Advertisement
Canadian Journal of Cardiology

The Effectiveness of Sodium-Glucose Cotransporter 2 Inhibitors and Glucagon-like Peptide-1 Receptor Agonists on Cardiorenal Outcomes: Systematic Review and Meta-analysis

      Abstract

      Background

      Evidence for the cardiorenal risk reduction properties of antihyperglycemic medications originally prescribed for type 2 diabetes, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) is rapidly emerging. We completed a meta-analysis of recent literature to provide evidence-based estimates of benefit across various populations and outcomes.

      Methods

      We searched Medline and Cochrane databases from 2015 to September 2021 for randomized controlled trials of SGLT2i and GLP-1RA with placebo control. Reviewers screened citations, extracted data, and assessed the risk of bias and certainty of evidence. We assessed statistical and methodological heterogeneity and performed a meta-analysis of studies with similar interventions and components.

      Results

      A total of 137,621 adults (51% male) from 19 studies were included; 14 studies with unclear risk of bias and 5 with low risk of bias. Compared with standard of care, use of SGLT2i showed significant reductions for the outcome of cardiovascular (CV) mortality (14%), any-cause mortality (13%), major adverse CV events (MACE) (12%), heart failure (HF) hospitalization (31%), CV death or HF hospitalization (24%), nonfatal myocardial infarction (10%), and kidney composite outcome (36%). Treatment with GLP-1RA was associated with significant reductions for the outcome of CV mortality (13%), any-cause mortality (12%), MACE (14%), CV death or HF hospitalization (11%), nonfatal stroke (16%), and kidney composite outcome (22%).

      Conclusions

      The use of GLP-1RA and SGLT2i leads to a statistically significant benefit across most cardiorenal outcomes in the populations studied. This review shows a role for SGLT2i and GLP-1RA in cardiorenal protection in adults, independent of type 2 diabetes status.

      Résumé

      Contexte

      Des données de plus en plus abondantes font état des effets cardioprotecteurs et néphroprotecteurs d’antihyperglycémiants initialement prescrits contre le diabète de type 2, les inhibiteurs du cotransporteur sodium-glucose de type 2 (iSGLT2) et les agonistes des récepteurs du peptide-1 apparenté au glucagon (arGLP-1). Nous avons effectué une méta-analyse de la littérature récente pour estimer, à partir de données probantes, les bénéfices dans diverses populations et selon divers paramètres.

      Méthodologie

      Nous avons effectué des recherches dans les bases de données MEDLINE et Cochrane pour la période de 2015 à septembre 2021 afin de trouver des essais randomisés, contrôlés par placebo, portant sur les iSGLT2 et les arGLP-1. Les examinateurs ont passé au crible les citations et les données extraites et ont évalué le risque de biais ainsi que le degré de fiabilité des données. Nous avons évalué l’hétérogénéité statistique et méthodologique et effectué une méta-analyse d’études comportant des interventions et des composantes similaires.

      Résultats

      Au total, 137 621 adultes (51 % de sexe masculin) inscrits à 19 études ont été inclus; 14 études présentaient un risque imprécis de biais et les cinq autres, un faible risque de biais. Par rapport au traitement de référence, le traitement par les iSGLT2 a réduit de façon significative les décès d’origine cardiovasculaire (CV) (14 %), les décès toutes causes confondues (13 %), les événements CV indésirables majeurs (ECVIM) (12 %), les hospitalisations pour cause d’insuffisance cardiaque (IC) (31 %), les décès d’origine CV ou les hospitalisations pour cause d’IC (24 %), les cas d’infarctus du myocarde non mortel (10 %) et les événements définissant le critère d’évaluation composite de la fonction rénale (36 %). Le traitement par les arGLP-1 a été associé à des réductions significatives des décès d’origine CV (13 %), des décès toutes causes confondues (12 %), des ECVIM (14 %), des décès d’origine CV ou des hospitalisations pour cause d’IC (11 %), des cas d’AVC non mortels (16 %) et des événements définissant le critère d’évaluation composite de la fonction rénale (22 %).

      Conclusions

      Le recours aux arGLP-1 et aux iSGLT2 se traduit par un bénéfice statistiquement significatif au regard de la plupart des critères d’évaluation cardiorénaux dans les populations étudiées. Notre article de synthèse montre que les iSGLT2 et les arGLP-1 ont un rôle à jouer en matière de protection cardiorénale chez les adultes, indépendamment de la présence ou de l’absence de diabète de type 2.
      Recent randomized controlled trials (RCTs) have shown a reduction in risk for cardiovascular (CV) and kidney events associated with the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i),
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      • Bhatt D.L.
      • Szarek M.
      • Steg P.G.
      • et al.
      Sotagliflozin in patients with diabetes and recent worsening heart failure.
      • Heerspink H.J.L.
      • Stefánsson B.V.
      • Correa-Rotter R.
      • et al.
      Dapagliflozin in patients with chronic kidney disease.
      and glucagon-like peptide-1 receptor agonists (GLP-1RA) in individuals with type 2 diabetes (T2D).
      • Hernandez A.F.
      • Green J.B.
      • Janmohamed S.
      • et al.
      Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • et al.
      Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
      • Marso S.P.
      • Bain S.C.
      • Consoli A.
      • et al.
      Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      There is also evidence of an associated improvement in CV and kidney outcomes in individuals independent of T2D.
      • Heerspink H.J.L.
      • Stefánsson B.V.
      • Correa-Rotter R.
      • et al.
      Dapagliflozin in patients with chronic kidney disease.
      ,
      • Packer M.
      • Anker S.D.
      • Butler J.
      • et al.
      for the EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure.
      ,
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      However, the accumulated evidence for both classes of drugs varies in the magnitude of benefit on outcomes across heterogeneous populations.
      In light of the rapidly emerging evidence regarding the cardiorenal risk reduction properties of SGLT2i and GLP-1RA, we undertook an independent meta-analysis of the most up-to-date literature to provide reliable and evidence-based estimates of benefit across various populations and outcomes. The meta-analysis, completed by the McMaster Evidence Review and Synthesis Team (MERST) was specifically commissioned by the Canadian Cardiovascular Society (CCS) to support their 2022 guideline for the use of GLP-1RA and SGLT2i for cardiorenal risk reduction in adults.
      • Mancini G.B.J.
      • O’Meara E.
      • Zieroth S.
      • et al.
      2022 Canadian Cardiovascular Society guideline for use of GLP-1 receptor agonists and SGLT2 inhibitors for cardiorenal risk reduction in adults.
      The decision was made to publish the guideline and the meta-analysis in parallel so that the processes and results about each would be made available as comprehensively as possible, including the provision of Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tables and analysis of quality and risk of bias (RoB).
      • Schünemann H.
      • Brożek J.
      • Guyatt G.
      • Oxman A.
      The guidelines and this supporting document were undertaken under the auspices of the Guideline Committee of the CCS without any support or involvement from outside groups, including industry.

