TYPE Review

PUBLISHED 24 June 2024

DOI 10.3389/fendo.2024.1402583

Tirzepatide against obesity

OPEN ACCESS and insulin-resistance:
EDITED BY
Katherine Samaras,
St. Vincent’s Hospital Sydney, Australia
pathophysiological aspects
REVIEWED BY
Raffaele Carraro,
and clinical evidence
La Princesa University Hospital, Spain
Laura Marroqui, Salvatore Corrao 1,2*, Chiara Pollicino 1, Dalila Maggio 1,
Miguel Hernández University of Elche, Spain
Alessandra Torres 1 and Christiano Argano 1
*CORRESPONDENCE
Salvatore Corrao 1
Department of Clinical Medicine, Internal Medicine Unit, National Relevance and High Specialization
[Link]@[Link]; Hospital Trust Azienda di Rilievo Nazionale ed Alta Specializzazione (ARNAS) Civico, Di Cristina,
[Link]@[Link] Benfratelli, Palermo, Italy, 2 Department of Health Promotion Sciences, Maternal and Infant Care,
Internal Medicine and Medical Specialties. Promozione della Salute, Materno-Infantile, di Medicina
RECEIVED 17 March 2024 Interna e Specialistica di Eccellenza (PROMISE), University of Palermo, Palermo, Italy
ACCEPTED 07 June 2024
PUBLISHED 24 June 2024

CITATION
Corrao S, Pollicino C, Maggio D, Torres A and
Obesity is a chronic, multifactorial disease in which accumulated excess body fat
Argano C (2024) Tirzepatide against obesity has a negative impact on health. Obesity continues to rise among the general
and insulin-resistance: pathophysiological population, resulting in an epidemic that shows no significant signs of decline. It is
aspects and clinical evidence.
Front. Endocrinol. 15:1402583. directly involved in development of cardiometabolic diseases, ischemic coronary
doi: 10.3389/fendo.2024.1402583 heart disease peripheral arterial disease, heart failure, and arterial hypertension,
COPYRIGHT producing global morbidity and mortality. Mainly, abdominal obesity represents a
© 2024 Corrao, Pollicino, Maggio, Torres and crucial factor for cardiovascular illness and also the most frequent component of
Argano. This is an open-access article
distributed under the terms of the Creative metabolic syndrome. Recent evidence showed that Tirzepatide (TZP), a new drug
Commons Attribution License (CC BY). The including both Glucagon Like Peptide 1 (GLP-1) and Glucose-dependent
use, distribution or reproduction in other
Insulinotropic Polypeptide (GIP) receptor agonism, is effective in subjects with
forums is permitted, provided the original
author(s) and the copyright owner(s) are type 2 diabetes (T2D), lowering body weight, fat mass and glycated hemoglobin
credited and that the original publication in (HbA1c) also in obese or overweight adults without T2D. This review discusses the
this journal is cited, in accordance with
accepted academic practice. No use, pathophysiological mechanisms and clinical aspects of TZP in treating obesity.
distribution or reproduction is permitted
which does not comply with these terms.

KEYWORDS

obesity, insulin-resistance, Tirzepatide, pathophysiology, GIP, GLP - 1, clinical trials,

arterial hypertension

1 Introduction
Obesity is a progressing and chronic condition defined by Body Mass Index (BMI) over
30 Kg/m2 levels. It is also defined as “abnormal or excessive fat accumulation that presents a
health risk”“ (1). Rates of overweight (defined as a BMI over 25) and obesity continue to rise
among the general population: between 1975 and 2016, in children and adolescents
worldwide (age 5–19 years), the incidence of overweight or obesity increased by four
times, from 4% to 18%. According to the WHO European report, 59% of adults and
children, about 27% of girls and 29% of boys, are overweight or obese (2).

Frontiers in Endocrinology 01 [Link]

Corrao et al. 10.3389/fendo.2024.1402583

A BMI between 30 and 35 is correlated with decreased longevity States Food and Drug Administration (FDA) for the treatment of
by three years, and also BMI between 40 and 50 reduces lifespan by T2D and in November 2023 for the treatment of obesity (37).
ten years confronted to people with fit BMI. Each increment in BMI Acting in weight loss, it also improves quality of life and reduces
of 5 kg/m2 greater than 22,5–25,0 kg/m2 corresponds to a rise in obesity-related complications. Innovative pharmacological
overall mortality of 30% (3), in obese people the major death cause therapies and surgical approaches are valid alternatives to
in CVD, followed by T2D (4). promote fat loss (38) to reverse the adverse effects triggered by
Obesity pathophysiology is multifactorial and involves social, weight gain.
psychological and behavioral factors, genetic and metabolic In view of this, a widespread search of SCOPUS, PubMed, and
predisposition (5). Obesity occurs when energy intake is more CENTRAL was performed using the following string” (obesity or
than whole body expenditure (6). In fact, the hypothalamus, insulin resistance) AND (tirzepatide or Dual GIP and GLP-1
mesolimbic area and prefrontal cortex, three areas involved in Receptor Agonist). Hand-searching for principal generalists,
executive functioning, are directly involved in controlling energy human nutrition and basic research journals was also done.
balance. Cerebral pathways correlated with appetite, satiety and This review aimed to analyze the knowledge available on the
energy expenditure are constantly activated (7, 8). Lastly, pathophysiological mechanisms and clinical aspects of TZP in
dysregulation of microRNAs (miRNAs) has been linked with treating obesity.
obesity and inflammation. MicroRNAs (miRNAs) are small, RNA
molecules non-coding, which regulate post-transcriptional gene
expression and play an essential role in physiologic and 1.1 The first twincretin,
pathologic processes. In fact, how dysregulation in miRNA Tirzepatide (LY3298176)
production and its role in obesity phenotypes is an object of
several studies (9). The chemical formula of TZP is C225H348N48O68, a linear
Obesity is directly related to the development of synthetic peptide composed of 39 aminoacids and with a molecular
cardiometabolic disease (arterial hypertension, coronaric weight of about 48 KDa, which arises from the “fusion” of
syndrome or heart failure (10) and in particular abdominal aminoacid sequences structurally similar to glucagon, human
obesity is the most frequent component of metabolic syndrome GIP, GLP-1, exendin-4. Nineteen amino acids show similarity to
along with T2D, dyslipidemia and hypertension (11–13). those of GIP. The peptide sequence contains an Aib residue at
It’s also associated, in addition, with obstructive sleep apnea position 2, which occupies the DPP-4 binding site, conferring DPP-
(OSAS), non-alcoholic fatty liver disease (NAFLD)/metabolic- 4 resistance. Furthermore, it presents, at position 20, a C20 fatty
associated fatty liver disease (MAFLD), osteoarthritis, gastro- acid chain attached via a linker to the lysine residue, which enables
esophageal reflux disease, malignancies (gastrointestinal, liver, the molecule to bind circulating albumin with high affinity, thus
breast, and endometrial cancer), and mental health issues, increasing the half-life up to 5 days (39), allowing a single weekly
especially in young people. Insulin resistance has a critical role in subcutaneous administration. In receptor binding studies, it has
the development and progression of NAFLD/MAFLD (14–16). In been shown to have a GLP-1R and GLP-1 binding affinity,
this sense, insulin resistance is a crucial factor shared by Obesity, respectively, about five times lower than that of native and similar
T2D, and NAFLD/MAFLD. to endogenous GIP (40). Indeed, from a molecular perspective, its
Adipose tissue contributes to endothelial dysfunction (17) due strength is comparable to native GIP but weaker than native GLP-1
to secretion of adipokines, paracrine hormones which have a crucial (approximately 13-fold) (41). Available data suggests that
role in the regulation of vascular tone. In obesity patients, pro- hyperglycemia may cause the downregulation of GIP-R, thus
inflammatory and vasoactive adipokines such as angiotensinogen, reducing its response (42). However, lots of data suggest that the
angiotensin II, aldosterone, and resisting, along with increased administration of molecules able to restore a condition of
plasma renin activity and cytokines are hypersecreted (18–28). euglycemia can revert this resistance (20). Simultaneously, GIPR
Notably, some peptides termed incretins, able to stimulate b- signaling blocks emesis and attenuates other adverse side effects
cells to release insulin, were discovered by Barre J.L. Campo in the of GLP-1R activation (43). Thus, TZP was introduced for the
early 1930s. The most commonly known incretins include first time, to enhance the effectiveness of incretins and reduce
glucagon-like peptide-1 (GLP-1) and glucose-dependent side effects.
insulinotropic polypeptide (GIP), formerly called Gastric
inhibitory peptide (29, 30). The gut (31) releases these factors due
to food intake and plays an essential role in appetite regulation and 1.2 The physiology of incretins
body weight (32), decreasing hunger and nutrient intake (32, 33),
and gastric emptying and gastrointestinal motility (29, 34). In light GIP (the one which provides the most of incretin effect in
of these effects, GLP-1 receptor agonists (GLP-1RA) can be used not humans (7)) and GLP-1, are peptide hormones secreted
only in the treatment of T2D but also to promote Weight Loss (WL) respectively, L cells of the bowel and K cells of duodenum after
(33). Subsequently, dual GLP-1 receptor (GLP1-R) and GIP- assumption of carbohydrates, triglycerides, proteins or amino acids
receptor (GIP-R) agonism is able to reduce BW by more than (44, 45). GLP-1R is expressed in b-cells, in a minor population of
20% (35, 36). TZP is a new pharmacological approach which a-cells, but also in lungs, kidneys, liver, gastric mucosa, heart, brain
includes dual agonism, approved in May 2022 by the United (in regions involved in the regulation of food intake and/or satiety)

