Received: 2 April 2020
`
`Revised: 24 July 2020
`
`Accepted: 29 July 2020
`
`DOI: 10.1111/dom.14160
`
`B R I E F R E P O R T
`
`WILEY
`
`Effects of glucagon-like peptide-1 receptor agonists liraglutide
`and semaglutide on cardiovascular and renal outcomes across
`body mass index categories in type 2 diabetes: Results of the
`LEADER and SUSTAIN 6 trials
`
`Subodh Verma MD1
`Deepak L. Bhatt MD4
`Tea Monk Fries MD5
`Hrvoje Vrazic MD5†
`
`| Darren K. McGuire MD2
`| Lawrence A. Leiter MD1
`| Richard E. Pratley MD6
`| Bernard Zinman MD7
`
`| Stephen C. Bain MD3
`| C. David Mazer MD1
`| Søren Rasmussen PhD5
`John B. Buse MD8
`|
`
`|
`
`|
`
`|
`
`1Li Ka Shing Knowledge Institute, St. Michael's
`Hospital and University of Toronto, Toronto,
`Ontario, Canada
`2Division of Cardiology, University of Texas
`Southwestern Medical Center, Dallas, Texas
`3Institute of Life Science, Swansea University,
`Swansea, UK
`
`4Brigham and Women's Hospital Heart and
`Vascular Center & Harvard Medical School,
`Boston, Massachusetts
`5Novo Nordisk A/S, Søborg, Denmark
`6AdventHealth Translational Research
`Institute, Orlando, Florida
`7Lunenfeld–Tanenbaum Research Institute,
`Mt. Sinai Hospital, University of Toronto,
`Toronto, Ontario, Canada
`8University of North Carolina School of
`Medicine, Chapel Hill, North Carolina
`
`Correspondence
`Subodh Verma, MD, PhD, FRCSC, Division of
`Cardiac Surgery, Li Ka Shing Knowledge
`Institute of St Michael's Hospital, University of
`Toronto, 30 Bond Street, Eighth Floor, Bond
`Wing, Toronto, Ontario M5B 1W8, Canada.
`Email: vermasu@smh.ca
`
`Funding information
`The LEADER and SUSTAIN 6 trials were
`sponsored by Novo Nordisk and are registered
`with ClinicalTrials.gov (NCT01179048 and
`NCT01720446).
`
`† Affiliation at time of manuscript development.
`
`Abstract
`Associations between body mass index (BMI) and the cardiovascular (CV) and kidney
`
`efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type
`
`2 diabetes (T2D) are uncertain; therefore, data analysed separately from the Liraglutide
`
`Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER)
`
`trial and the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with
`
`Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN 6) were examined. These inter-
`
`national, randomized, placebo-controlled trials investigated liraglutide and semaglutide
`
`(both subcutaneous) in patients with T2D and at high risk of CV events. In post hoc ana-
`(<25, ≥25-<30, ≥30-<35 and
`lyses, patients were categorized by baseline BMI
`≥35 kg/m2), and CV and kidney outcomes with GLP-1 RA versus placebo were analysed.
`All baseline BMI data from LEADER (n = 9331) and SUSTAIN 6 (n = 3290) were included
`
`(91% and 92% of patients with overweight or obesity, respectively). In SUSTAIN 6, nomi-
`
`nally significant heterogeneity of semaglutide efficacy by baseline BMI was observed for
`
`CV death/myocardial infarction/stroke (major adverse CV events, primary outcome of
`both; Pinteraction = .02); otherwise, there was no statistical heterogeneity for either
`GLP-1 RA versus placebo across BMI categories for key CV and kidney outcomes. The
`
`lack of statistical heterogeneity from these cardiorenal outcomes implies that liraglutide
`
`and semaglutide may be beneficial for many patients and is probable not to depend on
`
`their baseline BMI, but further study is needed.
`
`K E Y W O R D S
`
`body mass index, cardiovascular, liraglutide, major adverse cardiovascular events, semaglutide
`
`This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
`medium, provided the original work is properly cited and is not used for commercial purposes.
`© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
`
`Diabetes Obes Metab. 2020;22:2487–2492.
