Taktaz et al. Cardiovascular Diabetology
(2024) 23:242
https://doi.org/10.1186/s12933-024-02319-7
Cardiovascular Diabetology
Open Access
REVIEW
Bridging the gap between GLP1-receptor
agonists and cardiovascular outcomes:
evidence for the role of tirzepatide
Fatemeh Taktaz1, Rosaria Anna Fontanella1, Lucia Scisciola1*, Ada Pesapane1, Manuela Giovanna Basilicata1,
Puja Ghosh1, Martina Franzese1, Giovanni Tortorella1, Armando Puocci1, Maria Teresa Vietri2,3, Annalisa Capuano4,
Giuseppe Paolisso1,5 and Michelangela Barbieri1
Abstract
Tirzepatide is a new drug targeting glucagon-like peptide 1(GLP1) and gastric inhibitory polypeptide (GIP)
receptors. This drug has demonstrated great potential in improving the clinical outcomes of patients with type
2 diabetes. It can lead to weight loss, better glycemic control, and reduced cardiometabolic risk factors. GLP1
receptor agonists have been proven effective antidiabetic medications with possible cardiovascular benefits. Even
though they have been proven to reduce the risk of major adverse cardiovascular events, their effectiveness in
treating heart failure is unknown. Unlike traditional GLP1 receptor agonists, tirzepatide is more selective for the
GIP receptor, resulting in a more balanced activation of these receptors. This review article discusses the possible
mechanisms tirzepatide may use to improve cardiovascular health. That includes the anti-inflammatory effect, the
ability to reduce cell death and promote autophagy, and also its indirect effects through blood pressure, obesity,
and glucose/lipid metabolism. Additionally, tirzepatide may benefit atherosclerosis and lower the risk of major
adverse cardiac events. Currently, clinical trials are underway to evaluate the safety and efficacy of tirzepatide
in patients with heart failure. Overall, tirzepatide’s dual agonism of GLP1 and GIP receptors appears to provide
encouraging cardiovascular benefits beyond glycemic control, offering a potential new therapeutic option for
treating cardiovascular diseases and heart failure.
Introduction
Tirzepatide (LY3298176) is the first peptide dual agonist
for type 2 diabetes mellitus (T2DM), which targets both
GIPR and GLP1R. According to primary trials in T2DM,
tirzepatide significantly reduces clinical outcomes like
body weight, glycated hemoglobin (HbA1c), lipid profiles, and glucose-adjusted glucagon secretion compared to typical glucagon-like peptide1 receptor agonists
*Correspondence:
Lucia Scisciola
lucia.scisciola@unicampania.it
Full list of author information is available at the end of the article
(GLP1RAs) [1, 2]. Additionally, new research indicates
that tirzepatide potentially has some advantages over traditional metabolic regulation, such as insulin sensitivity
improvement and anti-inflammatory effect [2]. The dual
mechanism of tirzepatide has a synergistic impact that
is strong enough to significantly lower the risk of cardiovascular events [3, 4]. Studies suggest tirzepatide may
help improve cardiometabolic risk factors and reduce
the risk of atherosclerotic cardiovascular disease (CVD).
These risk factors include blood pressure, cholesterol,
and chronic inflammation [3]. In SURPASS 4 The risk of
suffering from any major adverse cardiovascular event
MACE-4 and MACE-3 (including myocardial infarction,
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Taktaz et al. Cardiovascular Diabetology
(2024) 23:242
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Graphical abstract
Keywords Tirzepatide, GLP-1 receptor, GIP receptor, GLP1 receptor agonists, Heart failure
stroke, hospitalization for angina, and all-cause death)
with the highest dose of tirzepatide (15 mg per week) has
been estimated at 0·50 (0·26–0·95), which was intended
to provide initial proof of the cardiovascular safety of
tirzepatide [2, 5]. The FIGHT trial specifically evaluated
using the GLP-1RAs, liraglutide, in patients with HF with
reduced ejection fraction (HFrEF). Although the trial did
not show a significant advantage in reducing cardiovascular events [6], or hospitalizations, it provided insights
into liraglutide’s safety and tolerability in this patient
population [6]. Ongoing research, such as the SUMMIT
trial, is presently assessing the safety and efficacy of tirzepatide in HF patients with preserved ejection fraction
(HFpEF). However, comprehensive data on the direct
effects of HF are still being developed (NCT04847557).
Additionally, the positive outcomes of ongoing trials
SURPASS-CVOT and SURMOUNT-MMO will provide
definitive evidence regarding the cardiovascular safety
and efficacy of tirzepatide compared to dulaglutide and
reduction in morbiditiy and mortality in adults with
obesity respectively. CVOT trial will help determine if
tirzepatide can demonstrate superior cardiovascular
safety and potential additional cardiovascular benefits
compared to the currently approved GLP-1RA dulaglutide. the data from these two large, well-powered clinical
trials will provide robust evidence on the cardiovascular
and metabolic benefits of tirzepatide, potentially expanding the treatment options for adults with T2DM, obesity,
and related cardiovascular complications [7] (Clinical
Traials.gov). SURMOUNT-1 trial suggests that tirzepatide may have a promising future as a therapy for obesity,
HF, and non-alcoholic fatty liver disease (NAFLD) [5,
8]. Previous meta-analyses have indicated that tirzepatide might potentially decrease the risk of cardiovascular
events by affecting cardiac cells, the pancreas, and other
tissues directly and indirectly [2]. Also, the efficacy and
safety of tirzepatide may have a wider perspective for its
use beyond patients with T2DM or obesity [9, 10]. This
review will discuss the limitation of GLP1RAs in patients
with HF, along with ongoing trials assessing the safety
Taktaz et al. Cardiovascular Diabetology
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and effectiveness of tirzepatide, look into the existing
data, and elucidate tirzepatides potential impact on cardiovascular disease.