Frontiers in Endocrinology 02 [Link]

Corrao et al. 10.3389/fendo.2024.1402583

and immune cells (3–6). GIP, secreted by K cells of the duodenum b-cell proliferation (predominantly GLP-1), improve b-cell
and the proximal part of the small intestine, is the principal incretin function (by reducing its apoptosis) and survival, and also through
hormone in humans, providing most of the incretin effect (7). GIP- the reduction of glucotoxicity (49, 51, 52). The gain in insulin
R are distributed in the pancreas but also in the heart, the pituitary, sensitivity could be related to the increased glucose internalization
the adrenal cortex, some areas of the central nervous system (CNS) in muscle and WAT promoted by TZP, results seen in obese
and both brown and white adipose tissues where it promotes fat IR mice.
deposition (8). For this reason, this hormone has been assumed to
promote obesity (38). Although, the function of GIP in weight
management needs to be clarified. Data in the literature support the 1.5 Other possible pleiotropic effects
hypothesis that GIP promotes fat deposition, and in vitro of Tirzepatide
experiments on GIP-R-deficient show a resistance to obesity (14).
However, in a transgenic mouse model, persistently high GIP levels Pleiotropic effects of GIP receptor stimulation in other tissues,
resulted in improvement of b-cell function, promote insulin mediated by mechanisms other than typical protein G-coupled
sensitivity and gene transcription, glucose tolerance, and receptor pathways, might bring additional benefits. Acting on
reduction in weight gain (15). insulin and glucagon levels, incretins, and thus TZP, may have
indirect effects also on the liver and muscle (4, 6). In various models,
GIP seems to stimulate LPL activity (53), modulating triglycerides
1.3 In vitro Tirzepatide’s effects (TG) release and favor its clearance (53) and deposition in white
adipose tissue (WAT); also increase WAT perfusion (54–56). TZP
In vivo and in vitro preclinical studies have demonstrated that co- decreases serum alanine aminotransferase and atherogenic
administration of GIP and GLP1 promotes insulin sensitivity, leading biomarkers (chylomicrons, small dense LDL-cholesterol levels,
to better blood glucose level control, more sustained reduction in apoB, apoC-III) (57). Relating to the presence of incretin
food intake and consequently better WL compared to the infusion of receptors on endothelial cells, TZP can also reduce blood pressure
a single agent (35, 41, 46), also exerts an additive effect on metabolism (BP) (58). In addition to enhancing lipid metabolism, the
of cyclic adenosine monophosphate (cAMP), thus increasing its combination GIP-GLP1 may improve weight parameters by
levels and consequently, potentiating insulin secretion glucose- acting on receptors located in the central nervous system (CNS).
dependent. Studies conducted on rat b-cells (47) and cell lines In high-fat-fed mice, the combined metabolic effect of incretins
expressing recombinant GLP-1R and GIP-R in vitro and human hesitates in more reduction of food intake and consequently more
islets (41) demonstrated that the adenylate cyclase was influenced by weight reduction (59). The reduction in food intake may be related
signals arising from the stimulation of both receptors, mainly to the activity of GIP, able to cross the blood barrier, on its receptors
deriving from GIP (Figure 1). Regarding pharmacodynamics, TZP sited in the arcuate (ARC) nucleus and other hypothalamic centers.
appears as a biased GLP-1R-GIPR co-agonist, because of its positive In CNS, GIP-R is expressed on the surface of cells both alone and in
effects on cAMP generation over b-arrestin recruitment, which is association with GLP1-R (60), acting on the same cells (facilitating
conversely stimulated by GLP-1R. This results in a lower ability to GLP-1 internalization to specific neuronal populations (61)) or, as
promote receptor internalization compared with endogenous GLP-1, documented in other studies, on different cells (62). Interestingly, in
so it allows to have an increased GLP-1R expression on the cell some cells of the ARC nucleus, it is also possible to find
surface, which translates in more robust insulinotropic properties, neuropeptide receptors (molecules with a role in the regulation of
possibly explaining the enhanced insulin secretion (in both diabetic calorie intake) together with GIP-R, probably implicated in the
and not diabetic human islets), induced by TZP (19) by regulation of food intake. Moreover, GIP seems to attenuate GLP-
approximately 25% more than the one induced by only one of the 1R-agonism mediated adverse effects thus making more tolerant
two agents. It also improves insulin sensitivity and reduces glucagon this therapy and favoring WL. Together, this evidence suggests that
secretion. Beyond the synergistic effects on insulin secretion and GIP may drive WL directly, inhibiting caloric intake, indirectly
synthesis, the double agonist therapy seems to strongly promote exploiting the anorectic action of GLP-1, or by reducing GLP-1RA
survival and differentiation of b-cell (48) (Figure 1). adverse effects (59, 60, 63). Also, it seems that there could be
another mechanism involved in the reduction of food intake,
probably related to the stimulation of POMC gene expression
1.4 In vivo Tirzepatide’s effects mediated by co-agonism (62). Co-treatment with GLP-1R and
GIP-R agonists also results in food intake reduction and BW
The above results are confirmed also in in-vivo studies. Co- reduction than either agonist alone in obese mice with T2D and
agonism showed, on murine models, the capability to improve rats (64–66). Beyond the reduction in energy intake, co-agonism
insulin secretion and sensitivity in a weight-dependent and seems to be able to affect food choice, favoring the consumption of
weight-independent manner, probably through its action on healthy nutrients, how documented in experiments on mice and
nutrient metabolism (49, 50), preventing their accumulation and rats (67). Moreover, in mice, the administration of TZP showed to
thus making these organs actively involved in metabolism with an inhibit gastro-enteric delay (52).
improvement in insulin sensitivity and WL, yielding long-lasting Experimental data on animal models have suggested that GIP
effects. In obese mice, co-agonism is demonstrated to enhance suppresses peripheral arterial remodeling, thus showing an anti-

