Received: 25 February 2021 | Revised: 22 April 2021 | Accepted: 23 April 2021
`DOI: 10.1002/edm2.259
`
`O R I G I N A L R E S E A R C H A R T I C L E
`
`A population- adjusted indirect comparison of cardiovascular
`benefits of once- weekly subcutaneous semaglutide and
`dulaglutide in the treatment of patients with type 2 diabetes,
`with or without established cardiovascular disease
`
`Lyndon Marc Evans1  | Linda Mellbin2 | Pierre Johansen3  | Jack Lawson3 |
`Abby Paine4  | Anna Sandberg3
`
`1Cardiff and Vale University, Cardiff, UK
`2Department of Medicine, Solna
`Karolinska Institutet, Stockholm, Sweden
`3Novo Nordisk A/S, Søborg, Denmark
`4Zedediah Consulting on behalf of DRG
`Abacus (part of Clarivate), Wokingham, UK
`
`Correspondence
`Abby Paine, Zedediah Consulting on
`behalf of DRG Abacus (part of Clarivate),
`Wokingham, UK.
`Email: abby.paine@zedconsult.co.uk
`
`Present address
`Pierre Johansen, Novo Nordisk North
`West Europe Pharmaceuticals A/S,
`Copenhagen, Denmark
`Anna Sandberg, Oncopeptides AB,
`Luntmakargatan 46, Stockholm, Sweden
`
`Funding information
`Novo Nordisk A/S
`
`Abstract
`Introduction: Cardiovascular (CV) effects of once- weekly subcutaneous (s.c.) sema-
`glutide 0.5 and 1 mg and dulaglutide 1.5 mg are reported in their respective placebo-
`controlled cardiovascular outcome trials (CVOTs), SUSTAIN 6 and REWIND. There
`is no head- to- head CVOT comparing these treatments and heterogeneity between
`their CVOTs renders conventional indirect comparison inappropriate. Therefore, a
`matching- adjusted indirect comparison (MAIC) was performed to compare the effects
`of s.c. semaglutide and dulaglutide on major adverse cardiovascular events (MACE) in
`patients with and without established cardiovascular disease (CVD).
`Methods: Individual patient data from SUSTAIN 6 were matched with aggregate data
`from REWIND, using a propensity score method to balance baseline effect- modifying
`patient characteristics. Hazard ratios (HRs) for three- point (3P) MACE (CV death, non-
`fatal myocardial infarction, non- fatal stroke), anchored via placebo, were then indi-
`rectly compared between balanced populations. Sensitivity analyses were performed
`to test the robustness of the main analysis.
`Results: After matching, included effect modifiers were balanced. In the main analy-
`sis, s.c. semaglutide was associated with a statistically significant 35% reduction in
`3P MACE versus placebo (HR, 0.65 [95% confidence interval [CI]; 0.48, 0.87]) and
`nonsignificantly greater reduction (26%) versus dulaglutide (HR, 0.74 [95% CI; 0.54,
`1.01]). Results were supported by all sensitivity analyses.
`Conclusions: This study demonstrated a statistically significant lower risk of 3P MACE
`for s.c. semaglutide versus placebo, in a population with lower prevalence of pre-
`existing CVD than that in the pre- specified primary analysis in SUSTAIN 6. Reduction
`in 3P MACE with s.c. semaglutide was greater than with dulaglutide, although not
`statistically significant.
`
`K E Y W O R D S
`cardiovascular risks, GLP- 1 receptor agonist, type 2 diabetes
`
`This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
`provided the original work is properly cited.
`© 2021 Novo Nordish A/S. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.
`
`Endocrinol Diab Metab. 2021;4:e00259.