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`1
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`|
`
`INTRODUCTION
`
`While some glucagon-like peptide-1 receptor agonists (GLP-1 RAs)
`have been shown to reduce major adverse cardiovascular (CV) events
`(MACE) in people with type 2 diabetes (T2D), they are also a rec-
`ommended treatment when there is a compelling need for such
`patients to lose weight.1,2 Several factors have been linked to these
`reported CV benefits, but their precise roles are unknown.3 One such
`factor is baseline body mass index (BMI), whose impact has only been
`investigated on limited treatment outcomes with GLP-1 RAs.4
`Although weight loss associated with GLP-1 RA use increases with
`increasing BMI,4 it is unknown if other effects vary by BMI. We inves-
`tigated if the CV and kidney outcomes with GLP-1 RAs are consistent
`across the spectrum of BMI, using data from the Liraglutide Effect
`and Action in Diabetes: Evaluation of Cardiovascular Outcome Results
`(LEADER5) trial and the Trial to Evaluate Cardiovascular and Other
`Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabe-
`tes (SUSTAIN 66) analysed separately.
`
`2
`
`| MATERIALS AND METHODS
`
`2.1
`
`|
`
`Study design
`
`The LEADER and SUSTAIN 6 trial designs have been published.5,6 In
`brief, both trials were double-blind and placebo-controlled. Patients
`with T2D and at high risk of CV events were randomly assigned to
`the GLP-1 RA or placebo (once-daily subcutaneous [s.c.] liraglutide
`1.8 mg or maximum tolerated dose vs. placebo in LEADER, 1:1 ratio;
`once-weekly s.c. semaglutide 0.5 or 1.0 mg vs. volume-matched pla-
`cebo in SUSTAIN 6, 1:1:1:1 ratio [pooled as semaglutide vs. placebo for
`analyses]), with all patients otherwise treated according to standard of
`care.5,6 Key inclusion criteria in both trials were being aged 50 years or
`older with established CV disease (previous coronary, cerebrovascular
`or peripheral vascular disease), heart failure (New York Heart Associa-
`tion class II or III), or chronic kidney disease stage 3 or higher; or being
`aged 60 years or older with at
`least one CV risk factor
`(microalbuminuria or proteinuria, hypertension with left ventricular
`hypertrophy,
`left ventricular systolic or diastolic dysfunction, or an
`ankle–brachial index of <0.9).5,6 Major exclusion criteria included use of
`GLP-1 RAs, dipeptidyl peptidase-4 inhibitors, pramlintide or rapid-
`acting insulin, and recent history of an acute coronary or cerebrovascu-
`lar event.5,6
`The primary composite outcome in both trials was first occur-
`rence of MACE (CV death, non-fatal myocardial infarction or non-fatal
`stroke). The key secondary expanded outcome (expanded MACE) also
`included hospitalization for unstable angina or heart failure, or revas-
`cularization. The secondary composite renal outcome (termed
`nephropathy) was comprised of new-onset or persistent macroalbuminuria,
`persistent doubling of serum creatinine level and creatinine clearance of less
`than 45 mL/min/1.73m2, the need for continuous renal-replacement ther-
`apy or death from kidney disease. Both trials were approved by institutional
`
`VERMA ET AL.
`
`review boards or ethics committees for each centre; all patients provided
`written informed consent.5,6
`Weight and height were measured by investigators at baseline
`and BMI was calculated. BMI was also assessed at designated visits
`throughout both trials.5,6
`
`2.2
`
`|
`
`Statistical methods
`
`Details of the primary statistical analyses conducted in these trials
`have been described.5,6 For the present post hoc analyses, the effects
`of liraglutide and semaglutide on the time-to-first primary MACE,
`expanded MACE, CV death and nephropathy were evaluated by base-
`line BMI category, separately for the two trials. BMI was categorized
`based on cut-off values described by the World Health Organization
`(<25, ≥5 to <30, ≥30 to <35 and ≥35 kg/m2, defining overweight as
`BMI ≥25 kg/m2 and obesity as BMI ≥30 kg/m2).7 The significance of
`the differences between the baseline characteristics across these BMI
`categories was assessed using a Kruskal–Wallis test for continuous
`variables and a chi-square test for categorical variables regardless of
`treatment group. The Cochran–Armitage trend test was used to ana-
`lyse event rates across BMI groups in the placebo groups of both tri-
`als. The hazard ratios (HRs) and 95% confidence intervals (CIs) for
`treatment versus placebo were calculated using Cox proportional haz-
`ard regression models with treatment and BMI category as fixed fac-
`tors and included a treatment-by-BMI term to test for quantitative
`interaction between both. The models were adjusted for baseline
`characteristics related to cardiorenal risk (sex, smoking status, antihy-
`perglycaemic treatments, prior CV events, geographic region, age, dia-
`betes duration, estimated glomerular
`filtration rate), with a
`P-interaction of less than .05 considered significant. No adjustments
`for multiple testing were performed.
