Davies et al. Cardiovascular Diabetology (2022) 21:144
`https://doi.org/10.1186/s12933-022-01575-9
`
`Cardiovascular Diabetology
`
`Open Access
`REVIEW
`Cardiovascular outcomes trials: a paradigm
`shift in the current management of type 2
`diabetes
`
`Melanie J. Davies1,2,3, Heinz Drexel4, François R. Jornayvaz5, Zoltan Pataky5, Petar M. Seferović6,7* and
`Christoph Wanner8
`
`Abstract
`Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in patients with type 2 diabetes (T2D).
`Historical concerns about cardiovascular (CV) risks associated with certain glucose-lowering medications gave rise
`to the introduction of cardiovascular outcomes trials (CVOTs). Initially implemented to help monitor the CV safety of
`glucose-lowering drugs in patients with T2D, who either had established CVD or were at high risk of CVD, data that
`emerged from some of these trials started to show benefits. Alongside the anticipated CV safety of many of these
`agents, evidence for certain sodium–glucose transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor
`agonists (GLP-1 RAs) have revealed potential cardioprotective effects in patients with T2D who are at high risk of CVD
`events. Reductions in 3-point major adverse CV events (3P-MACE) and CV death have been noted in some of these
`CVOTs, with additional benefits including reduced risks of hospitalisation for heart failure, progression of renal disease,
`and all-cause mortality. These new data are leading to a paradigm shift in the current management of T2D, with
`international guidelines now prioritising SGLT2 inhibitors and/or GLP-1 RAs in certain patient populations. However,
`clinicians are faced with a large volume of CVOT data when seeking to use this evidence base to bring opportunities
`to improve CV, heart failure and renal outcomes, and even reduce mortality, in their patients with T2D. The aim of this
`review is to provide an in-depth summary of CVOT data—crystallising the key findings, from safety to efficacy—and
`to offer a practical perspective for physicians. Finally, we discuss the next steps for the post-CVOT era, with ongoing
`studies that may further transform clinical practice and improve outcomes for people with T2D, heart failure or renal
`disease.
`Keywords: Cardiovascular disease, Cardiovascular outcomes trials, Chronic kidney disease, CVOTs, Cardiovascular
`safety, Heart failure, Glucose-lowering drug, GLP-1 RAs, Type 2 diabetes, SGLT2 inhibitors
`
`Introduction
`The prevalence of type 2 diabetes (T2D) has continued to
`rise over recent years. It is estimated that by 2045 there
`will be 693 million people diagnosed with the condition
`worldwide [1]. T2D poses significant health risks to indi-
`viduals, with a two-fold increase in mortality compared
`
`*Correspondence: seferovic.petar@gmail.com
`6 University of Belgrade, Faculty of Medicine, Belgrade, Serbia
`Full list of author information is available at the end of the article
`
`with a population without diabetes [2], as well as an
`increasing global health economic burden [3]. Associa-
`tions between T2D and cardiovascular disease (CVD)
`are well established; CVD is the leading cause of mortal-
`ity and morbidity in patients with T2D [2–4], and more
`than 30% of patients with T2D are diagnosed with CVD
`[4]. The most common CVD manifestations in patients
`with T2D are peripheral arterial disease, ischaemic
`stroke, stable angina, heart failure (HF) and nonfatal
`myocardial infarction (MI) [3, 5]. A recent meta-analysis
`
`© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
`permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
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`other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
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`regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this
`licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco
`mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
`
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`showed that patients with coexisting diabetes and HF
`have an increased risk of all-cause death, cardiovascu-
`lar (CV) death and hospitalisation [6]. Moreover, one in
`six patients with newly diagnosed T2D have evidence of
`silent MI associated with an increased risk of all-cause
`mortality (HR 1.26, 95% CI 1.06–1.50) and fatal MI (HR
`1.49, 95% CI 1.15–1.94) [7]. Reducing CV risk is a key
`part of T2D disease management [3].