`https://doi.org/10.1002/edm2.259
`
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`1  |  INTRODUCTION
`
`Type 2 diabetes (T2D) is a chronic and progressive metabolic dis-
`order associated with an elevated risk of microvascular and mac-
`rovascular complications, including cardiovascular disease (CVD),
`which can result in considerable morbidity and mortality.1- 4 Previous
`studies have shown that, while the effect of intensive blood glucose
`control decreases the risk of microvascular complications after a
`median of 5 years of follow- up,5 its effect on macrovascular compli-
`cations is only observed in the longer term for some cardiovascular
`(CV) outcomes.6 However, more recently, some glucose- lowering
`medication classes have demonstrated significant CV benefit versus
`placebo in far shorter timeframes in their cardiovascular outcomes
`trials (CVOTs). These include glucagon- like peptide receptor ago-
`nists (GLP- 1 RAs) and sodium- glucose co- transporter- 2 inhibitors
`(SGLT- 2is).7
`For patients with T2D who have established CVD or indicators
`of high risk of CVD, GLP- 1 RAs and SGLT- 2is are recommended by
`the American Diabetes Association (ADA) and European Association
`for the Study of Diabetes (EASD), European Society of Cardiology
`and American College of Cardiology.3,8,9 However, based on findings
`of CVOTs, the ADA and EASD recommend GLP- 1 RAs as the pre-
`ferred option when atherosclerotic CVD predominates and SGLT- 2is
`as the preferred option when heart failure (HF) or chronic kidney
`disease predominates.8 As well as differences between treatment
`classes, previous analyses suggest that CV benefit may vary within
`treatment class.7,10 There are currently no head- to- head random-
`ized controlled trials (RCTs) comparing CV benefit within treatment
`classes, and, in the absence of Food and Drug Administration (FDA)
`guidance on a standardized approach to the design of CVOTs, differ-
`ences in study design between some CVOTs can make indirect com-
`parison challenging. Robust, within- class comparison could help to
`guide decisions on which product in a treatment class should be used
`to treat individual patients with T2D with CVD or CV risk factors.
`Guidelines from the ADA and EASD specify that the GLP- 1 RA
`products used to treat patients with T2D and established CVD or at
`high risk of CVD should have proven CVD benefit, defined as hav-
`ing a label indication of reducing CVD events.8 In early 2020, two
`GLP- 1 RAs with once- weekly dosing regimens, subcutaneous (s.c.)
`semaglutide and dulaglutide, were both approved by the FDA in this
`indication.11,12 The CV effects of s.c. semaglutide were assessed in
`SUSTAIN 6, which demonstrated a statistically significant 26% re-
`duction in the risk of three- point (3P) major adverse cardiovascular
`events (MACE) (CV death, non- fatal myocardial infarction [MI] or
`non- fatal stroke) versus placebo in patients with T2D with estab-
`lished CVD and/or CV risk factors.13 The CV effects of dulaglutide
`were assessed in REWIND, which reported a statistically significant
`12% reduction in the risk of 3P MACE with dulaglutide versus pla-
`cebo with established CVD and/or CV risk factors.14 In the absence
`of head- to- head data comparing s.c. semaglutide with dulaglutide,
`an indirect comparison of these treatments based on their respec-
`tive CVOTs could help to determine the most suitable GLP- 1 RA for
`patients with T2D at high CV risk.
`
`Network meta- analysis (NMA) is a well- established method for
`conducting indirect treatment comparisons in the absence of head-
`to- head trials between treatments. Recently published NMAs have
`compared CVOTs to assess the effect of glucose- lowering drugs on
`CV outcomes.10,15– 17 However, NMA adopts assumptions of homo-
`geneity and similarity to provide unbiased estimates of treatment
`effects, and there must be no relevant heterogeneity between trials,
`which must have similar study designs, patient populations and out-
`come measures, and must be comparable on effect modifiers.18,19
`When significant heterogeneity exists between trials, NMA is ren-
`dered inappropriate. Alternative indirect comparative methods are
`available that seek to overcome heterogeneity, and the choice of
`an appropriate method will be determined by the type of evidence
`available, as described by Lingvay et al, 2020.20 Matching- adjusted
`indirect comparison (MAIC) is an alternative method that can be
`used when individual patient data (IPD) are available for a treatment
`of interest and only published aggregate data (collated by treatment
`arm) are available for the comparator. MAIC addresses differences
`in patient populations using a propensity score- based approach,
`which can provide a less biased estimate by weighting the IPD for an
`index treatment to match the aggregate baseline characteristics for
`a comparator.21– 23
`In an unpublished NMA feasibility analysis for comparison
`of GLP- 1 RAs, substantial heterogeneity was identified between
`CVOTs for s.c. semaglutide and dulaglutide in terms of patient
`baseline characteristics. Patients enrolled in SUSTAIN 6 were more
`likely to have experienced a prior CV event than those enrolled in
`REWIND, with approximately twice the proportion of patients ex-
`periencing prior ischaemic stroke (11.6% vs. 5.3%, respectively) and/
`or prior MI (32.5% vs. 16.2%, respectively). As such, an NMA was
`deemed unsuitable for comparing these CVOTs.
