 3 trial is a phase 3a compara-
`tive study that evaluated the efficacy,
`safety, and tolerability of once-weekly
`semaglutide 1.0 mg s.c. versus that of
`once-weekly exenatide ER 2.0 mg s.c. over
`56 weeks in adults with type 2 diabetes who
`are inadequately controlled on oral antidia-
`betic drugs (OADs).
`
`RESEARCH DESIGN AND METHODS
`Trial Design
`This 56-week, phase 3a, open-label, active-
`comparator, parallel-group randomized
`trial (SUSTAIN 3; clinicaltrials.gov identifier
`NCT01885208) was conducted at 141 sites
`
`in 12 countries in Europe, South America,
`and the U.S. between December 2013 and
`July 2015, in accordance with the Inter-
`national Conference on Harmonization
`Good Clinical Practice Guidelines (13)
`and the Declaration of Helsinki (14). The
`protocol is available in the Supplementary
`Data online.
`
`Subjects
`Subjects were eligible for inclusion if
`they were $18 years of age, diagnosed
`with type 2 diabetes (HbA1c 7.0–10.5%
`[53–91 mmol/mol]), and receiving stable
`treatment with one or two OADs (metformin
`$1500 mg or the maximum \tolerated
`dose, and/or thiazolidinediones, and/or sul-
`fonylureas [at least half of the maximum
`dose allowed], according to the national
`label) for $90 days before screening.
`Key exclusion criteria included estimated
`glomerular filtration rate ,60 mL/min/
`1.73 m2 per the MDRD formula (four-
`variable version); chronic treatment with
`glucose-lowering agents, other than those
`specified by the inclusion criteria, within
`90 days of screening; history of chronic
`or idiopathic acute pancreatitis; an acute
`coronary or cerebrovascular event within
`90 days before randomization; and New
`York Heart Association class IV heart
`failure. Supplementary Table 1 shows all
`inclusion and exclusion criteria. Written
`informed consent was obtained from all
`participants.
`
`Interventions
`Subjects were randomized (1:1) to once-
`weekly semaglutide 1.0 mg s.c. (adminis-
`tered with a prefilled pen injector) or
`once-weekly exenatide ER 2.0 mg s.c.
`(administered with a vial and syringe)
`for 56 weeks; all subjects had a 5-week
`follow-up, including those who stopped
`treatment early. Subjects were to remain
`in the trial regardless of whether they
`received randomized treatment. Sema-
`glutide treatment followed a fixed dose-
`escalation regimen: 0.25 mg for 4 weeks,
`then 0.5 mg for 4 weeks, then a mainte-
`nance dose of 1.0 mg for 48 weeks. Exe-
`natide ER was dosed at 2.0 mg throughout
`the trial, according to standard dosing rec-
`ommendations. Supplementary Fig. 1
`shows the trial design. Subjects were cen-
`trally randomized to treatment groups
`using an interactive voice/web response
`system. Injections were administered in
`the thigh, abdomen, or upper arm, ac-
`cording to subject preference. Background
`metformin and/or thiazolidinedione
`
`treatments were continued throughout
`the trial. Sulfonylurea could be titrated
`down, at the investigators’ discretion,
`if a subject experienced unacceptable hy-
`poglycemia. Subjects with unacceptable
`hyperglycemia despite trial medication
`were offered intensified treatment (res-
`cue medication), as an add-on to the ran-
`domized treatment (excluding GLP-1 RAs,
`dipeptidyl peptidase-4 inhibitors, and
`pramlintide), at the discretion of the
`investigator.
`
`Outcomes
`The primary end point was the change
`from baseline in HbA1c level at week 56.
`The confirmatory secondary end point
`was the change from baseline in body
`weight at week 56.