Frontiers in Endocrinology 03 [Link]

Corrao et al. 10.3389/fendo.2024.1402583

atherosclerotic activity, by acting on receptors in the heart and 2 Data of efficacy

vessels (19, 20). GIP appears also to reduce radical oxidative stress
species (48), but also it is known the implication of GIP in the 2.1 Clinical trials: the SURPASS program
inflammatory pathways. Data suggest that activation of GIP-R
decreases inflammation in adipose tissue and cytokines levels The central clinical trial program designed to demonstrate the
(such as IL-6) and promotes the rise of serum adiponectin levels, therapeutic effectiveness (in terms of GC and BW reduction),
a cytokine with anti-inflammatory effects and beneficial effects on tolerability and safety of TZP in diabetic patients was the
diabetic nephropathy, which can explain potential beneficial effects SURPASS program. It encompasses trials SURPASS from 1 to 6
on kidneys (even if GIP-R are not present) (47). It also induces (Figure 3A), SURPASS-J (mono and combo) and SURPASS-AP,
nitric oxide–mediated vasodilation and thus may have implications performed respectively on Japanese and Asian-Pacific population
for CV disease (37, 68) and kidneys. (Figure 3B), and SURPASS CVOT.
On the other hand, in kidneys, the activation of GLP1-R” All these trials amount standard features: TZP is surveyed at
without receptors, sited in the proximal tubule and pre- three decisive doses (5, 10, and 15 mg per week); the treatment is
glomerular portion, increases cAMP levels, which then triggers started at the dose of 2.5 mg and increased every four weeks. Some
PKA activity, inhibiting oxidative renal injury and thus delaying the SURPASS trials use active comparators like GLP-1RA, or basal
development of diabetic nephropathy. The action on kidneys insulin preparations, while others compare TZP to placebo.
appears to be directly through the effects also on renin-secreting In the most of the studies the primary endpoint is a change in
cells of the juxta-glomerular apparatus, whose stimulation may lead HbA1c from baseline, except for the SURPASS J combo, where the
to increased natriuresis and reduce hyperfiltration, and indirectly by primary endpoint is the number of patients with more than one
the reduction of angiotensin II levels, the increase in nitric oxide critical adverse event (69, 70).
with consequently endothelial vasodilation and the improvement of The SURPASS-1 trial studied the efficacy and safety of the three
risk factors of kidney disease (hyperglycemia, hypertension, obesity) doses of TZP versus placebo in diabetic drug-naïve patients not
(20). In this sense, the role of TZP may also be suggested (Figure 2). adequately controlled with a lifestyle mediation (diet and exercise).

FIGURE 1
Tirzepatide’s pathway signaling. TZP binds its receptor, leading to the activation of adenylyl cyclase-cAMP-protein kinase A (PKA) pathway and thus
stimulating glucose metabolism (glycolysis and Krebs Cycle). The increase of intracellular ATP levels hesitates in the closure of plasma membrane K+
channels, thus triggering b-cell depolarization. Due to depolarization, voltage-gated Ca2+ channels become open, favoring the entrance of Ca2+
into the cell, which concomitantly stimulates the releasing of calcium from the endoplasmic reticulum. This leads to the release of insulin into the
bloodstream. Additionally, PKA stimulates insulin gene transcription, leading to insulin synthesis. as, in vivo-subunit; ADP, adenosine diphosphate;
ATP, adenosine triphosphate; b/g, G protein b/gamma subunits; cAMP, cyclic adenosine monophosphate; GIP-R/GLP-1R, gastric inhibitory
polypeptide receptor/glucagon-like peptide 1 receptor; PKA, adenylyl cyclase-cAMP-protein kinase A.

Frontiers in Endocrinology 04 [Link]

Corrao et al. 10.3389/fendo.2024.1402583

FIGURE 2
Tirzepatide’s effects on various organs.

All the three doses of TZP confirmed an important decrease in of insulin glargine, with or without metformin. Weekly TZP
HbA1c and BW. It demonstrated to have a safety profile similar to compared with prandial insulin, administered in addition to
GLP-1RA not increasing the risk of hypoglycemia (19, 48). insulin glargine, proved reductions in HbA 1c and BW, not
In the SURPASS-2 study, TZP at the dose of 5, 10, and 15 mg increased the risk of hypoglycemia (78, 79).
were compared to the GLP-1RA semaglutide (1 mg once weekly) in The SURPASS-J-mono study was a phase 3 clinical trial
patients not well controlled in therapy only with metformin (44, performed in Japan. It comprised adults with T2D who had
71). In summary, TZP was greater to semaglutide in reducing discontinued an oral glucose-lowering medication or were
HbA1c (31, 44, 71). treatment-naïve. TZP was superior to dulaglutide in GC and
The SURPASS-3 study was started to study the efficacy and reduction of BW and the safety report of TZP was coherent with
safety of TZP versus basal insulin degludec in diabetic patients that of dulaglutide (80).
inadequately controlled by metformin with or without an SGLT2-i The SURPASS-J-combo trial embraced diabetic adults with
for 52 weeks (72–74). A sub-study of this trial focused on GC HbA1c 7% to 11% and BMI ≥ 23 kg/m2, stable weight and
through the use of continuous glucose monitoring (CGM) and the uncontrolled with therapy of metformin, thiazolidinedione,
proportion of time within a tight predefined “time in range” (TIR) sulfonylureas, meglitinide, alpha-glucosidase inhibitor or SGLT2-i
from 71 to 140 mg/dL at the end of the study was considerably more (81). TZP was well tolerated as an add-on to oral glucose-lowering
significant in the group of participants receiving either 10 or 15 mg drugs monotherapy in Japanese diabetic participants and showed
TZP competed to the group taking insulin degludec (72, 73, 75). development in GC and BW, irrespective of undercurrent glucose-
In the 52-week SURPASS-4 trial TZP was tested versus insulin lowering drugs (82).
glargine in diabetic adults and a high CV risk below not sufficient In SURPASS-AP trial insulin-naive diabetic patients not
GC at baseline and in therapy with one to three oral glucose- adequately controlled on therapy with metformin (with or
lowering drugs (metformin, sulfonylurea, SGLT2-i). In summary, without a sulphonylurea) in Australia, India, China and South
TZP attained more pronounced HbA1c reductions at the end of the Korea, were randomized to TZP 5 mg, 10 mg or 15 mg or insulin
study competed to insulin glargine, with also a lower incidence of glargine. TZP was generally well tolerated and confirmed greater
hypoglycemia. TZP treatment was not associated with increased CV diminution in HbA1c compared to insulin glargine in an Asia-
risk (72, 76). Pacific patients, in particular in Chinese population with T2D (83).
The SURPASS-5 study evaluated the efficacy and safety of an The SURPASS-CVOT trial, where dulaglutide at the dose of 1.5
injectable mixture therapy: TZP and insulin glargine. Diabetic mg/week or at the highest tolerated dose, is the comparator, has a
patients in therapy with metformin and insulin glargine as distinctive design from the other trials: the primary endpoint is the
baseline therapy and not adequately controlled received either time to the first manifestation of any major adverse CV event
TZP or placebo during the 40-week study span (72, 77). Patients (MACE), defined as myocardial infarction, stroke or CV death. The
with T2D who received the additional therapy with TZP reached study is fully recruited and ongoing (84).
statistically significant improvements in GC after 40 weeks (72). HbA1c was reduced in SURPASS 1–5, using from 5 to 15 mg of
In the SURPASS-6 trial, TZP was compared to insulin Lispro TZP per week, by between 1.69 to 2.58%, and a new plateau of
three times daily in diabetic patients previously treated with a dose HbA 1c and fasting serum glucose (FSG) was reached with

