Original Article
`
`Semaglutide and Cardiovascular Outcomes
`in Patients with Type 2 Diabetes
`Steven P. Marso, M.D., Stephen C. Bain, M.D., Agostino Consoli, M.D.,
`Freddy G. Eliaschewitz, M.D., Esteban Jódar, M.D., Lawrence A. Leiter, M.D.,
`Ildiko Lingvay, M.D., M.P.H., M.S.C.S., Julio Rosenstock, M.D.,
`Jochen Seufert, M.D., Ph.D., Mark L. Warren, M.D., Vincent Woo, M.D.,
`Oluf Hansen, M.Sc., Anders G. Holst, M.D., Ph.D., Jonas Pettersson, M.D., Ph.D.,
`and Tina Vilsbøll, M.D., D.M.Sc., for the SUSTAIN-6 Investigators*
`
`A BS TR AC T
`
`From the Research Medical Center, Kansas
`City, MO (S.P.M.); School of Medicine,
`Swansea University, Swansea, United King-
`dom (S.C.B.); Department of Medicine
`and Aging Science and Center of Excel-
`lence on Aging and Translational Medi-
`cine, G. d’Annunzio University, Chieti-
`Pescara, Italy (A.C.); CPClin Research
`Center/Hospital Israelita Albert Einstein,
`São Paulo (F.G.E.); Hospital Universitario
`Quirón Salud Madrid, Facultad de Cien-
`cias de la Salud, Universidad Europea de
`Madrid, Madrid (E.J.); Li Ka Shing Knowl-
`edge Institute and Keenan Research Cen-
`tre for Biomedical Science, St. Michael’s
`Hospital, University of Toronto, Toronto
`(L.A.L.), and the University of Manitoba,
`Winnipeg (V.W.) — both in Canada; Uni-
`versity of Texas Southwestern Medical
`Center (I.L.) and Dallas Diabetes Re-
`search Center at Medical City (J.R.) —
`both in Dallas; University of Freiburg
`Medical Center, Faculty of Medicine, Uni-
`versity of Freiburg, Freiburg, Germany
`(J.S.); Physicians East, Greenville, NC
`(M.L.W.); and Novo Nordisk, Søborg
`(O.H., A.G.H., J.P.), and the Center for
`Diabetes Research, Gentofte Hospital,
`University of Copenhagen, Hellerup (T.V.)
`— both in Denmark. Address reprint re-
`quests to Dr. Marso at Cardiovascular
`Services, HCA Midwest Health, Research
`Medical Center, 2316 E. Meyer Blvd., Kansas
`City, MO 64132, or at smarso@ gmail . com.
`
`* A complete list of the investigators in the
`Trial to Evaluate Cardiovascular and Other
`Long-term Outcomes with Semaglutide
`in Subjects with Type 2 Diabetes (SUS-
`TAIN-6) is provided in the Supplemen-
`tary Appendix, available at NEJM.org.
`
`This article was published on September
`16, 2016, at NEJM.org.
`
`N Engl J Med 2016;375:1834-44.
`DOI: 10.1056/NEJMoa1607141
`Copyright © 2016 Massachusetts Medical Society.
`
`BACKGROUND
`Regulatory guidance specifies the need to establish cardiovascular safety of new dia-
`betes therapies in patients with type 2 diabetes in order to rule out excess cardiovascu-
`lar risk. The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue
`with an extended half-life of approximately 1 week, in type 2 diabetes are unknown.
`
`METHODS
`We randomly assigned 3297 patients with type 2 diabetes who were on a standard-
`care regimen to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for
`104 weeks. The primary composite outcome was the first occurrence of cardiovascu-
`lar death, nonfatal myocardial infarction, or nonfatal stroke. We hypothesized that
`semaglutide would be noninferior to placebo for the primary outcome. The non-
`inferiority margin was 1.8 for the upper boundary of the 95% confidence interval of
`the hazard ratio.
`
`RESULTS
`At baseline, 2735 of the patients (83.0%) had established cardiovascular disease,
`chronic kidney disease, or both. The primary outcome occurred in 108 of 1648 patients
`(6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo
`group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for non-
`inferiority). Nonfatal myocardial infarction occurred in 2.9% of the patients receiving
`semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51
`to 1.08; P = 0.12); nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio,
`0.61; 95% CI, 0.38 to 0.99; P = 0.04). Rates of death from cardiovascular causes were
`similar in the two groups. Rates of new or worsening nephropathy were lower in the
`semaglutide group, but rates of retinopathy complications (vitreous hemorrhage, blind-
`ness, or conditions requiring treatment with an intravitreal agent or photocoagulation)
`were significantly higher (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P = 0.02). Fewer seri-
`ous adverse events occurred in the semaglutide group, although more patients discon-
`tinued treatment because of adverse events, mainly gastrointestinal.