The role of GLP-1/GIP receptors: tirzepatide
imbalanced and biased activation
Human atrial and ventricular cardiomyocytes express
the GLP1R within each of all chambers, and the sinoatrial (SA) node shows the highest level of GLP1R
expression [11, 12]. GIPR, unlike the GLP1R, is extensively expressed in the ventricular myocardium of both
rodents and humans. Boosting GIPR activity could
directly affect the myocardium and indirectly influence
cardiovascular function and outcomes through its systemic effects on other organs [13]. Identifying GLP1R
and GIPR in endothelial cells, vascular smooth muscle
cells, and blood has underscored their significant roles
in vascular function [11]. The activation of GLP1R and
GIPR by specific ligands triggers intracellular signaling cascades that regulate the structure and function of
the heart. Both receptors canonical signaling pathway
involves coupling to Gαs proteins, and in turn, triggers
adenylyl cyclase activation and leads to the production of cyclic adenosine monophosphate (cAMP). The
increased cAMP levels in cardiac cells activate exchange
protein directly activated by cAMP (EPAC) and protein
kinase A (PKA), which regulate a multitude of downstream effectors involved in cardiac contractility, relaxation, and hypertrophy [14]. and GIP receptors have
also been demonstrated to activate phosphoinositide
3-kinase (PI3K) and its downstream effector Akt, which
modulates mitochondrial function, metabolism, and cell
survival. Recent data indicates that both receptors may
interact through β-arrestin-dependent pathways, potentially contributing to their cardioprotective properties
without involving G protein signaling [15]. Interestingly,
the rise in hormone-sensitive lipase (HSL) phosphorylation within cardiac myocytes appears to rely on a GIPRmediated increase in ERK phosphorylation. This implies
that GIP activity may regulate myocardial triacylglycerol
(TAG) metabolism. Additionally, the infusion of native
human GIP (1–42) into cardiac myocytes isolated from
embryonic mouse hearts inhibited the increase in brain
natriuretic peptide (BNP) and transforming growth factor- β (TGF- β 1) mRNA expression induced by angiotensin II (Ang II) [13]. This could be the key to tirzepatide’s
remarkable efficacy. It is expected that tirzepatide will
occupy a greater percentage of GIPR than GLP1R (4.1,
4.6, and 6.3 fold, respectively, at 15, 10, and 5 mg) [16].
Tirzepatide is formulated to mimic the function of native
GIP at the GIPR while also interacting with the GLP1R in
a manner different from native GLP1. Additionally, tirzepatide was designed to bind to the GIPR with an affinity 5-fold stronger than that for the GLP1R, resulting in
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greater potency and selectivity in engaging the GIPR over
the GLP1R. Also, experiments conducted in primary islet
cells have shown that β-arrestin1 restricts the insulin
secretion response to GLP1R activation, but not to GIPR
activation or tirzepatide. This indicates that the biased
agonism properties of tirzepatide, which preferentially
activates specific signaling pathways, enhance its ability
to stimulate insulin secretion [17, 18]. Additionally, tirzepatide demonstrates bias at the GLP1R, favoring the
synthesis of cAMP over the recruitment of β-arrestin [1].
Studies have found that tirzepatide’s hormone-secreting
activities depend on GIPR, highlighting the critical role
that GIPR plays in the medication’s mechanism of action
and its therapeutic effects [19]. Tirzepatide appears to
activate GIPR stronger than GLP1R in cell systems with
high levels of both gene expressions [20]. Tirzepatide
has three critical improvements over first-generation
GLP1RAs. Firstly, it alters multiple residues in the peptide structure to mimic GIP role at GIPR. Additionally, it
extends the C-terminal with a sequence of exenatide, and
thirdly, it has an attached fatty acid side chain, similar to
semaglutide, to prolong its half-life [16].
Tirzepatide and cardiovascular disease
A previous study has shown that tirzepatide can protect
human cardiomyocytes by effectively ameliorating apoptosis, fibrosis, and hypertrophy when exposed to high
glucose. This highlights tirzepatide’s potential as an alternative treatment for clinical outcomes related to HF management. However, further research is needed to evaluate
its impact on HF outcomes in clinical settings [21].