`Therefore, with the availability of IPD from SUSTAIN 6 and ag-
`gregate data from REWIND, a MAIC was performed. The objective
`was to assess CV outcomes with s.c. semaglutide in the population
`with fewer prior CV events as assessed in REWIND and to indirectly
`compare the relative effects of s.c. semaglutide versus dulaglutide
`on rates of 3P MACE for patients with T2D with or without estab-
`lished CVD.
`
`2  |  METHODS
`
`2.1  |  Overview of the MAIC methodology
`
`The MAIC approach was first published in 201023 and has subse-
`quently been described in detail in a number of publications, includ-
`ing guidance published in 2016 by the National Institute for Health
`and Care Excellence (NICE) Decision Support Unit (DSU) in their
`Technical Support Document (TSD) 18.21 The NICE guidance was
`accompanied by published code for use with the statistical package
`R,24 to enable MAIC to be carried out according to the recommen-
`dations set out in TSD 18 (Appendix D of the publication). Within
`the therapeutic area of diabetes, the MAIC approach has previously
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`been used to compare the efficacy of two treatments within the
`same treatment class (dipeptidyl peptidase- 4 inhibitors) in a specific
`patient population.25 Further details of the MAIC methodology are
`provided in the Supporting Information.
`
`2.2  |  Empirical approach and model specification
`
`The methods used in the current study align with the NICE guid-
`ance.21 A systematic literature review (SLR) for interventions
`studied in CVOTs was conducted, alongside the unpublished
`NMA feasibility assessment, with a particular focus on GLP- 1 RA
`comparators. RCTs identified as relevant for the key treatments
`of interest were SUSTAIN 6,13 for which IPD were available, and
`REWIND14 with aggregate data. The 0.5 and 1 mg doses of s.c.
`semaglutide from the SUSTAIN 6 trial were pooled, as were the
`matching placebo arms, as the interest was in outcomes associ-
`ated with s.c. semaglutide, not the specific doses. This increased
`the potential pool of patient data for s.c. semaglutide and was
`consistent with the results presented in the SUSTAIN 6 publica-
`tion. These trials had a common comparator in placebo and thus
`an anchored MAIC could be conducted. PIONEER 626 was also
`identified as a CVOT for which a different formulation of sema-
`glutide (for once- daily oral administration) was reported. Although
`not included in the main analysis, PIONEER 6 was included in a
`sensitivity analysis to compare the CV effects of the semaglutide
`molecule with dulaglutide.
`Patient populations in SUSTAIN 6 and REWIND were similar
`in terms of age, gender and race (Table 1). However, patients in
`SUSTAIN 6 had a longer duration of diabetes than those in REWIND
`and a higher baseline HbA1c, with higher proportions of patients re-
`ceiving insulin therapy. In addition, SUSTAIN 6 included higher pro-
`portions of patients with a history of CVD than REWIND, along with
`higher proportions of patients with some CV risk factors (estimated
`glomerular filtration rate [eGFR] <60 ml/min/1.73 m2 and albumin-
`uria [urinary albumin- to- creatinine ratio (UACR) ≥3.39 mg/mmol]).
`Effect- modifying variables are not well established for CV out-
`comes in patients with T2D. Therefore, to enable matching in the
`analysis, potential effect modifiers were identified using input from
`clinical experts. For the purpose of this study, potential effect mod-
`ifiers were identified as prior HF, prior MI, prior stroke or transient
`ischaemic attack (TIA), peripheral arterial disease (PAD), eGFR and
`albuminuria. Of these, prior MI, prior stroke or TIA and existing al-
`buminuria were also described as ‘clinically relevant baseline charac-
`teristics for the primary endpoint’ in the REWIND trial publication.14
`The six potential effect modifiers were considered to allow evalua-
`tion of the effect of GLP- 1 RAs across the spectrum of CV risk. In
`SUSTAIN 6 and REWIND, all variables were specified as dichoto-
`mous variables, that is, as a proportion of the patients in the trial with
`or without the condition at baseline. The exceptions were eGFR and
`UACR. In the primary REWIND publication, for eGFR, patients’ renal
`function was categorized as normal/mild (eGFR ≥60 ml/min/1.73 m2)
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`and moderate/severe (eGFR <60 ml/min/1.73 m2) (dichotomous
`data), as well as mean and standard deviation (SD) measurements
`(continuous data) from the exploratory renal analysis publication.27
`Similarly, for UACR, both the proportion of patients with albumin-
`uria (dichotomous data) and the median and interquartile range (IQR)
`were available from the REWIND publications. Other risk factors,
`including diabetes duration, HbA1c at baseline and smoking status,
`were not adjusted for in the model as these were considered to be
`prognostic and not effect- modifying factors. In an anchored MAIC,
`provided prognostic factors are balanced between study arms, it is
`recommended not to adjust for them in the model since this can lead
`to loss of precision in the estimate of the relative treatment effect.21
`In the main analysis, summarized in Figure 1, IPD from SUSTAIN
`6 were matched to the aggregate effect modifier baseline data from
`REWIND, based on matching all identified potential effect modifiers,
`with eGFR and albuminuria categorized as dichotomous variables
`(<60 vs. ≥60 ml/min/1.73 m2 and <3.39 vs. ≥3.39 mg/mmol, respec-
`tively). The matching for potential effect modifiers was achieved by
`running the relevant portion of the published NICE code in R (ver-
`sion 3.5.3). Thus, the s.c. semaglutide IPD were weighted to match
`the dulaglutide baseline characteristics using a form of propensity
`score model.21,22 The weighting was calculated from the relevant
`baseline characteristic covariates only and was therefore indepen-
`dent of the outcome.