`Until around a decade ago, the standard of care for T2D
`involved the use of glucose-lowering drugs (GLDs) such
`as metformin, sulfonylureas, thiazolidinediones, megli-
`tinides and α-glucosidase inhibitors [8]. However, amid
`uncertainty about the CV safety of GLDs [9–12], in 2008
`the U.S. Food and Drug Administration (FDA) updated
`its guidance, mandating the assessment of all new T2D
`therapies in long-term CV outcomes trials (CVOTs),
`in addition to the requirement for registrational stud-
`ies demonstrating improvements in glycaemic control
`[13]. In the meantime, newer GLD classes have become
`firmly established treatments for T2D, i.e. dipeptidyl
`peptidase-4 (DPP-4) inhibitors, glucagon like peptide-1
`receptor agonists (GLP-1 RA) and sodium–glucose
`cotransporter-2 (SGLT2) inhibitors. To date, 18 CVOTs
`
`have been published for these newer GLDs (Fig. 1), which
`enrolled patients with T2D who had established CVD
`or were at high risk of CVD [13–24], and had to dem-
`onstrate a hazard ratio (HR) < 1.8 for major CV events
`(MACE; based on the upper bound of a two-sided 95%
`confidence interval [CI]). Most CVOTs included the key
`composite outcome of 3-point MACE (3P-MACE; com-
`prising CV death, nonfatal MI and nonfatal stroke), with
`the exceptions of additional events in a 4P-MACE in the
`ELIXA trial of lixisenatide (hospitalisation for unstable
`angina) and in the AMPLITUDE-O trial of efpeglenatide
`(death from undetermined causes) [10, 25, 26]. Notably,
`some CVOTs have not only illustrated CV safety, but
`also reported cardioprotective benefits. The first of these
`was EMPA-REG OUTCOME, completed in 2015, which
`showed that the SGLT2 inhibitor empagliflozin reduced
`3P-MACE and CV death in patients with T2D and estab-
`lished CVD [27]. Hospitalisation for heart failure (HHF),
`all-cause mortality and progression of kidney disease
`were also reduced with empagliflozin [27–29]. Subse-
`quently published CVOTs, as well as a small number of
`HF and renal outcomes studies, have added further par-
`adigm-shifting evidence for improvements in CV, HHF
`
`Fig. 1 A timeline of published diabetes CVOTs. The comparator in all trials was placebo, unless otherwise stated. Primary endpoints for each trial
`are listed. 3/4P-MACE, 3/4-point major adverse CV event; CV, cardiovascular; DPP-4, dipeptidyl peptidase-4; GLP-1 RA, glucagon-like peptide-1
`receptor agonist; HHF, hospitalisation for heart failure; SGLT2, sodium–glucose transporter 2. Source: clinicaltrials.gov. *3P-MACE is a composite of CV
`death, nonfatal myocardial infarction and nonfatal stroke. 4P-MACE is an expanded composite of 3P-MACE plus either hospitalisation for unstable
`angina (ELIXA, TECOS and FREEDOM-CVO) or death from undetermined causes (AMPLITUDE-O). †TECOS and FREEDOM-CVO included 3P-MACE
`as a secondary outcome. ‡CAROLINA was conducted in addition to regulatory requirements, as an active-controlled CVOT complementary to the
`core placebo-controlled CVOT CARMELINA. §Albiglutide is no longer a licensed treatment. ‖Efpeglenatide is not a currently licensed treatment.
`¶FREEDOM-CVO (exenatide subcutaneous implant; not a currently licensed treatment) was completed in 2016, but the primary outcome (4P-MACE)
`was reported in 2022
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`and renal outcomes during treatment with other GLDs,
`such as the SGLT2 inhibitor canagliflozin, in patients
`with T2D (Table 1; Additional file 1: Table S1) [15, 16, 27,
`30–37]. CVOT findings are now a major focus of updated
`treatment guidelines (Table 2) [38–44] and product labels
`[13].
`The purpose of this review is to provide an expert sum-
`mary that will help clinicians navigate the overwhelming
`wealth of CVOT data. We discuss how CVOTs can pro-
`vide valuable insights for management in clinical prac-
`tice, and consider remaining gaps in knowledge, as well
`as how diabetes CVOTs have led to further cardiorenal-
`focussed studies that seek to understand more about how
`some GLDs may improve outcomes for our patients.
`
`Can we compare diabetes CVOTs?
