Comparison of the Effects of Glucagon-Like Peptide Receptor Agonists and Sodium-Glucose Co-

Transporter 2 Inhibitors for Prevention of Major Adverse Cardiovascular and Renal Outcomes in Type

2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Cardiovascular Outcomes Trials

Thomas A. Zelniker MD, MSc (a), Stephen D. Wiviott MD (a), Professor Itamar Raz MD (b), KyungAh Im

PhD (a), Erica L. Goodrich MS (a), Remo H.M. Furtado MD (a), Marc P. Bonaca MD, MPH (a), Ofri

Mosenzon MD, MSc (b), Eri T. Kato MD, MPH, PhD (c), Avivit Cahn MD (b), Professor Deepak L. Bhatt

MD, MPH (a), Professor Lawrence A. Leiter MD (d), Professor Darren K. McGuire MD, MHSc (e),

Professor John P.H. Wilding MD (f), Professor Marc S. Sabatine MD, MPH (a)

a TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA

b The Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Hebrew

University of Jerusalem, The Faculty of Medicine, Jerusalem, Israel

c Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan

d Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Ontario, Canada

e Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX

f Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom

Counts:Manuscript: 2585 words (excluding references and legends)

41 References1 Table, 3 Figures

Appendix:2 Tables, 7 Figures

Author for correspondence: Marc S. Sabatine, MD, MPHTIMI Study Office 60 Fenwood Rd. | Suite 7022-7024WBostonMA 02115 Tel (617) 278-0318Fax (617) 264-5130 E-Mail: msabatine@bwh.harvard.edu

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Abstract:

Background: Glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose

contransporter-2 inhibitors (SGLT2i) have emerged as two new classes of antihyperglycemic

agents that also reduce cardiovascular risk. The relative benefits in patients with and without

established atherosclerotic cardiovascular disease (ASCVD) for different outcomes with these

classes of drugs remain undefined.

Methods: We performed a systematic review and trial-level meta-analysis of GLP1-RA and

SGLT2i cardiovascular outcomes trials using the PubMed and EMBASE databases. The primary

outcomes were: the composite of myocardial infarction, stroke, and cardiovascular death

(MACE); hospitalization for heart failure (HHF); and progression of kidney disease.

Results: In total, data from 8 trials and 77,242 patients, 42,920 (55.6%) in GLP1-RA trials and

34,322 (44.4%) in SGLT2i trials, were included. Both drug classes reduced MACE in a similar

magnitude with GLP1RA reducing the risk by 12% (HR 0.88, 95%-CI 0.84 to 0.94; p<0.001) and

SGLT2i by 11% (HR 0.89, 95%-CI 0.83 to 0.96; p=0.001). For both drug classes, this treatment

effect was restricted to a 14% reduction in those with established ASCVD (HR 0.86, 95%-CI 0.80

to 0.93, P=0.002) whereas no effect was seen in patients without established ASCVD (HR 1.01,

95%-CI 0.87 to 1.16, P=0.81; p-interaction 0.028). SGLT2i reduced HHF by 31% (HR 0.69, 95%-CI

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0.61-0.79, P<0.001) whereas GLP1-RA did not have a significant effect (HR 0.93, 95%-CI 0.83 to

1.04, p=0.20). Both GLP-1RA (HR 0.82, 95%-CI 0.75-0.89, p<0.001) and SGLT2i (HR 0.62, 95%-CI

0.58-0.67, p<0.001) reduced the risk of progression of kidney disease including

macroalbuminuria, but only SGLT2i reduced the risk of worsening eGFR, end-stage kidney

disease, or renal death (HR 0.55, 95%-CI 0.48-0.64, p<0.001).

Conclusion: In trials reported to date, GLP1-RA and SGLT2i reduce atherosclerotic MACE to a

similar degree in patients with established ASCVD, whereas SGLT2i have a more marked effect

on preventing HHF and progression of kidney disease. Their distinct clinical benefit profiles

should be considered in the decision-making process when treating patients with T2DM.

Abstract: 318 words

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Clinical Perspective

What is new?

SGLT2i and GLP1-RA reduce atherosclerotic MACE to a similar degree in patients with

established atherosclerotic cardiovascular, but have no appreciable effect on MACE over

the timeframe studied in patients without established disease.

SGLT2i but not GLP1-RA reduce the risk of heart failure.

In terms of renal outcomes, GLP1-RA primarily reduce the risk of macroalbuminuria

whereas SGLT2i reduce the risk of worsening eGFR.

What are the clinical implications?

GLP1-RA and SGLT2i reduce atherosclerotic MACE in patients with established ASCVD,

whereas SGLT2i also have effects on preventing HHF and reduction in eGFR in a broad

spectrum of patients.

These considerations should be included in the decision-making process when treating

patients with T2DM.

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Background

Recent large-scale cardiovascular outcomes trials that have been mandated by regulatory

authorities1, 2 to prove cardiovascular safety for the approval of new antihyperglycemic agents

in patients with type 2 diabetes (T2DM) have contributed to a better understanding of the

disease over the last decade. Their large sample sizes and robust results have dramatically

changed the landscape of clinical trials in the field of diabetes and caused a shift in therapeutic

focus from reducing glycated hemoglobin (HbA1c) in order to prevent microvascular

complications to also reducing risk of cardiovascular outcomes. To date, only members of two

drug classes, glucagon-like peptide 1 receptor agonists (GLP1-RA)3-5 and sodium-glucose co-

transporter-2 inhibitors (SGLT2i),6, 7 have been shown to reduce significantly the risk of major

cardiovascular events (MACE), the composite of myocardial infarction, stroke, and

cardiovascular death. For that reason, recent guidelines focus on initiation of these 2 classes of

medications.8, 9 A recent meta-analysis from our group showed that the favorable effects of

SGLT2i on reducing atherosclerotic cardiovascular events are confined to patients with

established ASCVD, but their salutary effects preventing hospitalization for heart failure (HHF)

and the progression of kidney disease were seen in all patients.10 A recent meta-analysis of

GLP1-RA cardiovascular outcomes trials showed a 10% reduction in MACE11 but differences in

the treatment effect of GLP1-RA on MACE between patients with and without ASCVD have not

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been confirmed, as primary prevention patients represent only a relatively small proportion of

the patient population in each of the trials yielding much fewer events thereby resulting in

underpowered analyses. As such, the present meta-analysis of cardiovascular outcomes trials

was designed to compare and contrast the clinical benefit of GLP1-RA and SGLT2i in patients

with and without established ASCVD.

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Materials and Methods

The authors declare that all supporting data are available within the article [and its online

supplementary files].

Data Search and Study Selection:

The present meta-analysis was performed using the methods proposed in the Preferred

Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA-P) statement.12-14 A data

search of all randomized, placebo-controlled, cardiovascular outcomes trials of GLP1-RA and

SGLT2i was performed using PubMed and EMBASE until November 11, 2018 and

complemented by results presented at the congress of the American Heart Association 2018.

The search algorithm is presented in detail in the Supplemental material. Data search and

extraction was performed by two independent reviewers (TAZ, RHMF) using a standardized

data form and any discrepancies were resolved by consensus or by consulting a third reviewer

(MSS). No patients were involved in the conduction of this meta-analysis and thus no informed

consent and institutional review board approval was required. All trials met criteria for being

well conducted and had low risk of bias using the Cochrane tool for assessing risk of bias in

randomized clinical trials15 (see Appendix, Risk of Bias Assessment).