      Methods

      This systematic review and meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRIMSA) guidelines.
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
      A focused number of questions were derived to guide this systematic review and meta-analysis of evidence about SGLT2i and GLP-1RA with proven cardiorenal risk reduction compared with standard care. Specifically, we sought to answer the following questions: (1) in patients with heart failure (HF) with reduced ejection fraction (HFrEF; ≤ 40%) what is the role of SGLT2i and GLP-1RA compared with placebo for reduction of CV disease (CVD) events or hospitalization for HF? (2) In patients with HF with preserved ejection fraction (HfpEF; > 40%) what is the role of SGLT2i and GLP-1RA compared with placebo for reduction of CV death or hospitalization for HF? (3) In patients with chronic kidney disease (CKD) what is the role of SGLT2i and GLP-1RA compared with placebo for reduction of the composite of kidney death, progression to dialysis, or reduction of estimated glomerular filtration rate (eGFR)? and (4) In patients with T2D and either atherosclerotic CVD (ASCVD) or high CV risk, what is the role of these agents compared with placebo for reduction of a composite of CV death, nonfatal myocardial infarction (MI), or nonfatal stroke?

      Search

      The electronic search strategy was developed by a health sciences librarian with expertise in systematic review search methodologies. Medline and Cochrane Library from January 2015 to September 2, 2021 were searched (original search was completed February 2021 and the search was updated on September 2, 2021). On-topic systematic review reference lists, supplemental online files, and the ClinicalTrials.gov database were reviewed to ensure all potentially relevant articles/data were located. Please see Supplemental Appendix S1 for the search strategy.

      Study selection, data extraction, and quality assessment

      We included peer-reviewed studies available in English. Title and abstract, and full-text screening were done in duplicate by MERST members. After title and abstract review, citations identified for inclusion by either reviewer moved forward to the full-text screening. At full-text screening, the following questions were used for inclusion: (1) population—adults with or without T2D, treated with medication; (2) intervention—GLP-1RA or SGLT2i; (c) study design—randomized control trial with a placebo control; and (4) outcomes—mortality (any-cause or CV), stroke, MI, hospitalization because of HF, composite CVD and composite CKD. After full-text review, agreement on the answers was achieved and disagreements were reached by consensus or by a third member of the review team. Results from the search were uploaded to a secure internet-based platform for screening (DistillerSR; Evidence Partners Inc, Ottawa, Ontario, Canada). We developed, piloted, and deployed standardized forms for data extraction. Two team members independently completed full data extraction of study characteristics (setting, sample size, inclusion and exclusion criteria, characteristics of participants, type of intervention). Numerical data were extracted and then verified by the team statistician before analysis. For the critical end points of interest, the time to event data were extracted as study-reported hazard or rate ratios adjusted for other covariates where possible. The quality assessment of each study was assessed using the Cochrane Risk of Bias 1 tool.
      • Higgins J.P.
      • Altman D.G.
      • Gøtzsche P.C.
      • et al.
      The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials.
      The assessment was conducted by 1 reviewer and the results were independently verified by a second person.

      Certainty of evidence

      We evaluated the certainty of the body of evidence using the GRADE method
      • Schünemann H.
      • Brożek J.
      • Guyatt G.
      • Oxman A.
      using GRADEpro software.
      GRADEpro GDT
      GRADEpro Guideline Development Tool [software].
      GRADE is used to rate the certainty of a body of evidence as high, moderate, low, or very low, and ratings are on the basis of an assessment of 5 conditions: (1) methodological quality; (2) consistency across effect estimates/statistical heterogeneity; (3) directness of the body of evidence to the populations, interventions, comparators and/or outcomes of interest; (4) precision of results; and (5) indications of reporting bias, such as industry involvement beyond funding.

      Data synthesis

      All data analyses were planned a priori. A meta-analysis was used to combine the results across studies according to each outcome from the included studies. For time-to-event outcomes such as CV mortality, any-cause mortality, hospitalization because of HF, nonfatal MI and stroke, 3-point major adverse CV events (MACE), and kidney composite outcomes we used trial reported time-to-event data (ie, hazard ratios [HRs] along with their 95% confidence intervals [CIs]) as a measure of variance to generate the summary measures of effect using DerSimonian and Laird random effects models with inverse variance method.
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      An additional outcome of interest was serious adverse events leading to study discontinuation. For this binary outcome, we used the number of events; proportion or percentage data to generate the summary measures of effect in the form of risk ratio (RR) using DerSimonian and Laird random effects models with inverse variance method.
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      In instances in which an outcome was reported using multiple subgroups from within the same study, such as using different CKD criteria, we used a multilevel meta-analytic approach to account for dependency between effect estimates.
      • Assink M.
      • Wibbelink C.J.M.
      Fitting three-level meta-analytic models in R: a step-by-step tutorial.
      ,
      • Pastor D.A.
      • Lazowski R.A.
      On the multilevel nature of meta-analysis: a tutorial, comparison of software programs, and discussion of analytic choices.
      Specifically, the multiple measures and comparisons from the same study were nested within studies first using a random effects intercept and variance in observed effect estimates was decomposed into sampling variance, within-study variance, and between-study variance.
      • Pastor D.A.
      • Lazowski R.A.
      On the multilevel nature of meta-analysis: a tutorial, comparison of software programs, and discussion of analytic choices.
      Overall I2 for each summary effect estimate was also estimated to represent within-study and between-studies heterogeneity. The Cochran Q (α = 0.05) was used to detect statistical heterogeneity and I2 statistic to quantify the magnitude of statistical heterogeneity between studies where I2 > 50% represents moderate and I2 > 75% represents substantial heterogeneity across studies.
      • Deeks J.J.
      • Higgins J.P.T.
      • Altman D.G.
      on behalf of the Cochrane Statistical Methods Group. Analysing data and undertaking meta-analyses.
      Publication bias was assessed using funnel plots when there were at least 10 studies in the meta-analysis.
      • Sterne J.A.C.
      • Hernán M.A.
      • McAleenan A.
      • Reeves B.C.
      • Higgins J.P.T.
      Assessing risk of bias in a non-randomized study.
      All analyses were performed using R software (metafor
      • Viechtbauer W.
      Conducting meta-analyses in R with the metafor package.
      and dmetar packages
      • Harrer M.
      • Cuijpers P.
      • Furukawa T.
      • Ebert D.D.
      dmetar: Companion R Package For The Guide ‘Doing Meta-Analysis in R’. R package version 0.0.9000.
      ).

