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Review Cardiol Res. 2024;15(1):1-11
Pulse of Progress: A Systematic Review of Glucagon-Like
Peptide-1 Receptor Agonists in Cardiovascular Health
Michael Sabinaa, b , M. Mrhaf Alsammana
Abstract
According to the World Health Organization (WHO), the prevalence
of type 2 diabetes mellitus (T2DM) and obesity has increased glob-
ally over the past 50 years, affecting over 500 million adults world-
wide in 2023. A novel class of drugs known as glucagon-like pep-
tide-1 (GLP-1) receptor agonists have emerged as a beacon of hope in
treating the pandemic of diabetes and obesity. This analysis’ objective
was to draw comparisons of how these medications reduce cardio-
vascular outcomes. The review revealed unique differences in GLP-
1s, highlighting some of their strengths and weaknesses and which
populations they can cater to preferentially. Even though all drugs in
question of this review are proven to be efficacious for diabetes and
obesity, differences in their cardiovascular safety profiles and efficacy
were noted. The analysis recognized the potential of drugs like sema-
glutide and tirzepatide, as leaders in the space. Although this current
assessment of where GLP-1 receptor agonists stand in regard to car-
diovascular outcomes may still be premature, the space is extremely
active, and there are trials that are highly anticipated to transform the
landscape of diabetes and obesity management in patients with more
established cardiovascular comorbidities in the near future.
Keywords: Cardiovascular; Diabetes; Obesity; GLP-1 agonist
Introduction
According to the World Health Organization (WHO), the
prevalence of type 2 diabetes mellitus (T2DM) and obesity has
increased globally over the past 50 years, affecting over 500
million adults worldwide in 2023. This population has an in-
creased risk of adverse cardiac events and stroke [1, 2]. While
both T2DM and obesity are being considered by many experts
around the globe as a “pandemic”, there has been a recent up-
surge of relentless research to find effective treatments. In the
midst of all this new research, a new class of drugs amongst
others, known as glucagon-like peptide-1 (GLP-1) recep-
tor agonists have emerged as a beacon of hope. Their unique
method of action affects glucose control via several different
mechanisms. They promote delayed gastric emptying, they
increase insulin secretion while inhibiting glucagon release,
but only when glucose levels are elevated via the incretin ef-
fect, thus reducing the likelihood of hypoglycemia [3]. These
agents are proven to provide glycemic and weight loss benefits
which in theory, present as potential cardiovascular benefits.
This review attempts to critically analyze the most up-to-date
evidence from trials and offer a detailed analysis in how they
rank amongst each other in terms of cardiovascular safety and
efficacy. The GLP-1 receptor agonists in question are lixi-
senatide, exenatide, albiglutide, efpeglenatide, semaglutide,
liraglutide, dulaglutide, and the novel tirzepatide (dual GLP-1
and GIP agonist). It will attempt to dissect each drug’s unique
aspects, strengths and weaknesses, and offer recommendations
on what needs to be done in the future to solidify their role in
the cardiovascular space. Lastly, it will discuss the emerging
trends and future directions in this rapidly evolving field.
Current state of GLP-1s in the management of
diabetes and weight management
Prior studies have already compared the efficacy of these
drugs in head-to-head trials in regard to A1c lowering and
weight loss management [4]. The LEAD-6 trial showed that
long-acting liraglutide had significantly greater improvements
in glycemic control when compared to short-acting exena-
tide [5]. The DURATION-6 trial showed that liraglutide daily
was also superior to exenatide weekly in A1c lowering [6]. In
the GETGOAL-X trial, lixisenatide once daily demonstrated
noninferior improvements in glycosylated hemoglobin A1c
(HbA1c) compared with exenatide twice daily [7]. Another
trial by Nauck et al showed liraglutide was more effective than
lixisenatide as an add-on to metformin in improving glyce-
mic control. Body weight reductions and gastrointestinal (GI)
adverse event profiles were similar [8]. The AWARD-1 and
AWARD-6 trial demonstrated dulaglutide had superior glyce-
mic control versus exenatide but was noninferior to liraglutide
[9, 10]. In the SUSTAIN-3 trial, semaglutide was superior to
exenatide in improving glycemic control and reducing body
weight after 56 weeks of treatment; the drugs had compara-
ble safety profiles [11]. The SUSTAIN-7 trial showed at low
Manuscript submitted December 5, 2023, accepted December 15, 2023
Published online January 10, 2024
aInternal Medicine Program, GME, Lakeland Regional Health Medical Cent-
er, Lakeland, FL 33805, USA
bCorresponding Author: Michael Sabina, Internal Medicine Program, GME,
Lakeland Regional Health Medical Center, Lakeland, FL 33805, USA.
Email: Michael.Sabina@mylrh.org
doi: https://doi.org/10.14740/cr1600
Articles © The authors | Journal compilation © Cardiol Res and Elmer Press Inc™ | www.cardiologyres.org
2
GLP-1 Receptor Agonists in Cardiovascular Health Cardiol Res. 2024;15(1):1-11
and high doses, semaglutide was superior to dulaglutide in
improving glycemic control and reducing body weight [12]. In
the SUSTAIN-10 trial, semaglutide was superior to liraglutide
in reducing HbA1c and body weight. There were higher rates of
GI adverse effects with semaglutide vs. liraglutide [13]. In PIO-
NEER-4 trial, oral semaglutide was noninferior to subcutaneous
liraglutide in decreasing HbA1c but was superior in decreasing
bodyweight compared with liraglutide. Safety and tolerability of
oral semaglutide were similar to subcutaneous liraglutide [14].