`In the absence of head-to-head studies, caution must
`be exercised when interpreting data from indirect com-
`parison of CVOTs. Among the potential heterogeneity
`in trial designs and baseline characteristics, particular
`attention should be paid to differing baseline criteria for
`CVD diagnosis and CV risk in trial cohorts; patients with
`established CVD or CV risk factors at baseline may be
`more likely to progress through the continuum of CVD
`[45]. The proportions of patients with established CVD
`varied substantially between the CVOTs. For instance, all
`patients in ELIXA had established CVD, compared with
`31–83% in LEADER, SUSTAIN-6 and REWIND (Addi-
`tional file 2: Figure S1). Other key baseline characteristics
`that varied substantially between the CVOTs included
`HF diagnosis and renal impairment. There have also been
`suggestions of differing outcomes by region or race/eth-
`nicity in the CVOTs, and in the HF and renal outcome
`trials, although these studies were not powered to reli-
`ably detect differences between subgroups [27, 30, 32,
`46]. For instance, as recently reported for the LEADER
`CVOT of the GLP-1 RA liraglutide, 3P-MACE HR (95%
`CI) ranged from 0.62 (0.37–1.04) in Asia to 1.01 (0.84–
`1.22) in North America, although there was a lack of
`clear statistical evidence of interaction between regions
`and the outcome (p = 0.20) [32, 47]. The task of assess-
`ing the profile of CV risk in CVOT populations is also
`complicated by the prevalence of unrecognised diabetic
`cardiac impairment in patients with T2D, which may
`include ischaemia, myocardial dysfunction and/or car-
`diac arrhythmia presenting with atypical symptoms [48].
`However, it is notable that post hoc analyses of EMPA-
`REG OUTCOME showed consistency of CV benefits
`with empagliflozin across patients with different baseline
`CV risk factors, including prior MI [49], prior stroke [49],
`Thrombolysis In Myocardial Infarction (TIMI) score [49],
`prior coronary artery bypass graft surgery [50], left ven-
`tricular hypertrophy [51], peripheral artery disease [52]
`
`and atrial fibrillation [53]. Canagliflozin has also shown
`consistency in CV outcomes across subgroups, including
`in patients with different levels of albuminuria [54], and
`enhanced 3P-MACE in patients with prior diuretic usage
`[55].
`
`From CV safety to CV efficacy in patients with T2D
`DPP‑4 inhibitors: no evidence for cardioprotection
`The first T2D CVOTs to be reported, SAVOR-TIMI 53
`and EXAMINE, assessed the CV safety of the DPP-4
`inhibitors saxagliptin and alogliptin, respectively. Before
`publication of these two CVOTs in 2013, post hoc anal-
`yses of phase 2 and 3 trials suggested a trend for lower
`incidence of major CV events with DPP-4 inhibitors than
`with placebo or other comparators [56]. Similarly, both
`CVOTs demonstrated non-inferiority in 3P-MACE for
`saxagliptin (HR [95% CI] 1.00 [0.89–1.12]) and alogliptin
`(HR [95% CI] 0.96 [upper < 1.16]), compared with pla-
`cebo (Additional file 1: Table S1) [57, 58]. However, saxa-
`gliptin had a significantly elevated risk of HHF compared
`with placebo (HR [95% CI] 1.27 [1.07–1.51], p < 0.01) [57]
`and there was a suggestion of increased risk of HHF in
`patients treated with alogliptin vs placebo (HR [95% CI]
`1.19 [0.90–1.58]), which led to the FDA issuing a safety
`warning for both alogliptin and saxagliptin [59]. Overall,
`subsequent CVOTs for DPP-4 inhibitors (sitagliptin and
`linagliptin) have demonstrated acceptable CV safety, con-
`sistently showing a neutral effect on 3P-MACE [13, 14,
`60]. CARMELINA (linagliptin) included a cohort with
`a majority of patients presenting with prevalent chronic
`kidney disease (CKD) at baseline (mean estimated glo-
`merular filtration rate [eGFR], 55  mL/min/1.73  m2)
`[20]. In the CAROLINA CVOT (mean eGFR at base-
`line, 77 mL/min/1.73  m2), linagliptin was non-inferior to
`glimepiride, based on 3P-MACE [21].
`
`SGLT2 inhibitors: cardioprotection with empagliflozin
`and canagliflozin
`Cardioprotective benefits of GLDs were first observed in
`the EMPA-REG OUTCOME trial, in which the SGLT2
`inhibitor empagliflozin showed a 14% reduction in the
`risk of 3P-MACE compared with placebo (HR [95%
`CI] 0.86 [0.74–0.99], p = 0.04) in patients with T2D
`and established CVD [27]. Among the components of
`3P-MACE, the risk of CV death was reduced by 38% with
`empagliflozin (HR [95% CI] 0.62 [0.49–0.77], p < 0.001),
`while the impact on each of nonfatal stroke and nonfatal
`MI was neutral [27] (Table 1; Additional file 1: Table S1).