Atherosclerosis
Up to 85% of cardiovascular deaths are related to atherosclerotic heart disease, which occurs as heart attacks
and strokes. In the cardiovascular system, atherosclerosis becomes apparent as the “invisible killer.” Atherosclerosis causes cerebral ischemia, or angina pectoris, with
the development of atherosclerotic plaques. This may
result in severe clinical manifestations like myocardial
infarction (MI) and HF [22–24]. In the LEADER trial,
liraglutide demonstrated cardiovascular benefit, and
GLP1RAs have similar effects, aligning with liraglutide’s
anti-atherosclerotic effect. GLP1RAs have shown the
ability to decrease the development and advancement of
atherosclerosis in preclinical and clinical investigations
[25, 26]. There is also a current clinical study examining
injectable semaglutide’s effect on coronary atherosclerosis development [27]. Moreover, a decrease in atherosclerotic cardiovascular disease (ASCVD) has been found
in people treated with semaglutide who were obese or
overweight, but, this trend was not statistically significant [28]. Based on SURMOUNT-1 data analysis, tirzepatide decreased the 10-year estimated risk of ASCVD
Taktaz et al. Cardiovascular Diabetology
(2024) 23:242
for obese or overweight patients. It has been shown that
tirzepatide can lower the risk of ASCVD by improving
lipid, glucose, and HbA1c levels, as well as blood pressure
and waist circumference. Interestingly enough, patients
with higher baseline ASCVD risk with tirzepatide therapy showed significantly more reductions in risk [3]. It is
crucial to address ASCVD disease in T2DM at an earlier
stage, with more intensively and precision. Several factors contribute to the heightened risk of atherosclerosis,
and a comprehensive approach is essential for preventing
or reducing atherosclerotic events[29]. Preclinical studies have indicated that GLP1RAs, such as tirzepatide,
may directly impact the vasculature by enhancing endothelial function and decreasing inflammation, which are
important in preventing atherosclerosis[30]. Tirzepatide has the potential to prevent atherosclerosis risk in
T2DM patients without pre-existing lesions. For those
with established atherosclerosis, the focus would be on
managing the existing condition and preventing further
progression [31]. Tirzepatide has been shown in clinical
trials to reduce the risk of cardiovascular events at various doses, suggesting a potential treatment option for
patients who are obese or overweight [2]. According to
the study conducted by Nagashima et al., treatment of
17-week-old mice with GIP via subcutaneous injection
showed a significant decrease in the size of aortic atherosclerotic lesions and macrophage infiltration. These
findings emphasize the importance of GIPR activity and
its anti-sclerotic role [32–34]. Moreover, according to
research by Ojima et al., a GIP concentration of 50 pM
effectively suppressed the generation of reactive oxygen
species (ROS) in human umbilical vein endothelial cells
(HUVECs) exposed to AGE. A reduction in the expression levels of the AGE receptor facilitated this effect. The
study also noted a decrease in the expression level of proatherogenic molecule factors such as plasminogen activator inhibitor-1 (Pai-1) [35]. GIP may reduce oxidative
stress in endothelial cells and visceral adipose tissue and
decrease the secretion of inflammatory cytokines [36].
Moreover, activation of endothelial nitric oxide synthase
(NOS) in HUVECs by GIP at 1 nM decreased inflammatory inducible NOS expression levels. It increased the
production of NO, which is an anti-atherogenic molecule
[37, 38]. Moreover, GIP at pharmaceutical doses may
prevent atherosclerosis, causing obesity, and the positive
benefits of GIP may also be maintained in animals [39].
Tirzepatide, with a dual activity target GIP and GLP1
receptor, may have consequences for preventing or mitigating atherosclerosis due to its impact on GIPR activity.
Major adverse cardiovascular events (MACE)
The research examined eight large cohorts of T2DM
patients, with cardiovascular outcome trials (CVOTs),
for main MACE outcomes, including cardiovascular
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death, nonfatal MI, and nonfatal stroke, which were
studied with GLP1RAs [40]. The primary and secondary outcome endpoints of MACE and nonfatal stroke
demonstrated significant reductions in the dulaglutidetreated REWIND trial and the subcutaneous semaglutide-treated SUSTAIN-6 study [41]. Recent evidence has
suggested that GLP1RAs may decrease the incidence
of stroke in people with T2DM. To evaluate the incidence of MACE-4 events in patients treated with tirzepatide compared to the control group, a meta-analysis
was conducted using data from 7778 patients enrolled
in the SURPASS-4 study, SURPASS Clinical Trails Program (which includes 7 randomized clinical trials), and
SURMOUNT-1. The overall hazard ratio (HR) estimate
was 0.59 (95% CI 0.40–0.79), indicating that tirzepatide resulted from a significant reduction in the risk of
MACE-4 compared to the control group [21]. As tirzepatide was compared to controls, the hazard ratios for
MACE-4 were 0.80 (95% confidence interval [CI], 0.57–
1.11), cardiovascular death was 0.90 (95% CI, 0.50–1.61),
and all-cause death was 0.80 (95% CI, 0.51–1.25) [2]. It is
essential to keep in mind that the current data suggests
tirzepatide may be efficient in downgrading the possibility of stroke; however, trials developed mainly to evaluate the long-term impact of tirzepatide on cardiovascular
events, including stroke, are currently in progress [42].