`Quadratic spline regression was applied using Cox proportional
`hazard regression to analyse treatment differences in time-to-first
`MACE by continuous baseline BMI. The percentage weight loss by
`BMI category was calculated over 3 years for LEADER and 104 weeks
`for SUSTAIN 6, including P-interaction for both. All analyses were per-
`formed using the software package SAS (version 9.4).
`
`3
`
`| RESULTS
`
`The disposition and baseline characteristics of trial participants have
`been published.5,6 In LEADER, a total of 9340 patients were random-
`ized (4668 to liraglutide; 4672 to placebo), with a median follow-up of
`3.8 years.5 In SUSTAIN 6, 3297 patients were randomized (1648 to
`semaglutide; 1649 to placebo), with a median follow-up of 2.1 years.6
`The proportions of patients in LEADER with a baseline BMI of less
`than 25 kg/m2, of 25 to less than 30 kg/m2, of 30 to less than 35 kg/m2,
`and of 35 kg/m2 or higher, were 9%, 29%, 32%, and 30%, respectively, and
`in SUSTAIN 6 these were 8%, 28%, 33%, and 31%, respectively (Table S1).
`Baseline characteristics varied across the BMI categories within each trial
`(Table S1). Notably, in LEADER, the mean diabetes duration was longest in
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`2489
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`the BMI less than 25 kg/m2 category versus the other BMI categories, with
`a similar trend in SUSTAIN 6. As expected, a greater percentage of patients
`were treated with insulin at baseline with increasing baseline BMI in both
`trials (Table S1). The percentage of patients with established CV disease
`was similar across the BMI categories in LEADER (P = .30; range: 80.3%-
`82.2%; Table S1), while, in SUSTAIN 6, it differed (P = .02; range: 78.7%-
`84.7%; Table S1). Within both trials, the mean estimated glomerular filtra-
`tion rates were similar across the BMI categories (P = .27 for LEADER;
`P = .14 for SUSTAIN 6; Table S1).
`The placebo event rates for MACE, expanded MACE and CV
`death were similar across BMI categories within each trial (Table S2).
`In SUSTAIN 6, the risk of nephropathy declined with increasing BMI
`category (Ptrend = .0002) and, although the nephropathy event rate
`it did not reach significance (Ptrend = .18)
`declined in LEADER,
`(Table S2).
`
`When analysing data from the treatment groups, only the interaction
`for MACE in SUSTAIN 6 showed significance; for all others, there was no
`statistically significant heterogeneity of the treatment effects of liraglutide
`or semaglutide versus placebo across baseline BMI groups (Figure 1). Cor-
`respondingly, P-interaction values for
`treatment-by-BMI
`for MACE,
`expanded MACE and CV death in LEADER were .34, .22 and .79, respec-
`tively; and in SUSTAIN 6 these were .02, .27 and .82, respectively.
`For new-onset or worsening nephropathy, there was no heteroge-
`neity of treatment efficacy across the BMI categories, with P-interaction
`values of .92 for LEADER and .21 for SUSTAIN 6 (Figure 2).
`In the regression analysis of baseline BMI as a continuous vari-
`able, liraglutide showed consistent benefits across BMI categories in
`analysis of time-to-first MACE, within the quartile boundaries, where
`50% of the events occurred. Semaglutide also showed similar results
`across baseline BMI values for MACE (Figure S1).