`
`CONCLUSIONS
`In patients with type 2 diabetes who were at high cardiovascular risk, the rate of
`cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was signifi-
`cantly lower among patients receiving semaglutide than among those receiving pla-
`cebo, an outcome that confirmed the noninferiority of semaglutide. (Funded by Novo
`Nordisk; SUSTAIN-6 ClinicalTrials.gov number, NCT01720446.)
`
`1834
`
`n engl j med 375;19 nejm.org November 10, 2016
`
`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on January 16, 2024. For personal use only. No other uses without permission.
`
` Copyright © 2016 Massachusetts Medical Society. All rights reserved.
`
`Novo Nordisk Exhibit 2101
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
`
`

`

`A Quick Take is
`available at
`NEJM.org
`
`Semaglutide and Cardiovascular Outcomes in Diabetes
`
`Cardiovascular disease is the lead-
`
`ing cause of death and complications in
`patients with type 2 diabetes.1 Recently,
`trials evaluating a sodium–glucose cotransporter
`2 inhibitor (empagliflozin) and a glucagon-like
`peptide 1 (GLP-1) analogue (liraglutide) have
`shown improved cardiovascular outcomes in pa-
`tients with type 2 diabetes who were at high risk
`for cardiovascular events.2,3
`Semaglutide, a GLP-1 analogue with an ex-
`tended half-life of approximately 1 week (which
`permits once-weekly subcutaneous administra-
`tion),4 is currently in development but not yet
`approved for the treatment of type 2 diabetes.
`Regulatory guidance specifies the need to estab-
`lish the cardiovascular safety of new therapies
`for type 2 diabetes in order to rule out excess
`cardiovascular risk.5 The preapproval Trial to
`Evaluate Cardiovascular and Other Long-term
`Outcomes with Semaglutide in Subjects with
`Type 2 Diabetes (SUSTAIN-6) was designed to
`assess the noninferiority of semaglutide as com-
`pared with placebo in terms of cardiovascular
`safety in patients with type 2 diabetes.
`
`Me thods
`
`Trial Design and Oversight
`We performed a randomized, double-blind,
`placebo-controlled, parallel-group trial at 230 sites
`in 20 countries. The trial protocol, available with
`the full text of this article at NEJM.org, was ap-
`proved by the institutional review board and
`ethics committee at each participating center.
`All patients provided written informed consent.
`Patients were randomized in a 1:1:1:1 ratio to
`receive either 0.5 mg or 1.0 mg of once-weekly
`subcutaneous semaglutide or volume-matched
`placebo, which maintained blinding within dose.
`The trial consisted of a planned observation
`period of 109 weeks for all patients (a 104-week
`treatment period with a 5-week follow-up period)
`in which patients who had prematurely discon-
`tinued a study treatment were also included.
`The sponsor, Novo Nordisk, designed the
`study. Data were gathered by the site investiga-
`tors, and the sponsor performed site monitoring,
`data collection, and data analysis. An indepen-
`dent data and safety monitoring committee per-
`formed ongoing surveillance and had access to
`all the data in an unblinded fashion.
`All the authors had confidential access to the
`final trial results and actively contributed to
`
`manuscript preparation. A working group that
`included the first and last authors wrote the first
`draft of the manuscript, which was revised and
`approved by all the authors, who made the deci-
`sion to submit the manuscript for publication.
`The authors assume responsibility for the accu-
`racy and completeness of the data and vouch for
`the fidelity of the trial to the protocol. Editorial
`support was funded by the sponsor and provided
`by independent medical writers under the guid-
`ance of the authors.
`
`Patients
`Patients with type 2 diabetes and a glycated hemo-
`globin level of 7% or more were eligible if they
`had not been treated with an antihyperglycemic
`drug or had been treated with no more than two
`oral antihyperglycemic agents, with or without
`basal or premixed insulin. Key inclusion criteria
`were an age of 50 years or more with established
`cardiovascular disease (previous cardiovascular,
`cerebrovascular, or peripheral vascular disease),
`chronic heart failure (New York Heart Associa-
`tion class II or III), or chronic kidney disease of
`stage 3 or higher or an age of 60 years or more
`with at least one cardiovascular risk factor (as
`defined in Table S1 in the Supplementary Appen-
`dix, available at NEJM.org).
`Key exclusion criteria included treatment with
`a dipeptidyl-peptidase 4 inhibitor within 30 days
`before screening or with a GLP-1–receptor ago-
`nist or insulin other than basal or premixed
`within 90 days before screening; a history of an
`acute coronary or cerebrovascular event within
`90 days before randomization; planned revascu-
`larization of a coronary, carotid, or peripheral
`artery; or long-term dialysis. (A complete list of
`exclusion criteria is provided in Table S2 in the
`Supplementary Appendix.)