Heart failure
Heart failure is a prevalent disease that impacts nearly
2% of the global population. Diagnosis of HF requires
the presence of an underlying cardiac abnormality. Usually, this is a cardiac abnormality that results in either
diastolic or systolic ventricular dysfunction (e.g., myocardial infarction or coronary artery disease). Moreover,
damage or weakness in the heart muscle itself, disorders
of the valves such as stenosis or regurgitation, endocardium, cardiac conduction and rhythm, pericardium, or
all of these changes can cause HF [43, 44]. Also, both
systolic and diastolic dysfunction stemming from the
interplay between atherosclerotic coronary disease and
diabetic cardiomyopathy are associated with the underlying pathophysiology of HF in patients with T2DM [45,
46]. Several mechanisms may contribute to the positive
effects of GLP1RAs in preventing HF and influencing the
outcomes for patients with either HFpEF or HFrEF. Also
GLP1RAs have been found to decrease epicardial fat,
which may help explain their potential in lowering the
risk of atherosclerosis. On the other hand the GLP1R in
both cardiomyocytes and sinoatrial node cells can activate cyclic AMP (cAMP)-dependent signaling pathways.
This may lead to an excessive influx of calcium into cells.
This calcium dysregulation could be associated with the
pathophysiology of HF in patients with diabetes [47].
Sardu et al. found that GLP1RAs significantly raised
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LVEF and 6-minute walking test (6MWT) in T2DM
with HF [48]. According to previous studies, liraglutide attenuates myocardial hypertrophy and fibrosis following angiotensin II infusion by suppressing TGF-β1/
Smads signaling pathways [49]. Nevertheless, GLP1RAs
did not statistically significantly improve systolic function, as demonstrated by Kumarathurai et al. [50]. The
findings revealed that GLP1RAs could extend 6MWT
and lower the risk of HF hospitalization in people without a history of HF; however, their effects on HF hospitalization with a history of HF, NT-proBNP levels, and
quality of life were not statistically significant. GLP1RAs
significantly decreased E-wave velocity, E/A ratio, E/e
_ ratio, and EDT but did not affect LVEF. In addition,
patients with HF can have their cardiac function and
prognosis assessed using 6MWT, NT-proBNP, and QoL
[51]. A single trial that evaluated GLP1RAs in patients
with a history of HF and HFpEF demonstrated reduced
HF hospitalizations. However, this trial was limited by
small sample size and potential flaws in the selection of
endpoints (NCT04916470 and NCT05371496) [52]. The
SUMMIT study assesses tirzepatide’s impact on HF with
HFpEF in obese patients. The research suggests that for
patients with HF with HFrEF, the dual therapy of tirzepatide and guideline-directed medical therapy (GDMT)
may be a viable treatment approach. GDMT for HFrEF
typically includes evidence-based beta-blockers, angiotensin receptor neprilysin inhibitors (ARNIs), angiotensin receptor blockers (ARBs), angiotensin-converting
enzyme (ACE) inhibitors, mineralocorticoid receptor
antagonists (MRA), and sodium-glucose cotransporter
2 inhibitors (SGLT2is), particularly in patients with obesity or T2DM [53]. Despite the lack of research on tirzepatide, especially in HF patients, its cardiovascular
effects indicate potential benefits for this population.
Tirzepatide is presently being examined in a clinical trial
(NCT04847557) for patients with moderate HF (NYHA
class II-IV) with HFpEF [54]. The research outcomes
suggest that human cardiac cells treatment with tirzepatide resulted in an augmentation of Sarco/Endoplasmic
Reticulum Calcium ATPase 2 (SERCA2) and p-Phospholamban (p-PLN) activity and expression while reducing Calcium/Calmodulin-Dependent ProtienKinase II
(CAMKII) expression. These markers are pivotal in regulating calcium signaling, and the intervention effectively
mitigates calcium overload in cardiomyocytes exposed to
elevated glucose levels. Furthermore, the study showed
that tirzepatide correlated with a marked decrease in
the levels of key indicators associated with fibrosis and
hypertrophy, such as TGF- β, Matrix Metalloprotieinase-9 (MMP9), Collagen Type I Alpha 1 (COLIA1) and
F-box only protein 32 (FBXO32) [21].
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Direct mechanisms of tirzepatide on cardiovascular health
Although the precise mechanism by which tirzepatide
could benefit HF is not known, several potential pathways have been suggested:
Anti-inflammatory effects
Patients with T2DM experience increased levels of
hyperinsulinemia, hyperglycemia, and insulin resistance.
These conditions result in the overproduction of AGEs,
accumulation of pro-inflammatory and pro-fibrotic factors, and free fatty acid oxidation. These outcomes lead
to the remodeling of the extracellular matrix, oxidative
stress, inflammation, cardiomyocyte apoptosis, fibrosis, and metabolic abnormalities [55]. It has been determined that inflammation has been identified as a severe
risk factor for the development of cardiovascular diseases
[56]. Excessive ROS production can lead to cellular damage by increasing the formation of AGEs, its receptor
(RAGE), protein kinase C (PKC), and NF-κB. GLP1RAs
can inhibit neutral lipid accumulation, ROS generation,
and (NADPH oxidase 4) NOX-4 expression in rat cardiomyocytes, thereby migrating interleukin-1 β (IL-1 β)
induced ROS production [57]. After 26 weeks of tirzepatide treatment at different doses, several biomarkers associated with inflammation were reduced. These
biomarkers include leptin, chitinase-3 like-protein-1
(YKL-40), growth differentiation factor 15 (GDF-15),
and intercellular adhesion molecule 1 (ICAM-1). These
circulating markers are linked to inflammation and
endothelial dysfunction, which can lead to cardiovascular events. C-reactive protein (CRP) and YKL-40 concentrations were lower after tirzepatide administration
compared to the baseline. Additionally, tirzepatide treatment decreased the levels of both markers compared to
placebo and dulaglutide [31]. Combining tirzepatide with
GLP-1 and GIP hormones may lead to a more significant reduction in inflammation compared to GLP1RAs
alone due to their anti-inflammatory effects [58]. Recent
research has shown that GIP helps reduce oxidative
stress in human endothelial cells and prevents the release
of inflammatory cytokines in visceral adipose tissue [59].