`
`(A)
`
`MACEt
`
`Expanded MACE*
`
`CV death
`
`LEADER overall5
`
`BMI 525
`
`Ill:
`
`1-<>H
`
`BMI ;;,25 to <30
`
`~
`
`BMI :.e30 to <35
`
`BMI :.e35
`
`0.1
`
`tot
`
`1-0i'
`
`I
`
`1
`
`HR
`(95% Cl)
`
`0.87
`(0 .78- 0.97)
`
`0.88
`(0.61-1.28)
`
`0.99
`(0.81-1.21)
`
`"<t
`"'.
`C
`.Q
`t5
`0.87
`~
`(0 .72-1 .05) 2
`C
`iI
`
`0.75
`(0.61-0.93)
`
`10
`
`0.1
`
`111:
`
`1-oH
`
`l<>I
`
`1qt
`
`I
`
`IOI '
`
`I
`
`1
`
`HR
`(95% Cl)
`
`0.88
`(0.81-0.96)
`
`0.89
`(0.65-1.20)
`
`0.87
`(0.74-1.03)
`
`N
`C'!
`C
`.Q
`t5
`0.97
`~
`(0.84-1 .14) 2
`C
`iI
`
`0.77
`(0.66-0.90)
`
`10
`
`0.1
`
`i.i:
`
`1-<>H
`
`l-0-tl
`
`l-<>-1
`1
`
`0.78
`(0.66--0 .93)
`~ 0.67
`(0.39-1.13)
`0.88
`(0.63-1 .23)
`
`HR
`(95% Cl)
`
`0)
`
`"-:
`C
`.Q
`t5
`0.80
`~
`(0.57-1 .12) 2
`C
`iI
`
`0.72
`(0.53--0.99)
`
`10
`
`Favours liraglutide Favours placebo
`
`--
`
`Favours liraglulide Favours placebo
`
`--
`
`Favours liraglutide Favours placebo
`
`(B)
`
`MACEt
`
`Expanded MACE*
`
`HR
`(95% Cl)
`
`SUSTAIN 6 overall6 l+i:
`
`I
`I
`
`1
`I
`
`I
`
`0.74
`(0.58-0.95)
`BMI 525 ~ 0.61
`(0.27-1 .40)
`N
`BMI ;e.25 to <30 ~ :
`~
`0.56
`C
`(0 .35-0.88)
`.Q
`t5
`1.42
`BMI :.e30 to <35 ~ ~
`(0.85-2.35) 2
`C
`iI
`0.57
`(0.37-0.87)
`
`--
`
`CV death
`
`I
`I
`
`t-+-t
`1-------+o-----
`:
`I
`r-----o-+-,
`
`I
`
`i------+----1
`
`I
`
`1---1>---i
`
`1
`
`--
`
`HR
`(95% Cl)
`
`0.98
`(0.65-1.48)
`
`1 . 28
`(0.34-4.81)
`
`0.70
`(0.32-1 .53)
`
`N
`~
`C
`0
`·-n
`1.06
`~
`(0.50-2 .27) 2
`C
`iI
`
`1.05
`(0.50-2.22)
`
`10
`
`Favours semaglutide Favours placebo
`
`HR
`(95% Cl)
`
`0.74
`(0.62-0.89)
`
`0.52
`(0.26-1.05)
`
`0.72
`(0.50-1 .02)
`
`r---
`C'!
`C:
`.Q
`t5
`0.95
`~
`(0.68-1 .32) 2
`C
`iI
`
`0.64
`(0.47-0.88)
`
`10
`
`0.1
`
`~ :
`1--o---1
`
`1--o-1
`
`I
`
`1-q--1
`
`I
`1-<>-t I
`I
`
`--
`
`BMI 235
`
`1--o--1 '
`
`I
`
`I
`
`--
`
`0.1
`
`1
`
`10
`
`0.1
`
`Favours semaglutide Favours placebo
`
`1
`Favours semaglutide Favours placebo
`
`F I G U R E 1
`Cardiovascular outcomes by baseline body mass index category in A, LEADER and B, SUSTAIN 6. Primary and expanded MACE
`analyses adjusted for sex, smoking status, antihyperglycaemic treatments, prior cardiovascular (CV) events, geographic region, age, diabetes
`duration, estimated glomerular filtration rate. Smoking status was not adjusted for in the SUSTAIN 6 analysis for CV death because of low event
`numbers. †Primary major adverse cardiovascular events (MACE): composite of CV death, non-fatal myocardial infarction (MI) and non-fatal stroke.