`Other secondary efficacy end points
`included the proportion of subjects who
`achieved HbA1c ,7.0% (,53 mmol/mol)
`or #6.5% (#48 mmol/mol) at 56 weeks;
`the proportion of subjects who achieved
`a composite outcome of HbA1c ,7.0%
`(,53 mmol/mol) without severe (based
`on American Diabetes Association [ADA]
`classi fication [15]) or blood glucose
`(BG)–confirmed symptomatic hypogly-
`cemia (plasma glucose #3.1 mmol/L
`or #56 mg/dL) and no weight gain;
`change in fasting plasma glucose (FPG)
`from baseline to week 56; mean self-
`measured plasma glucose (SMPG) at
`postprandial increments (over all meals)
`and mean seven-point profiles (before and
`after each main meal and at bedtime);
`other laboratory measurements asso-
`ciated with b-cell function and glucose
`metabolism (insulin, C-peptide, proinsu-
`lin, glucagon, proinsulin-to-insulin ra-
`tio, and HOMA of b-cell function and
`insulin resistance); proportion of subjects
`who achieved $5% and $10% weight
`loss; and change from baseline to week
`56 in BMI, waist circumference, fasting
`blood lipids, and systolic and diastolic
`blood pressures. Additional secondary ef-
`ficacy end points included biochemical
`markers and patient-reported outcome
`questionnaires (Diabetes Treatment
`Satisfaction Questionnaire [DTSQ] status
`scores and 36-item Short-Form Health
`Survey-V2 [SF-36v2] scores).
`Safety outcomes included the inci-
`dence of adverse events (AEs), severe or
`BG-confirmed (#3.1 mmol/L or 56 mg/dL)
`symptomatic hypoglycemic episodes,
`pulse rate, and anti-trial drug antibodies.
`An independent and blinded external
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`event adjudication committee (EAC)
`validated predefined types of events
`(Supplementary Table 2).
`
`Statistical Analysis
`The trial was powered to the primary ob-
`jective (change from baseline in HbA1c
`at week 56) of demonstrating noninferiority
`with 90% under the following assumptions:
`no treatment difference, a noninferiority
`margin of 0.3%, 1:1 randomization, SD of
`1.1%, one-sided 0.025 significance
`level, and 30% of subjects discontinuing
`the trial product. A consequent target
`sample size of 798 subjects was speci-
`fied to reach the required sample size of
`279 subjects per group. This sample size
`ensures at least 90% marginal power to
`confirm a treatment difference of 0.3
`percentage points for the primary end
`point and 99% marginal power to
`detect a 1.5-kg difference in change in
`body weight at 56 weeks, with an SD of
`4 kg. Conservatively assuming indepen-
`dence between the two end points, the
`joint power is 89.1%. To preserve the over-
`all type 1 error rate, hierarchical testing
`was used for noninferiority for the pri-
`mary end point, superiority for the primary
`
`end point, then superiority for the con-
`firmatory end point on change in body
`weight. Superiority for change in either
`HbA1c or body weight required an upper
`limit of the two-sided 95% CI for the
`estimated difference below 0% or 0 kg,
`respectively.
`Continuous end points were analyzed
`using a mixed model for repeated measure-
`ments with factors for treatment, country,
`and baseline value, all nested within visit,
`based on randomized and exposed subjects,
`and including only data obtained before ini-
`tiating rescue therapy or discontinuing
`randomized treatment. An unstructured
`covariance matrix was assumed for mea-
`surements within the same subject. End
`points evaluating the secondary HbA1c
`targets and weight loss responses were
`analyzed using logistic regression.
`The robustness of the conclusions from
`the primary and confirmatory secondary
`analyses was evaluated in several sta-
`tistical sensitivity analyses, including a
`comparator-based multiple imputa-
`tion analysis (Supplementary Fig. 3 and
`Supplementary Table 3). All analyses
`were performed using SAS version 9.3.
`
`Treatment-emergent AEs, defined as
`AEs with an onset or increase in severity at
`any time from the first day of treatment with
`the trial product to the follow-up visit sched-
`uled 5 weeks (plus a 7-day visit window) after
`the last dose, were evaluated by descriptive
`statistics.