The PIONEER-10 trial showed once-daily oral semaglutide sig-
nificantly reduced HbA1c and bodyweight versus weekly sub-
cutaneous dulaglutide in Japanese patients with type 2 diabetes
[15]. In the HARMONY-7 trial, patients who received once-
daily liraglutide had greater reductions in HbA1c than did those
who received once-weekly albiglutide, however, weight loss was
not assessed [16]. In an exploratory analysis comparing double-
blind treatment with efpeglenatide with open-label liraglutide as
a reference found that efpeglenatide 4-mg dose was noninferior
to open-label liraglutide treatment in reducing HbA1c levels,
and body weight reductions with efpeglenatide 3 mg or 4 mg
were comparable to those seen with liraglutide 1.8 mg [17]. The
SURPASS-2 trial showed tirzepatide at the same three weekly
doses (5, 10, and 15 mg) was superior against weekly injections
of semaglutide 1.0 mg at all doses for A1c lowering and weight
loss [18]. Tirzepatide was superior compared with dulaglutide
for glycemic control and reduction in bodyweight, in the SUR-
PASS J-MONO [19] trial (Table 1) [5-19].
A previous study done by Trujillo et al provided a detailed
meta-analysis of GLP-1 receptor agonists and ranked them in
A1c lowering, weight loss efficacy, and GI side effects when
comparing head-to-head trial data [4]. Three drugs, albiglutide,
efpeglenatide, and tirzepatide were not mentioned in the rankings.
We updated the table to account for these three drugs (Table 2).
When comparing A1c lowering efficacy, these agents could
be ranked (from highest to lowest) in the following order: tirze-
patide > semaglutide (subcutaneous) = semaglutide (oral) > du-
laglutide = liraglutide = efpeglenatide > exenatide extended re-
lease (ER) > exenatide (twice daily) = lixisenatide = albiglutide.
When comparing weight loss, these agents could be
ranked (from most to least) in the following order: tirzepatide
> semaglutide (subcutaneous) = semaglutide (oral) > liraglu-
tide = efpeglenatide > dulaglutide > exenatide ER = exenatide
(twice daily) = lixisenatide.
In regard to the treatment of type 2 diabetes and obesity,
tirzepatide has the strongest evidence for being a leader in the
GLP-1 community. This review attempts to further expand on
GLP-1s and their current standings when taking into consid-
eration cardiovascular outcomes.
Study Analysis
Lixisenatide
The ELIXA trial (2015)
This study assessed the cardiovascular effects of lixisenatide
in 6,068 patients with type 2 diabetes who had experienced
a myocardial infarction (MI) or had been hospitalized for un-
stable angina within the previous 180 days and were assigned
to receive either lixisenatide or a placebo, in addition to the
standard care. The primary composite endpoint included car-
diovascular death, MI, stroke, or hospitalization for unstable
angina. The results showed that a primary endpoint event oc-
curred in 13.4% of the patients in the lixisenatide group com-
pared to 13.2% in the placebo group. Importantly, lixisenatide
was not associated with a higher rate of serious adverse events,
severe hypoglycemia, pancreatitis, pancreatic neoplasms, or
allergic reactions compared to the placebo. In conclusion, lixi-
senatide did not demonstrate superiority over a placebo in re-
ducing cardiovascular events; however, it was deemed safe for
patients with acute coronary events within the previous 180
days. In conclusion, the results support that lixisenatide is safe
for cardiovascular disease but does not show clear cardiovas-
cular benefits [20].
Exenatide
The EXSCEL trial (2017)
The study’s primary focus was to assess whether adding once-
weekly exenatide ER treatment to standard care in patients
with T2DM was noninferior or superior to placebo in cardio-
vascular safety. This trial involved 14,752 patients, of whom
73.1% had previous cardiovascular disease, randomized to
receive 2 mg of ER-exenatide or placebo once weekly. The
primary outcome of the EXSCEL trial was defined as the first
occurrence of any component of a composite outcome, which
included death from cardiovascular causes, nonfatal MI, or
nonfatal stroke. The results showed that 11.4% in the exena-
tide group experienced a primary composite outcome event,
compared to 12.2% in the placebo group (P < 0.001 for non-
inferiority and P = 0.06 for superiority). Notably, there were
no significant differences between the two groups in terms of
death from cardiovascular causes, fatal or nonfatal MI, fatal
or nonfatal stroke, hospitalization for heart failure, hospitali-
zation for acute coronary syndrome, incidence of acute pan-
creatitis, pancreatic cancer, medullary thyroid carcinoma, and
serious adverse events. The trial’s findings suggest that exena-
tide can be a safe addition to the therapeutic regimen for these
patients without increasing their cardiovascular risk. However,
the study also puts in question the efficacy in improving car-
diovascular outcomes [21].
