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Page 2 of 10 Min et al. Metab Target Organ Damage 2023;3:6 https://dx.doi.org/10.20517/mtod.2023.09

INTRODUCTION
Diabetes is associated with a heightened threat of cardiovascular disease (CVD). It is thought that
approximately one-third of those with type 2 diabetes (T2DM) have comorbid CVD, namely
atherosclerosis, angina, heart failure (HF), myocardial infarction (MI), and stroke . CVD is also a major
[1]
[1]
cause of death in T2DM, contributing to approximately 50% of all-cause mortality . Prevention of CVD is
one of the major objectives in the management of T2DM. Multifactorial risk factor intervention can reduce
[2]
T2DM-related CV morbidity and mortality by as much as 50% , and this has led to a move away from the
traditional ‘glucocentric approach’ in the management of T2DM . Following the launch of US Food and
[3]
Drugs Administration (FDA) guidance towards the end of 2008, cardiovascular outcome trials (CVOTs)
and confirmation of CV safety are necessary for FDA approval of novel glucose-lowering drugs . In line
[4]
with the emerging evidence from the CVOTs, there has been a major shift in the management of T2DM.
Glucose-lowering therapies, which have established cardiovascular benefits, are recommended regardless of
metformin use and glycaemic status . In this concise review, we aim to summarise the CVOT results of
[3,5]
glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT-2)
inhibitors from the perspective of practising clinicians.

DIABETES CVOTS
In the past fifteen years, CVOTs have been conducted to demonstrate the CV safety of new glucose-
lowering therapies. These CVOTs recruited people with T2DM and either established CVD or with CV risk
factors and aimed to show a hazard ratio (HR) for major CV events of less than 1.8, an arbitrary safety
margin. Most CVOTs used a primary composite endpoint of major adverse CV events (MACE) comprising
the first occurrence of CV mortality, non-fatal myocardial infarction (MI), or non-fatal stroke [designated
the ‘3-point MACE’ (3P-MACE)]. Some CVOTs also included an additional CV event creating a 4-point
MACE (4P-MACE) primary composite: for example, hospitalisation for unstable angina in the ELIXA
lixisenatide trial . Although the main objective of CVOTs was to examine CV safety, some CVOTs of GLP-
[6]
1RAs, and SGLT-2 inhibitors demonstrated not only safety but also CV protection.

Cardiovascular benefits of GLP-1RAs
Currently, six GLP-1RA injectable formulations and one oral formulation (semaglutide once daily) are
approved in Europe and the United States (US). These are based on the exendin-4 molecule, which was
originally isolated from the Gila Monster lizard [exenatide (twice daily [BD]), exenatide (once weekly
[QW]) and lixisenatide (once daily[OD])] or human GLP-1 [liraglutide (OD), dulaglutide (QW) and
semaglutide (QW)]. A further preparation (albiglutide) was launched in 2018 but was quickly withdrawn
for commercial reasons. To date, there have been a total of nine randomised CVOTs investigating the use of
GLP-1RAs: ELIXA (lixisenatide) , LEADER (liraglutide) , SUSTAIN-6 (injectable semaglutide) , EXSCEL
[7]
[8]
[6]
[9]
(weekly exenatide) , HARMONY OUTCOMES (albiglutide) , REWIND (dulaglutide) , PIONEER-6
[11]
[10]
(oral semaglutide) , AMPLITUDE-O (efpeglenatide) and FREEDOM-CVO (continuous subcutaneous
[12]
[13]
infusion of exenatide) were published between 2015 and 2021. To date, efpeglenatide is not a licensed
[14]
treatment. An overview of GLP-1RA CVOTs is summarised in Table 1.
All of the above-mentioned CVOTS demonstrated CV safety (meeting the 3P-MACE or 4P-MACE non-
inferiority criteria) in individuals with T2DM and established CVD or with CV risk factors. In addition,
significant risk reductions (superior to placebo) in 3P-MACE/ 4P-MACE were observed in five of the
subcutaneously administered (daily or weekly) GLP-1RAs: liraglutide, semaglutide, albiglutide, dulaglutide
and efpeglenatide. The HRs for 3P-MACE/4P-MACE were 0.87 [95% confidence intervals (CI) 0.78-0.97; P
[8]
= 0.01] in LEADER (liraglutide) ; 0.74 (95%CI: 0.58-0.95; P = 0.02) in SUSTAIN-6 (semaglutide) ; 0.78
[7]
[10]
(95%CI: 0.68-0.90 P = 0.0006) in HARMONY OUTCOMES (albiglutide) ; 0.88 (95%CI: 0.79-0.99; P =