`
`RESULTS
`Subject Disposition and Baseline
`Characteristics
`Subjects were recruited between December
`2013 and April 2014. Of the 813 subjects ran-
`domized, 809 were exposed to treatment;
`82 semaglutide-treated subjects (20.3%) and
`85 exenatide ER–treated subjects (21.0%)
`discontinuedtreatment early (Supplementary
`Fig. 2). Rescue medication was adminis-
`tered to 29 subjects (7.2%) in the semaglu-
`tide group and 48 subjects (11.9%) in the
`exenatide ER group. Baseline characteris-
`tics were similar between groups (Table 1).
`
`Primary Outcome
`Mean HbA1c decreased over time (Fig. 1A)
`by 1.5% (16.8 mmol/mol) with semaglutide
`and 0.9% (10.0 mmol/mol) with exenatide
`ER at 56 weeks (estimated treatment differ-
`ence vs. exenatide ER [ETD] –0.62%; 95% CI
`
`Table 1—Baseline characteristics of trial populations
`Semaglutide 1.0 mg (n = 404)
`
`Exenatide ER 2.0 mg (n = 405)
`
`Total (n = 809)
`
`Age, years (min.–max.)
`HbA1c
`% (min.–max.)*
`mmol/mol (min.–max.)
`Diabetes duration, years (min.–max.)
`Body weight, kg (min.–max.)
`BMI, (kg/m2) (min.–max.)
`eGFR (MDRD), mL/min/1.73 m2 (min.–max.)
`Sex, n (%)
`Female
`Male
`Ethnicity, n (%)
`Hispanic or Latino
`Not Hispanic or Latino
`Race, n (%)
`White
`Black or African American
`Asian
`Other
`Diabetes medications at screening, n (%)
`Biguanides
`Sulfonylureas
`Thiazolidinediones
`Other BG-lowering drugs (excluding insulin)†
`Long-acting insulins and analogs for injection†
`
`56.4 (20–82)
`
`56.7 (21–83)
`
`56.6 (20–83)
`
`8.4 (6.7–11.1)
`67.9 (49.7–97.8)
`9.0 (0.4–37.1)
`96.2 (49.9–198.3)
`34.0 (21.0–72.8)
`100.5 (60.0–208.0)
`
`8.3 (6.5–11.2)
`67.6 (47.5–98.9)
`9.4 (0.3–54.0)
`95.4 (53.2–171.9)
`33.6 (21.2–55.8)
`100.5 (60.0–194.0)
`
`8.3 (6.5–11.2)
`67.7 (47.5–98.9)
`9.2 (0.3–54.0)
`95.8 (49.9–198.3)
`33.8 (21.1–72.8)
`100.5 (60.0–208.0)
`
`185 (45.8)
`219 (54.2)
`
`91 (22.5)
`313 (77.5)
`
`341 (84.4)
`28 (6.9)
`8 (2.0)
`27 (6.6)
`
`391 (96.8)
`181 (44.8)
`13 (3.2)
`1 (0.2)
`0 (0)
`
`177 (43.7)
`228 (56.3)
`
`106 (26.2)
`299 (73.8)
`
`338 (83.5)
`30 (7.4)
`6 (1.5)
`31 (7.6)
`
`390 (96.3)
`208 (51.4)
`6 (1.5)
`2 (0.5)
`1 (0.2)
`
`362 (44.7)
`447 (55.3)
`
`197 (24.4)
`612 (75.6)
`
`679 (83.9)
`58 (7.2)
`14 (1.7)
`58 (7.2)
`
`781 (96.5)
`389 (48.1)
`19 (2.3)
`3 (0.4)
`1 (0.1)
`
`Values are arithmetic means (minimum–maximum) or n (%). eGFR, estimated glomerular filtration rate. *Min./max. HbA1c may be outside the range
`specified in the inclusion criteria because measurements were taken at the randomization visit. †Subjects receiving other BG-lowering drugs, insulins, and
`analogs for injection were randomized in error.