`
`Procedures
`The randomization of patients was stratified ac-
`cording to cardiovascular disease status (estab-
`lished cardiovascular or chronic kidney disease
`or cardiovascular risk factors only), insulin treat-
`ment (none, basal insulin only, or premixed in-
`sulin), and estimated glomerular filtration rate
`(≤30 ml or >30 ml per minute per 1.73 m2 of
`body-surface area) at screening. A fixed dose-
`escalation procedure was used, with a starting
`dose of 0.25 mg for 4 weeks that escalated to
`0.5 mg for 4 weeks until the maintenance dose
`(0.5 mg or 1.0 mg) was reached. No change in
`
`n engl j med 375;19 nejm.org November 10, 2016
`
`1835
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on January 16, 2024. For personal use only. No other uses without permission.
`
` Copyright © 2016 Massachusetts Medical Society. All rights reserved.
`
`Novo Nordisk Exhibit 2101
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`the maintenance dose of either semaglutide or
`placebo was permitted during the treatment
`period.
`Patients were scheduled for quarterly site visits
`during the trial. All investigators were encour-
`aged to treat all the patients according to local
`guidelines to achieve the most effective glycemic
`control (Table S3 in the Supplementary Appen-
`dix), and additional noninvestigational antihyper-
`glycemic medication (nonincretin-based therapy)
`could be added or adjusted.
`
`Outcomes
`The primary composite outcome was the first
`occurrence of death from cardiovascular causes,
`nonfatal myocardial infarction (including silent),
`or nonfatal stroke. Prespecified secondary out-
`comes included the first occurrence of an ex-
`panded composite cardiovascular outcome (death
`from cardiovascular causes, nonfatal myocar-
`dial infarction, nonfatal stroke, revascularization
`[coronary or peripheral], and hospitalization for
`unstable angina or heart failure), an additional
`composite outcome (death from all causes, non-
`fatal myocardial infarction, or nonfatal stroke),
`the individual components of the composite out-
`comes, retinopathy complications, and new or
`worsening nephropathy. Each outcome, except
`for peripheral revascularization, was adjudicated
`in a blinded fashion by an external, independent
`event-adjudication committee.
`Continuous efficacy and safety outcomes were
`assessed as the change from baseline to week
`104. From baseline to week 109, we assessed
`serious and nonserious adverse events and hypo-
`glycemic episodes, which were defined as severe
`(according to American Diabetes Association
`criteria6) or as confirmed on analysis of plasma
`glucose (with symptomatic hypoglycemia defined
`as <56 mg per deciliter [3.1 mmol per liter]).
`Neoplasm and pancreatitis events were adjudi-
`cated. (All definitions of adjudicated events are
`provided in Table S4 in the Supplementary Ap-
`pendix.)
`
`Statistical Analysis
`The prespecified statistical analysis plan is avail-
`able with the protocol at NEJM.org. We based
`the sample size for the trial on an assumed an-
`nual primary-event rate of 1.98% in each group,
`a dropout rate of less than 10.0%, a mean in-trial
`observation time of 2.1 years, and a true hazard
`
`ratio of 1.00. We determined that the enrollment
`of 3260 patients would be required to determine
`the primary outcome in at least 122 patients and
`provide a power of 90% to reject a hazard ratio
`of at least 1.80 at the 0.05 level of significance.
`The prespecified analysis for the primary out-
`come was a Cox proportional-hazards model, with
`pooled treatment (semaglutide vs. placebo) as a
`fixed factor, and categorized according to all
`possible combinations of stratification factors
`used for randomization. The primary hypothesis
`was for noninferiority for the primary outcome.
`Such noninferiority was confirmed if the upper
`boundary of the two-sided 95% confidence inter-
`val of the hazard ratio was below the noninferior-
`ity margin of 1.80.5 Testing for superiority for the
`primary outcome was not prespecified or adjusted
`for multiplicity. We conducted prespecified sen-
`sitivity analyses of the primary outcome, using
`alternative patient selection and data-censoring
`strategies for exposure to treatment, and per-
`protocol sensitivity analyses were performed post
`hoc. (Details regarding analysis sets are provided
`in the Supplementary Appendix.)
`The primary outcome was evaluated in sub-
`groups according to demographic and disease
`measures at baseline. We evaluated the effect of
`dose on the primary outcome by repeating the
`primary analysis with the four treatment groups
`(semaglutide doses of 0.5 mg and 1.0 mg and
`corresponding placebo doses) using volume-
`matched treatment comparisons. Efficacy and
`safety outcome analyses were prespecified to
`include the four treatment groups.
`All P values are two-sided, with a level of 0.05
`considered to indicate statistical significance.
`P values other than that for the primary hypoth-
`esis have not been adjusted for multiplicity and
`have been calculated to test for null hypotheses
`of no difference. All results were analyzed on an
`intention-to-treat basis that included the full
`analysis set (i.e., all patients who underwent
`randomization according to the planned treat-
`ment), with the exception of adverse events lead-
`ing to premature discontinuation, which were
`included in the as-treated safety analysis.