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Patient Subtypes & Outcomes

Patients were stratified into those with established ASCVD versus patients with multiple risk

factors (MRF) for ASCVD (see Supplementary Table 1 for details). Efficacy outcomes of interest

included MACE (and its individual components), HHF, and progression of kidney disease. The

latter included both a broad composite consisting of new onset of macroalbuminuria,

worsening of estimated glomerular filtration rate (eGFR), end-stage kidney disease, or death

due to renal causes and a narrower kidney outcome excluding macroalbuminuria. For this latter

outcome, sustained doubling of serum creatinine was available for the GLP1-RA trials (except

for EXSCEL for which 40% worsening GFR, end-stage kidney disease, or death due to renal

causes was available), whereas a composite of doubling of serum creatinine or a ≥40%

worsening GFR, end-stage kidney disease, or death due to renal causes was available for the

SGLT2i trials, but the latter two elements constituted only 0.002% of the events (see Table S2

for details).

Statistical analysis:

Hazard ratios with 95% confidence intervals for the effect of randomized treatment allocation

on the aforementioned outcomes were pooled across trials overall by drug class and within

patients with ASCVD and MRF. Whenever data are summarized within a single drug class, fixed

effects models were considered to estimate the overall treatment effect under the hypothesis

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that there is one common treatment effect within the same drug class. When testing for

treatment effect modification by drug class, random effects models were considered with drug

class as the moderator to make an inference by applying the method of residual maximum

likelihood (REML) and Hartung-Knapp adjustment.16 When combining the two drug classes and

patient types to examine the treatment difference between patients with ASCVD and MRF, a

mixed-effects model was considered to account for heterogeneity of the drug class level and at

the trial level with an ASCVD and MRF population flag as a fixed effects moderator. Additional

trial level covariates such as pharmacological subclass (human GLP-1 analogues vs exendin-

based therapy) and ACS vs no ACS population (Acute coronary syndrome) were also examined

in meta-regression models to understand between trial differences for GLP1-RA class.

Heterogeneity was assessed using Cochrane Q statistic, and Higgins’ and Thompsons I2.

Heterogeneity was considered to be low, moderate, or high if I2 was 25%, 50%, or 75%,

respectively.17 All reported P values are two-sided and no adjustments for multiple testing were

performed. Statistical analyses were performed using R version 3.5.1 (R Core Team, Vienna,

Austria) and the R package “metafor” (version 2.0-0).18

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Results

Study characteristics

We identified a total of 8 trials, 5 GLP1-RA3-5, 19, 20 trials and 3 SGLT2i7, 21, 22 trials that were eligible

for inclusion (Table 1). Supplemental Figure S1 shows an overview of the search and the

selection process. In total, data from 77,242 patients, 42,920 (55.6%) patients in GLP1-RA trials

and 34,322 (44.4%) patients in SGLT2i trials, were included. The mean age of patients (range

60-65 years) and the proportion of women (range 28-40%) were similar across the trials. A total

of 56,473 patients (73.1%) had established ASCVD, but this proportion ranged from 41% to

100% across the trials. A total of 12,568 patients (16.3%) had a history of heart failure, and this

proportion ranged from 10 to 24% across the trials. The proportion of patients with eGFR <60

ml/min/1.73 m2 ranged from 20% to 29% across the trials, with the exception of DECLARE-TIMI

58 that had a substantially smaller proportion (7.4%).

Composite of myocardial infarction, stroke, and cardiovascular death (MACE)

In total, 8,213 of 77,242 patients (10.6%) experienced a MACE event (4,871 patients in the

GLP1-RA trials and 3,342 patients in the SGLT2i trials). A total of 84.7% of these events occurred

in the group with established ASCVD.

Overall, both drug classes reduced MACE by a similar magnitude, with GLP1-RA reducing the

relative risk by 12% (HR 0.88, 95% CI 0.84 to 0.94; p<0.001; Figure S2) and SGLT2i by 11% (HR

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0.89, 95% CI 0.83 to 0.96; p=0.001; p for heterogeneity 0.86). For both drug classes, this effect

was restricted to a 14% reduction in those with established ASCVD (HR 0.86, 95% CI 0.80 to

0.93), with nearly identical effects for GLP1-RA (HR 0.87, 95% CI 0.82-0.92) and SGLT2i (HR 0.86,

95% CI 0.80-0.93), whereas no treatment effect was seen in patients with MRF (HR 1.01, 95% CI

0.87 to 1.19) (Figure 1, P-interaction=0.028; Figure S3). The observed heterogeneity between

GLP1-RA (p-interaction 0.064) and SGLT2i (p-interaction 0.051)23 was similarly in both drug

classes. There was evidence of heterogeneity among the GLP1-RA trials ( I2=58.8%) for the effect

estimate on MACE. Stratifying the drug class by pharmacological subclass showed a non-

significant trend towards greater benefit for the human GLP-1 analogues (HR 0.82, 95% CI 0.76

to 0.89, P<0.001) than for the exendin-based therapies (HR 0.94, 95% CI 0.87 to 1.02, P=0.14)

but the difference was not statistically significant (p-interaction 0.12). However, one of the

trials using the exendin-based GLP1-RA lixisenatide was in the post-acute coronary syndrome

(ACS) setting, in which MACE risk may be less acutely modifiable by a metabolic agent.

Examining all of the non-ACS trials, the overall HR was 0.86 (95% CI 0.81 to 0.91, P<0.001) with

no significant heterogeneity (Q=4.75, p=0.19; I2=36.8%). Furthermore, the median trial duration

(p-interaction 0.69) did not modify significantly the treatment effect of GLP1-RA. There was a

trend for HbA1c lowering (P-interaction overall 0.055, ASCVD only 0.032) but was not significant

after the removal of the ELIXA trial (p-interaction overall 0.28, ASCVD only 0.22).

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Treatment effect on the individual components of MACE

There were 4,274 patients who experienced a myocardial infarction (2,670 patients in GLP1-RA

trials and 1,604 patients in SGLT2i trials), 2,237 a stroke (1,177 patients in GLP1-RA trials, 1,060

patients in SGLT2i trials), and 3,132 a cardiovascular death (1,876 in GLP1-RA trials, 1,256

patients in SGLT2i trials).

Both GLP1-RA and SGLT2i reduced the relative risk of myocardial infarction: by 9% with GLP1-

RA (HR 0.91, 95% CI 0.84 to 0.98, p=0.012) and by 11% with SGLT2i (HR 0.89, 95% CI 0.80 to

0.98, p=0.018; p for heterogeneity 0.87; Figure S4). In contrast, GLP1-RA reduced the relative

risk of stroke significantly by 14% (HR 0.86, 95% CI 0.77 to 0.97, p=0.012), whereas SGLT2i had

no effect (HR 0.97, 95% CI 0.86 to 1.10) (p for heterogeneity 0.25; Figure S5). Both drug classes

significantly reduced the relative risk of cardiovascular death: by 12% with GLP1-RA (HR 0.88,

95% CI 0.80 to 0.96, p=0.004) and by 16% with SGLT2i (HR 0.84, 95% CI 0.75 to 0.94, p=0.002; p

for heterogeneity 0.51; Figure S6).