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`Ahmann and Associates
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`261
`
`–0.80, –0.44 [–6.78 mmol/mol; 95% CI
`–8.70, –4.86]; P , 0.0001 for noninferior-
`ity and superiority; Fig. 1B, Table 2 and
`Supplementary Fig. 4A). This result was
`supported by all six sensitivity analyses
`(Supplementary Fig. 3).
`
`Secondary Efficacy Outcomes
`The ADA target of HbA1c ,7.0% (,53
`mmol/mol) was achieved by 67% of
`semaglutide-treated subjects and 40% of ex-
`enatide ER–treated subjects (P , 0.0001;
`Fig. 1C). Overall, 56% of semaglutide-treated
`
`subjects and 28% of exenatide ER–treated
`subjects achieved the composite outcome
`of HbA1c ,7.0% (,53 mmol/mol) without
`severe or BG-confirmed symptomatic
`hypoglycemia and without weight gain
`(P , 0.0001; Fig. 1D). The target of HbA1c
`
`Figure 1—Efficacy parameters when comparing semaglutide 1.0 mg once weekly with exenatide ER: mean HbA1c by week (A), change in mean HbA1c after
`56 weeks (B), the proportion of subjects achieving HbA1c ,7.0% (,53 mmol/mol) (C), the proportion of subjects achieving HbA1c ,7.0% (,53 mmol/mol)
`without severe or BG-confirmed hypoglycemia (BG ,3.1 mmol/L [,56 mg/dL]) and no weight gain at week 56 (D), mean body weight by week (E), and
`change in mean body weight after 56 weeks (F). *Significant at P , 0.0001. Values are estimated mean 6 SE from a mixed model for repeated measurements
`analysis (A, B, E, and F) or observed proportions (C and D) using “on treatment without rescue medication” data from subjects in the full analysis set. The
`dotted lines in A and C indicate the overall mean values at baseline. Missing data were imputed from a mixed model for repeated measurements analysis
`and subsequently classified.
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`Table 2—Key outcomes by treatment group
`
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`Overall value
`at baseline,
`mean (SD)*
`
`8.3 (0.95)
`67.7 (10.4)
`10.5 (2.7)
`
`10.9 (2.5)
`2.2 (1.9)
`95.8 (21.5)
`33.8 (6.7)
`111.2 (14.5)
`
`133.5 (14.5)
`79.9 (8.7)
`75.1 (10.5)
`
`Change from baseline
`at week 56, LSM (SE)
`
`Semaglutide 1.0 mg
`21.5 (0.06)
`216.8 (0.68)
`22.8 (0.13)
`
`Exenatide ER 2.0 mg
`20.9 (0.06)
`210.0 (0.70)
`22.0 (0.14)
`
`22.2 (0.10)
`20.6 (0.07)
`25.6 (0.29)
`22.0 (0.10)
`25.1 (0.31)
`
`21.5 (0.10)
`20.3 (0.07)
`21.9 (0.29)
`20.6 (0.10)
`22.3 (0.32)
`
`22.2 (0.70)
`24.6 (0.68)
`20.1 (0.46)
`21.0 (0.45)
`1.1 (0.44)
`2.1 (0.44)
`Subjects achieving target at week 56,‡ n (%)
`
`270 (67)
`190 (47)
`
`161 (40)
`89 (22)
`
`Estimated treatment
`difference [95% CI]
`20.62 [–0.80, –0.44]
`26.78 [–8.70, –4.86]
`20.84 [–1.21, –0.47]
`
`20.73 [–1.02, –0.44]
`20.24 [–0.44, –0.04]
`23.78 [–4.58, –2.98]
`21.36 [–1.64, –1.07]
`22.76 [–3.63, –1.89]
`
`22.37 [–4.29, –0.45]
`20.90 [–2.16, 0.36]
`1.03 [20.19, 2.25]
`
`226 (56)
`
`212 (52)
`86 (21)
`
`113 (28)
`
`70 (17)
`18 (4)
`
`P value†
`,0.0001
`,0.0001
`,0.0001
`
`,0.0001
`0.0189
`,0.0001
`,0.0001
`,0.0001
`
`0.0158
`0.1616
`0.0973
`
`,0.0001
`,0.0001
`
`,0.0001
`
`,0.0001
`,0.0001
`