`The canagliflozin CVOT programme, comprising
`CANVAS and CANVAS-R, also demonstrated a 14%
`reduction in 3P-MACE (HR [95% CI] 0.86 [0.75–0.97],
`p = 0.02) in patients with established CVD or high CV
`risk, although no significant reduction in CV deaths (HR
`
`
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`‡ 3P-MACE is shown for all CVOTs (a composite of CV death, nonfatal MI and nonfatal stroke), except for 4P-MACE for AMPLITUDE-O (3P-MACE outcomes plus death from undetermined causes)
`† In addition to the CVOTs shown, the HARMONY OUTCOMES trial showed reduced risks of 3P-MACE and MI with the GLP-1 receptor agonist albiglutide [35]; however, albiglutide is no longer an approved treatment
`*All drugs shown are currently licensed for T2D, except for efpeglenatide
`glomerular filtration rate; ER, event rate; GLP-1, glucagon-like peptide 1; HR, hazard ratio; MI, myocardial infarction; N.S., not significant; PY, patient-years; SGLT2, sodium–glucose transport protein 2; T2D, type 2 diabetes
`3P/4P-MACE, 3-/4-point major adverse cardiovascular event; ASCVD, atherosclerotic CVD; CI, confidence interval; CKD, chronic kidney disease; CV, cardiovascular; CVD, CV disease; CVOT, CV outcomes trial; eGFR, estimated
`trend towards a reduction of 3P-MACE [33]. References: EMPA-REG OUTCOME [27–29, 62]; CANVAS Program [30, 62, 92]; AMPLITUDE-O [23]; LEADER [32, 96]; SUSTAIN-6 [31, 136–138]; REWIND [34, 97]
`(dapagliflozin), which did not show a significant effect on 3P-MACE, and a reduced risk for the composite of CV death or HHF was driven by reduction in HHF [37]; EXSCEL (once-weekly exenatide) found a non-significant
`statistical significance. Differences in baseline CV risk are substantial between CVOTs, and even the definition of CV risk and individual risk factors differs between trials. CVOTs excluded here include: DECLARE-TIMI 58
`possible differences in study design, definitions and cohorts. For example, absence of a demonstrated benefit may be due to such factors, especially for secondary outcomes where studies may not be powered to reach
`glucose-lowering agents that have demonstrated ASCVD benefits in diabetes CVOTs [15, 27, 28, 31, 32, 34, 96, 97]. As most CVOTs were not head-to-head trials, direct comparisons of agents cannot be made, due to
`(For detailed overview of all diabetes CVOTs, and renal outcomes and HF studies, see Additional file 1: Table S1). Primary and key secondary endpoints, patient cohort composition, and key subgroup analyses for
`
`Relative risk reduction for 3P-MACE was in most cases broadly similar across demographic and clinical baseline characteristics, including a range of cardiovascular and renal characteristics
`0.87 (0.74–1.02) P = 0.97
`Primary prevention group:
`0.87 (0.74–1.02)
`Secondary prevention group:
`
`1.00 (0.41–2.46) P = 0.49
`Primary prevention group:
`0.72 (0.55–0.93)
`Secondary prevention group:
`
`1.20 (0.86–1.67) P = 0.04
`Primary prevention group:
`0.83 (0.74–0.93)
`Secondary prevention group:
`
`1.71 (0.48–6.07)
`Primary prevention group:
`0.71 (0.57–0.90)
`Secondary prevention group:
`
`0.98 (0.74–1.30) P = 0.18
`Primary prevention group:
`0.82 (0.72–0.95)
`Secondary prevention group:
`
`N/A
`
`Other subgroups
`
`MACE‡ HR (95% CI)
`prevention
`Secondary vs primary CVD
`Subgroup analyses
`
`factors
`• or ≥ 60 years with ≥ 2 CV risk
`renal condition
`• or ≥ 55 years with ≥ 1 cardio-
`disease
`• Age ≥ 50 years with vascular
`75
`31%
`9901
`
`risk factor
`• or ≥ 60 years with ≥ 1 CV
`(> stage 3)
`or chronic kidney disease
`established CVD, chronic HF
`• Age ≥ 50 years with
`76
`83%
`3297
`
`risk factor
`• or ≥ 60 years with ≥ 1 CV
`condition
`• Age ≥ 50 years with ≥ 1 CV
`80
`82%
`9340
`
`• Albuminuria
`• Impaired renal function
`Protective effect on:
`0.76 (0.61–0.95)
`0.96 (0.79–1.16)–N.S
`
`nuria
`Protective effect on albumi-
`0.61 (0.38–0.99)
`0.74 (0.51–1.08)–N.S
`
`0.91 (0.78–1.06)–N.S
`24 vs 27
`0.88 (0.79–0.99)
`
`Dulaglutide
`REWIND
`
`0.98 (0.65–1.48)–N.S
`32 vs 44
`0.74 (0.58–0.95)
`
`Semaglutide
`SUSTAIN‑6
`
`nuria
`Protective effect on albumi-
`0.89 (0.72–1.11) – N.S
`0.88 (0.75–1.03)–N.S
`All-cause death also reduced
`0.78 (0.66–0.93)
`34 vs 39
`0.87 (0.78–0.97)
`
`risk factor
`kidney disease and ≥ 1 CV
`≥ 55 years (female) with
`• or ≥ 50 years (male) or
`of CVD
`• Age ≥ 18 years with history
`73
`91%
`4076
`
`• Albuminuria
`renal function or albuminuria
`• A composite of impaired
`• HF
`Protective effect on:
`0.80 (0.48–1.31) – N.S
`0.78 (0.55–1.10)–N.S
`
`factors
`• or ≥ 50 years with ≥ 2 CV risk
`matic ASCVD
`• Age ≥ 30 years with sympto-
`77
`65%
`10,142
`
`• Albuminuria
`• Impaired renal function
`• HHF
`Protective effect on:
`0.90 (0.71–1.15) – N.S
`0.85 (0.69–1.05)–N.S
`
`0.72 (0.50–1.03)–N.S
`39 vs 53
`0.73 (0.58–0.92)
`
`0.87 (0.72–1.06)–N.S
`27 vs 32
`0.86 (0.75–0.97)
`
`lished CVD
`Age ≥ 18 years with estab-
`74
`99%
`7020
`
`addition to T2D)
`Key inclusion criteria (in
`Mean eGFR mL/min/1.73 m2
`Established CVD % pts
`Number of participants
`Cohort composition
`
`• Albuminuria
`• Impaired renal function
`• HHF
`Protective effect on:
`1.24 (0.92–1.67)–N.S
`0.87 (0.70–1.09)–N.S
`All-cause death also reduced
`0.62 (0.49–0.77)
`37 vs 44
`0.86 (0.74–0.99)
`
`points)
`(individual secondary end-
`Other cardiorenal benefits
`Nonfatal stroke HR (95% CI)
`Nonfatal MI HR (95% CI)
`
`CV death HR (95% CI)
`ER drug vs placebo/1,000 PY
`MACE‡ HR (95% CI)
`
`Liraglutide
`LEADER
`
`Liraglutide
`AMPLITUDE‑O
`
`Canagliflozin
`CANVAS Programme
`
`Empagliflozin
`EMPA‑REG OUTCOME
`
`GLP‑1 receptor agonists
`
`SGLT2 inhibitors
`
`Study
`
`Class*†
`
`Table 1 Overview of CVOTs reporting significant reductions in 3P/4P-MACE
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`Table 2 Current recommendations based on CVOTs for patients with established CVD or at high risk for CVD
`
`Guidelines
`
`ADA 2022
`
`ACC 2020
`
`ADA and EASD 2019
`
`ESC (in association
`with EASD) 2019
`
`Selected recommendations for CVD management based on diabetes CVOTs
`
`For patients with T2D who have established ASCVD or high / very high CV risk, SGLT2 inhibitors or GLP-1 RA with proven car-
`diovascular benefit are recommended as part of glycaemic management:*
`• Either a GLP-1 RA with proven CVD benefit or an SGLT2 inhibitor with proven CVD benefit
`• If further intensification is required or the patient is now unable to tolerate a GLP-1 RA and/or SGLT2 inhibitor choose agents
`demonstrating CV safety; consider adding the other class (GLP-1 RA or SGLT2 inhibitor) with proven CVD benefit†
`For patients with T2D who have established or high risk of ASCVD consider an SGLT2 inhibitor or GLP-1 RA with proven CV
`benefit
`For patients with T2D who have established ASCVD, an SGLT2 inhibitor or GLP-1 RA with proven cardiovascular benefit is rec-
`ommended as part of glycaemic management:
`• First-line therapy is metformin
`• Add an GLP-1 RA with proven CVD benefit or, if eGFR is adequate, an SGLT2 inhibitor with proven CVD benefit
`• If further intensification is required or the patient is now unable to tolerate a GLP-1 RA and/or SGLT2 inhibitor, choose agents
`demonstrating CV safety†
`Consider CV risk independently of Hb1Ac; for patients with T2D who have ASCVD, or high/very high CV risk (target organ dam-
`age or multiple risk factors)
`• SGLT2 inhibitor or GLP-1 RA (either as first add-on to metformin or as monotherapy; however, drug labels stipulate that metformin
`should be first line)
`• If HbA1c is above target, consider adding the other class (GLP-1 RA or SGLT2i) with proven CVD benefit