Frontiers in Endocrinology 05 [Link]

Corrao et al. 10.3389/fendo.2024.1402583

A B
SURPASS-1 SURPASS-2 SURPASS-3 SURPASS-4 SURPASS-5 SURPASS-6 SURPASS-J-MONO SURPASS-J-COMBO SURPASS-AP
Study Multicentre Multicentre Multicentre Multicentre Multicentre Multicentre Study design Multicentre Multicentre Multicentre
design Randomized Randomized Randomized Randomized Randomized Randomized Randomized Randomized Randomized
Double-blind Open-label Open- label Open-label Double-blind Open-label Double-blind Open-label Open- label
Parallel-group Parallel-group Parallel-group Parallel-group Parallel-group Parallel-group Parallel-group Parallel-group Parallel-group
Placebo- Active- Active- Active- Placebo- Active- Placebo-controlled Active-controlled Active-controlled
controlled controlled controlled controlled controlled controlled Phase 3 Trial Phase 3 trial Phase 3 trial
Phase 3 Trial Phase 3 trial Phase 3 trial Phase 3 trial Phase 3 Trial Phase 3 trial 52 weeks 52 weeks 40 weeks
40 weeks 40 weeks 52 weeks 52 weeks 40 weeks 52 weeks Period 7 May 2019 30 Mar 2019 31 Dec 2019
Period 3 Jun 2019 30 Jul 2019 1 Apr 2019 20 Nov 2018 30 Aug 2019 19 Oct 2020 - - -
- - - - - - 31 Mar 2021 4 Feb 2020 24 Nov 2021
28 Oct 2020 15 Feb 2021 4 Jan 2021 30 Dec 2019 13 Jan 2021 1 Nov 2022 Comparator Dulaglutide Different dose of TZP Insulin Glargine
Comparator Placebo Semaglutide Insulin Insulin Glargine Placebo Prandial thrice-
Degludec daily insulin Primary Endpoint Mean change from baseline Safety and Tolerability Mean change from baseline
Lispro in HbA1c assessed as incidence of in HbA1c
Primary Mean change Mean change Mean change Mean change Mean change Mean change TEAEs
Endpoint from baseline in from baseline in from baseline in from baseline in from baseline in from baseline in Secondary Endpoints Mean change from baseline Mean change from baseline Non-inferiority and
HbA1c HbA1c HbA1c HbA1c HbA1c HbA1c in FSG in HbA1c superiority of all TZP doses
Secondary Mean change Attainment of Mean change Mean change Achievement of Demonstrating Percentange of participants Mean change from baseline in HbA1c reduction
Endpoints from baseline in HbA1c level from baseline in from baseline in HbA1c level statistical with HbA1c <7% in BW Proportion of participants
FSG target <7% and BW BW target <7%, superiority of Change from baseline in 7- Mean change from baseline with HbA1c <7%
Proportion of <5.7% Proportion of Achievement of ≤6.5% and individual TZP point SMBG profiles in FSG Mean change from baseline
participants Mean change participants HbA1c level <5.7% doses (5 mg, in BW
Mean change from baseline Proportion of participants
with HbA1c <7% from baseline in with HbA1c <7% target <7% Mean change 10 mg and/or
in BW achieving an HbA1c < 7%,
and <5.7% BW from baseline in 15 mg) in
Mean change Proportion of Attainment of WL of at least ≤6.5% and <5.7%
FSG change in
Mean change Attainment of from baseline in participants HbA1c and BW 5% Change from baseline in 7-
from baseline in HbA1c ≤ 6.5% FSG with HbA1c Mean change point SMBG profiles
Achievement of Mean change from baseline
BW Attainment of Proportion of <6.5% and from baseline in
HbA1c level in fasting insulin Mean change from baseline
WL of at least participants <5.7% BW
target level Mean change from baseline in fasting insulin
5%, 10%, and achieving an Proportion of Attainment of target <7%, in fasting C-peptide Mean change from baseline
15% of BW HbA1c ≤6.5% participants WL of at least ≤6.5%
achieving WL 5%, 10%, and Change of HOMA2B-insulin in fasting C-peptide
Mean change and <5.7%
(5%, 10%, and 15% of BW Attainment of e in HOMA-2S Insulin Change of HOMA2
from baseline in Change from WL of at least
FSG baseline in 7- 15% of BW) Rate of Hypoglycemia Proportion of participants
5%
point SMBG Mean change achieving of WL of at least
Change from Mean change
profiles from baseline in 5%, 10%, and 15% of BW
baseline in 7- from baseline in
point SMBG Proportion of FSG Numbers of patients Randomized: 636 Randomized: 443 Randomized: 917
FSG
profiles, BMI, participants Change from Completed trial: 615 Completed trial: 398 Completed trial: 815
WC and serum achieving WL baseline in 7- Change from
baseline in 7- Population Mean age: 56.6 years Mean HbA1c :8.56% Mean duration T2D: 7.65
lipids (5%, 10%, and point SMBG
profiles, BMI, point SMBG Mean BW: 85.9kg Mean age: 57 years years
Results of 15% of BW)
WC and serum profiles, BMI, Mean HbA1c: 8.71%
HOMA2-IR WC and serum
lipids Mean age: 54.1 years
Results of lipids
fasting Mean BW: 76.6kg
glucagon level Mean FSG: 177.4 mg/dL
Results HbA1c (Mean change from SAEs TZP 5 mg vs 10 vs HbA1c (Mean change from
adjusted for the baseline) TZP vs 10mg: 0 vs 1 vs 1 baseline) TZP vs glargine:
FSG level dulaglutide: -2.4 % vs -1.3% HbA1c (Mean change from -2.39% vs -0.95%
BW (Mean change from baseline) TZP 5mg vs TZP BW (Mean change from
baseline) TZP vs 10mg vs TZP 15mg: -2.57% baseline) TZP vs glargine:
dulaglutide: -8.3 Kg vs vs -2.98% vs -3.02% -6.4 Kg vs +1.5 Kg
Numbers of Randomized: Randomized: Randomized: Randomized: Randomized: Randomized: -0.5 Kg FSG (Mean change from FSG (Mean change from
patients 478 1879 1444 2002 475 1428 FSG (Mean change from baseline) TZP 5mg vs TZP baseline) TZP vs glargine:
Completed trial: Completed trial: Completed trial: Completed trial: Completed trial: baseline) TZP vs 10mg vs TZP 15mg: -63 mg/dL vs -46 mg/dL
428 1325 1801 451 1304 dulaglutide: -58.6 mg/dL vs -71.2 mg/dL
63.3 mg/dL vs -31.9 mg/dL vs -74.4 mg/dL
Population Mean duration Mean duration Mean duration Mean duration Mean duration Mean duration
T2D: 4.7 years T2D: 8.6 years T2D: 8.4 years T2D: 10.5 T2D 13.3 years T2D: 13.8 BW (Mean change from
years years baseline) TZP 5 mg vs TZP
Mean HbA1c: Mean HbA1c: Mean HbA1c: Mean HbA1c : 10 vs TZP 10 mg:
7.94% 8.28% 8.17% Mean HbA1c: 8.31% Mean HbA1c: -3.8 Kg vs -7.5 Kg vs
Mean age: 54.1 Mean age: 56.6 Mean age: 57.4 8.52% Mean age: 60.7 8.8% -10.2 Kg
years years years Mean age: 63.6 years Mean age: 58.8
Mean BW: Mean BW: 93.7 Mean BW: years Mean BW: years
85.9kg kg 94.3kg Mean BW: 95.1kg Mean BW:
Mean FSG: Mean FSG: Mean FSG: 90.3kg Mean FSG: 90.5kg
153.6 mg/dL 172.9 mg/dL 169.3 mg/dL Mean FSG: 162.4 mg/dL Mean FSG:
171.2 mg/dL 157.35 mg/dL
Results HbA1c (Mean HbA1c (Mean HbA1c (Mean HbA1c (Mean HbA1c (Mean HbA1c (Mean
change from change from change from change from change from change from
baseline) TZP baseline) TZP baseline) TZP baseline) TZP baseline) TZP baseline) TZP
vs placebo: vs sema: vs degludec: vs glargine: vs placebo: vs Lispro:
-1.94% vs -2.18% vs -2.16% vs -2.41% vs -2.28% vs -2.11% vs
-0.04% -1.86% -1.34% -1.44% -0.86% -1.13%
BW (Mean BW (Mean BW (Mean BW (Mean BW (Mean BW (Mean
change from change from change from change from change from change from
baseline) TZP baseline) TZP baseline) TZP baseline) TZP baseline) TZP baseline) TZP
vs placebo: vs sema: vs degludec: vs glargine: vs placebo: vs Lispro:
-8.1 Kg vs -9.3 Kg vs -10.3 Kg vs -9.4 Kg vs -7.2 Kg vs -9 Kg vs
-0.7 Kg -5.7 Kg +2.3 Kg +1.9 Kg +1.6 Kg +3.2 Kg
FSG (Mean FSG mean TZP FSG (Mean FSG (Mean FSG (Mean
change from vs sema: 112.6 change from change from change from
baseline) TZP mg/dL vs 124.4 baseline) TZP baseline) TZP baseline) TZP
vs placebo: mg/dL vs degludec: vs glargine: vs placebo:
-46.2 mg/dL vs -54 mg/dL vs -54.8 mg/dL vs -61.6 mg/dL vs
-12.9 mg/dL -55.7 mg/dL -51.4 mg/dL -39.2 mg/dL