Hospitalization for heart failure

In total, HHF occurred in 2,240 individuals, 1,278 in the GLP1-RA trials (not including data from

the HARMONY trial that did not directly report that outcome) and 962 patients in the SGLT2i

trials. Overall, GLP1-RA did not statistically significantly reduce the relative risk of HHF (HR 0.93,

95% CI 0.83 to 1.04, p=0.20) whereas SGLT2i did reduce the relative risk for HHF by 31% (HR

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0.69, 95% CI 0.61-0.79, p<0.001) (P for heterogeneity 0.003, Figure 2). These findings, including

the significant interaction, remained similar in a sensitivity analysis after including estimated

treatment effect data from the HARMONY trial (see Supplementary Results).

Treatment Effects on Kidney Function

Overall, the broad composite kidney endpoint occurred in 5,071 patients. GLP-1RA reduced the

relative risk of the broad composite kidney outcome significantly by 18% (HR 0.82, 95% CI 0.75

to 0.89, p<0.001), whereas there was a 38% reduction with SGLT2i (HR 0.62, 95% CI 0.58 to

0.67, p<0.001; P for heterogeneity 0.010; Figure 3A). Moreover, the relative risk reduction of

the kidney composite with GLP1-RA appeared to be mainly driven by a reduction in

macroalbuminuria. Excluding that particular outcome, there was a non-significant effect of

GLP1-RA on the risk of doubling serum creatinine (HR 0.92, 95% CI 0.80 to 1.06, p=0.24).

Conversely, SGLT2i significantly reduced the relative risk of worsening eGFR, end-stage kidney

disease, or renal death by 45% (HR 0.55, 95% CI 0.48 to 0.64, p<0.001; P for heterogeneity

=0.001; Figure 3B). A sensitivity analysis using doubling of serum creatinine alone yielded an

almost identical effect estimate (HR 0.56, 95% CI 0.44-0.71, P<0.001).

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Discussion

GLP1-RA and SGLT2i are antihyperglycemic agents that have now been demonstrated to reduce

the risk of cardiovascular events in patients with type 2 diabetes mellitus.11 The relative

benefits of these drugs in different patient populations remains undefined. The present meta-

analysis showed that both GLP1-RA and SGLT2i reduce the risk of MACE by approximately 14%

in patients with known ASCVD, whereas in the trials published to date, neither reduces the risk

of MACE in patients with only MRF but without established ASCVD.

In terms of the individual components of MACE, both classes reduced the risk of MI and CV

death, but only GLP1-RA reduced the risk of stroke. In contrast, SGLT2i robustly reduced the

relative risk of HHF by 31%, whereas there was only a non-significant 7% relative risk reduction

with GLP1-RA.

Members of GLP1-RA have been found to reduce kidney events mainly driven by a reduction in

macroalbuminuria.24 Although albuminuria is a well-established biomarker reflecting risk for

diabetic kidney disease and cardiovascular disease,25, 26 it represents a surrogate marker and

may even be absent in patients with reduced eGFR.27, 28 As such, reductions in eGFR has

emerged as the more meaningful endpoint of greater importance and is used in ongoing

diabetes trials for kidney outcomes.29 When excluding macroalbuminuria, we found a non-

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significant relative reduction by 8%. This stands in contrast to a recent meta-analysis of SGLT2i

that showed robust relative risk reductions by 45% for the composite of reductions in eGFR,

end-stage kidney disease, and death due to renal causes.10

The exact pathobiological explanations how these two drug classes exert their favorable effects

are still unclear.30, 31 Both drug classes have modest and relatively similar reductions of HbA1c

and therefore appear to exert their beneficial cardiovascular effects independent of glucose

control through their individual pleiotropic properties. However, the natriuresis and inhibition

of the tubuloglomerular feedback by SGLT2i may play a central role and explain the observed

reduction in HHF and the delayed progression of diabetic kidney disease.32 Potentially adding to

the complexity, structural differences in the GLP1-RA group might explain somewhat more

pronounced effects with the human GLP-1 analogues compared with the exendin-based GLP1-

RAs. Recently, a press release has been issued stating that the REWIND trial, a cardiovascular

outcomes trial comparing the GLP1-RA dulaglutide in approximately 9900 patients (68.6% of

whom did not have known ASCVD), has met its primary endpoint of reducing the risk of

MACE.33 34 Detailed results have not yet been presented or published, including any

heterogeneity in benefit between patients with established ASCVD and those only with MRF for

ASCVD. However, its uniquely long duration of 8 years raises the possibility that a reduction in

MACE may require more time to become evident in patients with lower risk for MACE. It is

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biologically plausible that SGLT2i and GLP1-RA have the same benefit in both patient

populations, but the treatment effect may require more time to become evident in patients at

low-risk.

Limitations

There are several potential limitations to address. We have included aggregate trial-level data

instead of patient-level data, and as such, observed differences in treatment effects between

subgroups have been analyzed only based on a single factor of stratification. However, a more

complex interplay involving multiple baseline characteristics may exist. In addition, the exact

inclusion/exclusion criteria and definitions of endpoints differed slightly among the included

trials. As such, a higher risk patient cohort with a larger proportion of patients with ASCVD and

lower eGFR baseline levels was included in the GLP1-RA trials. This meta-analysis aimed to

provide clinical context and show their clinical efficacy of two drug classes in specific patient

populations. However, trials with head to head comparison would be necessary to demonstrate

possible superiority of one drug class over the other. Also, this meta-analysis is not able to

evaluate potential incremental or additive treatment effects when both drug classes are

combined. Further research is warranted to explore the cardiovascular and kidney effects of

combining the two treatment regimens. As noted above, the REWIND data were not included,

as this trial has not been published at the time of submission. However, based on topline

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results of superiority reported by press release, they raise the possibility that very long-term

treatment with a GLP1RA may reduce the risk of MACE in patients without established ASCVD.34

Conclusion

In conclusion, GLP1-RA and SGLT-2i reduce the risk of MACE to a similar degree in patients with

established ASCVD, but have no effect in patients without established ASCVD over a short-term

follow-up ranging from 2 to 4 years. The prevention of heart failure and progression of kidney

disease by SGLT2i should be considered in the decision-making process when treating patients

with T2DM.

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Authors contributions:

TAZ contributed to study design, data collection, statistical analysis, data interpretation, and

drafting of the manuscript. SDW contributed to study design, data collection, data

interpretation, and critical review of the manuscript. IR contributed to data interpretation, and

critical review of the manuscript. KI contributed to statistical analysis, and critical review of the

manuscript. ELG contributed to statistical analysis, and critical review of the manuscript. MPB

contributed to data collection, data interpretation, and critical review of the manuscript. OM

contributed to data interpretation, and critical review of the manuscript. EK contributed to data

interpretation, and critical review of the manuscript. AC contributed to data interpretation, and

critical review of the manuscript. RHMF contributed to data interpretation, data collection, and

critical review of the manuscript. DLB contributed to data interpretation, and critical review of

the manuscript. LAL contributed to data interpretation, and critical review of the manuscript.

DKM data interpretation, and critical review of the manuscript. JPHW data interpretation, and

critical review of the manuscript. MSS contributed to study design, data collection, statistical

analysis, data interpretation, and critical review of the manuscript. MSS is the guarantor of this

work and, as such, had full access to all the data in the study and takes responsibility for the

integrity of the data and the accuracy of the data analysis.

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Funding

TAZ was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft ZE

1109/1-1 to TAZ). RHMF was supported by the Lemann Foundation Cardiovascular Research

Postdoctoral Fellowship – Harvard University/Brigham and Women´s Hospital. The funding

source had no role in data collection, analysis, writing of the manuscript or the decision to

submit for publication. All authors had full access to all the data. All statistical analyses were

performed at the TIMI Study Group. MSS is the guarantor of this work and all authors take

responsibility for the integrity of the data and the accuracy of the data analysis.