`
`R esults
`
`Patients
`From February 2013 through December 2013, a
`total of 4346 patients were screened, and 3297
`
`1836
`
`n engl j med 375;19 nejm.org November 10, 2016
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on January 16, 2024. For personal use only. No other uses without permission.
`
` Copyright © 2016 Massachusetts Medical Society. All rights reserved.
`
`Novo Nordisk Exhibit 2101
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`

`

`Semaglutide and Cardiovascular Outcomes in Diabetes
`
`Table 1. Characteristics of the Patients at Baseline.*
`
`Characteristic
`
`Age — yr
`
`Male sex — no. (%)
`
`Body weight — kg
`
`Type 2 diabetes
`
`Duration — yr
`
`Glycated hemoglobin — %
`
`Cardiovascular risk factors
`
`Semaglutide
`(N = 1648)
`
`Placebo
`(N = 1649)
`
`Total
`(N = 3297)
`
`0.5 mg
`(N = 826)
`
`64.6±7.3
`
`495 (59.9)
`
`91.8±20.3
`
`1.0 mg
`(N = 822)
`
`64.7±7.1
`
`518 (63.0)
`
`92.9±21.1
`
`14.3±8.2
`
`8.7±1.4
`
`14.1±8.2
`
`8.7±1.5
`
`0.5 mg
`(N = 824)
`
`64.8±7.6
`
`482 (58.5)
`
`91.8±20.3
`
`14.0±8.5
`
`8.7±1.5
`
`1.0 mg
`(N = 825)
`
`64.4±7.5
`
`507 (61.5)
`
`91.9±20.8
`
`64.6±7.4
`
`2002 (60.7)
`
`92.1±20.6
`
`13.2±7.4
`
`8.7±1.5
`
`13.9±8.1
`
`8.7±1.5
`
`Systolic blood pressure — mm Hg
`
`136.1±18.0
`
`135.8±17.0
`
`135.8±16.2
`
`134.8±17.5
`
`135.6±17.2
`
`Diastolic blood pressure — mm Hg
`
`77.1±9.8
`
`76.9±10.2
`
`77.5±9.9
`
`76.7±10.2
`
`77.0±10.0
`
`Low-density lipoprotein cholesterol — mg/dl†
`
`81.6±47.1
`
`Never smoked — no. (%)
`
`History of cardiovascular disease — no. (%)
`
`Ischemic heart disease
`
`Myocardial infarction
`
`Heart failure
`
`Ischemic stroke
`
`Hemorrhagic stroke
`
`Hypertension
`
`390 (47.2)
`
`493 (59.7)
`
`266 (32.2)
`
`201 (24.3)
`
` 89 (10.8)
`
`28 (3.4)
`
`83.3±41.2
`
`364 (44.3)
`
`495 (60.2)
`
`264 (32.1)
`
`180 (21.9)
`
` 89 (10.8)
`
`24 (2.9)
`
`772 (93.5)
`
`771 (93.8)
`
`80.9±48.1
`
`391 (47.5)
`
`510 (61.9)
`
`267 (32.4)
`
`190 (23.1)
`
` 96 (11.7)
`
`27 (3.3)
`
`756 (91.7)
`
`83.6±45.9
`
`348 (42.2)
`
`82.3±45.6
`
`1493 (45.3)
`
`496 (60.1)
`
`275 (33.3)
`
`206 (25.0)
`
`109 (13.2)
`
`29 (3.5)
`
`1994 (60.5)
`
`1072 (32.5)
`
` 777 (23.6)
`
` 383 (11.6)
`
`108 (3.3)
`
`760 (92.1)
`
`3059 (92.8)
`
`* Plus–minus values are means ±SD unless otherwise indicated. Differences in baseline characteristics were assessed with the use of analysis
`of covariance for continuous characteristics and logistic regression for categorical characteristics. There were no significant differences be-
`tween the groups except for the duration of type 2 diabetes (P = 0.048). To convert the values for cholesterol to millimoles per liter, multiply
`by 0.02586.
`† Values are geometric means and coefficients of variation.
`
`underwent randomization; of these patients, 3232
`(98.0%) attended the last follow-up visit at an
`investigator site, were contacted by telephone, or
`died during the trial. The date of the last patient
`visit was March 15, 2016. Vital status was known
`for 99.6% of the patients by the end of the trial
`(Figs. S1A and S1B in the Supplementary Ap-
`pendix).
`The median observation time was 2.1 years.
`Rates of premature treatment discontinuation
`were similar across groups (20% overall) (Table
`S5 in the Supplementary Appendix). The mean
`percentage of time during which patients re-
`ceived semaglutide was 86.5% (87.7% among
`those receiving 0.5 mg and 85.3% among those
`receiving 1.0 mg), and the mean percentage dur-
`ing which patients received placebo was 89.5%
`(89.4% among those receiving 0.5 mg and 89.6%
`among those receiving 1.0 mg).