Albiglutide
HARMONY trial (2018)
This trial aimed to determine the safety and efficacy of albi-
glutide in preventing cardiovascular death, MI, or stroke in a
population with established cardiovascular disease. A total of
9,463 participants were randomly assigned to receive either a
Articles © The authors | Journal compilation © Cardiol Res and Elmer Press Inc™ | www.cardiologyres.org 3
Sabina et al Cardiol Res. 2024;15(1):1-11
Table 1. Summary of Head-to-Head Trials Comparing GLP-1 Agonists in A1c Lowering, Weight Reduction, and GI Side Effects
Trial Drugs compared Results of A1c
lowering
Results of weight
reduction
Results of GI side effects:
nausea/vomiting/diarrhea
LEAD-6 [5] Liraglutide (1.8 mg SC daily) 1.12% 3.24 kg 25.5%/6.0%/12.3%
Exenatide (10 µg SC twice daily) 0.79% 2.87 kg 28%/9.9%/12.1%
DURATION-6 [6] Liraglutide (1.8 mg SC daily) 1.48% 3.57 kg 20.7%/10.7%/13.1%
Exenatide ER (2.0 mg SC weekly) 1.28% 2.68 kg 9.3%/3.7%/6.1%
GETGOAL-X [7] Lixisenatide (20 µg SC daily) 0.79% 2.96 kg 24.5%/10.1%/10.4%
Exenatide ER (2.0 mg SC weekly) 0.96% 3.98 kg 35.1%/13.3%/13.3%
Trial by Nauck et al [8] Liraglutide (1.8 mg SC daily) 1.8% 4.3 kg 21.8%/6.9%/12.4%
Lixisenatide (20 µg SC daily) 1.20% 3.7 kg 21.8%/8.9%/9.9%
AWARD-1 [9] Dulaglutide (1.5 mg SC weekly) 1.51% 1.3 kg 28%/16.8%/11.1%
Dulaglutide (0.75 mg SC weekly) 1.30% Gained 0.2 kg 16.1%/6.1%/7.9%
Exenatide (10 µg SC twice daily) 0.99% 1.07 kg 25.7%/10.9%/5.8%
AWARD-6 [10] Dulaglutide (1.5 mg SC weekly) 1.42% 2.9 kg 20.4%/7.0%/12.0%
Liraglutide (1.8 mg SC daily) 1.36% 3.61 kg 18.0%/8.3%/12.0%
SUSTAIN-3 [11] Semaglutide (1.0 mg SC weekly) 1.5% 5.6 kg 22.3%/7.2%/11.4%
Exenatide ER (2.0 mg SC weekly) 0.90% 1.9 kg 11.9%/6.2%/8.4%
SUSTAIN-7 [12] Semaglutide (0.5 mg SC weekly) 1.5% 4.6 kg 23%/10%/14%
Semaglutide 1.0 mg SC weekly 1.8% 6.5 kg 21%/19%/14%
Dulaglutide (0.75 mg SC weekly) 1.1% 2.3 kg 13%/4%/8%
Dulaglutide (1.0 mg SC weekly) 1.4% 3.0 kg 20%/10%/18%
SUSTAIN-10 [13] Semaglutide (1.0 mg SC weekly) 1.7% 5.8 kg 21.8%/10.4%/15.6%
Liraglutide (1.2 mg SC daily) 1.0% 1.9 kg 15.7%/8%/12.2%
PIONEER-4 [14] Semaglutide (14 mg oral daily) 1.2% 1.5 kg 20%/9%/15%
Liraglutide (1.8 mg SC daily) 1.1% 0.9 kg 18%/5%/11%
PIONEER-10 [15] Semaglutide (3 mg oral daily) 0.9% 0 kg 5%/2%/2%
Semaglutide (7 mg oral daily) 1.4% 0.9 kg 8%/1%/2%
Semaglutide (14 mg oral daily) 1.7% 1.6 kg 9%/7%/8%
Dulaglutide (0.75 mg SC weekly) 1.4% 1.0 kg 9%/2%/6%
HARMONY-7 [16] Albiglutide (30 - 50 mg SC weekly) 0.78% N/A Total: 35.9%
Liraglutide (0.6 - 1.0 mg SC daily) 0.99% N/A Total: 49%
Rosenstock et al [17] Efpeglenatide (0.3, 1.0, 2.0,
3.0, or 4.0 mg SC weekly)
0.56%, 0.95%, 1.19%,
1.41%, 1.61%
1.21 kg 11%/0/14%
2.01 kg 8%/3%/3%
1.52 kg 27%/12%/9%
2.73 kg 22%/11%/11%
3.31 kg 33%/22%/5%
Liraglutide (1.8 mg SC daily) 1.38% 3.21 kg 33%/11%/14%
SURPASS-2 [18] Tirzepatide (5 mg SC weekly) 2.01% 7.96 kg 17.4%/13.2%/5.7%
Tirzepatide (10 mg SC weekly) 2.24% 9.3 kg 19.2%/16.4%/8.5%
Tirzepatide (15 mg SC weekly) 2.30% 11.2 kg 22.1%/13.8%/9.8%
Semaglutide (1 mg SC weekly) 1.86% 5.7 kg 17.9%/11.5%/8.3%
SURPASS J-MONO [19] Tirzepatide (5 mg SC weekly) 2.4% 5.8 kg 12%
Tirzepatide (10 mg SC weekly) 2.6% 8.5 kg 20%
Tirzepatide (15 mg SC weekly) 2.8% 10.7 kg 20%
Dulaglutide (0.75 mg SC weekly) 1.3% 0.5 kg 8%
GLP-1: glucagon-like peptide-1; SC: subcutaneous; ER: extended release; GI: gastrointestinal.
Articles © The authors | Journal compilation © Cardiol Res and Elmer Press Inc™ | www.cardiologyres.org
4
GLP-1 Receptor Agonists in Cardiovascular Health Cardiol Res. 2024;15(1):1-11
subcutaneous injection of albiglutide (30 - 50 mg, adjusted
based on glycemic response and tolerability) or a matched
dose of placebo once a week, alongside their standard care.