`
`A summary of recommendations in major international guidelines that are based on evidence from diabetes CVOTs. These guidelines include the American Diabetes
`Association (ADA) Standards of Medical Care in Diabetes 2022 [44]; American College of Cardiology (ACC) 2020 Expert Consensus Decision Pathway on Novel
`Therapies for Cardiovascular Risk Reduction in Patients with Type 2 Diabetes and Atherosclerotic Cardiovascular Disease [39]; Management of hyperglycaemia in
`type 2 diabetes, 2018: A consensus report by the ADA and the European Association for the Study of Diabetes (EASD), together with its 2019 update [40, 42]; 2019
`European Society of Cardiology (ESC) Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD [38]
`ASCVD, atherosclerotic cardiovascular disease; CV, cardiovascular; CVD, cardiovascular disease; CVOT, cardiovascular outcomes trial; GLP-1 RA, glucagon-like peptide-1
`receptor agonist; Hb1Ac, haemoglobin A1c; SGLT2, sodium–glucose transporter 2
`*Other options are thiazolidinediones, DPP-4 inhibitors if not on GLP RA, basal insulin, sulfonylureas
`† Based on the flowchart of treatment of patients with T2D in the ADA 2022 guidelines, “first-line therapy depends on comorbidities, patient-centred treatment factors,
`including cost and access considerations, and management needs and generally includes metformin and comprehensive lifestyle modification”, and treatment
`choices are subsequently shown on the flowchart according to the presence/absence of ASCVD, indicators of high risk, heart failure, and chronic kidney disease
`
`[95% CI] 0.87 [0.72–1.06]) [30]. The beneficial effect of
`canagliflozin on 3P-MACE was confirmed in patients
`with T2D and CKD in a subsequent renal outcomes trial,
`CREDENCE (HR [95% CI] 0.80 [0.67–0.95], p = 0.01),
`which also showed a trend towards a reduction in CV
`deaths that neared significance (HR [95% CI] 0.78 [0.61–
`1.00], p = 0.05) [36]. CKD in patients with T2D has been
`strongly linked to CV events and mortality in CVOTs
`[14], although the prevalence of CKD in diabetes CVOTs
`was typically much lower than in CREDENCE [14, 36].
`A recently reported meta-analysis of 11 clinical tri-
`als demonstrated cardiorenal benefits across the SGLT2
`inhibitor class versus placebo. CV benefits included a
`12% reduction in 3P-MACE (without significant hetero-
`geneity; I2 = 21.2%, p = 0.19), based on six cardiorenal
`studies that reported this outcome, and a 16% reduction
`in CV death [61]. However, these results should be cave-
`ated; there were differences in outcomes, study designs,
`patient populations, and medications across the car-
`diorenal studies included in the meta-analysis. The 12%
`reduction in 3P-MACE was based on data from EMPA-
`REG OUTCOME, CANVAS, CREDENCE, DECLARE-
`TIMI 58 (dapagliflozin), VERTIS CV (ertugliflozin)
`and SCORED (sotagliflozin). Notably, sotagliflozin has
`both SGLT1 and SGLT2 inhibitory activity and is not
`
`a licensed treatment for T2D (but is licensed for type 1
`diabetes in Europe), and SCORED was a cardiorenal
`study (patients had T2D and CKD) that used a different
`3P-MACE outcome (CV death, HHF and urgent visits for
`HF) than the other studies (CV death, nonfatal MI and
`nonfatal stroke). The dapagliflozin CVOT, DECLARE-
`TIMI 58, did not show a benefit in either 3P-MACE
`(HR [95% CI] 0.93 [0.84–1.03], p = 0.17) or CV deaths
`(0.98 [0.82–1.17]) [37, 62]. However, DECLARE-TIMI 58
`had a very different profile of baseline characteristics to
`EMPA-REG OUTCOME and CANVAS, as a majority of
`patients had high CV risk but not established CVD, and
`there were fewer patients with CKD [37]. Therefore, the
`different outcomes in DECLARE-TIMI 58, compared
`with EMPA-REG OUTCOME and CANVAS, may be