Liu et al. concluded that tirzepatide was found to be
effective in improving cardiac dysfunction and increasing survival rates in mice that were treated with LPS.
The study revealed that tirzepatide can reduce inflammation and apoptosis caused by LPS in the heart. This
suggests that tirzepatide inhibits the activation of TLR4/
NLRP3/ NF-κB inflammasome signaling pathways. The
study also found that tirzepatide reduces the risk of ventricular arrhythmia in LPS-treated mice [60]. It is generally accepted that TLR4 plays an essential role in cardiac
inflammation, and NF-κB serves as a downstream mediator of TLR4 in the heart. Previous research has shown
that the NLRP3 pathway is one of NF-κB’s downstream
Taktaz et al. Cardiovascular Diabetology
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pathways [61–63]. Ventricular arrhythmias are typical of
critically patients suffering from acute sepsis and have
been linked to poor outcomes. According to a study by
Chuang et al., exposure to LPS increases this population’s
risk of ventricular arrhythmias [64, 65]. Previous research
has shown that GLP1 (9–36) can decrease levels of IL-1
β, interleukin 6 (IL-6), and tumor necrosis factor-α (TNFα). Another research has evaluated that blocking NLRP3mediated inflammation and apoptosis can reduce cardiac
damage caused by LPS [66]. A study found that tirzepatide treatment can reduce inflammation in the hearts of
sepsis mice. This suggests that tirzepatide may have cardioprotective benefits by acting as an anti-inflammatory
agent [67]. Furthermore, tirzepatide therapy in diabetic
rats restored specific abnormal alterations in signal molecules related to inflammatory signaling pathways via
PI3K/Akt/GSK3β signaling pathway [68].
Cell death and autophagy
Mitochondria, the powerhouse of cells, require proper
maintenance through processes like mitophagy, fusion,
fission, and biogenesis to perform their physiological
functions. However, in diabetic cardiomyopathy, there is
a disruption in the quality control of mitochondria, which
results in an inadequate fusion process, increased fission,
and fragmentation [69]. Although only a small number of
cardiomyocytes experience cell death due to apoptosis,
activating apoptotic pathways can worsen cardiac dysfunction. Therefore, apoptosis is frequently associated
with the mechanisms that cause sepsis-induced cardiac
depression [70–72]. In our previous studies, tirzepatide
therapy elevated the levels of anti-apoptotic marker Bcl2
and reduced the levels of Bax in human cardiac cells.
Additionally, it significantly reduced the activation of
CASP3, a crucial component of apoptotic pathways. It
also led to a significant reduction in the autophagy biomarkers Beclin1 and p62, which indicates an increase in
autophagy flux [21] Fig. 1.
Tirzepatide’s indirect impact on cardiovascular system
Glucose and lipid metabolism
The study conducted by Karagiannis et al. found that tirzepatide led to significant dose-dependent reductions in
HbA1c levels when compared to a placebo, once-weekly
GLP-1RAs, and basal insulin regimens. Interestingly,
there was no correlation between the positive effect on
glycemic control and an increased risk of hypoglycemia
[73]. Tirzepatide’s insulinotropic effects on human islets
depend on GIPR activity, according to Ei et al. [19]. It is
possible to hypothesize that activation of GIPR has the
potential to protect from ischemic heart, given its similar
effects on insulin production and myocardial Akt phosphorylation in mice and also a cardioprotective effect of
ligargudide further supports this hypothesis [74]. It is
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suggested that activating GIPR can increase the development of white adipose tissue (WAT), which can enhance
long-term lipid storage and improve adipocytes’ ability
to remove dietary triglycerides (TAG) [75, 76]. Also, GIP
is a substance that enhances insulin sensitivity in adipocytes. It may increase glucose uptake by breaking down
TAGs in chylomicrons through LPL activity and transporting glucose through a protein called GLUT4. These
effects seem to be mediated by GLUT4, which triggers
PI3K/PKB, and glucose, which inhibits the LKB1/AMPK
pathway. Additionally, pCREB, nuclear translocation,
and transcriptional activity of TORC2, a protein complex, also play a role in LPL recruitment. These mechanisms are different from the classical signaling pathway
of GIPR [75]. Tirzepatide is a medication that improves
insulin sensitivity, which can be evaluated indirectly
through fasting biomarkers such as glucose and insulin
and the homeostasis model assessment of insulin resistance (HOMA2-IR). When compared to GLP1RAs,
which improve insulin sensitivity primarily through
weight reduction, a post-doc regression analysis of
HOMA2-IR indicates that only 20–30% of the improvement in insulin sensitization observed with tirzepatide
is due to weight loss (NCT03951753) [77, 78]. In poorly
managed T2DM treated with basal insulin, tirzepatide
can improve glucose control without hypoglycemia risk,
alone or in combination with other oral hypoglycemic