`Details of the form of the propensity score modelling and
`weighting calculations can be found in the Supporting Information.
`
`2.3  |  Outcomes of interest
`
`Three- point MACE was chosen as the primary outcome of interest as
`this was the primary endpoint in the identified trials. It was defined
`as first occurrence of death from CV causes (including undetermined
`death), non- fatal MI or non- fatal stroke. The published NICE code
`was modified to be suitable for use with time- to- event analyses such
`that, following matching, an adjusted hazard ratio (HR) for s.c. sema-
`glutide versus placebo for 3P MACE was estimated in the target
`REWIND population. This was achieved by applying the calculated
`s.c. semaglutide patient weightings to the corresponding 3P MACE
`patient outcomes in a weighted Cox regression. The standard errors
`for the estimates were calculated using a robust sandwich estimator.
`The relative treatment effect of s.c. semaglutide and dulaglutide in
`the REWIND population could then be indirectly calculated using
`the HR for s.c. semaglutide versus placebo calculated in the first
`step, along with the HR reported in the REWIND publication for du-
`laglutide versus placebo.14
`
`2.4  |  Sensitivity analyses
`
`Three sensitivity analyses were performed to test the robustness
`of the results. The motivation for these was to explore the impact
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`TA B L E 1  Baseline characteristics of patients enrolled in SUSTAIN 6 and REWIND
`
`Age, years, mean (SD)
`Gender, n (%)
`Female
`Male
`Race, n (%)
`White
`History of CVD, n (%)
`CVD
`CV event
`Previous HF
`CV risk factors
`Current tobacco use, n (%)
`Hypertension, n (%)
`SBP, mmHg, mean (SD)
`DBP, mmHg, mean (SD)
`LDL cholesterol, mmol/L, mean (SD)
`eGFR <60 ml/min/1.73 m2, n (%)
`Albuminuria, n (%)
`T2D
`Duration of diabetes, years, mean (SD); median (IQR)
`
`HbA1c, %, mean (SD)
`Change from baseline in HbA1c, %, mean
`Glucose- lowering drugs, n (%)
`Metformin
`Sulphonylurea
`Insulin
`DPP- 4i
`TZD
`SGLT- 2i
`CV medication, n (%)
`ACE inhibitor
`ARB
`β- blocker
`Calcium- channel blocker
`Other anti- hypertensive
`Statin
`Fibrate
`Platelet aggregation inhibitors
`
`SUSTAIN 6
`
`Semaglutide 0.5 and
`1 mg (n = 1648)
`
`Placebo (n = 1649)
`
`REWIND
`
`Dulaglutide 1.5 mg
`(n = 4949)
`
`Placebo (n = 4952)
`
`64.7 (7.2)
`
`64.6 (7.5)
`
`66.2 (6.5)
`
`66.2 (6.5)
`
`635 (38.5)
`1013 (61.5)
`
`660 (40.0)
`989 (60.0)
`
`2306 (46.6)
`2643 (53.4)
`
`2283 (46.1)
`2669 (53.9)
`
`1384 (84.0)
`
`1352 (82.0)
`
`3754 (75.9)
`
`3744 (75.6)
`
`1262 (76.6)a 
`673 (40.8)c 
`290 (17.6)
`
`204 (12.4)
`1543 (93.6)
`136.0 (17.47)
`76.99 (10.00)
`2.32 (0.95)
`455 (27.6)
`668 (41.3)
`