In the albiglutide group, the primary composite outcome oc-
curred in 7% compared to 9% in the placebo group, indicating
both noninferiority and superiority of albiglutide (P < 0.0001
and P = 0.0006, respectively). Notably, the incidence of other
serious adverse events, including acute pancreatitis, pancre-
atic cancer, and medullary thyroid carcinoma, did not signifi-
cantly differ between the two groups. However, there were
moderate glycemic differences between groups, limiting the
assessment of cardiovascular effects independent of glucose-
lowering [22]. Nonetheless, the data are strongly in favor of
albiglutide and its ability to reduce cardiovascular outcomes.
Efpeglenatide
The AMPLITUDE-O trial (2021)
This study focused on the cardiovascular and renal effects of
efpeglenatide in patients with type 2 diabetes who were also at
high risk for adverse cardiovascular events. Participants either
had a history of cardiovascular disease or current kidney dis-
ease, defined as an estimated glomerular filtration rate (eGFR)
of 25.0 to 59.9 mL/min/1.73 m2 of body-surface area, plus at
least one other cardiovascular risk factor. A total of 4,076 pa-
tients were randomized; 1,359 participants were assigned to
receive the 4-mg dose of efpeglenatide, 1,358 to receive the
6-mg dose of efpeglenatide, and 1,359 to receive placebo.
The primary outcome of the study was the occurrence of ma-
jor adverse cardiovascular events (MACEs), which included
nonfatal MI, nonfatal stroke, or death from cardiovascular or
undetermined causes. The key secondary outcomes included
an expanded MACE composite outcome (incorporating coro-
nary revascularization or hospitalization for unstable angina)
and a composite renal outcome (encompassing incident mac-
roalbuminuria, a significant increase in the urinary albumin-
to-creatinine ratio, a sustained decrease in the eGFR of ≥ 40%
for ≥ 30 days, renal-replacement therapy for ≥ 90 days, or a
sustained eGFR of < 15 mL/min/1.73 m2 for ≥ 30 days). In
the efpeglenatide group, an incident MACE occurred in 7.0%
compared to 9.2% in the placebo group, showing noninferior-
ity (P < 0.001) and superiority (P = 0.007) of efpeglenatide
compared to placebo. Additionally, a composite renal outcome
event occurred in 13.0% compared to 18.4% in the placebo
group, indicating a significant renal benefit (P < 0.001). How-
ever, GI side effects like diarrhea, constipation, nausea, vom-
iting, or bloating were more frequently reported with efpe-
glenatide than with placebo (P = 0.03). However, there was no
evidence of pancreatic, thyroid, or malignancy-related adverse
effects. Efpeglenatide improves cardiovascular outcomes and
provides renal benefits, critical considerations in managing pa-
tients with type 2 diabetes [23].
Dulaglutide
REWIND trial (2019)
The REWIND trial compared dulaglutide to placebo in patients
with T2DM and increased cardiovascular risk with the aim to
measure incidence of cardiovascular death, MI, and stroke. The
results showed a significant reduction in the composite outcome
for the dulaglutide group compared to the placebo group (12.0%
vs. 13.4%). The subgroups in the composite had varying re-
sults, however. Specifically, cardiovascular death and nonfatal
MI did not show significant differences. Only nonfatal strokes
showed a significant reduction (2.7% vs. 3.5% P = 0.017). Nota-
bly, eye or kidney microvascular outcome showed a significant
difference in the semaglutide group versus placebo (18.4% vs.
20.6%) (P = 0.002), concerning retinopathy as a side effect. On
the other hand, dulaglutide demonstrated a moderate effect on
macroalbuminuria (2.5% lower than placebo), a marker of kid-
ney health. Dulaglutide is in a great position when comparing
renal outcomes in GLP-1s, however, its efficacy in cardiovascu-
lar outcomes, although positive, does not appear to be as strong
as other competitors [24].
Table 2. Updated Ranking and Side Effects of GLP-1 Receptor Agonists When Comparing A1c Lowering and Weight Reduction
Drug (dose) Within class comparabili-
ty of A1c lowering efficacy
Within class comparabil-
ity of effect on weight
Within class compa-
rability of side effects
Albiglutide (30 - 50 mg SC weekly) Lowest N/A Low
Exenatide (10 µg SC twice daily) Lowest Lowest Highest
Lixisenatide (20 µg SC daily) Lowest Lowest Intermediate
Exenatide ER (2.0 mg SC weekly) Low Lowest Low
Dulaglutide (0.75 mg and 1.5 mg SC weekly) Intermediate Low Intermediate/high
Liraglutide (1.8 mg SC daily) Intermediate Intermediate Intermediate
Efpeglenatide (0.3, 1.0, 2.0, 3.0, or 4.0 mg SC weekly) Intermediate Intermediate High
Semaglutide (0.5 mg and 1.0 mg SC weekly) High High High
Semaglutide (7 mg and 14 mg oral daily) High High Intermediate/high
Tirzepatide (5 mg, 10 mg, 15 mg SC weekly) Highest Highest High
GLP-1: glucagon-like peptide-1; GI: gastrointestinal.SC: subcutaneous; ER: extended release; N/A: not available.