`
`Demographic and clinical characteristics of
`the patients at baseline were similar across treat-
`ment groups (Table 1, and Table S6 in the Supple-
`mentary Appendix). Of the 3297 patients, 2735
`(83.0%) had established cardiovascular disease
`(including chronic kidney disease of stage 3 or
`higher), 1940 patients (58.8%) had established
`cardiovascular disease without chronic kidney dis-
`ease, 353 (10.7%) had chronic kidney disease only,
`and 442 (13.4%) had both cardiovascular disease
`and kidney disease; 17% of the patients had car-
`diovascular risk factors and were 60 years of age
`or older. The overall mean duration of type 2
`diabetes was 13.9 years, and the mean glycated
`hemoglobin level was 8.7%. The use of anti-
`hyperglycemic and cardiovascular medications
`was well balanced between the groups (Tables
`S7A and S8A in the Supplementary Appendix).
`Most patients (93.5%) were taking antihyperten-
`
`n engl j med 375;19 nejm.org November 10, 2016
`
`1837
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on January 16, 2024. For personal use only. No other uses without permission.
`
` Copyright © 2016 Massachusetts Medical Society. All rights reserved.
`
`Novo Nordisk Exhibit 2101
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00004
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`sive medication, including angiotensin-convert-
`ing–enzyme inhibitors (49.8%) and angiotensin-
`receptor blockers (33.7%); 76.5% were receiving
`lipid-lowering medications; and 76.3% were re-
`ceiving antithrombotic medications, including
`acetylsalicylic acid (63.9%) and adenosine diphos-
`phate receptor inhibitors (21.1%) (Table S8A in
`the Supplementary Appendix).
`
`Cardiovascular Outcomes
`The composite primary outcome occurred in 108
`of 1648 patients (6.6%) in the semaglutide group
`and 146 of 1649 (8.9%) in the placebo group
`(hazard ratio, 0.74; 95% confidence interval [CI],
`0.58 to 0.95; P<0.001 for noninferiority; P = 0.02
`for superiority) (Fig. 1A). Sensitivity analyses sup-
`ported the findings from the primary analysis
`(Fig. S2 in the Supplementary Appendix). Nonfa-
`tal myocardial infarction occurred in 47 patients
`(2.9%) in the semaglutide group and 64 (3.9%)
`in the placebo group, a difference that was not
`significant (hazard ratio, 0.74; 95% CI, 0.51 to
`1.08; P = 0.12) (Fig. 1B). Nonfatal stroke occurred
`in 27 patients (1.6%) in the semaglutide group
`and 44 (2.7%) in the placebo group (hazard ratio,
`0.61; 95% CI, 0.38 to 0.99; P = 0.04) (Fig. 1C). The
`risk of cardiovascular death was similar in the
`two groups, with deaths reported in 44 patients
`(2.7%) in the semaglutide group and 46 (2.8%)
`in the placebo group (hazard ratio, 0.98; 95% CI,
`0.65 to 1.48; P = 0.92) (Fig. 1D).
`No significant treatment interactions were
`identified for any subgroups (Fig. S3 in the Sup-
`plementary Appendix). Similar risk reductions for
`the primary outcome and its components were
`observed for both doses of semaglutide (Fig. S4
`in the Supplementary Appendix). Cardiovascular
`outcomes are provided in Table 2, and in Table
`S9 in the Supplementary Appendix. Throughout
`the trial, a greater proportion of patients in the
`placebo group than in the semaglutide group
`received additional cardiovascular medications,
`including antihypertensive agents, diuretics, and
`lipid-lowering medications (Table S8B in the
`Supplementary Appendix).
`
`Glycemic Control
`At week 104, among patients receiving sema-
`glutide, the mean glycated hemoglobin level de-
`creased from 8.7% at baseline to 7.6% in the
`group receiving 0.5 mg and to 7.3% in the group
`receiving 1.0 mg, for changes of −1.1% and
`
`−1.4%, respectively; in the placebo group, the
`mean level decreased to 8.3% in the two dose
`groups, for a reduction of 0.4% in each group.
`Thus, the mean glycated hemoglobin level in the
`semaglutide group, as compared with the pla-
`cebo group, was 0.7 percentage points lower in
`the group receiving 0.5 mg and 1.0 percentage
`point lower in the group receiving 1.0 mg (esti-
`mated treatment difference) (P<0.001 for both
`comparisons) (Fig. 2A, and Table S10 in the Sup-
`plementary Appendix). During the trial, signifi-
`cantly more patients in the placebo group than
`in the semaglutide group received additional anti-
`hyperglycemic agents, including insulin, which
`was initiated more than twice as frequently in
`the placebo group (Table S7B in the Supplemen-
`tary Appendix).