`‡Expanded MACE: components of primary MACE plus revascularization (coronary only in LEADER; coronary or peripheral in SUSTAIN 6) or
`hospitalization for unstable angina pectoris or heart failure. BMI, body mass index (in kg/m2); CI, confidence interval; HR, hazard ratio
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`2490
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`VERMA ET AL.
`
`(A)
`Nephropathyt
`
`LEADER overall5
`
`BMI s25
`
`BMI .?25 to <.30
`
`BMI .e30 to <.35
`
`BMI .e35
`
`0.1
`
`HR (95% Cl)
`
`0.78 (0.67-0.92)
`
`0.80 (0.50-1 .29)
`
`0.79 (0.59-1 .05)
`
`0.79 (0.59-1 .07)
`
`0.70 (0.52-0.94)
`
`10
`
`C\J
`~
`C
`0 :g
`~
`$
`C
`d.
`
`I
`
`i-1 •
`
`I
`I
`I
`
`l--0--I
`
`I
`
`t-<>4
`
`I
`
`1-<>-i
`
`I
`
`1-<>-1:
`
`1
`
`--
`
`Favours liraglutide Favours placebo
`
`(B)
`Nephropathyt
`
`SUSTAIN 6 overall6
`
`HR (95% Cl)
`
`0.64 (0.46-0.88)
`
`BMI s25
`
`1-----------<>-
`
`0.28 (0.10-0.77)
`
`BMI .e25 to <30
`
`1----0----i
`
`0.49 (0.28-0.89)
`
`BMI .e30 to <35
`
`BMI .e35
`
`0.1
`
`i--------o-+---
`
`0. 7 5 ( 0 .42-1 . 33)
`
`I
`I
`~ 0. 86 ( 0 .4 7-1 . 60)
`
`1
`
`10
`
`--
`
`Favours semaglutide Favours placebo
`
`F I G U R E 2
`Renal outcomes by baseline body mass index category in A, LEADER and B, SUSTAIN 6. LEADER analysis adjusted for sex,
`smoking status, antihyperglycaemic treatments, prior cardiovascular events, geographic region, age, diabetes duration, estimated glomerular
`filtration rate. SUSTAIN 6 analysis adjusted for sex, antihyperglycaemic treatments, prior cardiovascular events, geographic region, age, diabetes
`duration, estimated glomerular filtration rate (smoking status was omitted because of low event numbers). †Nephropathy: new or persistent
`macroalbuminuria, doubling of serum creatinine, creatinine clearance of less than 45 mL/min/1.73m2, end-stage kidney disease or death from
`kidney disease. BMI, body mass index (in kg/m2); CI, confidence interval; HR, hazard ratio
`
`There was no significant interaction between treatment and BMI cat-
`egory for percentage weight loss with either liraglutide (Pinteraction = .07;
`Figure S2A) or semaglutide (Pinteraction = .51; Figure S2B).
`
`4
`
`| DISCUSSION
`
`The present results of post hoc analyses from LEADER and SUSTAIN 6
`show that there was no heterogeneity in the CV and renal benefits of
`liraglutide and semaglutide versus placebo across the spectrum of base-
`line BMI evaluated either categorically or continuously, excepting a nom-
`inally significant interaction observed by baseline BMI category for the
`effect of semaglutide on MACE. These data should be considered by
`prescribers when choosing these agents for CV risk reduction in appro-
`priate patients.
`The exact nature of the relationship between any baseline charac-
`teristic, including BMI, and CV benefit of liraglutide and semaglutide (via
`glycaemic control and/or weight loss and/or other mechanisms) remains
`difficult to establish,3,8 with published meta-analysis results showing
`that baseline BMI was not associated with achieved glycaemic control
`across seven different antihyperglycaemic treatments.9 Thus, the dose–
`response curves for any treatment may differ for MACE, glucose levels
`and weight, and our analyses have shown that there appeared to be
`generally no effect of baseline BMI on MACE.