FIGURE 3
(A) The SURPASS Program (SURPASS1–6). TZP, Tirzepatide; FSG, Fasting serum glucose; BW, Body Weight; HbA1c, Glycated Hemoglobin; T2D, Type
2 Diabetes; SMBG, self-monitored blood glucose; WC, waist circumference; HOMA2-IR, homeostasis model assessment–insulin resistance. (B) The
SURPASS Program (J-mono, J-combo e AP) TZP, Tirzepatide; FSG, Fasting serum glucose; BW, Body Weight; HbA1c, Glycated Hemoglobin; T2D,
Type 2 Diabetes; SMBG, self-monitored blood glucose; WC, waist circumference; HOMA2B-Insulin, homeostasis model assessment B–insulin;
HOMA2S-Insulin, homeostasis model assessment S–insulin; TEAEs, treatment-emergent adverse events; SAEs, serious Adverse Event(s).

approximately 24–30 weeks of treatment. FSG was reduced in However, the substantially better efficacy (concerning HbA1c
SURPASS 1–5 between 43 and 63 mg/dL, and BW was reduced and BW reductions) compared to semaglutide at the standard dose
by between 5.4 to 11.7 kg in SURPASS 1–5. Extraordinarily, a used in most type 2 T2D trials was the most remarkable finding (85,
plateau wasn’t achieved in trials with a duration shorter than 52 86). From this treatment difference we can deduce that GIP-R
weeks; to reach a new steady state about BW it may take more than agonism contributes considerably to the global efficacy of TZP.
a year after initiating TZP treatment (85). The relative reductions in HbA1c and BW observed with TZP in
Furthermore, TZP was significantly more efficacious than titrated all its final doses were comparable among the SURPASS trials. The
basal insulins degludec and glargine (75). In these trials, higher doses reduction in HbA1c is independent of age (85), duration of T2D
of TZP were at least as successful as basal insulin in monitoring FSG. (87), or baseline HbA1c, with meaningful reductions in all of the

Frontiers in Endocrinology 06 [Link]