Articles © The authors | Journal compilation © Cardiol Res and Elmer Press Inc™ | www.cardiologyres.org 5
Sabina et al Cardiol Res. 2024;15(1):1-11
Liraglutide
The LEADER trial (2016)
This trial was a significant double-blind study evaluating the
cardiovascular effects of liraglutide in 9,340 patients with
type 2 diabetes and a high risk of cardiovascular disease. The
primary objective was to assess whether liraglutide was non-
inferior to placebo regarding major cardiovascular events,
defined as death from cardiovascular causes, nonfatal MI, or
nonfatal stroke. The results demonstrated that liraglutide was
noninferior and superior to placebo in reducing the incidence
of the primary composite outcome. Specifically, 13.0% of pa-
tients in the liraglutide group experienced a primary outcome
event compared to 14.9% in the placebo group. Furthermore,
liraglutide was associated with lower rates of death from car-
diovascular causes and death from any cause. However, the
differences in rates of nonfatal MI, nonfatal stroke, and hos-
pitalization for heart failure between the two groups were not
statistically significant. Compared to placebo, there was also
a reduction in systolic and diastolic blood pressure in the lira-
glutide group. Notably, there was a significant increased inci-
dence rate of gallbladder disease, nausea, vomiting, diarrhea,
and adverse events in the liraglutide group in comparison to
placebo. In conclusion, the LEADER trial provided evidence
of cardiovascular benefits of liraglutide in patients with type 2
diabetes and high cardiovascular risk, although not as strong
as other competitors. Also, the increased risk of GI side effects
is of concern [25].
Semaglutide
SUSTAIN-6 (2016)
The SUSTAIN-6 trial assessed semaglutide’s cardiovascular
safety in type 2 diabetes patients. It involved 3,297 participants
with established cardiovascular disease or chronic kidney dis-
ease (CKD). Participants were randomized to receive weekly
semaglutide (0.5 mg or 1 mg) or placebo alongside standard
care for 104 weeks; the trial’s primary composite outcome was
the first occurrence of cardiovascular death, nonfatal MI, or
nonfatal stroke. The outcome occurred in 6.6% of the sema-
glutide group versus 8.9% of placebo (P ≤ 0.001). Nonfatal MI
was 2.9% in the semaglutide group and 3.9% in placebo (P =
0.12); nonfatal stroke was 1.6% versus 2.7%, respectively (P =
0.04). Nephropathy rates were lower in the semaglutide group
(3.8% vs 6.1% in placebo). Semaglutide groups had more sig-
nificant systolic blood pressure reduction (1.3 mm Hg in 0.5
mg group and 2.6 mm Hg in 1 mg group, P < 0.001) than pla-
cebo. On the downside, retinopathy complications were higher
(3% vs. 1.8% in placebo, P = 0.02). GI side effects led to more
treatment discontinuations; they occurred in 50.7% and 52.3%
in the 0.5 mg and 1 mg semaglutide groups, respectively, com-
pared to 35.7% and 35.2% in placebo. The main GI side effects
were diarrhea, nausea, and vomiting. The pulse rate increase
was higher in the semaglutide group, particularly 2.0 beats per
minute (bpm) in the 1.0 mg group. Incidence of acute pancrea-
titis, gallbladder disorders, pancreatic cancer, and hypoglyce-
mia episodes were comparable between groups. No medullary
thyroid carcinomas were confirmed. In summary, the trial pro-
vided evidence for the cardiovascular safety of semaglutide in
type 2 diabetes patients, although not as strong as other com-
petitors, due to findings in nonfatal MI subgroup showing no
significant difference. The higher rates of retinopathy compli-
cations and significant GI side effects in the semaglutide group
highlighted potential safety concerns [26].
The PIONEER 6 trial (2019)
This trial compared oral semaglutide to placebo in patients
with T2DM with the aim of assessing its cardiovascular safety
by measuring MACEs, which include cardiovascular death,
nonfatal MI, and nonfatal stroke. It enrolled 3,183 patients
with established CKD or cardiovascular disease. The results
showed there was a 21% reduction in major adverse cardiovas-
cular outcomes in the oral semaglutide group in comparison to
placebo. However, rates of nonfatal MI and stroke were similar
between both groups. There was also a significant increase in
GI side effects in the semaglutide group. In summary, this trial
approves of oral semaglutide in use with patients with estab-
lished cardiovascular disease or CKD; however, its efficacy
may not be up to par as its competitors or subcutaneous for-
mulas [27].
SELECT trial (2023)
The SELECT trial, assessing semaglutide once a week sub-
cutaneously at 2.4 mg for 33 months in overweight or obese
(body mass index (BMI) 27 or greater) patients without dia-
betes, randomized 17,604 participants (8,803 to semaglutide,
8,801 to placebo) to evaluate cardiovascular risk reduction.