Conflicts of interest

TAZ reports a research grant from Deutsche Forschungsgemeinschaft (ZE 1109/1-1), and grants

to his institution from Astra Zeneca, grants from Bristol-Myers Squibb, during the conduct of

the study. SDW reports grants and personal fees from AstraZeneca, grants and personal fees

from Bristol Myers Squibb, during the conduct of the study; grants from AMGEN, grants and

personal fees from Arena, grants and personal fees from Daiichi Sankyo, grants and personal

fees from Eisai, grants and personal fees from EliLilly, grants and personal fees from Janssen,

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grants, personal fees and other from Merck, grants from Sanofi Aventis, personal fees from

Aegerion, personal fees from Allergan, personal fees from Angelmed, personal fees from

Boehringer Ingelheim, personal fees from Boston Clinical Research Institute, personal fees from

Icon Clinical, personal fees from Lexicon, personal fees from St Jude Medical, personal fees

from Xoma, outside the submitted work. IR reports personal fees from AstraZeneca, personal

fees from Bristol-Myers Squibb, during the conduct of the study; personal fees from Boehringer

Ingelheim, personal fees from Concenter BioPharma/Silkim Ltd, personal fees from Eli Lilly and

Company, personal fees from Merck Sharp & Dohme Limited, personal fees from Novo Nordisk,

Inc, personal fees from Orgenesis, personal fees from Pfizer, personal fees from Sanofi,

personal fees from SmartZyme Innovation Ltd, personal fees from Panaxia, personal fees from

FuturRx Ltd, personal fees from Insuline Medical, personal fees from Medial EarlySign Ltd,

personal fees from CameraEyes, personal fees from Exscopia, personal fees from Dermal

Biomics Inc, personal fees from Johnson & Johnson, personal fees from Novartis Pharma AG,

personal fees from Teva, personal fees from Glucome Ltd, personal fees from DarioHealth,

outside the submitted work.

KI: None. ELG: None. MPB reports grants from Amgen, AstraZeneca, Merck, Pfizer, personal

fees from Aralez, Amgen, AstraZeneca, Bayer, Janssen, Pfizer, Sanofi, during the conduct of the

study. OM reports grants and personal fees from AstraZeneca, grants and personal fees from

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Bristol-Myers Squibb, during the conduct of the study; grants and personal fees from

NovoNordisk, personal fees from Eli Lilly, personal fees from sanofi, personal fees from Merck

Sharp & Dohme, personal fees from Boehringer Ingelheim, personal fees from Jansen and

Jansen, personal fees from Novartis, outside the submitted work. ETK reports personal fees

from AstraZeneca, personal fees from Ono Pharmaceutical, personal fees from Daiichi Sankyo ,

personal fees from Bristol-Myers Squibb, personal fees from Tanabe-Mitsubishi Pharma,

outside the submitted work. AC reports personal fees from Novonordisk, personal fees from Elli

Lilly, personal fees from Sanofi, grants and personal fees from AstraZeneca, personal fees from

Boeehringer Ingelheim, personal fees from Merck Sharp & Dohme, personal fees from

Glucome, outside the submitted work. RHMF reports the following: Honoraria; Modest;

AstraZeneca; Research Grant; Modest; AstraZeneca, DalCor, Boehinger, Pfizer, Bayer, Sanofi.

DLB discloses the following relationships - Advisory Board: Cardax, Elsevier Practice Update

Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research

Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association

Quality Oversight 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, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School

of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research

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Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials 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), Belvoir Publications (Editor in Chief, Harvard Heart Letter),

Duke Clinical Research Institute (clinical trial steering committees), HMP Global (Editor in Chief,

Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor;

Associate Editor), Population Health Research Institute (for the COMPASS operations

committee, publications committee, 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, Amarin, Amgen,

AstraZeneca, (including for the DECLARE-TIMI 58 Executive Committee), Bayer, Boehringer

Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood,

Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, The

Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to

Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude Medical

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(now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo,

Merck, Novo Nordisk, PLx Pharma, Takeda.

LAL reports grants and personal fees from AstraZeneca, grants and personal fees from

Boehringer Ingelheim, grants and personal fees from Eli Lilly, grants and personal fees from

Janssen, grants and personal fees from Merck, grants and personal fees from Novo Nordisk,

grants and personal fees from Sanofi, personal fees from Servier, grants from GSK, outside the

submitted work. DKM reports personal fees from AstraZeneca, during the conduct of the

study; personal fees from Boehringer Ingelheim, personal fees from Janssen Research and

Development LLC, personal fees from Sanofi US, personal fees from Merck Sharp and Dohme

Corp., personal fees from Eli Lilly and Company, personal fees from Novo Nordisk, personal fees

from GlaxoSmithKline, personal fees from AstraZeneca, personal fees from Lexicon, personal

fees from Eisai Inc., personal fees from Esperion, personal fees from Metavant, personal fees

from Pfizer, personal fees from Applied Therapeutics, outside the submitted work. JW reports

personal fees and other from Brigham and Women's Hospital, during the conduct of the study;

grants, personal fees and consultancy fees (paid to his institution) from AstraZeneca, personal

fees and consultancy fees (paid to his institution) from Boehringer Ingelheim, personal fees and

consultancy fees (paid to his institution) from Lilly, grants, personal fees and consultancy fees

(paid to his institution) from Novo Nordisk, personal fees and consultancy fees (paid to his

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institution) from Janssen, personal fees and consultancy fees (paid to his institution) from

Napp, personal fees and consultancy fees (paid to his institution) Mundipharma, personal fees,

consultancy fees (paid to his institution) from Sanofi, grants, personal fees and consultancy fees

(paid to his institution) from Takeda, consultancy fees (paid to his institution) from Wilmington

Healthcare, outside the submitted work. MSS reports grants from AstraZeneca, during the

conduct of the study; grants and personal fees from Amgen, grants and personal fees from

AstraZeneca, grants from Daiichi-Sankyo, grants from Eisai, grants from GlaxoSmithKline, grants

and personal fees from Intarcia, grants and personal fees from Janssen Research and

Development, grants and personal fees from Medicines Company, grants and personal fees

from Medimmune, grants and personal fees from Merck, grants and personal fees from

Novartis, grants from Pfizer, grants from Poxel, grants from Takeda, personal fees from Bristol-

Myers Squibb, personal fees from CVS Caremark, personal fees from Dyrnamix, personal fees

from Esperion, grants from Abbott Laboratories, grants from Critical Diagnostics, grants from

Genzyme, grants from Gilead, grants from Roche Diagnostics, personal fees from Alnylam,

personal fees from Ionis, personal fees from MyoKardia, outside the submitted work.