      Results

      The search resulted in 1476 primary reports of which 19 studies, many with multiple publications, met the inclusion criteria (Fig. 1). For this review we used the study protocols, when available, and or the first publication to provide information for the RoB assessment. All trials were large multicountry trials; 11 RCTs with SGLT2i treatment interventions
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      • Bhatt D.L.
      • Szarek M.
      • Steg P.G.
      • et al.
      Sotagliflozin in patients with diabetes and recent worsening heart failure.
      • Heerspink H.J.L.
      • Stefánsson B.V.
      • Correa-Rotter R.
      • et al.
      Dapagliflozin in patients with chronic kidney disease.
      ,
      • Packer M.
      • Anker S.D.
      • Butler J.
      • et al.
      for the EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure.
      ,
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      ,
      • Neal B.
      • Perkovic V.
      • Matthews D.R.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      • Bhatt D.L.
      • Szarek M.
      • Pitt B.
      • et al.
      for the SCORED Investigators
      Sotagliflozin in patients with diabetes and chronic kidney disease.
      • Cannon C.P.
      • Pratley R.
      • Dagogo-Jack S.
      • et al.
      for the VERTIS CV Investigators
      Cardiovascular outcomes with ertugliflozin in type 2 diabetes.
      • Anker S.D.
      • Butler J.
      • Filippatos G.
      • et al.
      for the EMPEROR-Preserved Trial Investigators
      Empagliflozin in heart failure with a preserved ejection fraction.
      and 8 RCTs with GLP-1RA treatment interventions.
      • Hernandez A.F.
      • Green J.B.
      • Janmohamed S.
      • et al.
      Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • et al.
      Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
      ,
      • Holman R.R.
      • Bethel M.A.
      • Mentz R.J.
      • et al.
      for the EXSCEL Study Group
      Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
      • Leiter L.A.
      • Bain S.C.
      • Hramiak I.
      • et al.
      Cardiovascular risk reduction with once-weekly semaglutide in subjects with type 2 diabetes: a post hoc analysis of gender, age, and baseline CV risk profile in the SUSTAIN 6 trial.
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • et al.
      Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
      • Gerstein H.C.
      • Sattar N.
      • Rosenstock J.
      • et al.
      for the AMPLITUDE-O Trial Investigators
      Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes.
      Across all of the included studies, the total sample size was 137,621 adults, with 77,541 adults in SGLT2i trials and 60,080 in GLP-1RA trials. The mean age ranged from 59.9 to 67.2 years of age. A total of 70,724 male participants were included at baseline; n = 37,462 for SGLT2i (2/11; no baseline data), and n = 33,262 for GLP-1RA (1/8 no baseline data). Characteristics of included studies are reported in Supplemental Table S1.
      Figure thumbnail gr1
      Figure 1Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram for literature search. GLP-1RA, glucagon-like peptide-1 receptor agonists; SGLT2i, sodium-glucose cotransporter 2 inhibitors.