The primary endpoint (a composite of cardiovascular death,
nonfatal MI, or stroke) occurred in 6.5% of the semaglutide
group versus 8.0% of the placebo group over 39.8 months,
demonstrating a 20% risk reduction with semaglutide. Addi-
tionally, semaglutide led to a 9.39% weight reduction com-
pared to 0.88% in the placebo group over 104 weeks. Glycated
hemoglobin level above 6.5% was seen in 3.5% of the sema-
glutide group and 12% in the placebo group. These findings
are significant as they demonstrate the cardioprotective effects
of semaglutide at higher doses. However, its renal protective
effects highlighted in the SUSTAIN-6 trial were not apparent,
as 1.8% in the semaglutide group reached the endpoint versus
2.2% in the placebo. Notably, GI disorders caused discontinu-
ation in 9.39% of semaglutide participants versus 2.0% of pla-
cebo participants. It also showed a miniscule difference that
was significant for gallbladder-related disorders, more pre-
sent in the semaglutide group (2.8%) versus placebo (2.3%)
(P = 0.04). The study also presents with its limitations. It has
a narrow patient profile with a limited enrollment of women
(27.7%) and black individuals (3.8%). Also, patients with al-
ready established atherosclerotic cardiovascular disease (AS-
Articles © The authors | Journal compilation © Cardiol Res and Elmer Press Inc™ | www.cardiologyres.org
6
GLP-1 Receptor Agonists in Cardiovascular Health Cardiol Res. 2024;15(1):1-11
CVD) were excluded from the study, which might be a more
realistic generalizable population to consider [28]. In sum-
mary, this trial showed the increased semaglutide dose sub-
cutaneously (2.4 mg) did improve efficacy in cardiovascular
outcomes, glycemic control, and weight loss, however, at the
price of renal benefit previously provided in the lower doses
of the SUSTAIN-6 trial. Also, GI side effects were still present
along with an increase in gallbladder-related disorders not pre-
viously seen.
STEP-HFPEF trial (2023)
This study was recently completed and contributes immensely
to the potential use-case of GLP-1s in patients with heart fail-
ure and obesity. In this trial, 529 patients with heart failure
with preserved ejection fraction (HFpEF) and a BMI of 30 or
higher were randomized to receive either semaglutide 2.4 mg
once weekly or a matching placebo. The results showed a mean
change of 16.6 points in the clinical summary score (CSS) of
the Kansas City Cardiomyopathy Questionnaire (KCCQ),
which is a scoring system that provides a measure of symp-
toms and physical limitations associated with heart failure, in
favor of semaglutide compared to placebo. The 6-min walk
distance change averaged 21.5 m with semaglutide versus only
1.2 m with placebo. Notably, unlike past trials that highlighted
possible side effects of semaglutide, serious adverse events
were lower in the semaglutide group (13.3%) compared to the
placebo group (26.7%). This indicates that in this particular
patient population, semaglutide appears to have an improved
safety profile. In conclusion, the study demonstrates that
semaglutide can have a considerable role in managing obese
patients with HFpEF, providing considerable improvements
in symptoms, exercise function, reducing physical limitations,
and promoting significant weight loss [29].
SOUL trial (anticipated completion in 2025)
This trial is expected to be completed sometime in 2025 and
aims to establish oral semaglutide’s efficacy in reducing car-
diovascular outcomes, specifically those with ASCVD and
CKD. The primary endpoint focuses on the time to the first
occurrence of MACEs, including cardiovascular death, non-
fatal MI, or nonfatal stroke. Secondary outcomes encompass a
range of cardiovascular and kidney-related events. The study
also includes cognitive assessments, considering the potential
links between GLP-1 receptor agonists and cognitive decline.
This is a highly anticipated trial, which has the potential to
solidify semaglutide amongst the top of GLP-1s [30].
Tirzepatide
SURPASS-CVOT trial (anticipated completion in 2024)
The SURPASS-CVOT trial is a significant research study
evaluating the cardiovascular safety and efficacy of tirzepatide
compared to dulaglutide in individuals with type 2 diabetes and
established ASCVD. Participants were randomized to receive
either tirzepatide or dulaglutide once weekly by subcutaneous
injection in addition to their standard care. The trial’s primary
goal is to assess the effect of time on the first occurrence of
MACEs, defined as cardiovascular death, MI, or stroke. The
primary analysis includes noninferiority and superiority as-
sessments of tirzepatide versus dulaglutide and a putative pla-
cebo. The study population was high-risk, with 65% having
coronary disease, 47.3% reporting prior MI, 57.4% having
undergone coronary revascularization, 19.1% with a history of
stroke, and 25.3% with peripheral artery disease. In summary,
the SURPASS-CVOT trial aims to establish definitive evi-
dence of the cardiovascular safety and efficacy of tirzepatide.
Its first trial in doing so will be in comparison to dulaglutide,
a drug with known cardiovascular benefits. An ambitious goal
has been set for the novel dual agonist drug [31].
SUMMIT trial (anticipated completion in 2024)
This is a randomized, double-blind, placebo-controlled, phase
3 study comparing the efficacy and safety of tirzepatide ver-
sus placebo in patients with HFpEF and obesity. The primary
outcome measure is a hierarchical composite of all-cause mor-
tality, nonfatal MI, or nonfatal stroke. Secondary outcomes
include the percent change from baseline in body weight loss
at 104 weeks and changes in glycemic control markers. Sched-
uled for completion in July 2024, this study will attempt to join
semaglutide’s current standing amongst GLP-1s and cardio-
vascular benefits in patients with HFpEF [32].
Discussion
This review of GLP-1 receptor agonists comprehensively
analyzes their role in cardiovascular outcomes and presents a
streamlined discussion and conclusion of these drugs’ current
state and potential future.