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References

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27. Porrini E, Ruggenenti P, Mogensen CE, Barlovic DP, Praga M, Cruzado JM, Hojs R, Abbate M, de Vries AP and group E-Edw. Non-proteinuric pathways in loss of renal function in patients with type 2 diabetes. Lancet Diabetes Endocrinol. 2015;3:382-91.28. Tuttle KR, Bakris GL, Bilous RW, Chiang JL, de Boer IH, Goldstein-Fuchs J, Hirsch IB, Kalantar-Zadeh K, Narva AS, Navaneethan SD, Neumiller JJ, Patel UD, Ratner RE, Whaley-Connell AT and Molitch ME. Diabetic kidney disease: a report from an ADA Consensus Conference. Diabetes Care. 2014;37:2864-83.29. Jardine MJ, Mahaffey KW, Neal B, Agarwal R, Bakris GL, Brenner BM, Bull S, Cannon CP, Charytan DM, de Zeeuw D, Edwards R, Greene T, Heerspink HJL, Levin A, Pollock C, Wheeler DC, Xie J, Zhang H, Zinman B, Desai M, Perkovic V and investigators Cs. The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Study Rationale, Design, and Baseline Characteristics. Am J Nephrol. 2017;46:462-472.30. Zelniker TA and Braunwald E. Cardiac and Renal Effects of Sodium-Glucose Co-Transporter 2 Inhibitors in Diabetes: JACC State-of-the-Art Review. J Am Coll Cardiol. 2018;72:1845-1855.31. Sattar N, Petrie MC, Zinman B and Januzzi JL, Jr. Novel Diabetes Drugs and the Cardiovascular Specialist. J Am Coll Cardiol. 2017;69:2646-2656.32. Heerspink HJ, Perkins BA, Fitchett DH, Husain M and Cherney DZ. Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications. Circulation. 2016;134:752-72.33. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, Probstfield J, Riddle MC, Ryden L, Xavier D, Atisso CM, Avezum A, Basile J, Chung N, Conget I, Cushman WC, Franek E, Hancu N, Hanefeld M, Holt S, Jansky P, Keltai M, Lanas F, Leiter LA, Lopez-Jaramillo P, Cardona-Munoz EG, Pirags V, Pogosova N, Raubenheimer PJ, Shaw J, Sheu WH, Temelkova-Kurktschiev T and Investigators RT. Design and baseline characteristics of participants in the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial on the cardiovascular effects of dulaglutide. Diabetes Obes Metab. 2018;20:42-49.34. Press Release. Trulicity® (dulaglutide) demonstrates superiority in reduction of cardiovascular events for broad range of people with type 2 diabetes: https://investor.lilly.com/news-releases/news-release-details/trulicityr-dulaglutide-demonstrates-superiority-reduction. 2018.35. Verma S, Bhatt DL, Bain SC, Buse JB, Mann JFE, Marso SP, Nauck MA, Poulter NR, Pratley RE, Zinman B, Michelsen MM, Monk Fries T, Rasmussen S, Leiter LA and Investigators LPCobotLT. Effect of Liraglutide on Cardiovascular Events in Patients With Type 2 Diabetes Mellitus and Polyvascular Disease: Results of the LEADER Trial. Circulation. 2018;137:2179-2183.36. Muskiet MHA, Tonneijck L, Huang Y, Liu M, Saremi A, Heerspink HJL and van Raalte DH. Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2018;6:859-869.37. Mann JFE, Orsted DD, Brown-Frandsen K, Marso SP, Poulter NR, Rasmussen S, Tornoe K, Zinman B and Buse JB. Liraglutide and Renal Outcomes in Type 2 Diabetes. N Engl J Med. 2017;377:839-848.38. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, Woo V, Hansen O, Holst AG, Pettersson J and Vilsboll T. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375:1834-1844.39. Bethel MA, Mentz RJ, Merrill P, Buse JB, Chan JC, Goodman SG, Iqbal N, Jakuboniene N, Katona BG, Lokhnygina Y, Lopes RD, Maggioni AP, Ohman PK, Poulter NR, Ramachandran A, Tankova T, Zinman B, Hernandez AF and Holman RR. Renal Outcomes in the EXenatide Study of Cardiovascular Event Lowering (EXSCEL). Diabetes. 2018;67:522-P.

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40. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen OE, Woerle HJ, Broedl UC and Zinman B. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016;375:323-34.41. Perkovic V, Zeeuw D, Mahaffey KW, Fulcher G, Erondu N, Shaw W, Barrett TD, Weidner-Wells M, Deng H, Matthews DR and Neal B. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol. 2018.

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Tables

Table 1: Summary of GLP1-RA and SGLT2i cardiovascular outcomes trials

GLP-1RA SGLT2iTrial ELIXA LEADER SUSTAIN-6 EXSCEL HARMONY EMPA-REG

OUTCOMECANVAS Program

DECLARE-TIMI 58

Drug Lixisenatide Liraglutide Semaglutide Exenatide Albiglutide Empagliflozin Canagliflozin DapagliflozinMedian Follow-Up Time (years) 2.1 3.8 2.1 3.2 1.6 3.1 2.4 4.2

Trial participants (n) 6068 9340 3297 14752 9463 7020 10142 17160

Age (mean) 60.3 64.3 64.6 62.0 64.1 63.1 63.3 63.9Female Sex 2894 (30.7%) 3337 (35.7%) 1295 (39.3%) 5603 (38.0%) 2894 (30.6%) 2004 (28.5%) 3633 (35.8%) 6422 (37.4%)Proportion of Patients with Established Atherosclerotic Cardiovascular Disease (n, %)

6068 (100%) 6775 (72.5%) 2735 (83.0%) 10782 (73.1%) 9463 (100%) 7020 (100%) 6656 (66%) 6974 (41%)

History of Heart Failure (n, %) 1922 (20.3%) 1667 (17.8%) 777 (23.6%) 2389 (16.2%) 1922 (20.3%) 706 (10.1%) 1461 (14.4%) 1724 (10.0%)

eGFR <60 ml/min/1.73m2 (n, %)

1407 (23.2%) 2158 (23.1%) 939 (28.5%) 3191 (21.6%) NA 1819 (25.9%) 2039 (20.1%) 1265 (7.4%)

The CANVAS Program consisted of 2 trials, the CANVAS and CANVAS-R trials, but are presented combined.

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Figures

Figure 1: Meta-Analysis of GLP1-RA and SGLT2i trials on the composite of myocardial infarction,

stroke, and CV death (MACE) stratified by presence of atherosclerotic cardiovascular disease

Forest plot showing the treatment estimates of each drug class in each subgroup using fixed effects. The summary estimates for each subgroup were modeled using random effects accounting for heterogeneity of the different drug classes. The test for subgroup differences was based on a F-test in a random effect meta-regression using mixed effects accounting heterogeneity for drug class and patient population. P-value for subgroup differences: 0.028

Established ASCVD: GLP-1RA: Q-statistic= 10.89, p=0.028; I2=63.3%SGLT2i: Q-statistic= 0.94, p=0.63; I2= 0% Total: Q-statistic= 11.85, p=0.11MRF: GLP-1RA: Q statistic=0.24, p=0.89; I2=0%SGLT2i: Q-statistic= 0.033, p=0.86; I2=0%Total: Q-statistic=0.34, p=0.99

Figure 2: Meta-Analysis of GLP1-RA and SGLT2i trials on hospitalization for heart failure stratified

drug class

Forest plot showing the treatment estimates of each drug class using fixed effects. The test for subgroup differences between the 2 drug classes was based on a F-test in a random effect meta-regression using mixed effects accounting heterogeneity for drug class. P-value for subgroup differences 0.003GLP1-RA: Q-statistic= 1.48, p=0.69; I2=0%SGLT2i: Q statistic=0.60, p=0.74; I2=0%

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Figure 3:

A. Meta-Analysis of GLP1-RA and SGLT2i trials on hospitalization for a broad kidney endpoint (sustained doubling of serum creatinine or a 40% decline in eGFR, new-onset macroalbuminuria, ESRD, or death of renal cause) stratified drug class