      RoB, quality of included studies, and certainty of evidence

      The RoB assessment resulted in 14 studies having an unclear RoB and 5 with a low RoB.
      • Heerspink H.J.L.
      • Stefánsson B.V.
      • Correa-Rotter R.
      • et al.
      Dapagliflozin in patients with chronic kidney disease.
      ,
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      ,
      • Holman R.R.
      • Bethel M.A.
      • Mentz R.J.
      • et al.
      for the EXSCEL Study Group
      Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
      ,
      • Leiter L.A.
      • Bain S.C.
      • Hramiak I.
      • et al.
      Cardiovascular risk reduction with once-weekly semaglutide in subjects with type 2 diabetes: a post hoc analysis of gender, age, and baseline CV risk profile in the SUSTAIN 6 trial.
      ,
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • et al.
      Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
      For the included SGLT2i studies, an unclear RoB was determined on the basis of the lack of reporting on randomization and allocation concealment procedures; blinding of participants and outcome assessment; incomplete/selective outcome reporting; and other sources of bias such industry involvement beyond funding (Table 1). The unclear RoB for the GLP-1RA trials resulted in a lack of reporting on randomization, and allocation concealment procedures; blinding of participants and outcome assessment; and other sources of bias such as sponsor’s involvement in the study design, the writing of the report or results, and the decision to submit the article for publication (Table 1). The GRADE assessment for the overall studies included resulted in moderate certainty of evidence on the basis of an unclear RoB assessment across most studies for treatment benefit outcomes, and moderate to very low certainty of the evidence for subgroups (HFrEF, HFpEF, CKD, and T2D) and harms outcome (Supplemental Tables S2 and S3). The further downgrading of certainty of the evidence for such subgroups and harms outcome was primarily because of observed inconsistency (direction of effect not consistent and CIs do not overlap with substantial statistical heterogeneity observed across studies) and imprecision (pooled effect estimate with imprecise or wide CIs that do no rule out a null effect or harm). The definition of kidney composite outcome varied across studies with primary components of sustained decline in eGFR, renal replacement, or renal death, and some studies included doubling of the serum creatinine level, and incident macroalbuminuria. Publication bias was assessed with results shown in Supplemental Figure S1. We present the results according to outcome rather than according to questions to facilitate comparisons for SGLT2i and GLP-1RA.
      Table 1Risk of bias for all included studies (n = 19)
      StudySequence generationAllocation concealmentBlinding patients and personnelBlinding outcome assessmentIncomplete outcome dataSelective reportingOther bias
      SOLOIST-WHF
      • Bhatt D.L.
      • Szarek M.
      • Steg P.G.
      • et al.
      Sotagliflozin in patients with diabetes and recent worsening heart failure.
      LUUUHHL
      DAPA-CKD
      • Heerspink H.J.L.
      • Stefánsson B.V.
      • Correa-Rotter R.
      • et al.
      Dapagliflozin in patients with chronic kidney disease.
      LLLLLLH
      EMPEROR-Reduced
      • Packer M.
      • Anker S.D.
      • Butler J.
      • et al.
      for the EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure.
      UULLLLL
      REWIND
      • Gerstein H.C.
      • Colhoun H.M.
      • Dagenais G.R.
      • et al.
      Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
      LLLLLLL
      DAPA-HF
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      LUUULLU
      DECLARE-TIMI 58
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      UUUUHLU
      CREDENCE
      • Perkovic V.
      • Jardine M.J.
      • Neal B.
      • et al.
      Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
      LLLLLLU
      PIONEER 6
      • Husain M.
      • Birkenfeld A.L.
      • Donsmark M.
      • et al.
      Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
      LUULLLU
      SUSTAIN 6
      • Leiter L.A.
      • Bain S.C.
      • Hramiak I.
      • et al.
      Cardiovascular risk reduction with once-weekly semaglutide in subjects with type 2 diabetes: a post hoc analysis of gender, age, and baseline CV risk profile in the SUSTAIN 6 trial.
      UULULLU
      Harmony Outcomes
      • Hernandez A.F.
      • Green J.B.
      • Janmohamed S.
      • et al.
      Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.
      LLLUHLL
      LEADER
      • Marso S.P.
      • Daniels G.H.
      • Brown-Frandsen K.
      • et al.
      Liraglutide and cardiovascular outcomes in type 2 diabetes.
      UUUULLL
      EXSCEL
      • Holman R.R.
      • Bethel M.A.
      • Mentz R.J.
      • et al.
      for the EXSCEL Study Group
      Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
      LLUULLU
      CANVAS
      • Neal B.
      • Perkovic V.
      • Matthews D.R.
      Canagliflozin and cardiovascular and renal events in type 2 diabetes.
      LULULLU
      ELIXA
      • Pfeffer M.A.
      • Claggett B.
      • Diaz R.
      • et al.
      Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
      LUUULLU
      EMPA-REG OUTCOME
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • et al.
      Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      LUULLLL
      VERTIS-CV
      • Cannon C.P.
      • Pratley R.
      • Dagogo-Jack S.
      • et al.
      for the VERTIS CV Investigators
      Cardiovascular outcomes with ertugliflozin in type 2 diabetes.
      LUUUHLU
      SCORED
      • Bhatt D.L.
      • Szarek M.
      • Pitt B.
      • et al.
      for the SCORED Investigators
      Sotagliflozin in patients with diabetes and chronic kidney disease.
      UUUULLU
      AMPLITUDE-O
      • Gerstein H.C.
      • Sattar N.
      • Rosenstock J.
      • et al.
      for the AMPLITUDE-O Trial Investigators
      Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes.
      LUUULLU
      EMPEROR-Preserved
      • Anker S.D.
      • Butler J.
      • Filippatos G.
      • et al.
      for the EMPEROR-Preserved Trial Investigators
      Empagliflozin in heart failure with a preserved ejection fraction.
      LLUULLU
      AMPLITUDE-O, Effect of Efpeglenatide on Cardiovascular Outcomes; CANVAS, Canagliflozin Cardiovascular Assessment Study; CREDENCE, Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation; DAPA-CKD, Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; DAPA-HF, Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; DECLARE-TIMI 58, Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; EMPA-REG OUTCOME, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose; EMPEROR-Preserved, Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction; EMPEROR-Reduced, Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction; EXSCEL, Exenatide Study of Cardiovascular Event Lowering; H, high; Harmony Outcomes, Effect of Albiglutide, When Added to Standard Blood Glucose Lowering Therapies, on Major Cardiovascular Events in Subjects With Type 2 Diabetes Mellitus; L, low; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; PIONEER, Peptide Innovation for Early Diabetes Treatment; REWIND, Researching Cardiovascular Events With a Weekly Incretin in Diabetes; SCORED, Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk; SOLOIST-WHF, Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure; SUSTAIN 6, Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes; U, unclear; VERTIS-CV, Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease.

      CV mortality

      The pooled analysis for the overall effect of GLP-1RA and SGLT2i on CV mortality is presented in Supplemental Figure S2A. The test for subgroup differences in overall effect on CV mortality for GLP-1RA and SGLT2i was nonsignificant (P = 0.86; Supplemental Fig. S2A). For the outcome of CV mortality in patients with T2D (ASCVD/high CVD risk), GLP-1RA showed a significant reduction of 13% (8 RCTs; HR, 0.87; 95% CI, 0.80-0.94) compared with standard of care (Fig. 2). Treatment with SGLT2i also showed a significant reduction of 15% (10 RCTs; HR, 0.85; 95% CI, 0.78-0.92) compared with standard of care (Fig. 3). The test for subgroup differences in effect on CV mortality between GLP-1RA and SGLT2i in patients with T2D was nonsignificant (P = 0.75; Supplemental Fig. S2B).
      Figure thumbnail gr2
      Figure 2Evidence summary for glucagon-like peptide-1 (GLP1) agonists and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) certainty of evidence ratings for overall, and according to subpopulations. ASCVD, atherosclerotic cardiovascular disease; CVM, cardiovascular mortality; HF, heart failure; HR, hazard ratio; MACE, major adverse cardiovascular events; MI, myocardial infarction; N-A, not applicable; T2D, type 2 diabetes.
      Figure thumbnail gr3
      Figure 3Evidence summary for sodium-glucose cotransporter 2 inhibitors and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) certainty of evidence ratings for overall, and according to subpopulations. ASCVD, atherosclerotic cardiovascular disease; CVM, cardiovascular mortality; HF, heart failure; HpEF, heartfailure preserved ejection fraction; HrEF, heartfailure reduced ejection fraction; HR, hazard ratio; LVEF, left ventricular ejection fraction; MACE, major adverse cardiovascular events; MI, myocardial infarction; N-A, not applicable; T2D, type 2 diabetes.
      For the outcome of CV mortality in patients with CKD, only treatment with SGLT2i showed a significant reduction of 15% (5 RCTs; HR, 0.85; 95% CI, 0.77-0.94) compared with standard of care (Fig. 3). The test for subgroup differences in effect on CV mortality between GLP-1RA and SGLT2i in patients with CKD was not statistically significant (P = 0.94; Supplemental Fig. S2C). In patients with HFrEF, treatment with SGLT2i led to a significant reduction of 16% in CV mortality (4 RCTs; HR, 0.84; 95% CI, 0.71-0.98) compared with standard of care (Fig. 3). The test for subgroup differences in effect on CV mortality for GLP-1RA and SGLT2i for HFpEF and HFrEF was nonsignificant (P = 0.14; Supplemental Fig. S2D).