`
`Body Weight
`At week 104, among patients receiving sema-
`glutide, the mean body weight decreased from
`92.1 kg at baseline to 88.5 kg in the group re-
`ceiving 0.5 mg and to 87.2 kg in the group receiv-
`ing 1.0 mg, for changes of −3.6 kg and −4.9 kg,
`respectively; in the placebo group, the mean body
`weight decreased to 91.4 kg and 91.6 kg, for
`changes of −0.7 kg and −0.5 kg, respectively.
`Thus, the mean body weight in the semaglutide
`group, as compared with the placebo group,
`was 2.9 kg lower in the group receiving 0.5 mg
`and 4.3 kg lower in the group receiving 1.0 mg
`(P<0.001 for both comparisons) (Fig. 2B, and
`Table S10 in the Supplementary Appendix).
`
`Microvascular Outcomes
`Diabetic retinopathy complications occurred in
`50 patients (3.0%) in the semaglutide group and
`29 (1.8%) in the placebo group (hazard ratio,
`1.76; 95% CI, 1.11 to 2.78; P = 0.02) (Table 2, and
`Table S9 and Fig. S5 in the Supplementary Ap-
`pendix). The treatment difference between groups
`was first seen very early in the trial. The num-
`bers of patients who required retinal photocoagu-
`lation were 38 (2.3%) in the semaglutide group
`versus 20 (1.2%) in the placebo group, the num-
`bers of those who required the use of an intra-
`vitreal agent were 16 (1.0%) versus 13 (0.8%), the
`numbers of those who had a vitreous hemor-
`rhage were 16 (1.0%) versus 7 (0.4%), and the
`numbers of those who had an onset of diabetes-
`related blindness were 5 (0.3%) versus 1 (0.1%)
`(Table S9 in the Supplementary Appendix). Of
`
`1838
`
`n engl j med 375;19 nejm.org November 10, 2016
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on January 16, 2024. For personal use only. No other uses without permission.
`
` Copyright © 2016 Massachusetts Medical Society. All rights reserved.
`
`Novo Nordisk Exhibit 2101
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
`

`

`Semaglutide and Cardiovascular Outcomes in Diabetes
`
`1579
`1566
`
`1589
`1584
`
`1607
`1600
`
`1617
`1617
`
`109
`
`104
`
`96
`
`88
`
`80
`
`72
`
`64
`
`56
`
`48
`
`109
`
`104
`
`96
`
`88
`
`80
`
`72
`
`64
`
`56
`
`48
`
`40
`
`32
`
`Semaglutide
`
`Placebo
`
`1543
`1516
`
`1560
`1542
`
`1582
`1562
`
`1595
`1587
`
`109
`
`104
`
`96
`
`88
`
`80
`
`72
`
`64
`
`56
`
`48
`
`109
`
`104
`
`96
`
`88
`
`80
`
`72
`
`64
`
`56
`
`48
`
`40
`
`32
`
`Semaglutide
`
`Placebo
`
`1627
`1623
`
`1634
`1637
`
`1648
`1649
`
`Semaglutide
`Placebo
`No.atRisk
`
`WeekssinceRandomization
`
`40
`
`32
`
`24
`
`16
`
`8
`
`0
`
`109
`
`24
`
`16
`
`8
`
`0
`
`P=0.92
`Hazard ratio, 0.98 (95% CI, 0.65–1.48)
`
`5
`
`4
`
`23
`
`1
`
`0
`
`0
`
`10
`20
`30
`40
`50
`60
`70
`80
`90
`100
`
`PatientswithEvent(%)
`
`DDeathfromCardiovascularCauses
`
`1609
`1598
`
`1623
`1624
`
`1648
`1649
`
`Semaglutide
`Placebo
`No.atRisk
`
`WeekssinceRandomization
`
`40
`
`32
`
`24
`
`16
`
`8
`
`0
`
`109
`
`24
`
`16
`
`8
`
`0
`
`P=0.12
`Hazard ratio, 0.74 (95% CI, 0.51–1.08)
`
`5
`
`4
`
`23
`
`1
`
`0
`
`0
`
`10
`20
`30
`40
`50
`60
`70
`80
`90
`100
`
`PatientswithEvent(%)
`
`BNonfatalMyocardialInfarction
`
`axis.
`week treatment period with a 5-week follow-up period). In Panel C, there were no events in the semaglutide group after week 104. Insets show the same data on an expanded y
`farction (Panel B), nonfatal stroke (Panel C), and death from cardiovascular causes (Panel D). The trial included a planned observation period of 109 weeks for all patients (a 104-
`Shown are Kaplan–Meier plots of the primary outcome (a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) (Panel A), nonfatal myocardial in-
`Figure 1. Cardiovascular Outcomes.