medications [79]. A recent clinical trial has found that in
patients with T2DM, tirzepatide performed better than
GLP1RAs and dulaglutide monotherapy regarding glycaemic management and body weight reduction. In the
same trial, tirzepatide and semaglutide were compared
once weekly in the open-label, phase III SURPASS-2
experiment. Regarding average changes in HbA1c levels, tirzepatide demonstrated both non-inferiority and
superiority to semaglutide at all doses [80, 81]. HbA1c is
crucial for assessing diabetes severity and HF development risk [82]. Tirzepatide may improve glycemic control by directly and indirectly affecting the pancreas and
other tissues. It increases insulin secretion from pancreatic β-cells, reduces glucose-adjusted glucagon secretion, and improves insulin sensitivity more than what can
be typically achieved through weight loss. This means
that tirzepatide has the potential to improve glycemic
control better than GLP1RAs [77, 83]. Studies such as
SURPASS 1–5 and J-mono have demonstrated that tirzepatide is more effective than other therapy alternatives
in reducing HbA1C levels [84, 85]. In a study conducted
on Japanese patients with T2DM, those who received
tirzepatide doses ranging from 5 to 15 mg for 52 weeks
experienced a significant decrease in HbA1c levels by
2.4–3.02%. Furthermore, compared to dulaglutide, tirzepatide at a dose of 0.75 mg once weekly was more effective at controlling blood glucose levels in this cohort.
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Fig. 1 Comprehensive picture of molecular and cellular interaction relevant to beneficial effect of tirzepatide in metabolic and cardiovascular disorders. It is signaling pathways associated with GIP and GLP1 receptors, as well as key molecules cAMP and PKA involved in cellular processes related to
cardiovascular pathophysiology. The diagram highlights an in-depth understanding of the complex network of pathways that influence conditions like
atherosclerotic, inflammatory response, and metabolic dysregulation
In all SURPASS programs, tirzepatide demonstrated a
much greater HbA1c-lowering impact than placebo or
active comparators, such as basal insulin and GLP1RAs
[83, 86]. Over 250 patients underwent metabolomics and
lipidomic investigations, which revealed that unlike the
baseline and placebo, tirzepatide, taken over 26 weeks,
significantly impacted a group of lipids and metabolites
like 3-hydroxybutyrate reduced branched-chain ketoacids (BCKA), branched-chain amino acids (BCAA), and
direct catabolic products linked with obesity and insulin
resistance. It is worth noting that the changes observed in
HbA1c, proinsulin levels, and indication of insulin resistance were more pronounced with tirzepatide than with
dulaglutide. This suggests that tirzepatide is more effective in improving glucose control in patients with T2DM
[87, 88]. Tirzepatide has been observed to decrease the
levels of low-density lipoprotein particles (LDLP) and
massive low-density lipoprotein particles (TRLP) over
time and also can reduce triglyceride, apoB, and apoCIII levels dose-dependently. The most significant changes
were observed at the highest dosages of tirzepatide, i.e.,
10 and 15 mg [89, 90]. Directly activating GIPR in hepatocytes is an unlikely explanation for the decrease in
apoC-III levels with tirzepatide [91, 92]. Tirzepatide is a
promising drug for patients with T2DM who also have
hypertension and hyperlipidemia. It has been found to
increase the concentration of HDL (high-density lipoprotein) while decreasing the concentration of VLDL (very
low-density lipoprotein) and triglycerides. Moreover, a
recent SURPASS-3 MRI substudy has shown that tirzepatide may be more effective in reducing liver fat than
insulin degludec [93].
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Obesity and blood pressure
Several GLP-1RAs, such as liraglutide, lixsenatide,
semaglutide, dulaglutide, and exenatide, are utilized in
clinical outcomes for the treatment of T2DM as well as
obesity [94]. Liraglutide and semaglutide are GLP1RAs
licensed for treating obesity (BMI > 30 kg/m²) and overweight people with comorbidities [95]. Also, Liraglutide
treatment reduced blood pressure (BP) and plasma lipid
levels among SCALE weight-loss program participants
[96]. The primary outcome measure for the SELECT trial
is the incidence of three-point MACE. SELECT CVOT
trial investigated the cardiovascular safety of semaglutide
2.4 mg therapy once a week in a group of 17,605 overweight or obese adults over the age of 45 with no history
of T2DM. [97]. Furthermore, GIPR antagonists increase
metabolism in obese mice, and when combined with
GLP1RAs, both GIPR agonists and antagonists have
beneficial therapeutic effects. Also, GLP1/GIP receptors
antibody fused protein was previously found to improve
body weight loss [98]. Compared to dulaglutide, tirzepatide at both 5 and 10 mg doses has shown improved
glycemic control as well as weight management with
similar levels of tolerability. This suggests that the GLP1/
GIP pathway can increase efficacy over GLP-1RAs [99].