Corrao et al. 10.3389/fendo.2024.1402583

subgroups, even if the reduction is more significant in patients with MAFLD and stimulating WL as well as weight-independent
higher HbA1c at the baseline. mechanisms (91) (92). The reduction in BW and the improved
Concerning BW, a higher baseline BMI predicts absolute weight GC are important factors in reducing NAFLD parameters, reducing
reduction. However, a substantial body WL is detected even in hepatic steatosis and fibrosis (93) and improving hepatic necro-
patients with a BMI <27 kg/m2. So, there is no significant difference inflammation (94, 95). Various mechanisms have been theorized to
about sex between females and males in patients treated with TZP. describe how dual agonism, as GLP-1 RA, could directly reduce
Another remarkable finding from the SURPASS trials is that there triglycerides’ hepatocyte storage, lipogenesis and improving hepatic
is a significant relationship between WL and the decrease in HbA1c, glucose metabolism (96) and promoting lipolysis and fatty acid
demonstrating that more significant WL attainable with TZP, has a oxidation (97). So, it can reduce macrophage infiltration of adipose
considerable impact on GC and, accordingly, on the HbA1c (Figure 4). tissue, inhibit inflammatory pathways in adipocytes and ameliorate
Approximately 38% of patients cared for TZP reached an insulin sensitivity (98). Compared with GLP1-RA, TZP had more
HbA 1 c <5.7%, a nondiabetic value. This subgroup was potent hypoglycemic and weight-loss effects (99, 100).
characterized by a shorter duration of T2D, slightly younger age, There is a randomized controlled phase 2 study with the
lower baseline FSG and HbA1c, and more significant BW reduction. objective to explore the use of TZP as a treatment for
There wasn’t a difference in the baseline BMI value in patients who MAFLD, providing strong evidence [NCT04166773]. However,
didn’t reach an HbA1c <5.7%. Thus, there is a higher likelihood of cornerstones of management are, if needed, promoting a healthy
response in patients with less advanced T2D; there is a substantial lifestyle and WL. Adherence remains an important challenge, but
inter-individual variability in treatment effects (85). it may not be sufficient for critical disease activity or advanced
fibrosis (101).
2.1.1 Effects on lipid structure and on the liver
The SURPASS-2, where TZP (with metformin) was compared
to semaglutide (74, 88), showed adjunctive effects, such as lowering 2.2 SURMOUNT study program
the concentrations of LDL and triglycerides and elevating the
concentration of HDL. TZP treatment induced a significant BW reduction in diabetic
The main suppliers to the progression of MAFLD are hepatic patients who were obese or overweight. Based on these findings, the
steatosis and insulin resistance. SURMOUNT trials program was designed to study TZP’s efficacy
Due to the above-mentioned effects of TZD on glycemic, hepatic and safety in the treatment and management of obesity. It is a
metabolism, and inflammation, treatment with dual-agonism may clinical trial program that includes randomized controlled studies
reduce or reverse liver damage (lobular inflammation, hepatic with a duration of at least 72 weeks. In SURMOUNT-2,
steatosis, liver cell damage, and fibrosis) and metabolic dysfunction SURMOUNT-3 and SURMOUNT-4 were used TZP doses of 10
(35, 41). and 15 mg and all three doses, including the 5-mg dose, were used
GLP-1RA has multiple hepatic effects on MAFLD, involving an in SURMOUNT-1. The primary endpoint for all studies is the per
adaptation of portal and plasma glucagon and insulin cent change from randomization in BW (Figure 5). Another study,
concentrations, hepatic insulin sensitivity and improving not yet published, is SURMOUNT-OSA, a clinical trial of 52-weeks
hepatocyte mitochondrial function (89) liver enzymes and hepatic that examined the efficacy and safety of TZP versus placebo in obese
fat accumulation (90) and reducing adipose tissue lipotoxicity as participants and an established OSA diagnosis for treatment of
well as promoting improvement of steatohepatitis in patients with moderate and severe OSA (102).

FIGURE 4
Tirzepatide’s effects on body weight and in HbA1c (SURPASS 2).

Frontiers in Endocrinology 07 [Link]

Corrao et al. 10.3389/fendo.2024.1402583

The SURMOUNT-1 study was a clinical trial of 72 weeks reabsorption in the distal nephron, are responsible for familial
performed in 2539 obese patients without T2D that were hypertension (112, 116).
randomized in four arms with placebo or TZP at the dose of In the SURPASS-1 trial, TZP 10 mg resulted in a mean decrease
5mg,10 mg or 15 mg (72). TZP treatment was correlated with in SBP of 5.2 mmHg, which is more significant than that with a
reduced systolic blood pressure (SBP), waist circumference, plasma placebo. Likewise, in the SURPASS-3 trial, all three doses of TZP
lipid concentrations and fasting insulin (103). caused a significant decrease in mean SBP from baseline (from 4.9
The SURMOUNT-2 study is a clinical study that enrolled 938 to 6.6 mmHg).
diabetic patients, receiving 10 mg or 15 mg of TZP or placebo. In We can use SURMOUNT 3 as a reference within the
this 72-week trial TZP 10 mg and 15 mg determinate a clinically surmount program to confirm the effectiveness of TZP in
meaningful reduction in BW, with a safety profile comparable to improving tension values.
GLP1-RA- based therapies (104). In this trial, from randomization to week 72, TZP determinates
The SURMOUNT-3 study, after an organized intensive lifestyle more significant improvements versus placebo in both SBP (TZP
intervention of 12-week, is a randomized 72-week clinical trial −5.1 mmHg, placebo, 4.1 mmHg (Figure 6A) and DBP (TZP −3.2
where patients receive placebo or TZP at the maximally tolerated mmHg, placebo 2.3 mmHg) (105) (Figure 6B).
dose. When administered following an initial 12-week intensive
lifestyle intervention, TZP increased the WL (105).
In the end, SURMOUNT-4 is a trial that studies BW 2.4 Other clinical trials of
preservation in participants with obesity or overweight. The main Tirzepatide’s efficacy
purpose is to learn more about how TZP maintains WL. The study
has two phases: a lead-in phase in which all participants take TZP Recently, in addition to the clinical trials mentioned above,
and a treatment phase in which participants, after randomization, which have given impressive results, a trial based on SURPASS-2
will either continue TZP or switch to placebo. The general mean study’s general protocol was recently stated, including physiological
weight reduction for TZP and placebo from weeks 0 to 88 were outcomes. It’s a multicenter, double-blind, randomized, phase 1
respectively 25.3% and 9.9% (106). study, edited by Heise et al. to estimate insulin sensitivity in patients
treated with placebo, TZP or semaglutide after 28 weeks of
treatment, achieving a hyperinsulinemic, euglycemic clamp
2.3 Tirzepatide and hypertension: the role experiment, followed by a hyperglycemic clamp (216 mg/dL) to
of insulin resistance and hyperinsulinemia estimate insulin secretory responses. On the second day, glycemia,
glucagon and insulin responses were documented afterwards a
Clinical studies showed that concomitant developments in mixed meal test with a concurrent valuation of ratings of hunger,
insulin sensitivity, b-cell, and a-cell function underpin the effects satiety and prospective food consumption; on the occasion of an ad
of TZP on GC. libitum meal, energy intake was measured.
Furthermore, clinically meaningful blood pressure reductions The clinical outcomes imitated the same findings of SURPASS-
were observed in participants receiving TZP. The mean changes in 2 in terms of HbA1c reduction and WL. With TZP treatment,
SBP of -2.8 to -12.6 mm Hg and mean reductions in diastolic blood insulin sensitivity rises by 65.7%, measured by the glucose infusion
pressure (DBP) of -0.8 to -4.5 mm Hg were reported (107). rate indispensable to maintain euglycemia, and the rise was 20.5%
The factors behind obesity-induced hypertension are numerous, greater with TZP than with semaglutide 37.5% with semaglutide 1
and often, they are effective concurrently. They include changes in the mg). Some of this effect is likely due to the change in WL (6.9 kg
production of constricting and relaxing factors endothelium-derived, with semaglutide versus 11.2 kg with TZP).
interruption of molecular signaling, increased oxidative stress, renal There may be weight-independent and weight-dependent factors
injury, insulin resistance, hyperinsulinemia, sleep apnea syndrome, associated with TZP treatment that improve insulin sensitivity and a
that make hemodynamic alterations (108, 109). Also, adipose tissue more substantial improvement in insulin sensitivity with TZP
provides to determine endothelial dysfunction by secreting compared to semaglutide per unit WL.
adipokines (109–111). There was also a significant reduction in fasting and post-meal
Insulin resistance and hyperinsulinemia are often present in glycemia with both semaglutide and TZP compared with placebo,
obese individuals and play a significant role in the genesis of with no difference at the baseline-subtracted plasma glucose
hypertension (112, 113). Some studies have evidenced that between TZP and semaglutide.
hyperinsulinemia may activate the renin-angiotensin system, Meal-related insulin secretory responses were meaningfully
increase sympathetic nervous system activity and renal sodium higher with semaglutide and placebo than TZP treatment. These
retention and, if sustained, all these elements could increase blood findings help to explain some aspects of TZP’s clinical efficacy, but
pressure (112, 114). Insulin can activate transporters such as the from this experiment, it’s impossible to discriminate whether the
Sodium-proton exchanger type 3 (NHE3) in the proximal tubule different effects of TZP are the result of GIPR signaling (85, 117, 118).
and the epithelial sodium channel (ENaC) in the distal nephron and In another Clinical Trial, Thomas et al. showed that TZP in
in the connecting tubule, another vital contributor to sodium diabetic patients resulted in substantially greater GC and WL versus
reabsorption (112, 115). In addition, insulin regulates w-no-lysine dulaglutide. This is a post hoc exploratory biomarker study that
(WNK) kinases, which, through the stimulation of sodium explored the results of TZP on insulin sensitivity and pancreatic b-