Forest plot showing the treatment estimates of each drug class using fixed effects. The test for subgroup differences between the 2 drug classes was based on a F-test in a random effect meta-regression using mixed effects accounting heterogeneity for drug class. P-value for subgroup differences 0.010GLP1-RA: Q-statistic= 3.60, p=0.31; I2=16.6%SGLT2i: Q statistic=3.48, p=0.18; I2=42.5%

B. Meta-Analysis of GLP1-RA and SGLT2i trials on a kidney outcome excluding macroalbuminuria stratified drug class

Forest plot showing the treatment estimates of each drug class using fixed effects. The test for subgroup differences between the 2 drug classes was based on a F-test in a random effect meta-regression using mixed effects accounting heterogeneity for drug class. P-value for subgroup differences <0.001GLP1-RA: Q-statistic= 2.18, p=0.54; I2=0%SGLT2i: Q statistic= 0.59, p=0.74; I2=0%

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579580581582583584585

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Figure 1. Meta-Analysis of GLP1-RA and SGLT2i trials on the composite of myocardial infarction, stroke, and CV death (MACE) stratified by presence of atherosclerotic cardiovascular disease

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Figure 2. Meta-Analysis of GLP1-RA and SGLT2i trials on hospitalization for heart failure stratified drug class

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Figure 3A. Meta-Analysis of GLP1-RA and SGLT2i trials on hospitalization for a broad kidney endpoint (sustained doubling of serum creatinine or a 40% decline in eGFR, new-onset macroalbuminuria, ESRD, or death of renal cause) stratified drug class

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Figure 3B. Meta-Analysis of GLP1-RA and SGLT2i trials on a kidney outcome excluding macroalbuminuria stratified drug class

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Appendix:

Search Algorithm:................................................................................................................................................................34

Pubmed Search:..............................................................................................................................................................34

Embase Search:...............................................................................................................................................................34

Supplementary Methods:....................................................................................................................................................35

Supplementary Results:......................................................................................................................................................35

Risk of Bias Summary:.........................................................................................................................................................36

Table S1: Definition of Cardiovascular Disease and Multiple Risk Factors in the Included Trials........................................37

Table S2: Definitions of the kidney Endpoint of the included trials.....................................................................................42

Figure S1: PRISMA-P Flow Diagram: Study selection...........................................................................................................43

Figure S2: Pooled GLP1-RA trials for the composite of myocardial infarction, stroke, and cardiovascular death (MACE). .44

Figure S3: Pooled GLP1-RA trials stratified by presence of established atherosclerotic cardiovascular disease for the composite of myocardial infarction, stroke, and cardiovascular death (MACE)..................................................................45

Figure S4: Meta-Analysis of GLP1-RA and SGLT2i trials on myocardial infarction stratified by drug class..........................46

Figure S5: Meta-Analysis of GLP1-RA and SGLT2i trials on stroke stratified by drug class..................................................47

Figure S6: Meta-Analysis of GLP1-RA and SGLT2i trials on cardiovascular death stratified by drug class...........................48

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Search Algorithm:

Pubmed Search: (“Diabetes Mellitus, Type 2”[Mesh] OR “diabetes mellitus type 2”[tiab] OR “type 2 diabetes”[tiab] OR

“T2D*”[tiab]) AND ( “Empagliflozin”[tiab] OR “Dapagliflozin”[tiab] OR “Canagliflozin”[tiab] OR

“lixisenatide"[tiab] OR “liraglutide” [tiab] OR “semaglutide” [tiab] OR “exenatide” [tiab] OR “albiglutide” [tiab]

) AND (random*[tw] OR "Letter"[pt] OR “trial”[tiab]) AND (“Myocardial Infarction”[Mesh] OR “Myocardial

Infarction” [tiab] OR “stroke”[Mesh] OR “stroke”[tiab] OR “death”[Mesh] OR “death”[tiab] OR “MACE”[tiab]

OR “major adverse cardiovascular events”[tiab] OR “major adverse cardiac events”[tiab] OR “heart

failure”[Mesh] OR “heart failure”[tiab]) NOT (Review[ptyp])

Embase Search:('non insulin dependent diabetes mellitus'/exp OR T2DM:ab,ti) AND (empagliflozin:ab,ti OR Canagliflozin:ab,ti

OR dapagliflozin:ab,ti OR lixisenatide:ab,ti OR liraglutide:ab,ti OR semaglutide:ab,ti OR exenatide:ab,ti OR

albiglutide:ab,ti ) AND (random*:ti,ab,de AND placebo:ab,ti) AND 'controlled study'/de AND ('heart

infarction'/exp OR 'myocardial infarction':ab,ti OR 'cerebrovascular accident'/exp OR 'stroke':ab,ti OR

'death'/exp OR 'death':ab,ti OR 'major adverse cardiac event'/exp OR 'MACE':ab,ti OR 'major adverse

cardiovascular event':ab,ti OR 'heart failure'/exp OR 'heart failure':ab,ti) NOT ('chapter'/it OR 'conference

review'/it OR 'editorial'/it OR 'review'/it OR 'meta-analysis':ti)

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Supplementary Methods:

The primary endpoint major adverse cardiovascular events (MACE) was the composite of myocardial

infarction, stroke, and cardiovascular death. DECLARE-TIMI 58 used ischemic stroke for MACE, but for

consistency with other trials, all stroke was used in this meta-analysis. If hazard ratios were not available, the

risk ratio was used.

Heart failure and chronic kidney failure were enrollment criteria for patients with cardiovascular disease in

both the LEADER and SUSTAIN-6 trial. To best reflect atherosclerotic cardiovascular disease for LEADER the

combined summary estimates (by meta-analyzing them using a fixed effect model) of patients with single and

poly-vascular disease were used.35 When testing for effect modification by HbA1c lowering, short-term

difference in HbA1c lowering was used to account for possible background therapy adjustment. The following

values were used: ELIXA 0.4% (at 3 months), LEADER 0.8% (at 16 weeks), SUSTAIN-6 1.3% (at 16 weeks),

EXCSEL 0.7% (at 6 months), HARMONY 0.79% (at 4 months).

Supplementary Results:

The HARMONY trial did not report HHF as a separate outcome. The treatment effect was estimated calculating

the risk ratio by subtracting the number of CV deaths from the composite of HHF/CV death. A sensitivity

analysis including these results yielded a similar pooled estimated for GLP1-RA (HR 0.91, 95%-CI 0.82 to 1.01,

p=0.074).