Tirzepatide was found to be effective in promoting insulin secretion dependent on glucose through GIPR and
GLP1R activation in both in vivo and in vitro models. The
therapy led to weight loss in a mouse model of obesity by
decreasing food intake and increasing energy expenditure [100]. Tirzepatide is a medication that can help people lose weight by slowing down food movement from
the stomach to the small intestine and reducing appetite.
As obesity is known to increase the risk of cardiovascular
disease, including HF, therefore, anti-obesity interventions like tirzepatide may have cardioprotective effects
[101]. Additionally, the activation of GIP may amplify the
weight loss and insulin secretion effects of GLP1 activation in the central nervous system and pancreas, respectively. GIP activation may also improve lipid processing
and growth of white adipose tissue, resulting in complementary processes. However, GIPR agonism can potentially decrease the nauseous effects of GLP1 agonism by
inhibiting area postrema inhibitory neurons. This could
allow higher therapeutic doses of GLP1 analogs to be
administrated with fewer side effects [75]. Based on the
SURPASS-2 trial, tirzepatide, when taken once a week in
doses of 10 or 15 mg, is more effective in reducing blood
pressure than semaglutide, which is taken once a week
in a dose of 1 mg. The difference in effectiveness could
be attributed to tirzepatide’s GIP agonism and its more
robust ability to promote weight loss. The mean systolic
blood pressure reduction was 5.3 mm Hg for semaglutide, 6.5 mm Hg for tirzepatide 15 mg, and 3.6 mm Hg for
tirzepatide 10 mg. It is believed that the blood pressure
Page 8 of 13
reduction caused by tirzepatide results from various factors such as weight loss, vasodilation, natriuresis, concurrent medication, and reduction in extracellular volume
[102]. Tirzepatide has been shown to positively affect
blood pressure, possibly due to improved endothelial
function or decreased inflammation. A post hoc analysis
of the phase IIb trial showed that tirzepatide was associated with a reduction in the level of high-sensitivity
ICAM-1, CRP, and YKL-40 after 26 weeks of treatment
in a dose-dependent manner [83, 103]. A phase 3 study
conducted on patients with T2DM has shown that tirzepatide improves HbA1c levels at all doses (5–15 mg).
Tirzepatide is twice as effective as semaglutide in average
weight loss after a 40-week treatment period (– 12.4 kg
compared to– 6.2 kg) [8]. According to the SURPASS
program, which included five studies, researchers
reported that a weekly dose of tirzepatide at 15 mg significantly reduced systolic blood pressure by as much as
12.6 mm Hg [97]. By contrast, GLP-1RAs dosing over the
long term may only slightly increase systolic blood pressure by 2 mmHg [104].
Vasodilatory effect
Studies showed that GIPR and GLP1R are present in
the smooth muscle cells and endothelial arterioles and
may have a cardioprotective effect due to endotheliumdependent vasodilation [105]. In a study comprising 16
patients with T2DM and 12 non-diabetic controls, flowmediated vasodilation was enhanced in both groups by
GLP1 infusion of 0.4 pmol/kg/min, administered during a 2-hour hyperglycemic clamp [106]. It is currently
unclear whether GLP1RAs resistant to degradation produce the same effects on blood flow as native GLP1. In
control experiments, both native GLP1 and GLP1(9–36)
have been shown to produce vasodilation and increase
cGMP release from isolated, preconstricted blood vessels
when tested ex vivo. On the other hand, exenatide did not
affect endothelial function in rat conduit arteries when
tested ex vivo after intralipid infusion [107, 108]. It has
been proposed that GIP regulates inflammation and leukocyte adhesion through endothelin 1 while promoting
vasodilation via nitric oxide secretion [109]. Researchers
have discovered that GIP is crucial in regulating vascular and cardiac function and lipid metabolism. GIP influences not only endothelial cells but also adipose tissue
and circulating triglycerides, which suggests that it may
significantly impact the cardiovascular system. Studies
have shown that variations in the GIPR gene are linked to
cardiovascular disease and metabolic syndrome characteristics, which supports this idea [110]. Tirzepatide has
the potential benefit of improving metabolic control and
cardiovascular function because of its dual activity on
GIP and GLP-1 receptors. Further research is required
to comprehensively understand tirzepatides impact on
Taktaz et al. Cardiovascular Diabetology
(2024) 23:242
vasodilation and its precise effects on cardiovascular
function.
Common adverse events and side effects
Tirzepatide may cause common side effects in irritable
bowel syndrome, such as diarrhea, constipation, nausea, vomiting, upper abdominal discomfort, decreased
appetite, and abdominal pain. This might suggest that
tirzepatide affects the gut microbiota [81]. Numerous
gastrointestinal conditions, such as irritable bowel syndrome, inflammatory bowel disease, and small intestinal
bacterial overgrowth, have been associated with dysbiosis (an imbalance or disruption in the composition and
diversity of the gut microbiome) [111]. According to
research, modifying the gut microbiota can impact various physiological functions, including cognitive behavior
and muscle performance [112]. The potential relationship
between tirzepatide and the gut microbiome is not fully
understood, making it an appealing area of study. Understanding these interactions could provide insight into the
mechanisms behind tirzepatide’s metabolic benefits and
inform future strategies for improving its efficacy and
minimizing side effects [113]. During the phase 3 trial
of tirzepatide, 6.6% of patients discontinued the medication due to side effects [114]. Furthermore, pancreatitis
or cholelithiasis patients should use tirzepatide with caution [84].