Frontiers in Endocrinology 08 [Link]

Corrao et al. 10.3389/fendo.2024.1402583

SURMOUNT-1 SURMOUNT-2 SURMOUNT-3 SURMOUNT-4

Study design Multicentre Multicentre Multicentre Multicentre

Randomized Randomized Randomized Randomized
Double-blind Double-blind Double-blind Parallele-group
Placebo-controlled Parallel-group trial Placebo-controlled Open-label in 36 weeks
Phase 3 Trial Placebo-controlled Phase 3 trial Double-blind and
72 weeks Phase 3 Trial 72 weeks placebo-controlled in 52
weeks
72 weeks
Phase 3 trial
88 weeks
Period December 2019 29 Mar 2021 20 Mar 2021 29 Mar 2021
- - - -
April 2022 10 Apr 2023 12 May 2023 18 May 2023
Comparator Placebo Placebo Placebo Placebo
Primary Endpoint(s) Percentage change in Percentage change in Percentage change in Percentage change in
BW BW BW BW from randomization
Participants achieving of Participants achieving of Participants achieving of (week 36) to week 88
WL of at least 5% WL of at least 5% WL of at least 5%
Secondary Endpoints WL of 10% or more, WL of 10% or more, WL of 10% or more, Proportion of
15% or more, and 20% 15% or more, and 20% 15% or more, and 20% participants at week 88
or more or more or more maintaining at least 80%
Change from baseline Mean change from Participants maintaining of the WL during the 36-
in BW from baseline to baseline in HbA1c ≥80% of lead-in WL week open-label period
week 20 and time during the 52-
Participants achieving Change from baseline in week double-blind
Change from baseline an HbA1c < 7%, ≤6.5% WC treatment period to first
in WC, SBP, DBP, and <5.7% Change from baseline occurrence of
fasting insulin, lipid Change from baseline in BW, BMI, SBP, DBP, participants returning to
levels and SF-36 in FSG, WC and lipid FSG and lipid levels greater than 95%
physical function score levels baseline BW for those
Change in SF-36v2
Percentage change in Change from baseline Physical Functioning who lost at least 5%
total body-fat mass in fasting insulin, WL > domain score during the open-label
from baseline 25% or more, BMI, BW lead-in period.
Change in IWQOL-
Lite-CT Physical Change in BW and WC
Function composite during the double-blind
score period
Proportion of
participants achieving
WL thresholds of at least
5%, at least 10%, at
least 15% and at least
20% since enrollment
Proportion of
participants achieving at
least 25% WL since
enrollment
Numbers of patients Randomized: 2539 Randomized: 938 Randomized: 579 Enrolled: 783
Completed trial: 859 Completed trial: 479 Randomized: 670
Completed trial: 575
Population Mean duration Obesity: Mean duration Obesity: Mean duration Obesity: Mean duration Obesity:
14.4 years 17.7 years 15.1 years 15.5 years
Mean age: 44.9 years Mean age: 54.2 years Mean age: 45.6 years Mean age: 48 years
Mean BW: 104.8kg Mean BW: 100.7 kg Mean BW: 109.5 kg Mean BW: 107.3 kg
Mean BMI: 38 kg/m2 Mean BMI: 36.1 kg/m2 Mean BMI: 38.6 kg/m2 Mean BMI: 38.4 kg/m2
Mean WC: 114.1 cm Mean WC: 114.9 cm Mean WC: 116.1 cm Mean WC: 115.2 cm
Results BW (Mean change from BW % (Mean change BW % (Mean change BW % (Mean change
baseline) TZP vs from baseline) TZP vs from randomization) TZP from randomization) TZP
placebo: -18.4 Kg vs placebo: -13.75% vs vs placebo: -18.4 % vs vs placebo: -6.7 % vs
-3.1 Kg -3.2% +2.5% +14.8%
WC (Mean change from WC (Mean change from BMI (Mean change from WC (Mean change from
baseline) TZP vs baseline) TZP vs randomization) TZP vs randomization) TZP vs
placebo: -16.7 cm vs placebo: -11.95 cm vs placebo: -7.7 kg/m2 vs placebo: -4.6 cm vs
-4 cm -3.3 cm +1.2 kg/m2 +8.3 cm
SBP (Mean change from HbA1c (Mean change WC (Mean change from BMI (Mean change from
baseline) TZP vs from baseline) TZP vs randomization) TZP vs randomization) TZP vs
placebo: -7.2 mmHg vs placebo: -2.07% vs placebo: -14.6 cm vs placebo: -2.1 kg/m2 vs
-1 mmHg -0.51% +0.2 cm +4.3 kg/m2
DBP (Mean change from BMI (Mean change from SBP (Mean change from
baseline) TZP vs baseline) TZP vs randomization) TZP vs
placebo: -4.8 mmHg vs placebo: -5.05 kg/m2 vs placebo: -5.1 mmHg vs
-0.8 mmHg -1.2 kg/m 2 +4.1 mmHg
DBP (Mean change from
randomization) TZP vs
placebo: -3.2 mmHg vs
+2.3 mmHg

FIGURE 5
The Surmount Program. TZP, Tirzepatide; BW, Body Weight; WL, Weight Loss; WC, waist circumference; SBP, Systolic Blood Pressure; DBP, Diastolic
Blood Pressure.

cell function. The results are that b-cell function was improved, and increasing HOMA2-B indices. These data may be suggestive of
fasting glucagon levels were reduced in patients treated with TZP, developments in pancreatic b-cell function because increased
better than dulaglutide, improving several markers of pancreatic b- circulating proinsulin/insulin ratios and proinsulin/C-peptide are
cell function, as exposed by dose-dependently decreasing proinsulin important markers of initial and increasing pancreatic b-cell
levels, proinsulin/insulin ratios and proinsulin/C-peptide ratios and secretory dysfunction.