`1271 (77.0)a 
`694 (42.1)c 
`299 (18.1)
`
`202 (12.2)
`1516 (91.9)
`135.3 (16.82)
`77.10 (10.04)
`2.33 (0.99)
`450 (27.3)
`636 (39.2)
`
`1560 (31.5)b 
`1028 (20.8)d 
`421 (8.5)
`
`694 (14.0)
`4605 (93.0)
`137.1 (16.6)
`78.4 (9.8)
`2.56 (0.98)
`1081 (21.8)
`1707 (34.5)
`
`1554 (31.4)b 
`1007 (20.3)d 
`432 (8.7)
`
`713 (14.4)
`4619 (93.3)
`137.3 (17.0)
`78.5 (9.9)
`2.56 (0.98)
`1118 (22.6)
`1760 (35.5)
`
`14.2 (8.2); 13.2
`(8.2– 18.6)
`8.7 (1.5)
`−1.25
`
`13.6 (8.0); 12.6
`(7.4– 18.5)
`8.7 (1.5)
`−0.40
`
`10.5 (7.3); 9.5
`(5.5– 14.5)
`7.3 (1.1)
`−0.46
`
`10.6 (7.2); 9.5
`(5.5– 14.5)
`7.4 (1.1)
`−0.16
`
`1211 (73.5)
`698 (42.4)
`956 (58.0)
`3 (0.1)
`35 (2.1)
`1 (0.06)
`
`829 (50.3)
`548 (33.3)
`934 (56.7)
`519 (31.5)
`123 (7.5)
`1199 (72.8)
`184 (11.2)
`1200 (72.8)
`
`1206 (73.1)
`712 (43.2)
`957 (58.0)
`2 (0.1)
`41 (2.5)
`4 (0.2)
`
`813 (49.3)
`563 (34.1)
`960 (58.2)
`536 (32.5)
`135 (8.2)
`1200 (72.8)
`163 (9.9)
`1209 (73.3)
`
`4022 (81.3)
`2270 (45.9)
`1189 (24.0)
`266 (5.4)
`100 (2.0)
`2 (<0.1)
`
`2452 (49.5)
`1679 (33.9)
`2237 (45.2)
`NR
`2767 (55.9)
`3279 (66.3)
`452 (9.1)
`2662 (53.8)
`
`4015 (81.1)
`2282 (46.1)
`1174 (23.7)
`298 (6.0)
`68 (1.4)
`1 (<0.1)
`
`2463 (49.7)
`1693 (34.2)
`2274 (45.9)
`NR
`2833 (57.2)
`3268 (66.0)
`446 (9.0)
`2680 (54.1)
`
`Abbreviations: ACE, angiotensin- converting enzyme; ARB, angiotensin II receptor blocker; CV, cardiovascular; CVD, cardiovascular disease; DBP,
`diastolic blood pressure; DPP- 4i, dipeptidyl peptidase- 4 inhibitors; eGFR, estimated glomerular filtration rate; HbA1c, glycated haemoglobin; HF,
`heart failure; IQR, interquartile range; LDL, low- density lipoprotein; MI, myocardial infarction; NR, not reported; SBP, systolic blood pressure; SD,
`standard deviation; SGLT- 2i, sodium- glucose co- transporter- 2 inhibitor; T2D, type 2 diabetes; TZD, thiazolidinedione.
`aStroke, ischaemic heart disease (including myocardial infarction), peripheral arterial disease, ≥50% arterial stenosis in any artery, coronary
`revascularization (percutaneous coronary intervention or coronary artery bypass graft) or HF.
`bMI, ischaemic stroke, unstable angina with electrocardiogram changes, myocardial ischaemia on imaging or stress test, or coronary, carotid or
`peripheral revascularization.
`cMI or ischaemic, haemorrhagic or undetermined stroke.
`dMI or ischaemic stroke.
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`F I G U R E 1 Summary of step- by- step MAIC process for the main analysis.
`Abbreviations: 3P MACE, 3- point major adverse cardiovascular event; DULA, dulaglutide; PBO, placebo; SEMA, s.c. semaglutide
`
`of the choice of effect modifiers and to examine the action of the
`semaglutide molecule, regardless of formulation.