Efficacy and safety in cardiovascular management
Each GLP-1 receptor agonist exhibits unique characteristics
regarding efficacy, safety, and suitability for specific patient
needs. Lixisenatide and exenatide ER, although both deemed
safe, have not been conclusively shown to reduce cardiovas-
cular outcomes, as shown by the ELIXA and EXSCEL trials
[20, 21]. Conversely, albiglutide, efpeglenatide, semaglutide,
liraglutide, and dulaglutide have established roles in reducing
cardiovascular outcomes. The HARMONY trial highlighted
albiglutide’s potential in this regard. Although its poor glyce-
mic control in comparison to other GLP-1s is of concern, the
HARMONY trial showed it has cardiovascular benefits with
superiority over placebo [22]. Efpeglenatide and dulaglutide,
in particular, also offer renal benefits, a significant factor in
type 2 diabetes management. Efpeglenatide showed superior-
ity over placebo in reducing cardiovascular outcomes, at the
Articles © The authors | Journal compilation © Cardiol Res and Elmer Press Inc™ | www.cardiologyres.org 7
Sabina et al Cardiol Res. 2024;15(1):1-11
price of increased GI side effects [23]. Dulaglutide showed
evidence of reduced cardiovascular outcomes although not as
strong as others, and despite some setbacks in head-to-head
trials, it remains a valuable option, especially for patients re-
quiring renal protection. Notably, patients did have increased
incidence of retinopathy [24]. Liraglutide appears to have
similar cardiovascular benefits as dulaglutide, however does
not offer renal protection, instead, it showed to offer reduc-
tions in systolic blood pressure [25]. Semaglutide, available
in subcutaneous and oral formulations, has emerged as a sig-
nificant therapeutic agent. Its efficacy extends beyond glyce-
mic control, demonstrating cardiovascular and renal benefits
in diverse patient populations, including those with diabe-
tes, prediabetes, obesity, and HFpEF. While the therapeutic
advantages of semaglutide are clear, it is not without side
effects. In low dose subcutaneous injection, there is a renal
and blood pressure benefit. In high dose subcutaneous injec-
tion (2.4 mg), the cardiovascular benefits are apparent and
strong, however, the renal benefit is lost. GI disturbances are
a notable concern, and there is a potential risk of retinopathy
and gallbladder disorders at the higher dose. The SOUL trial
is currently underway, which intends to compare efficacy in
Table 3. Results of Head-to-Head Trials When Comparing CV Outcomes in GLP-1 Receptor Agonists
Trial Drug (dose) vs. placebo Results in CV outcome reduction
(CV death/nonfatal MI/nonfatal stroke) P value Results of side effects
that were significant
ELIXA [20] Lixisenatide (10 µg SC daily) 21%/62.8%/13.3% 0.81 N/A
Placebo 23.3%/61.9%/12.3%
EXSCEL [21] Exenatide ER (2.0
mg SC weekly)
4.6%/6.6%/2.5% 0.06 Increased HR by 2.51 bpm
Placebo 7.9%/6.7%/2.9%
HARMONY [22] Albiglutide (30 - 50 mg) 7% P < 0.0006 None were significant.
Placebo 9%
AMPLITUDE
[23]
Efpeglenatide (4 or 6
mg SC weekly)
7% P = 0.007 Increased GI side effects
(constipation, diarrhea,
nausea, vomiting, bloating)
Placebo 9.20% Significantly fewer decreases
in kidney function
REWIND [24] Dulaglutide (1.5
mg SC weekly)
12% P = 0.026 Increased GI side effects
Placebo 13.40%
LEADER [25] Liraglutide (1.8 mg
SC weekly)
13% P = 0.01 Decreased incidence of renal
or retinal microvascular events
Placebo 14.90%
SUSTAIN-6 [26] Semaglutide (0.5 and
1.0 mg SC weekly)
6.60% P = 0.02 Increased incidence
of retinopathy
Decreased incidence of new
or worsening nephropathy
Placebo 8.90% Decreased blood pressure
by 2.6 mm Hg
PIONEER-6 [27] Semaglutide (14
mg oral daily)
0.9%/2,3%/0.8% P < 0.001 Increased GI side effects
Placebo 1.9%/1.9%/1.0%
SELECT [28] Semaglutide (2.4
mg SC weekly)
6.50% P < 0.001 Increased incidence of
gallbladder disorders
Placebo 8%
STEP HFPEF
[29]
Semaglutide (2.4
mg SC weekly)
+7.8 difference in KCCQ-CSS
score, +20.3 m difference in
6-min walk distance change
P < 0.001 Improved symptom and
physical limitations in HFpEF
Placebo
CV: cardiovascular; GLP-1: glucagon-like peptide-1; GI: gastrointestinal.SC: subcutaneous; ER: extended release; N/A: not available, bpm: beat per
minute; HFpEF: heart failure with preserved ejection fraction.
Articles © The authors | Journal compilation © Cardiol Res and Elmer Press Inc™ | www.cardiologyres.org
8
GLP-1 Receptor Agonists in Cardiovascular Health Cardiol Res. 2024;15(1):1-11
reducing cardiovascular outcomes in those with established
ASCVD in a 3.5 - 5-year long-term follow-up and will also
look into cognitive assessments to answer questions about
cognitive decline and its associations with GLP-1s [26-30].
Tirzepatide, with its dual-acting mechanism, has shown im-
pressive results in A1c reduction and weight loss, challeng-
ing semaglutide’s leadership in these areas. However, its car-
diovascular safety and efficacy are still under investigation
in the SURPASS-CVOT and SUMMIT trials. These trials,
testing tirzepatide against dulaglutide in patients with AS-
CVD and evaluating its impact on obese patients with HF-
pEF, respectively, are highly anticipated. Their outcomes are
intended to challenge semaglutide’s current hold on T2DM
and obesity when considering cardiovascular outcomes. We
have summed up the results of each trial discussed in this
analysis in Table 3 [20-29].