      Any-cause mortality

      The pooled analysis for the overall effect of GLP-1RA and SGLT2i on any-cause mortality is presented in Supplemental Figure S3A. The test for subgroup differences in overall effect on any-cause mortality for GLP-1RA and SGLT2i was nonsignificant (P = 0.93; Supplemental Fig. S3A). For the outcome of any-cause mortality in patients with T2D (ASCVD/high CVD risk), GLP-1RA showed a reduction of 12% (8 RCTs; HR, 0.88; 95% CI, 0.82-0.94; Fig. 2) and SGLT2i showed a reduction of 15% (9 RCTs; HR, 0.85; 95% CI, 0.79-0.92; Fig. 3) compared with standard of care. The test for subgroup differences in effect on any-cause mortality for GLP-1RA and SGLT2i in patients with T2D was nonsignificant (P = 0.62; Supplemental Fig. S3B).
      For the outcome of any-cause mortality in patients with CKD, treatment with SGLT2i showed a significant reduction of 18% (7 RCTs; HR, 0.82; 95% CI, 0.74-0.90) compared with standard of care (Fig. 3). The test for subgroup differences in effect on any-cause mortality for GLP-1RA and SGLT2i in patients with CKD was nonsignificant (P = 0.60; Supplemental Fig. S3C).
      In patients with HFrEF, SGLT2i showed a significant reduction of 16% (4 RCTs; HR, 0.84; 95% CI, 0.72-0.97) for any-cause mortality, compared with standard of care (Fig. 3). The test for subgroup differences in effect on any-cause mortality for SGLT2i in patients with HFpEF and HFrEF was significant (P = 0.04; Supplemental Fig. S3D).

      CV mortality or HF hospitalization

      The pooled analysis for the overall effect of GLP-1RA and SGLT2i on CV mortality or HF hospitalization is presented in Supplemental Figure S4A. The test for subgroup differences in overall effect on CV mortality or HF hospitalization for GLP-1RA and SGLT2i was significant (P = 0.01; Supplemental Fig. S4A). For the outcome of CV mortality or HF hospitalization in patients with T2D (ASCVD/high CVD risk), GLP-1RA showed a reduction of 11% (8 RCTs; HR, 0.89; 95% CI, 0.81-0.98; Fig. 2) and SGLT2i a reduction of 24% (11 RCTs; HR, 0.76; 95% CI, 0.72-0.80; Fig. 3) compared with standard of care. The test for subgroup differences in effect on CV mortality or HF hospitalization for GLP-1RA and SGLT2i in patients with T2D was significant (P = 0.01; Supplemental Fig. S4B).
      For the outcome of CV mortality or HF hospitalization in patients with CKD, treatment with SGLT2i showed a significant reduction of 27% (9 RCTs; HR, 0.73; 95% CI, 0.68-0.78) compared with standard of care (Supplemental Fig. S4C). For the outcome of CV mortality or HF hospitalization in patients with HFpEF, SGLT2i showed a significant reduction of 23% (5 RCTs; HR, 0.77; 95% CI, 0.68-0.87) compared with standard of care (Fig. 3). In patients with HFrEF, SGLT2i showed a significant reduction of 25% (6 RCTs; HR, 0.75; 95% CI, 0.69-0.81) compared with standard of care (Fig. 3). The test for subgroup differences in effect on CV mortality or HF hospitalization for SGLT2i in patients with HFpEF and HFrEF was nonsignificant (P = 0.63; Supplemental Fig. S4D).

      Hospitalization due to HF

      The pooled analysis for the overall effect of GLP-1RA and SGLT2i on hospitalization due to HF is presented in Supplemental Figure S5A. The test for subgroup differences in overall effect on hospitalization due to HF for GLP-1RA and SGLT2i was significant (P < 0.001; Supplemental Fig. S5A). For the outcome of hospitalization due to HF in patients with T2D (ASCVD/high CVD risk), treatment with SGLT2i showed a significant a reduction of 32% (9 RCTs; HR, 0.68; 95% CI, 0.63-0.74) compared with standard of care (Fig. 3). The test for subgroup differences in effect on hospitalization due to HF for GLP-1RA and SGLT2i in patients with T2D was significant (P < 0.001; Supplemental Fig. S5B). For the outcome of hospitalization due to HF in patients with CKD treatment with SGLT2i showed a significant reduction of 37% (9 RCTs; HR, 0.63; 95% CI, 0.58-0.70) compared with standard of care (Fig. 3). The test for subgroup differences in effect on hospitalization due to HF for GLP-1RA and SGLT2i in patients with CKD was significant (P < 0.001; Supplemental Fig. S5C).
      Finally, for the outcome of hospitalization due to HF in patients with HFpEF, SGLT2i showed a significant reduction of 29% (3 RCTs; HR, 0.71; 95% CI, 0.62-0.82) compared with standard of care. In patients with HFrEF, SGLT2i also showed a significant reduction of 31% (4 RCTs; HR, 0.69; 95% CI, 0.64-0.75) compared with standard of care (Fig. 3). The test for subgroup differences in effect on hospitalization due to HF for SGLT2i in patients with HFpEF and HFrEF was nonsignificant (P = 0.76; Supplemental Fig. S5D).