`
`1619
`1611
`
`1630
`1629
`
`1648
`1649
`
`Semaglutide
`Placebo
`No.atRisk
`
`WeekssinceRandomization
`
`32
`
`24
`
`16
`
`8
`
`0
`
`24
`
`16
`
`8
`
`0
`
`P=0.04
`Hazard ratio, 0.61 (95% CI, 0.38–0.99)
`
`5
`
`4
`
`23
`
`1
`
`0
`
`0
`
`10
`20
`30
`40
`50
`60
`70
`80
`90
`100
`
`PatientswithEvent(%)
`
`1601
`1586
`
`1619
`1616
`
`CNonfatalStroke
`
`1648
`1649
`
`Semaglutide
`Placebo
`No.atRisk
`
`WeekssinceRandomization
`
`32
`
`24
`
`16
`
`8
`
`0
`
`24
`
`16
`
`8
`
`0
`
`P=0.02 for superiority
`P<0.001 for noninferiority
`Hazard ratio, 0.74 (95% CI, 0.58–0.95)
`
`
`
`98 657
`
`4
`
`23 1
`
`0
`
`10
`
`0
`
`10
`20
`30
`40
`50
`60
`70
`80
`90
`100
`
`PatientswithEvent(%)
`
`APrimaryOutcome
`
`n engl j med 375;19 nejm.org November 10, 2016
`
`1839
`
`1558
`1528
`
`1572
`1548
`
`1593
`1571
`
`1606
`1597
`
`104
`
`96
`
`88
`
`80
`
`72
`
`64
`
`56
`
`48
`
`40
`
`109
`
`104
`
`96
`
`88
`
`80
`
`72
`
`64
`
`56
`
`48
`
`40
`
`32
`
`Semaglutide
`
`Placebo
`
`1524
`1479
`
`1543
`1508
`
`1568
`1534
`
`1584
`1567
`
`104
`
`96
`
`88
`
`80
`
`72
`
`64
`
`56
`
`48
`
`40
`
`109
`
`104
`
`96
`
`88
`
`80
`
`72
`
`64
`
`56
`
`48
`
`40
`
`32
`
`Semaglutide
`
`Placebo
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on January 16, 2024. For personal use only. No other uses without permission.
`
` Copyright © 2016 Massachusetts Medical Society. All rights reserved.
`
`Novo Nordisk Exhibit 2101
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`Table 2. Primary and Secondary Cardiovascular and Microvascular Outcomes.
`
`Outcome
`
`Semaglutide
`(N = 1648)
`
`Placebo
` (N = 1649)
`
`Hazard Ratio
`(95% CI)*
`
`P Value
`
`Primary composite outcome†
`
`no. (%)
`
`108 (6.6)
`
`no./100
`person-yr
`
`3.24
`
`Expanded composite outcome‡
`
`All-cause death, nonfatal myocardial
`infarction, or nonfatal stroke
`
`199 (12.1)
`
`122 (7.4)
`
`Death
`
`From any cause
`
`From cardiovascular cause
`
`62 (3.8)
`
`44 (2.7)
`
`6.17
`
`3.66
`
`1.82
`
`1.29
`
`no. (%)
`
`146 (8.9)
`
`264 (16.0)
`
`158 (9.6)
`
`60 (3.6)
`
`46 (2.8)
`
`64 (3.9)
`
`no./100
`person-yr
`
`4.44
`
`0.74 (0.58–0.95)
`
`<0.001 for
`noninferiority;
`0.02 for
`superiority
`
`8.36
`
`4.81
`
`1.76
`
`1.35
`
`1.92
`
`0.74 (0.62–0.89)
`
`0.77 (0.61–0.97)
`
`0.002
`
`0.03
`
`1.05 (0.74–1.50)
`
`0.98 (0.65–1.48)
`
`0.74 (0.51–1.08)
`
`0.79
`
`0.92
`
`0.12
`
`Nonfatal myocardial infarction
`
`Nonfatal stroke
`
`Hospitalization for unstable angina
`pectoris
`
`Revascularization
`
`Hospitalization for heart failure
`
`Retinopathy complications§
`
`New or worsening nephropathy¶
`
`47 (2.9)
`
`27 (1.6)
`
`22 (1.3)
`
`83 (5.0)
`
`59 (3.6)
`
`50 (3.0)
`
`62 (3.8)
`
`1.40
`
`0.80
`
`0.65
`
`2.50
`
`1.76
`
`1.49
`
`1.86
`
`44 (2.7)
`
`27 (1.6)
`
`126 (7.6)
`
`54 (3.3)
`
`29 (1.8)
`
`100 (6.1)
`
`1.31
`
`0.80
`
`3.85
`
`1.61
`
`0.86
`
`3.06
`
`0.61 (0.38–0.99)
`
`0.82 (0.47–1.44)
`
`0.65 (0.50–0.86)
`
`1.11 (0.77–1.61)
`
`1.76 (1.11–2.78)
`
`0.64 (0.46–0.88)
`
`0.04
`
`0.49
`
`0.003
`
`0.57
`
`0.02
`
`0.005
`
`* Hazard ratios and P values were estimated with the use of a Cox proportional-hazards model with the study treatments as fixed factors and
`stratified according to all combinations of stratification factors used in the randomization.