`HbA1c, %
`HbA1c, mmol/mol
`FPG, mmol/L
`7-Point SMPG, mmol/L
`Mean
`Increment
`Body weight, kg
`BMI, kg/m2
`Waist circumference, cm
`Blood pressure, mmHg
`Systolic
`Diastolic
`Pulse rate, bpm
`
`HbA1c targets
`,7.0% (,53 mmol/mol)
`#6.5% (#48 mmol/mol)
`HbA1c target ,7.0%
`(,53 mmol/mol)
`without severe or
`BG-confirmed
`hypoglycemia and no
`weight gain at week 56
`Body weight reduction
`$5%
`$10%
`
`Values are observed means, or observed proportions, based on “on treatment without rescue medication” data from subjects in the full analysis set, with
`the exception of pulse rate values, which are based on “on-treatment” data from subjects in the safety analysis set. LSM, least squares mean. *Baseline
`values are for the entire trial population. †P values are two-sided, testing the null hypothesis of no treatment difference. ‡For the proportions of subjects
`achieving targets at week 56, missing data were imputed from a mixed model for repeated measurements and subsequently classified. Severe
`hypoglycemia was based on the ADA classification. BG-confirmed hypoglycemia was defined as plasma glucose ,3.1 mmol/L (56 mg/dL).
`
`#6.5% (#48 mmol/mol), specified by the
`American Association of Clinical Endocrinol-
`ogists, was achieved by 47% of semaglutide-
`treated subjects and 22% of exenatide
`ER–treated subjects (P , 0.0001; Table 2).
`Mean FPG was reduced by 2.8 mmol/L
`with semaglutide and 2.0 mmol/L with
`exenatide ER (ETD –0.84 mmol/L; 95%
`CI –1.21, –0.47; P , 0.0001) (Table 2).
`The mean postprandial increment in BG
`across all meals, calculated using the
`seven-point SMPG profile, was reduced
`by 0.6 mmol/L with semaglutide and
`0.3 mmol/L with exenatide ER (ETD
`–0.24; 95% CI –0.44, –0.04; P = 0.0189)
`(Table 2). The mean of all glucose values
`from the seven-point SMPG profile was
`reduced by 2.2 mmol/L with semaglutide
`and 1.5 mmol/L with exenatide ER (ETD
`–0.73; 95% CI –1.02, –0.44; P , 0.0001).
`Fasting insulin, plasma glucagon, proin-
`sulin, proinsulin-to-insulin ratio, and HOMA–
`insulin resistance were significantly lower
`at week 56 with semaglutide than with
`
`exenatide ER. The change in HOMA–b-cell
`function was similar between groups. The in-
`crease in fasting C-peptide was significantly
`smaller at week 56 with semaglutide than
`with exenatide ER (Supplementary Table 4).
`Mean body weight was reduced by
`5.6 kg with semaglutide and by 1.9 kg
`with exenatide ER (ETD –3.78 kg; 95%
`CI –4.58, –2.98; P , 0.0001; Fig. 1E and F
`and Supplementary Fig. 4B), showing the
`superiority of semaglutide over exenatide
`ER in weight loss. The results were sup-
`ported by the statistical sensitivity analy-
`ses. A weight loss response of $5% was
`achieved by 52% of semaglutide-treated
`subjects and 17% of exenatide ER–treated
`subjects (P , 0.0001; Table 2). A weight
`loss response of $10% was achieved by
`21% of semaglutide-treated subjects and
`4% of exenatide ER–treated subjects (P ,
`0.0001; Table 2). BMI and waist circum-
`ference were also reduced to a greater
`extent with semaglutide than with exena-
`tide ER (both P , 0.0001; Table 2).