`Also, prior data evaluating the associations of weight loss on CV out-
`comes are varied. The Look AHEAD trial randomized patients with over-
`weight/obesity and T2D to intensive lifestyle (diet and exercise)
`intervention versus control.10 Despite significantly greater weight loss
`achieved in the intervention group, there was no significant difference in
`CV disease-related morbidity and mortality.10 Conversely,
`in the
`Albiglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes
`and Cardiovascular Disease (Harmony Outcomes) trial that randomized
`patients with T2D at high CV risk to the GLP-1 RA albiglutide or placebo,
`
`a statistically significant 22% reduction in first occurrence of CV death,
`myocardial
`infarction or stroke (HR, 0.78 [95% CI 0.68; 0.90]) was
`observed with albiglutide versus placebo. While weight loss was margin-
`ally greater in the albiglutide group versus placebo at 8 and 16 months,
`the differences were less than 1 kg (−0.66 and − 0.83 kg, respectively),
`and at 28 months, weight in both the placebo and albiglutide groups was
`similar to their baseline values.11 Yet another type of association was evi-
`dent in the Researching Cardiovascular Events with a Weekly Incretin in
`Diabetes (REWIND) trial, in which treatment of patients with T2D with
`dulaglutide resulted in a significant decrease in CV events (HR, 0.88 [95%
`CI 0.79; 0.99]) and a significant decrease in body weight (−1.46 kg [95%
`CI 1.25; 1.67]) versus placebo.12 Mediation analyses utilizing data from
`such trials may provide evidence as to how weight loss impacts upon CV
`risk, but to date, it appears that the size of any such mediation of body
`weight on CV outcomes may be small with liraglutide.13
`The many mechanisms that have been proposed to underlie the cardi-
`oprotective effects of GLP-1 RAs are complex. They include anti-
`inflammatory effects, attenuation of cardiac ischaemic injury through a vari-
`ety of direct and indirect actions on the myocardium and coronary arteries,
`modification of lipid synthesis and secretion, and improvement in endothe-
`lial dysfunction, among others.3 For example, in one study, liraglutide and
`semaglutide reduced plaque lesion development through altering inflamma-
`tory pathways in mouse models of atherosclerosis.14 These pathways could
`be involved in the significant improvements in the carotid intima-media
`thickness of patients who were treated with liraglutide for 8 months versus
`baseline.15 Such cardioprotective mechanisms of GLP-1 RAs appear to be
`independent of the lipid levels of patients.15
`The renal protective effects of GLP-1 RAs have been less well
`studied than the cardioprotective effects, and may be linked to renal
`tubular effects, oxidative stress and haemodynamic effects.16 For
`liraglutide and semaglutide, renal benefits were found in LEADER and
`SUSTAIN 6, where they were investigated as secondary, composite
`endpoints.5,6 Analysis of the nephropathy components revealed that
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`persistent
`new or
`by
`driven
`benefits were
`renal
`the
`macroalbuminuria.6,17 Within our post hoc analyses, the renal benefit
`with semaglutide appeared to decrease with increasing BMI, but this
`effect modification by BMI status was not statistically significant.
`However, in the placebo-treated population of SUSTAIN 6, it was evi-
`dent that nephropathy decreased with increasing BMI, which may
`seem counterintuitive, but fits with some studies of patients with
`chronic kidney disease and end-stage renal disease.18 The reason for
`the discrepancy between the LEADER and SUSTAIN 6 data in this
`particular regard remains unknown, but could be related to any of the
`baseline characteristics that varied by BMI category in SUSTAIN 6,
`but not in LEADER (e.g. established CV disease).
`There were limitations to this study. These were post hoc analyses
`with numerous potential confounding factors (including not being
`powered to assess efficacy for CV and renal outcomes across baseline
`BMI strata and being of comparatively short follow-up), and the analyses
`were not adjusted for differences in insulin, sodium-glucose co-
`transporter-2 inhibitor and CV medication use. Baseline BMI categories
`were not corrected for application to Asian patients, who comprised 9.6%
`of the study population, and the BMI categories were not protected by
`the trial randomization, resulting in heterogeneous subgroups. Only base-
`line BMI was analysed, and results were more consistent with the larger,
`postapproval LEADER trial compared with the smaller, preapproval
`SUSTAIN 6 trial. With just one of the many interaction tests yielding a
`nominally significant P-value, the validity of this finding is uncertain and
`may be a spurious finding as these analyses were post hoc and did not
`include correction for multiplicity of testing. Given limited power in the
`present analyses for interaction testing, we are not able to exclude the
`possibility of effect modification by BMI. These analyses used data per-
`taining to liraglutide and semaglutide only; further analyses with datasets
`utilizing other GLP-1 RA data will help clinicians to understand if a class
`effect underpins these results. Although pooling data from the two trials
`may have increased the power of this analysis, because of the larger size
`of LEADER versus SUSTAIN 6, we chose to analyse the data separately,
`to provide a clear indication of what happened with each treatment.