`For the first sensitivity analysis (sensitivity analysis 1), IPD from
`the SUSTAIN 6 and PIONEER 6 trials were used to calculate an ad-
`justed HR value for semaglutide versus placebo in the population
`matched to the REWIND patient characteristics. Identical MAICs
`were used to match each semaglutide trial population separately to
`the REWIND data. The estimated HRs from both MAICs were then
`pooled using standard meta- analysis techniques to estimate a single
`HR for the semaglutide molecule compared with placebo, matched
`to the REWIND trial. This was in accordance with the recommended
`approach in the NICE guidance, which proposes matching trials sep-
`arately as a better approach than simply pooling the IPD and treating
`it as one large population in a single MAIC calculation.21 As in the
`main analysis, this pooled HR could then be used along with the HR
`from REWIND to indirectly compare the semaglutide molecule with
`dulaglutide.
`Another sensitivity analysis (sensitivity analysis 2), which used
`IPD from SUSTAIN 6 only as in the main analysis, explored the
`choice of potential effect modifiers with re- classification of eGFR
`and UACR data to balance the mean value and SD for eGFR as a con-
`tinuous variable and the mean and SD of the log UACR. The log scale
`was chosen for UACR because only median and IQR were available
`from the published REWIND data, suggesting some skew in the data.
`Consequently, an estimation of mean and SD was first calculated
`on the natural scale from the median and IQR using the methods
`proposed by Wan et al, 201428 and then the log values calculated
`for matching.
`The final sensitivity analysis (sensitivity analysis 3) also used IPD
`from SUSTAIN 6 only and considered exclusion of baseline kidney
`function factors (eGFR and albuminuria) entirely.
`
`3  |  RESULTS
`
`3.1  |  Baseline characteristic matching
`
`For the main analysis, all six identified potential effect modifiers
`were included, with both eGFR and albuminuria measured as di-
`chotomous variables (<60 vs. ≥60 ml/min/1.73 m2 and UACR <3.39
`vs. ≥3.39 mg/mmol, respectively). A histogram showing the distribu-
`tion of the re- scaled weightings for each individual patient in the
`SUSTAIN 6 trial is provided in the Supporting Information.
`A comparison of the adjusted potential effect- modifying base-
`line patient characteristics in the SUSTAIN 6 and REWIND trials
`before and after matching is presented in Table 2. After matching,
`the characteristics were exactly balanced between the trials, with
`the effective sample sizes of the population in SUSTAIN 6, a mea-
`sure of the patient overlap between trials, being approximately 20%
`smaller than the original trial data (Table 2). Results of the matching
`of PIONEER 6 baseline data for the sensitivity analysis are presented
`in the Supporting Information.
`
`3.2  |  Estimated relative treatment effect on 3P
`MACE— results of the main analysis
`
`In the main analysis, following the re- weighting of the observed 3P
`MACE patient outcomes in SUSTAIN 6, s.c. semaglutide was associ-
`ated with a statistically significant 35% reduction in 3P MACE com-
`pared with placebo (HR, 0.65 [95% CI; 0.48, 0.87]) (Table 3). The
`relative treatment effect of dulaglutide versus placebo was taken
`from the REWIND trial (HR, 0.88 [95% CI; 0.79, 0.99], p = .026), and
`this allowed the indirect comparison between s.c. semaglutide and
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`6 of 10 |    
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`dulaglutide to be calculated, resulting in a nonsignificantly greater
`reduction (26%) with s.c. semaglutide compared with dulaglutide
`(HR, 0.74 [95% CI; 0.54, 1.01]).
`
`placebo and versus dulaglutide were comparable with those esti-
`mated in the main analysis (Table 4). A forest plot showing all the
`relative treatment effects after matching IPD from semaglutide trials
`with REWIND aggregate data is presented in Figure 2.
`
`3.3  |  Sensitivity analyses results
`
`In sensitivity analysis 1, when IPD from the SUSTAIN 6 and PIONEER
`6 trials were matched separately to the REWIND data and outcomes
`pooled using meta- analysis to estimate a single HR value for the
`semaglutide molecule (subcutaneous and oral formulations) versus
`dulaglutide, semaglutide demonstrated a statistically significant re-
`duction in 3P MACE compared with dulaglutide (HR, 0.76 [95% CI;
`0.58, 0.99]; p = .04) (Table 4).
`In sensitivity analysis 2, which explored the impact of reclassi-
`fying eGFR and UACR data as continuous rather than dichotomous
`data, and sensitivity analysis 3, which excluded eGFR and albumin-
`uria data entirely, the mean HR values for s.c. semaglutide versus
`
`4  |  DISCUSSION
`
`This study compared the relative effect of two GLP- 1 RAs (s.c. sema-
`glutide vs. dulaglutide) on rates of 3P MACE (CV death, non- fatal MI,
`or non- fatal stroke) in patients with T2D with or without established
`CVD, using a MAIC approach.