`
`Free fatty acid, VLDL cholesterol, and
`triglycerides were improved with sem-
`aglutide compared with exenatide ER
`(P = 0.0342 for free fatty acid; P ,
`0.0001 for both VLDL cholesterol and tri-
`glycerides; Supplementary Table 4). Sys-
`tolic blood pressure was reduced by
`4.6 mmHg with semaglutide and 2.2 mmHg
`with exenatide ER (ETD –2.37 mmHg; P =
`0.0158). No statistically significant differ-
`ence was found between treatments
`for change in diastolic blood pressure
`(Table 2).
`Compared with subjects treated with
`exenatide ER, those treated with sema-
`glutide experienced a significantly greater
`improvement in overall treatment satis-
`faction (P = 0.0068) and self-perceived
`hyperglycemia (P = 0.0200), as measured
`by DTSQ scores. No significant differences
`were found between the treatment
`groups for domains of health status as-
`sessed by the SF-36v2 health survey
`(Supplementary Fig. 5).
`
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`Safety Outcomes
`AEs were reported by similar proportions
`of subjects in each treatment group:
`75.0% (semaglutide) and 76.3% (exena-
`tide ER). Serious AEs were reported
`in 9.4% of subjects treated with semaglu-
`tide and 5.9% of those treated with exe-
`natide ER (Table 3 and Supplementary
`Table 5). AEs leading to premature treat-
`ment discontinuation were reported in
`9.4% of subjects treated with semaglutide
`and 7.2% of subjects treated with exena-
`tide ER (Table 3 and Supplementary Fig.
`6). Of these, 5.7% of semaglutide-treated
`subjects discontinued treatment because
`of gastrointestinal (GI) AEsd2.5% for
`nausea, 1.2% for vomiting, and 0.7% for
`diarrheadwhereas 2.7% of exenatide
`ER–treated subjects discontinued treat-
`ment for the same AEs: 1.5% for nausea,
`0.5% for vomiting, and 0.2% for diarrhea.
`Nine subjects, all in the exenatide ER
`group, stopped treatment prematurely
`because of injection-site nodules (1.2%),
`mass (0.5%), or reaction (0.5%). Two fatal
`events occurred in the semaglutide group
`(one from hepatocellular carcinoma and
`the other from invasive lobular breast car-
`cinoma) and were judged by the investi-
`gator to be unrelated to treatment with
`the trial product. Both subjects had a short
`duration of exposure before the onset of
`the events (65 and 11 days, respectively).
`The most common AEs in both treat-
`ment groups were GI (semaglutide 41.8%,
`exenatide ER 33.3%). Nausea was reported
`in 22.3% and 11.9% of semaglutide- and
`exenatide ER–treated subjects, respectively
`
`(Table 3). Diarrhea was reported in 11.4%
`and 8.4% of semaglutide- and exenatide
`ER–treated subjects, while vomiting oc-
`curred in 7.2% and 6.2%, respectively (Ta-
`ble 3). The proportions of subjects with
`nausea, diarrhea, or vomiting tended to
`diminish over time (Supplementary Fig. 7).
`Overall, 15 EAC-confirmed (treatment-
`emergent) neoplasms (8 malignant and
`7 benign) were reported with semaglu-
`tide and 8 (2 malignant and 6 benign)
`with exenatide ER; we found no evident
`pattern to the organ distribution of
`malignant neoplasms. Two instances of
`EAC-confirmed mild acute pancreatitis oc-
`curred with semaglutide and three with
`exenatide ER. Mean lipase and amylase
`levels increased similarly at 56 weeks in
`the two groups (by 19% and 29% with
`semaglutide and by 15% and 32% with
`exenatide ER, respectively) (Supplementary
`Fig. 8). Six cases of cholelithiasis were re-
`ported in the semaglutide group and two
`in the exenatide ER group.