38

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646

647

648

649

650

651

652

653

654

655

656

657658

659

660

661

662

39

663

664

Risk of Bias Summary:

Rand

om se

quen

ce g

ener

ation

(s

elec

tion

bias

)

Allo

catio

n co

ncea

lmen

t (s

elec

tion

bias

)

Blin

ding

of p

artic

ipan

ts a

nd

pers

onne

l (pe

rfor

man

ce b

ias)

Blin

ding

of o

utco

me

asse

ssm

ent (

dete

ction

bia

s)

(pati

ent-

repo

rted

out

com

es)

Blin

ding

of o

utco

me

asse

ssm

ent (

dete

ction

bia

s)

(Mor

talit

y)

Inco

mpl

ete

outc

ome

data

ad

dres

sed

(att

rition

bia

s)

(Sho

rt-t

erm

out

com

es (

2-6

wee

ks))

Inco

mpl

ete

outc

ome

data

ad

dres

sed

(att

rition

bia

s)

(Lon

ger-

term

out

com

es (

>6

wee

ks))

Sele

ctive

repo

rting

(rep

ortin

g bi

as)

EMPA-REG Outcome Low Low Low Low Low Low Low Low

CANVAS Program Low Low Low Low Low Low Low Low

DECLARE-TIMI 58 Low Low Low Low Low Low Low Low

ELIXA Low Low Low Low Low Low Low Low

LEADER Low Low Low Low Low Low Low Low

SUSTAIN-6 Low Low Low Low Low Low Low Low

EXSCEL Low Low Low Low Low Low Low Low

HARMONY Low Low Low Low Low Low Low Low

40

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Table S1: Definition of Cardiovascular Disease and Multiple Risk Factors in the Included Trials

Trial Definition of Cardiovascular Disease Definition of Multiple Risk Factor

Glucagon-like Peptide-1 Receptor Agonists ELIXAStudy Drug: LixisenatideInclusion: HbA1c ≥6.0% and <10%

Myocardial infarction or unstable angina within 180 days before enrollment

Not included

LEADERStudy Drug: LiraglutideInclusion:

HbA1c ≥7.0%

Age ≥50 and ≥1 of the following criteria:1. Prior MI2. Prior stroke or TIA3. Prior coronary, carotid or peripheral arterial

revascularization4. >50% stenosis of coronary, carotid, or lower extremity

arteries5. History of symptomatic CHD documented by positive

exercise stress test or any cardiac imaging or unstable angina with ECG changes

6. Asymptomatic cardiac ischemia documented by positive nuclear imaging test, exercise test or dobutamine stress echo

7. Chronic heart failure NYHA class II-III8. Chronic kidney failure (eGFR <60 ml/min/1.73m2)

Age ≥60 y and ≥1 of the following criteria:1.) Microalbuminuria or proteinuria2.) Hypertension and left ventricular

hypertrophy by ECG or imaging3.) Left ventricular systolic or diastolic

dysfunction by imaging4.) Ankle-brachial index <0.9

Subgroup Analysis: No ASCVD vs Single vs Poly (excluding CKD pts from eCVD)

SUSTAIN-6Study Drug: SemaglutideInclusion:

HbA1c ≥7.0%

Age ≥50 and ≥1 of the following criteria:1. Prior MI2. Prior stroke or TIA3. Prior coronary, carotid or peripheral arterial

revascularization4. >50% stenosis on angiography or imaging of coronary,

carotid or lower extremities arteries

Age ≥60 y and ≥1 of the following criteria:1.) persistent microalbuminuria (30‒

299 mg/g) or proteinuria2.) hypertension and left ventricular

hypertrophy by electrocardiogram or imaging

3.) left ventricular systolic or diastolic dysfunction by imaging

41

667

Trial Definition of Cardiovascular Disease Definition of Multiple Risk Factor

5. History of symptomatic coronary heart disease documented by e.g. positive exercise stress test or any cardiac imaging or unstable angina with ECG changes

6. Asymptomatic cardiac ischemia documented by positive nuclear imaging test or exercise test or stress echo or any cardiac imaging

7. Chronic heart failure New York Heart Association (NYHA) class II-III

8. Chronic kidney impairment (eGFR <60 ml/min/1.73 m2 per MDRD)

4.) Ankle/brachial index less than 0.9

EXCSELStudy Drug: ExenatideInclusion:

HbA1c ≥6.5% to ≤10.0%

≤3 oral glucose lowering agents OR Insulin therapy, either alone or in combination with up to two (i.e. 0 – 2) oral glucose lowering agents

Prior Cardiovascular event defined as: 1. History of a major clinical manifestation of coronary artery

disease i.e. myocardial infarction, surgical or percutaneous (balloon and/or stent) coronary revascularization procedure, or coronary angiography showing at least one stenosis ≥50% in a major epicardial artery or branch vessel

2. Ischemic cerebrovascular disease, including: History of ischemic stroke; strokes not known to be hemorrhagic will be allowed as part of this criterion; transient ischemic attacks (TIAs) are not included

3. History of carotid arterial disease as documented by ≥50% stenosis documented by carotid ultrasound, magnetic resonance imaging (MRI), or angiography, with or without symptoms of neurologic deficit

4. Atherosclerotic peripheral arterial disease, as documented by objective evidence such as amputation due to vascular disease, current symptoms of intermittent claudication confirmed by an ankle-brachial pressure index or toe-

No prior CV event

Recruitment was constrained such that approximately 30% will not have had a prior CV event and 70% will have had a prior CV event.

42

Trial Definition of Cardiovascular Disease Definition of Multiple Risk Factor

brachial pressure index less than 0.9, or history of surgical or percutaneous revascularization procedure

HARMONYStudy Drug: AlbitglutideInclusion:

≥40 years HbA1c >7.0%

Established cardiovascular disease, including at least 1 of the following:Coronary artery disease with either of the following:

a. Documented history of spontaneous myocardial infarction, at least 30 days prior to Screening.

b. Documented coronary artery disease (CAD) ≥ 50% stenosis in 1 or more

c. Major epicardial coronary arteries, determined by invasive angiography, or history of surgical or percutaneous (balloon and/or stent) coronary revascularization procedure (at least 30 days prior to Screening for percutaneous procedures and at least 5 years prior to Screening for coronary artery bypass graft.

Cerebrovascular disease – any of the following:a. Documented history of ischaemic stroke, at least 90 days

prior to study entry.b. Carotid arterial disease with 50% stenosis documented by

carotid ultrasound, magnetic resonance imaging or angiography, with or without symptoms of neurologic deficit.

c. Carotid vascular procedure (e.g. stenting or surgical revascularisation), at least 30 days prior to Screening.

Peripheral arterial disease (PAD) with either of the following:a. intermittent claudication and ankle:brachial index < 0.9 in at

least one ankle b. prior non-traumatic amputation, or peripheral vascular

procedure (e.g. stenting or surgical revascularisation), due to

Not included

43

Trial Definition of Cardiovascular Disease Definition of Multiple Risk Factor

peripheral arterial ischaemia.Sodium Glucose Co-Transporter 2 Inhibitors (as presented previously10)

EMPA-REG OutcomeStudy Drug: EmpagliflozinInclusion:

≥18 years HbA1c ≥7.0% and

≤10.0% BMI ≤45kg/m2

eGFR ≥30 ml/min/1.73m2

Presence of cardiovascular disease

Ischemic Heart Disease: MI (>2 months prior to informed consent), orMultivessel CAD (50% stenosis in ≥2 major coronary arteries or the left main artery (i.e., previous revascularization ≥2 major coronary arteries or left main artery; or combination of revascularization in at least 1 main artery and 50% stenosis in 1 main coronary artery), ORSingle vessel CAD (50% stenosis in ≥1 main coronary artery and a positive stress test OR hospital discharge for unstable angina ≤12 months prior to consent), orUnstable angina with evidence of single or multivessel CAD (>2 months prior to consent), ORHistory of stroke (ischemic or hemorrhagic), ORPeripheral artery disease prior revascularization, OR previous limb or foot amputation due to circulatory insufficiency; or angiographic evidence of significant (>50%) peripheral artery stenosis in at least one limb; or evidence from a non-invasive measurement of significant (>50% or as reported as hemodynamically significant) peripheral artery stenosis in at least one limb; or ankle brachial index of < 0.9 in at least one limb.