`The main analysis showed that, compared with placebo, s.c. sema-
`glutide was associated with a statistically significant 35% reduction in
`3P MACE in a population with a lower prevalence of pre- existing CVD
`than that enrolled in the SUSTAIN 6 trial. This adjusted reduction was
`greater than that demonstrated in the pre- specified primary analysis
`from SUSTAIN 6 in which s.c. semaglutide was associated with a 26%
`
`SUSTAIN 6
`
`s.c. SEMA vs. PBO
`
`Before matching
`(N = 3297)
`
`17.9% (n = 589)
`12.1% (n = 400)
`32.5% (n = 1072)
`14.0% (n = 460b )
`27.4% (n = 905c )
`40.3% (n = 1329)
`
`After matching
`(ESS = 2633)
`
`8.6% (n = 226)
`9.1% (n = 240)
`16.2% (n = 427)
`8.7% (n = 229)
`22.2% (n = 585)
`35.0% (n = 922)
`
`REWIND
`
`DULA vs. PBO
`
`As reported
`(N = 9901)
`8.6%a  (n = 853)
`9.1% (n = 899)
`16.2% (n = 1602)
`8.7% (n = 856)
`22.2% (n = 2199)
`35.0% (n = 3467)
`
`Baseline characteristics
`
`Prior HF (NYHA II– III)
`Prior stroke or TIA
`Prior MI
`Prior PAD
`eGFR <60 ml/min/1.73 m2
`Albuminuria, UACR
`≥3.39 mg/mmol
`
`Note: N = total number of randomized patients; n = number of patients with prior event across all
`treatment arms.
`Abbreviations: DULA, dulaglutide; eGFR, estimated glomerular filtration rate; ESS, effective
`sample size; HF, heart failure; MI, myocardial infarction; NYHA, New York Heart Association; PAD,
`peripheral arterial disease; PBO, placebo; s.c., subcutaneous; SEMA, semaglutide; TIA, transient
`ischaemic attack; UACR, urinary albumin- to- creatinine ratio.
`aNYHA stage unclear at time the analysis was conducted; stage II– III was chosen for matching
`from SUSTAIN 6 as this was considered a more conservative approach, that is the difference in
`proportions of patients with prior HF between trials with I- III would have been even wider than the
`17.9% versus 8.6%.
`bIncludes 7 patients with >50% stenosis in peripheral arteries on angiography or imaging, but no
`prior diagnosis of PAD.
`cAt baseline, compared with values at screening reported in (Marso et al.13), n = 939.
`
`Comparison
`
`s.c. SEMA vs. PBO
`s.c. SEMA vs. DULA
`
`Before matching, as published,
`HR (95% CI)
`
`0.74 (0.58, 0.95)
`N/A
`
`After matching
`
`HR (95% CI)
`
`0.65 (0.48, 0.87)
`0.74 (0.54, 1.01)
`
`p-
`value
`
`.004
`.06
`
`Abbreviations: 3P MACE, 3- point major adverse cardiovascular event; CI, confidence interval;
`DULA, dulaglutide; HR, hazard ratio; MAIC, matching- adjusted indirect comparison; N/A, not
`applicable; PBO, placebo; s.c., subcutaneous; SEMA, semaglutide.
`
`TA B L E 2  Comparison of effect-
`modifying baseline patient characteristics
`from SUSTAIN 6 and REWIND trials
`before and after matching
`
`TA B L E 3  MAIC results of main analysis.
`Comparison of relative treatment effect
`on 3P MACE
`
`EVANS Et Al.
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`TA B L E 4  MAIC sensitivity analyses.