`In conclusion, these results from post hoc analyses of the
`LEADER and SUSTAIN 6 trials suggest that there are consistent CV
`and renal benefits of liraglutide and semaglutide across baseline BMI
`categories in patients with T2D and high CV risk, but they need to be
`confirmed in future studies.
`
`ACKNOWLEDGMENTS
`The authors thank Emre Yildirim (Novo Nordisk) for reviewing this
`manuscript. Editorial and submission support were provided by Gillian
`Groeger, PhD, and Izabel James, MBBS, of Watermeadow Medical, an
`Ashfield company, part of UDG Healthcare plc, funded by Novo
`Nordisk. The LEADER and SUSTAIN 6 trials were sponsored by Novo
`Nordisk and are registered with ClinicalTrials.gov (NCT01179048 and
`NCT01720446).
`
`CONFLICT OF INTEREST
`SV reports personal fees and other from Boehringer Ingelheim, Eli Lilly,
`AstraZeneca, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, Valeant,
`
`Amgen, Sun Pharma and HLS Therapeutics. DKM reports consultancy fees
`for clinical trial
`leadership from AstraZeneca, Sanofi Aventis, Janssen,
`Boehringer Ingelheim, Merck & Co, Pfizer, Lilly US, Novo Nordisk, Lexicon,
`Eisai, GlaxoSmithKline and Esperion; consultancy fees from AstraZeneca,
`Sanofi Aventis, Lilly US, Boehringer Ingelheim, Merck & Co, Novo Nordisk,
`Applied Therapeutics, Afimmune and Metavant. SCB reports personal fees
`and other
`from Abbott, AstraZeneca, Boehringer
`Ingelheim, BMS,
`Cellnovo, Diartis, Eli Lilly, GlaxoSmithKline, Merck Sharp & Dohme,
`Novartis, Novo Nordisk, Pfizer, Roche, Sanofi-Aventis, Schering-Plough,
`Servier and Takeda; other from Cardiff University, Doctors.net, Elsevier,
`Onmedica, Omnia-Med, Medscape, All-Wales Medicines Strategy Group,
`National
`Institute for Health and Care Excellence (NICE) UK and
`Glycosmedia. DLB discloses the following relationships: advisory board:
`Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex,
`Medscape Cardiology, PhaseBio, PLx Pharma, Regado Biosciences; board
`of directors: Boston VA Research Institute, Society of Cardiovascular
`Patient Care, TobeSoft; chair: American Heart Association Quality Over-
`sight Committee; data monitoring committees: Baim Institute for Clinical
`Research (formerly Harvard Clinical Research Institute, for the PORTICO
`trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including
`for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute,
`Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial,
`funded by Daiichi Sankyo), Population Health Research Institute; hono-
`raria: American College of Cardiology (Senior Associate Editor, Clinical Tri-
`als and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim
`Institute for Clinical Research (formerly Harvard Clinical Research Institute;
`RE-DUAL PCI clinical trial steering committee funded by Boehringer
`Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir
`Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research
`Institute (clinical trial steering committees, including for the PRONOUNCE
`trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief,
`Journal of Invasive Cardiology), Journal of the American College of Cardiology
`(Guest Editor; Associate Editor), Medtelligence/ReachMD (CME steering
`committees), Level Ex, MJH Life Sciences, Population Health Research
`Institute (for the COMPASS operations committee, publications commit-
`tee, steering committee, and USA national co-leader, funded by Bayer),
`Slack Publications (Chief Medical Editor, Cardiology Today's Intervention),
`Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD
`(CME steering committees); other: Clinical Cardiology (Deputy Editor),
`NCDR-ACTION Registry Steering Committee (Chair), VA CART Research
`and Publications Committee (Chair); research funding: Abbott, Afimmune,
`Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers
`Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuti-
`cals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly,
`Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi
`Aventis, Synaptic, The Medicines Company; royalties: Elsevier (Editor, Car-
`diovascular Intervention: A Companion to Braunwald's Heart Disease); site
`co-investigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now
`Abbott), Svelte; trustee: American College of Cardiology; unfunded
`research: FlowCo, Merck, Novo Nordisk, Takeda. LAL reports consultant
`and speaker fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly,
`Janssen, Merck, Novo Nordisk, Sanofi and Servier; research grant or sup-
`port from AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline,
`
`Novo Nordisk Exhibit 2111
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
`

`

`2492
`VERMA ET AL.