`due to differences in study design and cohort composi-
`tion rather than intrinsic differences between the study
`drugs. Two HF and renal outcomes studies, designed to
`assess the effect of dapagliflozin vs placebo in patients
`with HF with reduced ejection fraction (HFrEF; DAPA-
`HF) or CKD (DAPA-CKD) with or without T2D, both
`reported trends towards reductions in CV death in the
`T2D subgroups (HR [95% CI] 0.79 [0.63–1.01] and 0.85
`[0.59–1.21], respectively) [63, 64]. In the VERTIS CV
`study of ertugliflozin, all patients had established CVD at
`
`
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`baseline, but no benefit was observed in 3P-MACE (HR
`[95% CI] 0.97 [0.85–1.11]) or CV death (HR [95% CI] 0.92
`[0.77–1.11]) [16]. These findings suggest that significant
`improvements in CV outcomes, which were observed in
`CVOTs of empagliflozin and canagliflozin, may not apply
`to all SGLT2 inhibitors.
`
`GLP‑1 RAs: cardioprotection with subcutaneous
`and long acting GLP‑1 RAs, but inconclusive evidence
`for short‑acting and oral long‑acting medications
`A meta-analysis of eight CVOTs recently demonstrated
`reductions in 3P/4P-MACE and CV death of 14% and
`13%, respectively, across the GLP-1 RA class, compared
`with placebo [65]. These findings were based on data
`from five studies of subcutaneously administered long-
`acting GLP-1 RAs (AMPLITUDE-O, LEADER, SUS-
`TAIN-6, REWIND, and HARMONY OUTCOMES), a
`study of orally administered long-acting semaglutide
`(PIONEER-6) and two studies of subcutaneously admin-
`istered short-acting GLP-1 RAs (ELIXA, EXSCEL). The
`FREEDOM-CVO non-inferiority study of continuously
`infused exenatide, which recently showed no CV benefits
`over placebo based on the primary outcome of 4P-MACE
`(HR [95% CI] 1.21 [0.90–1.63]), 3P-MACE and their
`individual component outcomes [24] (Additional file  1:
`Table S1), was not included in the meta-analysis.
`Significant reductions in 3P/4P-MACE have been
`reported for all five of the CVOTs of subcutaneously
`administered long-acting GLP-1 RAs, including the
`recently reported AMPLITUDE-O study (efpeglena-
`tide; HR [95% CI] 0.73 [0.58–0.92]; p < 0.01), LEADER
`(liraglutide; 0.87 [0.78–0.97], p = 0.01), SUSTAIN-6
`(semaglutide; 0.74 [0.58–0.95], p = 0.02), REWIND (dula-
`glutide; 0.88 [0.79–0.99], p = 0.03), and HARMONY
`OUTCOMES (albiglutide; 0.78 [0.68–0.90], p < 0.01)
`(Table 1) [31, 32, 34, 35]. The latter GLP-1 RA, albiglu-
`tide, is no longer commercially available.
`When the oral formulation of semaglutide was com-
`pared with placebo in the PIONEER-6 trial [15], a trend
`was observed towards reduction in 3P-MACE (HR [95%
`CI] 0.79 [0.57–1.11], p = 0.17). However, PIONEER-6
`was a small study (N = 3183) of short duration, designed
`to rule out excess risk of 3P-MACE, and not powered
`to demonstrate superiority [15]. Based on clinicaltri-
`als.gov, a large CVOT investigating an oral formulation
`of semaglutide, the SOUL trial, is underway (estimated
`N = 9642). Primary and study completion are scheduled
`for July 2024.
`Across the long-acting GLP-1 RA CVOTs, the out-
`comes for individual components of 3P-MACE were
`much less uniform than for the composite endpoint: only
`two of the five trials demonstrated a significant reduc-
`tion in CV death, LEADER (liraglutide; HR [95% CI] 0.78
`
`[0.66–0.93], p = 0.01) and PIONEER-6 (oral semaglu-
`tide; HR [95% CI] 0.49 [0.27–0.92], p = 0.03) [15, 32, 66];
`however, neither study showed a significant reduction
`in nonfatal stroke or nonfatal MI, whereas SUSTAIN-6
`(semaglutide) and REWIND (dulaglutide) significantly
`reduced the risk of nonfatal stroke, while HARMONY
`OUTCOMES (albiglutide) significantly reduced the risk
`of fatal or nonfatal MI [31, 34, 35].