`Comparison of relative effect on 3P
`MACE
`
`Comparison
`
`Before matching, as published,
`HR (95% CI)
`
`    |  7 of 10
`
`After matching with REWIND
`trial
`
`HR (95% CI)
`
`p- value
`
`Sensitivity analysis 1 (S6 + P6, all EMs, eGFR and UACR dichotomousa )
`SEMA vs. PBO
`0.76 (0.62, 0.92)
`0.67 (0.53, 0.85)
`SEMA vs. DULA
`N/A
`0.76 (0.58, 0.99)
`Sensitivity analysis 2 (S6, all EMs, eGFR and UACR continuous)
`s.c. SEMA vs. PBO
`0.74 (0.58, 0.95)
`s.c. SEMA vs. DULA
`N/A
`Sensitivity analysis 3 (S6, CVD EMs only)
`s.c. SEMA vs. PBO
`0.74 (0.58, 0.95)
`s.c. SEMA vs. DULA
`N/A
`
`0.68 (0.50, 0.93)
`0.78 (0.56, 1.07)
`
`0.67 (0.50, 0.90)
`0.76 (0.56, 1.04)
`
`p < .001
`.04
`
`.01
`.11
`
`.007
`.09
`
`Abbreviations: 3P MACE, 3- point major adverse cardiovascular event; CI, confidence interval;
`CVD, cardiovascular disease; DULA, dulaglutide; eGFR, estimated glomerular filtration rate;
`EM, effect modifier; HR, hazard ratio; MAIC, matching- adjusted indirect comparison; N/A, not
`applicable; P6, PIONEER 6; PBO, placebo; s.c., subcutaneous; S6, SUSTAIN 6; SEMA, semaglutide;
`UACR, urinary albumin- to- creatinine ratio.
`aAs eGFR <60/eGFR ≥60 ml/min/1.73 m2 and UACR <3.39/UACR ≥3.39 mg/mmol.
`
`F I G U R E 2 Forest plot for matching IPD from semaglutide trials with REWIND aggregate data— 3P MACE†
`Abbreviations: 3P MACE, 3- point major adverse cardiovascular event; CI, confidence interval; CVD, cardiovascular disease; DULA,
`dulaglutide; eGFR, estimated glomerular filtration rate; HF, heart failure HR, hazard ratio; IPD, individual patient data; MAIC, matching-
`adjusted indirect comparison; MI, myocardial infarction; PAD, peripheral arterial disease; PBO, placebo; SEMA, semaglutide; UACR, urinary
`albumin- to- creatinine ratio.
`†Sensitivity analysis 1: SUSTAIN 6 + PIONEER 6, CVD effect modifiers (MI, stroke, HF, PAD), eGFR and UACR dichotomous (eGFR <60/
`eGFR ≥60 ml/min/1.73 m2; UACR <3.39 vs. ≥3.39 mg/mmol); Sensitivity analysis 2: SUSTAIN 6, CVD effect modifiers (MI, stroke, HF, PAD),
`eGFR and UACR continuous; Sensitivity analysis 3: SUSTAIN 6, CVD effect modifiers (MI, stroke, HF, PAD). References: 1. (Marso et al.13); 2.
`(Husain et al.13); 3. (Gerstein et al.13)
`
`reduction in 3P MACE compared with placebo. The main analysis also
`indicated that s.c. semaglutide resulted in at least as great a reduction
`in the risk of 3P MACE as dulaglutide, with a nonsignificantly lower
`risk of events as shown by the point estimate for the relative treat-
`ment effect, which was <1.0 (HR 0.74, [95% CI; 0.54, 1.01]).
`
`Results of the main analysis were supported by all sensitivity
`analyses conducted. In one of these sensitivity analyses, SUSTAIN
`6 adjusted 3P MACE results for s.c. semaglutide were pooled with
`the corresponding results for PIONEER 6 for oral semaglutide
`to provide an estimate of treatment effect for the semaglutide
`
`EVANS Et Al.
`
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`8 of 10 |    
`
`molecule. In this analysis, statistically significant 33% and 24%
`reductions in 3P MACE were demonstrated for the semaglutide
`molecule compared with placebo and dulaglutide, respectively.
`Results from this MAIC are in line with those reported in a pub-
`lished pooled post hoc analysis of SUSTAIN 6 and PIONEER 6 IPD,
`which showed a statistically significant 24% reduction in 3P MACE
`for semaglutide versus placebo in patients with established CVD
`and/or CV risk factors.29
`Although NMAs have previously been used to compare CVOTs to
`assess the effect of glucose- lowering drugs on CV outcomes,10,15– 17
`none of the published NMAs have incorporated measures to adjust
`for any differences between trials in their model, which may result in
`bias. Furthermore, with a sparse network of treatments consisting of
`just one or two trials per treatment, indirect comparisons are vulner-
`able to systematic bias resulting from imbalances in effect modifier
`distributions.21
`While some previous studies have compared CV effects between
`treatment classes, guidelines make recommendations regarding the
`treatment class to be used for particular patient groups.8 Therefore,
`the current study focuses on the comparison between two treat-
`ments of the same class, s.c. semaglutide and dulaglutide, two GLP- 1