      Nonfatal MI

      The pooled analysis for the overall effect of GLP-1RA and SGLT2i on nonfatal MI is presented in Supplemental Figure S6A. The test for subgroup differences in overall effect on nonfatal MI for GLP-1RA and SGLT2i was nonsignificant (P = 0.42; Supplemental Fig. S6A). For the outcome of nonfatal MI in patients with T2D (ASCVD/high CVD risk), treatment with SGLT2i showed a significant reduction of 10% (5 RCTs; HR, 0.90; 95% CI, 0.83-0.98) compared with standard of care (Fig. 3). The test for subgroup differences in effect on nonfatal MI for GLP-1RA and SGLT2i in patients with T2D was nonsignificant (P = 0.42; Supplemental Fig. S6B).
      For the outcome of nonfatal MI in patients with CKD, treatment with SGLT2i showed a reduction of 23% (3 RCTs; HR, 0.77; 95% CI, 0.62-0.95) compared with standard of care (Fig. 3). The test for subgroup differences in effect on nonfatal MI for GLP-1RA and SGLT2i in patients with CKD was nonsignificant (P = 0.47; Supplemental Fig. S6C).

      Nonfatal stroke

      The pooled analysis for the overall effect of GLP-1RA and SGLT2i on nonfatal stroke is presented in Supplemental Figure S7A. The test for subgroup differences in overall effect on nonfatal stroke for GLP-1RA and SGLT2i was significant (P = 0.04; Supplemental Fig. S7A). For the outcome of nonfatal stroke in patients with T2D (ASCVD/high CVD risk), GLP-1RA showed a significant reduction of 16% (7 RCTs; HR, 0.84; 95% CI, 0.76-0.94) compared with standard of care (Fig. 2). The test for subgroup differences in effect on nonfatal stroke for GLP-1RA and SGLT2i in patients with T2D was significant (P = 0.04; Supplemental Fig. S7B).

      Major adverse cardiac events (CV mortality, nonfatal MI, nonfatal stroke)

      The pooled analysis for the overall effect of GLP-1RA and SGLT2i on MACE is presented in Supplemental Figure S8A. The test for subgroup differences in overall effect on MACE for GLP-1RA and SGLT2i was nonsignificant (P = 0.81; Supplemental Fig. S8A). For the outcome of MACE in patients with T2D (ASCVD/high CVD risk), GLP-1RA showed a reduction of 14% (8 RCTs; HR, 0.86; 95% CI, 0.80-0.93; Fig. 2) and SGLT2i also showed a reduction of 12% (7 RCTs; HR, 0.88; 95% CI, 0.82-0.93) compared with standard of care (Fig. 3). The test for subgroup differences in effect on MACE for GLP-1RA and SGLT2i in patients with T2D was nonsignificant (P = 0.87; Supplemental Fig. S8B). For the outcome of MACE in patients with CKD, treatment with SGLT2i showed a significant reduction of 17% (5 RCTs; HR, 0.83; 95% CI, 0.75-0.91) compared with standard of care (Fig. 3). The test for subgroup differences in effect on MACE for GLP-1RA and SGLT2i in patients with CKD was nonsignificant (P = 0.58; Supplemental Fig. S8C).

      Kidney composite outcomes

      The pooled analysis for the overall effect of GLP-1RA and SGLT2i on kidney composite outcome is presented in Supplemental Figure S9A. The test for subgroup differences in overall effect on kidney composite outcome for GLP-1RA and SGLT2i was significant (P = 0.04; Supplemental Fig. S9A). For the kidney composite outcome in patients with T2D (ASCVD/high CVD risk), GLP-1RA showed a reduction of 22% (5 RCTs; HR, 0.78; 95% CI, 0.70-0.87; Fig. 2) and SGLT2i also showed a reduction of 35% (10 RCTs; HR, 0.65; 95% CI, 0.57-0.742) compared with standard of care (Fig. 3). The test for subgroup differences in effect on kidney composite outcome for GLP-1RA and SGLT2i in patients with T2D was significant (P = 0.03; Supplemental Fig. S9B).
      For the kidney composite outcome in patients with CKD, GLP-1RA showed a reduction of 15% (3 RCTs; HR, 0.85; 95% CI, 0.78-0.92; Fig. 2) and SGLT2i also showed a significant reduction of 36% (10 RCTs; HR, 0.64; 95% CI, 0.57-0.73) compared with standard of care (Fig. 3). The test for subgroup differences in effect on kidney composite outcome between GLP-1RA and SGLT2i in patients with CKD was significant (P < 0.001; Supplemental Fig. S9C).
      For the kidney composite outcome in patients with HFrEF, SGLT2i showed a significant reduction of 41% (2 RCTs; HR, 0.59; 95% CI, 0.42-1.07) compared with standard of care (Fig. 3). The test for subgroup differences in effect on kidney composite outcome for SGLT2i in patients with HFpEF and HFrEF was significant (P = 0.04; Supplemental Fig. S9D).

      Serious adverse events leading to study discontinuation

      GLP-1RA were associated with a 1.28 times higher risk of serious adverse events leading to study discontinuation compared with standard of care (8 RCTs; RR, 1.28; 95% CI, 1.04-1.57). Regarding SGLT2i, evidence showed no differences in risk of serious adverse events leading to study discontinuation (10 RCTs; RR, 1.06; 95% CI, 0.98-1.15) compared with standard of care. The certainty of this evidence was also rated as very low and downgraded for serious concerns regarding the RoB, inconsistency, and imprecision. The test for subgroup differences in effect on serious adverse events leading to study discontinuation for GLP-1RA and SGLT2i was nonsignificant (P = 0.06, Supplemental Fig. S10).