After analysis of these trials, we have also established an
updated ranking system that takes into consideration cardio-
vascular outcomes and other benefits that were found (Table
4).
In terms of cardiovascular safety and efficacy, the ranks
are as follows: semaglutide (subcutaneous (SC) 2.4 mg) = ef-
peglenatide = albiglutide > semaglutide (0.5 mg and 1 mg SC)
= dulaglutide = liraglutide > semaglutide (oral) > lixisenatide
= exenatide ER.
Future prospects and research needs
There is a pressing need for long-term data on the efficacy
and safety of GLP-1 receptor agonists, particularly for pe-
riods extending beyond 3 years. Such data are essential for
Table 4. Ranking of GLP-1 Receptor Agonists When Comparing CV Outcomes
Drug (dose) Within class comparabili-
ty of A1c lowering efficacy
Within class compara-
bility of effect on weight
Within class comparability of
cardiovascular safety/efficacy
Strengths and
weaknesses
Albiglutide (30 - 50 mg) Lowest Unknown High Poor glycemic control
Exenatide (10 µg
SC twice daily)
Lowest Lowest Unknown
Lixisenatide (10
µg SC daily)
Lowest Lowest Lowest No significant
difference from
placebo
Exenatide ER (2.0
mg SC weekly)
Low Lowest Lowest No significant
difference from
placebo
Dulaglutide (1.5
mg SC weekly)
Intermediate Low Intermediate Renal benefit
Increased GI
side effects
Liraglutide (1.8
mg SC weekly)
Intermediate Intermediate Intermediate Renal benefit
BP lowering
Efpeglenatide (4 mg
or 6 mg SC weekly)
Intermediate Intermediate High Renal benefit
Semaglutide (14
mg oral daily)
High High Low Increased GI
side effects
Semaglutide (0.5 mg
and 1.0 mg SC weekly)
High High Intermediate Renal benefits,
BP lowering
Increased retinopathy
Increased GI
side effects
Semaglutide (2.4
mg SC weekly)
Highest Highest High HFpEF benefits
Increased incidence
of gallbladder
disorders
Tirzepatide Highest Highest Unknown No studies
completed yet
CV: cardiovascular; GLP-1: glucagon-like peptide-1; GI: gastrointestinal.SC: subcutaneous; ER: extended release; HFpEF: heart failure with pre-
served ejection fraction; BP: blood pressure.
Articles © The authors | Journal compilation © Cardiol Res and Elmer Press Inc™ | www.cardiologyres.org 9
Sabina et al Cardiol Res. 2024;15(1):1-11
understanding the sustainability of benefits and long-term
risks. Head-to-head trials have been established when com-
paring obesity and A1c-lowering management, but there is a
gap in the literature when comparing cardiovascular outcomes
head-to-head. Observational studies and registries could pro-
vide valuable insights into the performance of these drugs
in more diverse and real-world patient populations. Most, if
not all, studies are industry driven, providing a risk of bias.
Furthermore, cost-effectiveness analysis and patient-centered
outcomes research are vital to inform policy decisions and en-
hance patient care. It is important to cater to patient needs,
even when considering economic feasibility. One particular
study has already shown tirzepatide to be more cost-effective
than semaglutide [33]. The potential introduction of new
drugs, like the triple agonist retatrutide, shows promise, es-
pecially in obesity management [34]. We are still in the early
stages of the development and unfolding of a new class of
medications that are highly anticipated to answer the increas-
ingly worsening pandemic of T2DM, obesity, and its cardio-
vascular implications in the world. The next couple of years
plan to catapult GLP-1s into the world of everyday care of
cardiologists and their patients.
We have summed up below trials that are highly antici-
pated (Table 5) to add to the discussion of GLP-1s and their
safety and efficacy in reducing cardiovascular outcomes.
Conclusions
The landscape of GLP-1 receptor agonists is dynamic and
competitive, with each drug contributing uniquely to cardio-
vascular outcomes in patients with type 2 diabetes. The com-
ing years are critical for determining the most effective and
safe treatments, with the potential for new therapies to revolu-
tionize this field further. The continued focus on comprehen-
sive, long-term, and patient-centered research will be pivotal
in shaping the future of diabetes and cardiovascular disease
management.
Acknowledgments
None to declare.
Financial Disclosure
None to declare.
Conflict of Interest
None to declare.
Author Contributions
Michael Sabina conducted a comprehensive systematic re-
view, encompassing the identification, screening, eligibility,
and inclusion of relevant studies, performed an extensive lit-
erature search, ensuring the inclusion of pertinent publications
and data sources, executed a thorough analysis of the collected
data, interpreting findings with a focus on relevance and im-
pact, designed and compiled all tables presented in the manu-
script, ensuring clarity and accuracy of the data displayed, and
authored the discussion and conclusions sections, synthesiz-
ing the findings into coherent insights and recommendations.
M Mrhaf Alsamman provided overall oversight for the pro-
ject, ensuring adherence to research objectives and academic
standards, performed critical final edits to the manuscript,
enhancing its clarity, coherence, and overall quality, ensured
that the paper was comprehensive and accurate, with par-
ticular attention to the verification of data and information
presented, and supplied essential resources necessary for the
successful completion of the research and preparation of the
manuscript.
Data Availability
The authors declare that data supporting the findings of this
study are available within the article.
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