`Two episodes of severe hypoglycemia
`were reported in two semaglutide-treated
`subjects. One subject was taking sulfonylureas
`and metformin, and a BG level of 2.33 mmol/L
`was recorded during the episode; the
`other subject was taking metformin
`only, and a BG level of 3.66 mmol/L was
`recorded during this episode. In total,
`33 subjects (8.2%) treated with semaglu-
`tide reported severe or BG-confirmed
`symptomatic episodes, compared with
`33 subjects (8.1%) receiving exenatide
`ER. Rates of severe or BG-confirmed hy-
`poglycemia were 13.0 and 14.0 events
`
`per 100 observation years for semaglutide
`and exenatide ER, respectively. The major-
`ity of events were reported in subjects
`concomitantly receiving sulfonylureas in
`both the semaglutide 1.0 mg and exena-
`tide ER 2.0 mg groups.
`Pulse rate increased by 2.1 bpm with
`semaglutide and by 1.1 bpm with exena-
`tide ER (P = 0.0973). Injection-site reactions
`(defined by prespecified Medical Dictio-
`nary for Regulatory Activities–preferred
`terms) occurred in 1.2% of semaglutide-
`treated and 22.0% of exenatide ER–
`treated subjects. Anti-semaglutide antibodies
`developed in 13 subjects; none were neu-
`tralizing to semaglutide or endogenous
`GLP-1. Anti-exenatide antibodies devel-
`oped in 355 subjects; in 39 subjects
`these were neutralizing to exenatide,
`but none were neutralizing to endogenous
`GLP-1.
`
`CONCLUSIONS
`Main Findings and Interpretations
`Treatment with once-weekly semaglutide
`1.0 mg s.c. showed superior glycemic con-
`trol compared with once-weekly exenatide
`ER 2.0 mg s.c. in adults with type 2 diabetes
`inadequately controlled on one or two
`OADs. The conclusion of superiority was
`supported by all sensitivity analyses. De-
`spite subjects having a mean diabetes du-
`ration .9 years, 67% of the subjects
`achieved an HbA1c target ,7.0% (,53
`mmol/mol) with semaglutide treatment.
`Mean baseline HbA1c was reduced by
`0.9% (10.0 mmol/mol) with exenatide
`ER in this trial, which is lower than the
`
`Table 3—Treatment-emergent adverse events*
`
`Semaglutide 1.0 mg
`
`Exenatide ER 2.0 mg
`
`Subjects experiencing
`$1 event, n (%) (n = 404)
`
`Events, n
`
`AEs
`Serious AEs
`AEs leading to treatment discontinuation
`AEs occurring in $5% of subjects
`Nausea
`Diarrhea
`Lipase increased
`Nasopharyngitis
`Headache
`Decreased appetite
`Vomiting
`Dyspepsia
`Constipation
`Injection-site nodule
`
`303 (75.0)
`38 (9.4)
`38 (9.4)
`
`90 (22.3)
`46 (11.4)
`41 (10.1)
`39 (9.7)
`38 (9.4)
`32 (7.9)
`29 (7.2)
`27 (6.7)
`26 (6.4)
`0 (0.0)
`
`1,551
`52
`48
`
`159
`86
`51
`46
`81
`34
`37
`33
`28
`0
`
`Event
`rate†
`
`374.7
`12.6
`11.6
`
`38.4
`20.8
`12.3
`11.1
`19.6
`8.2
`8.9
`8.0
`6.8
`0
`
`Subjects experiencing
`$1 event, n (%) (n = 405)
`
`Events, n
`
`309 (76.3)
`24 (5.9)
`29 (7.2)
`
`48 (11.9)
`34 (8.4)
`49 (12.1)
`38 (9.4)
`39 (9.6)
`21 (5.2)
`25 (6.2)
`19 (4.7)
`21 (5.2)
`49 (12.1)
`
`1,511
`27
`47
`
`70
`58
`64
`51
`65
`24
`40
`23
`26
`55
`
`Event
`rate†
`
`370.4
`6.6
`11.5
`
`17.2
`14.2
`15.7
`12.5
`15.9
`5.9
`9.8
`5.6
`6.4
`13.5
`
`*Treatment-emergent AE (by preferred term) include events with onset at or after the date of the first trial product dose and before or at the date of the
`last trial medication dose plus 5 weeks plus the 7-day visit window for the end-of-treatment follow-up visit (42 days). †Event rate per 100 years of
`treatment exposure.