      Discussion

      To our knowledge, this is the first review to investigate the effectiveness of GLP-1RA and SGLT2i for cardiorenal outcomes on the basis of clinically relevant subpopulations and granularity of critical end points. This review served as the statistical basis for the subsequent clinical evaluation and interpretations of studies in this rapidly emerging field and the review was strongly considered in the process of shaping the recommendations in the parallel CCS guideline that were vetted through a modified Delphi process.
      • Mancini G.B.J.
      • O’Meara E.
      • Zieroth S.
      • et al.
      2022 Canadian Cardiovascular Society guideline for use of GLP-1 receptor agonists and SGLT2 inhibitors for cardiorenal risk reduction in adults.
      Accordingly, although there are certain areas in which clinical interpretation diverges from this statistical analysis as described subsequently, the formal review showed that SGLT2i, compared with standard of care, provided significant reductions for the outcome of CV mortality (14%), any-cause mortality (13%), MACE (12%), HF hospitalization (31%), CV death or HF hospitalization (24%), nonfatal MI (10%), and kidney composite outcome (36%). Similar effects were observed in a subgroup of patients with T2D (ASCVD or multiple risk factors) and patients with CKD. In the subgroup of HFrEF, significant reductions were observed for the outcome of CV mortality (16%), any-cause mortality (16%), HF hospitalization (31%), CV mortality or HF hospitalization (25%), and kidney composite outcome (41%). In a subgroup of HFpEF, significant reductions were only observed for the outcome of HF hospitalization (29%) and CV death or HF hospitalization (23%). However, SGLT2i, compared with standard of care, had no effect on the outcome of nonfatal stroke.
      For GLP-1RA (all trials in patients with T2D and ASCVD or multiple risk factors), compared with standard of care, the evidence showed significant reductions for the outcome of CV mortality (13%), any-cause mortality (12%), MACE (14%), CV death or HF hospitalization (11%), nonfatal stroke (16%), and kidney composite outcome (22%). For a subgroup of patients with CKD, a significant benefit was only observed for kidney composite outcomes (15%). Treatment with a GLP-1RA, compared with standard of care, did not have an effect on the outcome of nonfatal MI and HF hospitalization. No evidence was found that reported on a subgroup of HF patients with preserved or reduced ejection fraction. In the absence of dedicated trials using GLP-1RA in patients with established HF or CKD, and in consideration of the highly diverse definitions of renal composite end points, including reductions in albuminuria sometimes dominating the renal composite among GLP-1RA trials, that conclusions regarding any current role for GLP-1RA in preventing or treating HF or CKD needed to await further studies.
      • Mancini G.B.J.
      • O’Meara E.
      • Zieroth S.
      • et al.
      2022 Canadian Cardiovascular Society guideline for use of GLP-1 receptor agonists and SGLT2 inhibitors for cardiorenal risk reduction in adults.
      The test for subgroup differences should be interpreted with caution because these are on the basis of indirect comparison across the pooled summary effect estimates because none of the included trials had head-to-head comparisons for GLP-1RA vs SGLT2i. Conversely, significantly greater reduction of nonfatal stroke was seen with the GLP-1RA class. Finally, there was very low certainty of evidence to suggest a higher risk of serious adverse events leading to study discontinuation for GLP-1RA compared with standard of care; such an effect was not observed for SGLT2i.

      Strengths and Limitations

      To our knowledge, our review is the first to quantify the effectiveness of GLP-1RA and SGLT2i on the basis of clinically relevant subpopulations (patients with HF and ejection fraction > 40%, HF and ejection fraction ≤ 40%, CKD, and T2D) and granularity of critical end points. Our review followed the methods and procedures necessary to conduct a high-quality review on the basis of Cochrane-recommended methodology. Although our review was selective in defining our population and outcomes, it was informed by the values and preferences of the guideline writing group. Specifically, the main one being that in the absence of dedicated trials of GLP-1RA in patients with HF or CKD, the analyses shown are considered to be hypothesis-generating and not of sufficient importance to inform or justify formal recommendations for use of this class for treatment. In addition, we only considered trial-reported time to event data (HRs/rate ratios) and raw events were not converted to risk estimates. This might have resulted in the exclusion of some data for certain outcomes from studies in which no time-to-event data or effect estimates were provided. However, this can be considered as a possible strength of our review, because the most appropriate way to summarize time-to-event outcomes is to express intervention effect as hazard or rate ratios, which accounts for censoring of participants over the trial period.

      Higgins JPT, Li T, Deeks JJ, eds. Chapter 6: Choosing effect measures and computing estimates of effect. In: Higgins JPT, Thomas J, Chandler J, eds. Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022). Cochrane, 2022. Available at: https://training.cochrane.org/handbook/current/chapter-06. Accessed October 4, 2021.

      Another possible limitation is the heterogeneity of the definition of kidney composite outcome, which varied across studies with most trials including a sustained decline in eGFR, renal replacement, or renal death, and some studies included doubling of the serum creatinine level (that factors into calculated eGFR), and incident macroalbuminuria as discussed previously. Finally, publication bias was assessed as part of GRADE certainty of evidence ratings and none of the tests for publication bias were statistically significant (P > 0.05; Supplemental Fig. S1). The visual inspection of funnel plots also did not reveal any noticeable asymmetry with most studies lying symmetrically around our pooled effect estimates.

      Conclusions

      This report provides a rigourous and fully up-to-date systematic review and meta-analysis of the role of SGLT2i and GLP-1RA for cardiorenal risk reduction and served as the basis for the clinical recommendations vetted through the CCS Guidelines Committee.
      • Mancini G.B.J.
      • O’Meara E.
      • Zieroth S.
      • et al.
      2022 Canadian Cardiovascular Society guideline for use of GLP-1 receptor agonists and SGLT2 inhibitors for cardiorenal risk reduction in adults.
      The review of the evidence shows cardiorenal benefit across most critical end points in patients with and without T2D, patients with CKD, and patients with HF across a broad ejection fraction spectrum.

      Acknowledgements

      The authors thank Angela Eady for developing the search strategy.
      Members of the CCS guideline committee developed the research questions and their involvement helped inform the protocol of the review and editing of the manuscript. All screening of articles, data extraction, analysis, and interpretation was conducted by MERST members, independent from the guideline Committee or funders.

      Funding Sources

      This research was funded by the CCS . MERST was independently responsible for the data extraction, analysis, interpretation, and reporting. Dr Diana Sherifali holds the Heather M. Arthur Population Health Research Institute/Hamilton Health Sciences Chair in Interprofessional Health Research, which supported her role in this work.

      Disclosures

      Dr Sherifali reports financial support was provided by Canadian Cardiovascular Society. The other authors have no conflicts of interest to disclose.