`Unlike the findings for long-acting GLP-1 RAs, the
`short-acting GLP-1 RA lixisenatide showed no signifi-
`cant CV benefits in the ELIXA study, taking into account
`4P-MACE (HR [95% CI] 1.02 [0.89–1.17]; p = 0.81),
`its individual components, and HHF [26] (Additional
`file 1: Table S1). The EXSCEL study of prolonged-release
`exenatide, another short-acting GLP-1 RA, showed a
`trend towards a reduction in 3P-MACE that neared
`significance (HR [95% CI] 0.91 [0.83–1.00], p = 0.06)
`[33] although, as previously mentioned, no CV benefits
`were observed for continuously infused exenatide in the
`FREEDOM-CVO trial [24]. In addition to the possibility
`of patients’ baseline characteristics affecting study out-
`comes, the differing results of the long- and short-act-
`ing GLP-1 RA CVOTs suggest that the kinetics of both
`receptor agonism and drug exposure may play roles in
`conferring cardioprotection. More research is needed to
`determine whether the documented differences between
`the pharmacokinetics, delivery and effects of short- and
`long-acting GLP-1 RAs [67] translate into differences in
`CV outcomes.
`
`Can modern glucose‑lowering drugs reduce
`all‑cause mortality?
`The data emerging from CVOTs means that clinicians
`can, for the first time, consider therapeutic options
`among GLDs that may reduce mortality and improve CV
`outcomes in certain patient groups. Unlike DPP-4 inhibi-
`tors, SGLT2 inhibitors and some GLP-1 RAs are associ-
`ated with significant reductions in all-cause mortality
`(Table 1 and Additional file 1: Table S1).
`
`SGLT2 inhibitors: evidence for reduced all‑cause mortality
`No significant reduction of all-cause death with dapagli-
`flozin was seen in DECLARE-TIMI 58 (HR [95% CI] 0.93
`[0.82–1.04]) [37]. However, reductions in all-cause death
`were observed in DAPA-HF (HR [95% CI] 0.83 [0.71–
`0.97]) and in DAPA-CKD (0.69 [0.53–0.88]), in popula-
`tions of patients with HFrEF or CKD, with or without
`T2D. These reductions in all-cause death were compat-
`ible with CV death outcomes in DAPA-HF (HR [95% CI]
`0.82 [0.69–0.98]) and in DAPA-CKD (0.81 [0.58–1.12])
`[68, 69].
`Notably, EMPA-REG OUTCOME (empagliflozin) dem-
`onstrated a significantly reduced all-cause death rate (HR
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`[95% CI] 0.68 [0.57–0.82]) (Additional file  1: Table  S1),
`which was primarily driven by a reduced risk of CV death
`(Table  1) [27, 32]. Another study, EMPEROR-Reduced,
`was designed to assess the effect of empagliflozin vs pla-
`cebo in patients with HFrEF, with or without T2D. In
`this patient population, trends towards reductions in CV
`death were reported in patients with T2D (HR [95% CI]
`0.92 [0.71–1.20]) and without T2D (0.92 [0.68–1.24])
`[70].
`In the canagliflozin diabetes CVOT programme (CAN-
`VAS and CANVAS-R), no statistically significant reduc-
`tions were detected in all-cause mortality (HR [95% CI]
`0.87 [0.74–1.01]) or CV deaths (0.87 [0.72–1.06]) in
`patients with T2D [30].
`
`GLP‑1 RAs: evidence for reduced all‑cause mortality
`The LEADER CVOT demonstrated significantly reduced
`all-cause mortality with liraglutide vs placebo (HR [95%
`CI] 0.85 [0.74–0.97]) (Additional file 1: Table S1), com-
`patible with reduced risk of CV death (Table 1) [27, 32].
`A reduced risk of all-cause death in patients with T2D
`was also noted in EXSCEL (exenatide) (HR [95% CI] 0.86
`[0.77–0.97]) and PIONEER-6 (oral semaglutide) (0.51
`[0.31–0.84]), although these resul