`
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`Semaglutide and Exenatide ER in Type 2 Diabetes
`
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`
`1.0–2.0% (11–22 mmol/mol) mean
`change from baseline to the end of treat-
`ment reported in the Diabetes Therapy
`Utilization: Researching Changes in A1C,
`Weight and Other Factors Through Inter-
`vention with Exenatide Once Weekly
`(DURATION) clinical trial program that in-
`vestigated exenatide ER against a range
`of comparators (16–21). While trials
`should be indirectly compared with cau-
`tion, we cannot exclude the possibility
`that the open-label design of the trial
`and the more complex device system
`used to administer exenatide ER contrib-
`uted to the lower performance of this
`treatment. Mean HbA1c gradually in-
`creased in the exenatide ER group from
`week 23, and a less pronounced analo-
`gous increase occurred in the semaglu-
`tide group from week 30; HbA1c levels in
`both groups stayed well below baseline
`by week 56. These findings are consistent
`with HbA1c trajectory reported in trials of
`other GLP-1 RAs (22,23).
`At the start of treatment, 182 of 404
`subjects treated with semaglutide re-
`ceived a concomitant sulfonylurea com-
`pared with 209 of 405 subjects receiving
`exenatide ER; by the end of the obser-
`vation period, these numbers rose to
`193 semaglutide-treated subjects and
`213 exenatide ER–treated subjects. We
`believe that the influence of this differen-
`tial use of a concomitant sulfonylurea on
`HbA1c level by the end of treatment
`would be small.
`Long-acting GLP-1 RAs such as sema-
`glutide and exenatide ER are known to
`reduce both fasting and postprandial BG
`levels (24). In this study, semaglutide led
`to greater improvements in FPG and post-
`prandial glucose (seven-point SMPG)
`than did exenatide ER, as well as im-
`provements in a range of glycemic param-
`eters, including insulin, glucagon, C-peptide,
`proinsulin, and the proinsulin-to-insulin
`ratio. A significant decrease was found
`in insulin resistance (as measured by
`HOMA–insulin resistance) in semaglutide-
`treated subjects compared with that
`in exenatide ER–treated subjectsd
`particularly notable when comparing
`two GLP-1 RAsdwhereas b-cell function
`increased similarly in both groups. Sema-
`glutide treatment also resulted in a pro-
`nounced mean change in body weightda
`reduction of 5.6 kg over the 1-year
`treatment perioddwhich was almost
`three times larger than that occurring
`with exenatide ER (1.9 kg). In addition,
`
`markedly more subjects receiving sema-
`glutide than exenatide ER achieved a clini-
`cally meaningful weight loss response of
`$5% (52% vs. 17%). This sustained
`weight loss is particularly encouraging be-
`cause of the high proportion of patients
`with type 2 diabetes who are over-
`weight or obese and the propensity of
`some antihyperglycemic medications
`to lead to further weight gain in these
`individuals (25). While weight gain can
`lead to frustration, reduced motivation,
`and decreased adherence to treatment
`(26), a weight loss of 5% or more is asso-
`ciated with improvements in metabolic
`and cardiovascular risk factors in patients
`with type 2 diabetes (27).
`Overall, diabetes treatment satisfac-
`tion and self-perceived hyperglycemia im-
`proved more with semaglutide than with
`exenatide ER, consistent with the differ-
`ences observed in glycemic control,
`without a significant difference in overall
`health-related quality of life, as measured
`by the SF-36v2 questionnaire.
`A higher proportion of GI-related AEs
`were reported with semaglutide (41.8%)