      Supplementary Material

      References

        • Zinman B.
        • Wanner C.
        • Lachin J.M.
        • et al.
        Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
        N Engl J Med. 2015; 373: 2117-2128
        • Bhatt D.L.
        • Szarek M.
        • Steg P.G.
        • et al.
        Sotagliflozin in patients with diabetes and recent worsening heart failure.
        N Engl J Med. 2021; 384: 117-128
        • Heerspink H.J.L.
        • Stefánsson B.V.
        • Correa-Rotter R.
        • et al.
        Dapagliflozin in patients with chronic kidney disease.
        N Engl J Med. 2020; 383: 1436-1446
        • Hernandez A.F.
        • Green J.B.
        • Janmohamed S.
        • et al.
        Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.
        Lancet. 2018; 392: 1519-1529
        • Pfeffer M.A.
        • Claggett B.
        • Diaz R.
        • et al.
        Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.
        N Engl J Med. 2015; 373: 2247-2257
        • Marso S.P.
        • Bain S.C.
        • Consoli A.
        • et al.
        Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
        N Engl J Med. 2016; 375: 1834-1844
        • Packer M.
        • Anker S.D.
        • Butler J.
        • et al.
        for the EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure.
        N Engl J Med. 2020; 383: 1413-1424
        • McMurray J.J.V.
        • Solomon S.D.
        • Inzucchi S.E.
        • et al.
        Dapagliflozin in patients with heart failure and reduced ejection fraction.
        N Engl J Med. 2019; 381: 1995-2008
        • Mancini G.B.J.
        • O’Meara E.
        • Zieroth S.
        • et al.
        2022 Canadian Cardiovascular Society guideline for use of GLP-1 receptor agonists and SGLT2 inhibitors for cardiorenal risk reduction in adults.
        Can J Cardiol. 2022; 38: 1153-1167
        • Schünemann H.
        • Brożek J.
        • Guyatt G.
        • Oxman A.
        GRADE handbook.
        (Available at:) (Accessed September 7, 2021)
        • Liberati A.
        • Altman D.G.
        • Tetzlaff J.
        • et al.
        The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
        J Clin Epidemiol. 2009; 62: e1-e34
        • Higgins J.P.
        • Altman D.G.
        • Gøtzsche P.C.
        • et al.
        The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials.
        BMJ. 2011; 343: d5928
        • GRADEpro GDT
        GRADEpro Guideline Development Tool [software].
        McMaster University and Evidence Prime, 2022 (Available at:) (Accessed September 7, 2021)
        • DerSimonian R.
        • Laird N.
        Meta-analysis in clinical trials.
        Control Clin Trials. 1986; 7: 177-188
        • Assink M.
        • Wibbelink C.J.M.
        Fitting three-level meta-analytic models in R: a step-by-step tutorial.
        The Quantitative Methods for Psychology. 2016; 12: 154-174
        • Pastor D.A.
        • Lazowski R.A.
        On the multilevel nature of meta-analysis: a tutorial, comparison of software programs, and discussion of analytic choices.
        Multivariate Behav Res. 2018; 53: 74-89
        • Deeks J.J.
        • Higgins J.P.T.
        • Altman D.G.
        on behalf of the Cochrane Statistical Methods Group. Analysing data and undertaking meta-analyses.
        in: Higgins J.P.T. Thomas J. Chandler J. Cochrane Handbook for Systematic Reviews of Interventions. 2nd ed. Wiley, 2019: 241-284
        • Sterne J.A.C.
        • Hernán M.A.
        • McAleenan A.
        • Reeves B.C.
        • Higgins J.P.T.
        Assessing risk of bias in a non-randomized study.
        in: Higgins J.P.T. Thomas J. Chandler J. Cochrane Handbook for Systematic Reviews of Interventions. 2nd ed. Wiley, 2019: 621-641
        • Viechtbauer W.
        Conducting meta-analyses in R with the metafor package.
        J Stat Soft. 2010; 36
        • Harrer M.
        • Cuijpers P.
        • Furukawa T.
        • Ebert D.D.
        dmetar: Companion R Package For The Guide ‘Doing Meta-Analysis in R’. R package version 0.0.9000.
        (Available at:) (Accessed June 12, 2021)
        • Neal B.
        • Perkovic V.
        • Matthews D.R.
        Canagliflozin and cardiovascular and renal events in type 2 diabetes.
        N Engl J Med. 2017; 377: 644-657
        • Perkovic V.
        • Jardine M.J.
        • Neal B.
        • et al.
        Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.
        N Engl J Med. 2019; 380: 2295-2306
        • Wiviott S.D.
        • Raz I.
        • Bonaca M.P.
        • et al.
        Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2019; 380: 347-357
        • Bhatt D.L.
        • Szarek M.
        • Pitt B.
        • et al.
        • for the SCORED Investigators
        Sotagliflozin in patients with diabetes and chronic kidney disease.
        N Engl J Med. 2021; 384: 129-139
        • Cannon C.P.
        • Pratley R.
        • Dagogo-Jack S.
        • et al.
        • for the VERTIS CV Investigators
        Cardiovascular outcomes with ertugliflozin in type 2 diabetes.
        N Engl J Med. 2020; 383: 1425-1435
        • Anker S.D.
        • Butler J.
        • Filippatos G.
        • et al.
        • for the EMPEROR-Preserved Trial Investigators
        Empagliflozin in heart failure with a preserved ejection fraction.
        N Engl J Med. 2021; 385: 1451-1461
        • Holman R.R.
        • Bethel M.A.
        • Mentz R.J.
        • et al.
        • for the EXSCEL Study Group
        Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2017; 377: 1228-1239
        • Leiter L.A.
        • Bain S.C.
        • Hramiak I.
        • et al.
        Cardiovascular risk reduction with once-weekly semaglutide in subjects with type 2 diabetes: a post hoc analysis of gender, age, and baseline CV risk profile in the SUSTAIN 6 trial.
        Cardiovasc Diabetol. 2019; 18: 73
        • Marso S.P.
        • Daniels G.H.
        • Brown-Frandsen K.
        • et al.
        Liraglutide and cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2016; 375: 311-322
        • Husain M.
        • Birkenfeld A.L.
        • Donsmark M.
        • et al.
        Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
        N Engl J Med. 2019; 381: 841-851
        • Gerstein H.C.
        • Colhoun H.M.
        • Dagenais G.R.
        • et al.
        Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
        Lancet. 2019; 394: 121-130
        • Gerstein H.C.
        • Sattar N.
        • Rosenstock J.
        • et al.
        • for the AMPLITUDE-O Trial Investigators
        Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes.
        N Engl J Med. 2021; 385: 896-907
      1. Higgins JPT, Li T, Deeks JJ, eds. Chapter 6: Choosing effect measures and computing estimates of effect. In: Higgins JPT, Thomas J, Chandler J, eds. Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022). Cochrane, 2022. Available at: https://training.cochrane.org/handbook/current/chapter-06. Accessed October 4, 2021.