`† The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal
`stroke.
`‡ The expanded composite outcome included death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, revasculariza-
`tion (coronary or peripheral), and hospitalization for unstable angina or heart failure.
`§ Retinopathy complications include vitreous hemorrhage, onset of diabetes-related blindness, and the need for treatment with an intravitreal
`agent or retinal photocoagulation.
`¶ New or worsening nephropathy includes persistent macroalbuminuria, persistent doubling of the serum creatinine level and a creatinine
`clearance of less than 45 ml per minute per 1.73 m2 of body-surface area (according to the Modification of Diet in Renal Disease criteria),
`or the need for continuous renal-replacement therapy.
`
`the 79 patients with retinopathy complications,
`66 (83.5%) had preexisting retinopathy at base-
`line (42 of 50 [84.0%] in the semaglutide group
`and 24 of 29 [82.8%] in the placebo group). New
`or worsening nephropathy occurred in 62 pa-
`tients (3.8%) in the semaglutide group and 100
`(6.1%) in the placebo group (hazard ratio, 0.64;
`95% CI, 0.46 to 0.88; P = 0.005) (Table 2, and
`Table S9 and Fig. S5 in the Supplementary Ap-
`pendix).
`
`Other Outcomes
`At week 104, among patients receiving semaglutide,
`the mean systolic blood pressure decreased from
`135.6 mm Hg at baseline to 132.2 mm Hg among
`those receiving 0.5 mg and to 130.3 mm Hg
`
`among those receiving 1.0 mg, for reductions of
`3.4 mm Hg and 5.4 mm Hg, respectively; in the
`placebo group, the mean systolic blood pressure
`decreased to 133.5 mm Hg and 132.8 mm Hg,
`for reductions of 2.2 mm Hg and 2.8 mm Hg,
`respectively. Thus, the mean systolic blood pres-
`sure in the semaglutide group, as compared with
`the placebo group, was 1.3 mm Hg lower in the
`group receiving 0.5 mg (P = 0.10) and 2.6 mm Hg
`lower in the group receiving 1.0 mg (P<0.001)
`(Table S10 and Fig. S6 in the Supplementary Ap-
`pendix).
`At week 104, among patients in the semaglu-
`tide group, the mean pulse rate increased from
`a baseline value of 72.0 bpm by 2.1 bpm among
`those receiving 0.5 mg and by 2.4 bpm among
`
`1840
`
`n engl j med 375;19 nejm.org November 10, 2016
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on January 16, 2024. For personal use only. No other uses without permission.
`
` Copyright © 2016 Massachusetts Medical Society. All rights reserved.
`
`Novo Nordisk Exhibit 2101
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00007
`
`

`

`Semaglutide and Cardiovascular Outcomes in Diabetes
`
`A GlycatedHemoglobin
`9.0
`
`(mmol/mol)
`
`MeanGlycatedHemoglobin
`
`72.1
`
`67.1
`
`62.1
`
`57.1
`
`52.1
`
`47.1
`
`Placebo, 1.0 mg
`
`Placebo, 0.5 mg
`
`Semaglutide, 0.5 mg
`
`Semaglutide, 1.0 mg
`
`0
`
`8
`
`16
`
`80
`44
`56
`68
`30
`WeekssinceRandomization
`
`0.0
`104
`
`92
`
`8.5
`
`8.0
`
`7.5
`
`7.0
`
`6.5
`
`0.0
`
`MeanGlycatedHemoglobin(%)
`
`B BodyWeight
`93
`
`Placebo, 1.0 mg
`
`Placebo, 0.5 mg
`
`Semaglutide, 0.5 mg
`
`Semaglutide, 1.0 mg
`
`0
`
`8
`
`16
`
`30
`
`44
`
`56
`
`68
`
`80
`
`92
`
`104
`
`WeekssinceRandomization
`
`92
`
`91
`
`90
`
`89
`
`88
`
`87
`
`0
`
`MeanBodyWeight(kg)
`
`Figure 2. Glycated Hemoglobin and Body Weight.
`Shown are the mean values for glycated hemoglobin (Panel A) and body
`weight (Panel B) during the trial period. The I bars represent standard errors.
`Data were estimated on the basis of scheduled visits in the full analysis set
`with the use of a mixed model for repeated measures with treatment group
`(semaglutide doses of 0.5 mg and 1.0 mg and corresponding placebo doses)
`and all possible combinations of stratification factors used for randomization
`as fixed factors.
`
`Similar numbers and occurrence rates of se-
`vere hypoglycemic episodes or hyp