Not included

CANVAS ProgramStudy Drug: CanagliflozinInclusion:

HbA1c ≥7.0% to ≤10.5%

Age ≥30 years with either: 1. stroke; 2. MI; 3. hospital admission for unstable angina;4. coronary revascularization (CABG, PCI); 5. peripheral revascularization (angioplasty or surgery);6. symptomatic with documented hemodynamically-significant

Age ≥50 years with ≥2 of the following risk factors:

1. Duration of type 2 diabetes of 10 years or more,

2. Systolic blood pressure >140 mmHg3. Current daily cigarette smoker, 4. Documented microalbuminuria or

macroalbuminuria,

44

Trial Definition of Cardiovascular Disease Definition of Multiple Risk Factor

carotid or peripheral vascular disease; or 7. amputation secondary to vascular disease.

5. documented high-density lipoprotein (HDL) cholesterol of <1 mmol/l (<39 mg/dl).

DECLARE-TIMI 58Study Drug: Dapagliflozin

HbA1c ≥6.5% to <12%

Age ≥40 years with either: Ischemic heart disease (any of the following): Documented Myocardial Infarction, Percutaneous Coronary Intervention, Coronary Artery Bypass Grafting, Objective Findings of Coronary Stenosis (> 50%) in at least 2 coronary artery territories (ie, left anterior descending, ramus intermedius, left circumflex, rightcoronary artery) involving the main vessel, a major branch, or a bypass graftCerebrovascular disease (any of the following): Documented ischemic Stroke (known transient ischemic attack, primary intracerebral haemorrhage or sub-arachnoid hemorrhage do not qualify), Carotid stenting or endarterectomyPeripheral Arterial Disease (any of the following): Peripheral arterial intervention, stenting or surgical revascularization, lower extremity amputation as a result of peripheral arterial obstructive disease, or Current symptoms of intermittent claudication AND ankle/brachial index < 0.90 documented within last 12 months

Age > 55 years in men and > 60 in women and presence of at least 1 of the following additional risk factors:

1. Dyslipidemia (LDL-C>130 mg/dl)2. Hypertension (either systolic BP (>

140 mmHg) and elevated diastolic BP (> 90 mmHg) at enrollment or on anti-hypertensive therapy lowering

3. Current Tobacco use (≥5 cigarettes per day)

45

668

Table S2: Definitions of the kidney Endpoint of the included trials. Trial: Definition of the Broad Kidney Endpoint

GLP1-RA Trials

ELIXA36 New-onset macroalbuminuria.

LEADER37 New onset, persistent macroalbuminuria, persistent doubling of serum creatinine accompanied by an eGFR <45 ml/min/1.73m2, the need for renal-replacement therapy with no reversible cause of the kidney disease, or death from kidney disease.

SUSTAIN-638 Persistent macroalbuminuria, persistent doubling of the serum creatinine and a creatinine clearance <45 ml/min/1.73m2 (using the MDRD equation), or the need for continuous renal-replacement therapy.

EXSCEL39 New-onset macroalbuminuria, 40% reduction in eGFR, initiation of renal replacement therapy, and death from renal causes. (No additional information reported.)

HARMONY5 No outcomes reported.

SGLT2i Trials

EMPA-REG OUTCOME40 New onset macroalbuminuria, doubling of serum creatinine accompanied by an eGFR <45 ml/min/1.73 m2 (using the MDRD equation), initiation of renal-replacement therapy, or death from renal disease.

CANVAS PROGRAM41 New-onset macroalbuminuria, sustained 40% reduction in eGFR (using the MDRD equation), sustained end-stage kidney disease, and death from renal causes.

DECLARE-TIMI 58New-onset macroalbuminuria, sustained 40% reduction in eGFR (using CKD-EPI equation), sustained end-stage kidney disease, and death from renal causes.

The narrower composite kidney outcome comprised sustained doubling of serum creatinine was available for the GLP1-RA trials (except for the EXSCEL trial for which the results of the composite of 40% worsening GFR, end-stage kidney disease, or death due to renal causes was available) whereas a composite of doubling of serum creatinine or a ≥40% worsening GFR, end-stage kidney disease, or death due to renal causes was

46

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670671672

available for the SGLT2i trials, but the latter two elements constituted only 86 events. A sensitivity analysis meta-analyzing SGLT2i trials for sustained doubling of serum creatinine yielded nearly identical results (HR 0.56, 95 CI 0.44 to 0.71, p<0.001, p for heterogeneity between drug classes <0.001).

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Figure S1: PRISMA-P Flow Diagram: Study selection

48

Key Search Terms: (“Diabetes Mellitus, Type 2”) AND

("Canagliflozin" OR "Dapagliflozin" OR “Empagliflozin” OR "Lixisenatide" OR “Liraglutide“ OR “Semaglutide” OR “Exenatide”) AND

("randomized controlled trial“) AND

(“myocardial infarction” OR “stroke” OR “death” OR “heart failure”)

Unique trials included (n = 8) - 5 GLP1-RA trials- 3 SGLT2i trials- 7 Contributory Secondary

Analyses

Excluded (n = 272)- No Cardiovascular Outcomes Trial or Not Contributory

Secondary Analysis (n=203)- Design Manuscripts (n=32)- Commentary. Editorial, or Review (n=37)

Duplicates (n = 64)

Record abstracts screened (n=287)

Identification

Eligibility

Included

Screening

Total citations identified (n=351)PubMed: 150EMBASE: 200AHA Symposium: 1

676677

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Figure S2: Pooled GLP1-RA trials for the composite of myocardial infarction, stroke, and cardiovascular death (MACE)

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Q statistic=9.72, p=0.046; I2=58.8% A random effects model using REML and Hartung Knapp adjustment yielded a similar treatment effect (HR 0.87; 95% CI 0.76-1.01; p=0.061).

Figure S3: Pooled GLP1-RA trials stratified by presence of established atherosclerotic cardiovascular disease for the composite of myocardial infarction, stroke, and cardiovascular death (MACE)

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ASCVD: Q statistic=10.89, p=0.028; I2=63.2%. A random effects model using REML and Hartung Knapp adjustment yielded a similar treatment effect (HR 0.86; 95% CI 0.73-1.00; p=0.051). MRF: Q statistic=0.24, p=0.89; I2=0% P value for interaction between ASCVD and MRF using fixed effects: 0.064. P value for interaction between ASCVD and MRF using random effects and Hartung Knapp adjustment: P=0.14.

Figure S4: Meta-Analysis of GLP1-RA and SGLT2i trials on myocardial infarction stratified by drug class

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GLP1-RA: Q-statistic= 8.46, p=0.076; I2=52.7%SGLT2i: Q statistic=0.032, p=0.98; I2=0%P value for subgroup differences between the 2 drug classes: 0.87

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Figure S5: Meta-Analysis of GLP1-RA and SGLT2i trials on stroke stratified by drug class

GLP1-RA: Q-statistic= 4.22, p=0.38; I2=5.1%

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SGLT2i: Q statistic=2.76, p=0.25; I2=27.5%P value for subgroup differences between the 2 drug classes: 0.25

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Figure S6: Meta-Analysis of GLP1-RA and SGLT2i trials on cardiovascular death stratified by drug class

GLP1-RA: Q-statistic= 3.25, p=0.52; I2=0%. A random effects model using REML and Hartung Knapp adjustment yielded a similar treatment effect (HR 0.88, 95% CI 0.78 to 0.98, p=0.034)SGLT2i: Q statistic=9.95, p=0.007; I2=79.9 P value for subgroup differences between the 2 drug classes: 0.51

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