Conclusion
A new drug named tirzepatide has been approved
to treat T2DM, and it is expected to be approved for
weight loss by activating both GLP-1 and GIP receptors
through a unique mechanism. Currently, there are other
dual GIPR/GLP-1R agonists available, such as GLP-1R/
GR (glucagon receptor), GLP-1R/AR (amylin receptor),
and GLP-1R/NPYR (peptide YY binds to neuropeptide
Y receptors) [36, 115] and even triple agonists that can
activate GIPR to treat obesity and T2DM. This has led
to renewed interest in understanding the safety of GIP/
GIPR in humans. It is essential to gain a deeper understanding of GIP safety to guide future research projects
and develop GIP-based treatments [116]. The post hoc
analysis found that tirzepatide at all doses investigated
reduced the prevalence of metabolic syndrome related
to cardiovascular risk factors more than placebo, semaglutide 1 mg, insulin degludec, and insulin glargine [117].
Comparing tirzepatide to GLP1RAs using the results
of prior comparison trials is challenging. However, the
added agonism of GIPR seems to have a more positive
impact on weight loss. It is important to develop a single pharmacological medication with multiple functions,
such as tirzepatide. This medication can increase insulin sensitivity, decrease weight, and treat dyslipidemia at
an early clinical stage, while also dramatically lowering
Page 9 of 13
blood sugar levels. Therefore, it seems that tirzepatide is
more than just a new antidiabetic drug. The development
of further dual GLP-1/GIP receptor agonists seems to be
a promising next step in managing various cardiovascular disease. However, further research is needed to determine the long-term impacts of these substances. The role
of tirzepatide in therapy will become more evident as
more research is conducted.
Abbreviations
T2DMType 2 Diabetes Mellitus
GLP1Glucagon-like peptide1
GIPGlucose-dependent insulinotropic polypeptide
HbA1cHemoglobin A1c
GLP1RAsGlucagon-like peptide1 receptor agonists
GIPRGlucose-dependent insulinotropic polypeptide receptor
GLP1RGlucagon-like peptide1 receptor
CVDCardiovascular Disease
MACEMajor Adverse Cardiovascular Event
HFHeart Failure
HFrEFHeart Failure with Reduced Ejection Fraction
HFpEFHeart Failure with Preserved Ejection Fraction
ASCVDAtherosclerotic Cardiovascular Disease
CVOTsCardiovascular Outcome Trials
SASinoatrial
ICAM-1Intercellular Adhesion Molecule 1
GDF15Growth Differentiation Factor 15
CRPC-reactive protein
LPSLipopolysaccharide
TLR4Toll-like receptor 4
NLRP3NOD-like receptor protein 3
TNF-αTumor Necrosis Factor-alpha
IL-1βInterleukin-1 beta
IL-6Interleukin-6
TUNELTerminal deoxynucleotidyl transferase dUTP nick end labeling
BCAABranched-chain amino acids
BCKABranched-chain ketoacids
HOMA2-IRHomeostasis Model Assessment of Insulin Resistance
LDLLow-Density Lipoprotein
VLDLVery Low-Density Lipoprotein
BPBlood Pressure
Author contributions
F.T., G.P., M.B. concept, design and writing. R.A.F., L.S., A.Pe., M.G.B., P.G., M.F., G.T.,
A.P., M.T.V., A.C. drafting of the manuscript. All authors have read and agreed
to the published version of the manuscript. All authors read and approved the
final manuscript.
Funding
This work was supported by: open access funding provided by the: National
Plan for NRRP Complementary Investments (PNC, established with the decreelaw 6 May 2021, n. 59, converted by law n. 101 of 2021) in the call for the
funding of research initiatives for technologies and innovative trajectories in
the health and care sectors (Directorial Decree n. 931 of 06-06-2022) - project
n. PNC0000003 - AdvaNced Technologies for Human-centrEd Medicine
(project acronym: ANTHEM). This work reflects only the authors’ views and
opinions, neither the Ministry for University and Research nor the European
Commission can be considered responsible for them. PRIN: PROGETTI DI
RICERCA DI RILEVANTE INTERESSE NAZIONALE / Bando 2022 Prot. 2022CX7HTJ;
PNRR-MAD-2022-12376543.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
Not applicable.
Taktaz et al. Cardiovascular Diabetology
(2024) 23:242
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Author details
1
Department of Advanced Medical and Surgical Sciences, University of
Campania “Luigi Vanvitelli”, Naples, Italy
2
Department of Precision Medicine, University of Campania “Luigi
Vanvitelli”, Naples, Italy
3
Clinical and Molecular Pathology, A.O.U. University of Campania “Luigi
Vanvitelli”, Naples, Italy
4
Department of Experimental Medicine, University of Campania “Luigi
Vanvitelli”, Naples, Italy
5
UniCamillus, International Medical University, Rome, Italy
Received: 6 May 2024 / Accepted: 16 June 2024
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