`_ l_W ILEY - - - - - - - - - - - - - - - - - -
`
`Janssen, Novo Nordisk and Sanofi. CDM reports research grants to institu-
`tion and/or consulting honoraria from Amgen, Boehringer Ingelheim, CSL
`Behring, OctaPharma and Quark Pharmaceuticals. TMF and SR are
`employees of and shareholders in Novo Nordisk. HV was an employee of
`Novo Nordisk during the development of this manuscript. REP reports
`research grants from Gilead Sciences, Lexicon Pharmaceuticals, Ligand
`Pharmaceuticals Inc., Lilly, Merck, Novo Nordisk, Sanofi-Aventis US LLC
`and Takeda; speaker for AstraZeneca, Novo Nordisk and Takeda; consul-
`tant for AstraZeneca, Boehringer Ingelheim, Eisai, Inc., GlaxoSmithKline,
`Janssen Scientific Affairs LLC, Ligand Pharmaceuticals Inc., Lilly, Merck,
`Novo Nordisk, Pfizer and Takeda. All payments made directly to his
`employer (Florida Hospital/AdventHealth). BZ reports personal fees from
`Merck, Sanofi-Aventis, Eli Lilly, AstraZeneca and Janssen; personal fees
`and other from Novo Nordisk and Boehringer Ingelheim. JBB's contracted
`consulting fees are paid to the University of North Carolina by Adocia,
`AstraZeneca, Dance Biopharm, Dexcom, Eli Lilly, Fractyl, GI Dynamics,
`Intarcia Therapeutics, Lexicon, MannKind, Metavention, NovaTarg, Novo
`Nordisk, Orexigen, PhaseBio, Sanofi, Senseonics, vTv Therapeutics and
`Zafgen; he reports grant support from AstraZeneca, Eli Lilly, Intarcia Thera-
`peutics, Johnson & Johnson, Lexicon, Medtronic, Novo Nordisk, Sanofi,
`Theracos, Tolerion and vTv Therapeutics; he is a consultant to Cirius Thera-
`peutics Inc, CSL Behring, Mellitus Health, Neurimmune AG, Pendulum
`Therapeutics and Stability Health; he holds stock/options in Mellitus
`Health, Pendulum Therapeutics, PhaseBio and Stability Health; and he is
`supported by grants from the National Institutes of Health (UL1TR002489,
`U01DK098246, UC4DK108612, U54DK118612), PCORI and ADA.
`
`AUTHOR CONTRIBUTIONS
`Design (of the post hoc analysis, not the trial): all authors. Conduct/
`data collection (all investigators on LEADER or SUSTAIN 6): LAL, SCB,
`JBB, REP and BZ. Analysis: SR. All the authors had access to the final
`study results. SV and DKM contributed equally to writing this manu-
`script. SV wrote the first draft of the paper, which was edited signifi-
`cantly by DKM and subsequently reviewed and approved by all
`authors, who also assume responsibility for its content.
`
`DATA-SHARING STATEMENT
`Data supporting these analyses are available from the corresponding
`author on reasonable request.
`
`ORCID
`E)
`https://orcid.org/0000-0002-4018-8533
`Subodh Verma
`E)
`https://orcid.org/0000-0001-8519-4964
`Stephen C. Bain
`E)
`https://orcid.org/0000-0002-0041-1876
`Bernard Zinman
`
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