Frontiers in Endocrinology 09 [Link]

Corrao et al. 10.3389/fendo.2024.1402583

A B

FIGURE 6
(A) Tirzepatide’s Effects on Systolic Blood Pressure (SURMONT 3). (B) Tirzepatide’s Effects on Diastolic Blood Pressure (SURMONT 3).

HOMA2-IR indices of insulin resistance and fasting insulin analysis, Data curation. AT: Writing – original draft,
levels was reduced by TZP treatment. TZP’s IS effects were only Investigation, Formal analysis, Data curation. CA: Writing –
partially attributable to WL, recommending that dual agonism gives review & editing, Writing – original draft, Validation,
distinct instruments of GC (119). Supervision, Methodology, Conceptualization.

3 Conclusion Funding
The troubling rise in the number of subjects affected by obesity The author(s) declare financial support was received for the
worldwide has necessitated new scientific developments to blunt research, authorship, and/or publication of this article. Omnia
previous adverse effects of medication and facilitate administration, Congress s.r.l. supported publishing costs for educational purposes.
addressing different problems with a single drug. TZP has shown
encouraging results in WL, high blood pressure, and HbA1c. Patient
compliance is encouraged since it has the vantage of a once-week
Conflict of interest
dosing. In this sense, TZP could represent a breakthrough due to its
The authors declare that the research was conducted in the
magnitude of effects on WL, blood pressure, and glycemia. It also
absence of any commercial or financial relationships that could be
opens a new scenario in obesity treatment with the promise of
construed as a potential conflict of interest.
finally being the silver bullet against obesity.

Publisher’s note
Author contributions
All claims expressed in this article are solely those of the authors
SC: Writing – review & editing, Writing – original draft, and do not necessarily represent those of their affiliated organizations,
Validation, Supervision, Methodology, Conceptualization. CP: or those of the publisher, the editors and the reviewers. Any product
Writing – original draft, Investigation, Formal analysis, Data that may be evaluated in this article, or claim that may be made by its
curation. DM: Writing – original draft, Investigation, Formal manufacturer, is not guaranteed or endorsed by the publisher.

References
1. WHO. Obesity . Available online at: [Link] 6. Spiegelman BM, Flier JS. Obesity and the regulation of energy balance. Cell.
(Accessed 21 January 2024). (2001) 104:531–43. doi: 10.1016/S0092–8674(01)00240–9
2. Townsend N, Vogel C, Allender S, Halloran A, Sorensen K, John PH, et al. WHO 7. Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, Kriketos A, et al.
European Regional Obesity: Report 2022. Copenhagen: World Health Organization, Long-term persistence of hormonal adaptations to weight loss. N Engl J Med. (2011)
Regional Office for Europe (2022). 365:1597–604. doi: 10.1056/NEJMoa1105816
3. Di Angelantonio E, Bhupathiraju SN, Wormser D, Gao P, Kaptoge S, De Gonzalez 8. Gadde KM, Martin CK, Berthoud H-R, Heymsfield SB. Obesity. J Am Coll
AB, et al. Body-mass index and all-cause mortality: individual-participant-data meta- Cardiol. (2018) 71:69–84. doi: 10.1016/[Link].2017.11.011
analysis of 239 prospective studies in four continents. Lancet. (2016) 388:776–86. 9. Hijmans JG, Diehl KJ, Bammert TD, Kavlich PJ, Lincenberg GM, Greiner JJ, et al.
doi: 10.1016/S0140–6736(16)30175–1 Influence of overweight and obesity on circulating inflammation-related microRNA.
4. Afshin A, Forouzanfar M, Reitsma M, Sur P, Estep K, Lee A, et al. The GBD 2015 MIRNA. (2018) 7:148–54. doi: 10.2174/2211536607666180402120806
obesity collaborators health effects of overweight and obesity in 195 countries over 25 10. Scaglione R, Argano C, Chiara TD, Licata G. Obesity and cardiovascular risk: the
years. N Engl J Med. (2017) 377:13–27. doi: 10.1056/NEJMoa1614362 new public health problem of worldwide proportions. Expert Rev Cardiovasc Ther.
(2004) 2:203–12. doi: 10.1586/14779072.2.2.203
5. Sanyaolu A, Okorie C, Qi X, Locke J, Rehman S. Childhood and adolescent obesity
in the United States: A public health concern. Global Pediatr Health. (2019) 6, 11. Licata G, Argano C, Di Chiara T, Parrinello G, Scaglione R. Obesity: A main
2333794X1989130. doi: 10.1177/2333794X19891305 factor of metabolic syndrome? Panminerva Med. (2006) 48:77–85.

Frontiers in Endocrinology 10 [Link]

Corrao et al. 10.3389/fendo.2024.1402583

12. Powell-Wiley TM, Poirier P, Burke LE, Despré s J-P, Gordon-Larsen P, Lavie CJ, 35. Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, et al. Efficacy and
et al. Obesity and cardiovascular disease: A scientific statement from the american heart safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with
association. Circulation. (2021) 143:e984–e1010. doi: 10.1161/CIR.0000000000000973 type 2 diabetes: A randomised, placebo-controlled and active comparator-controlled
13. Corrao S, Calvo L, Amico S, Argano C. The critical role of abdominal obesity as a phase 2 trial. Lancet. (2018) 392:2180–93. doi: 10.1016/S0140–6736(18)32260–8
crucial cardiovascular risk factor. Diabetes Obes Metab. (2024) 26:1967–70. 36. Rosenstock J, Wysham C, Frı́as JP, Kaneko S, Lee CJ, Ferná ndez Landó L, et al.
doi: 10.1111/dom.15467 Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in
14. Usdin TB, Mezey E, Button DC, Brownstein MJ, Bonner TI. Gastric inhibitory patients with type 2 diabetes (SURPASS-1): A double-blind, randomised, phase 3 trial.
polypeptide receptor, a member of the secretin-vasoactive intestinal peptide receptor Lancet. (2021) 398:143–55. doi: 10.1016/S0140–6736(21)01324–6
family, is widely distributed in peripheral organs and the brain. Endocrinology. (1993) 37. Frı́as JP, Davies MJ, Rosenstock J, Pé rez Manghi FC, Ferná ndez Landó L,
133(6):2861–70. doi: 10.1210/endo.133.6.8243312 Bergman BK, et al. Tirzepatide versus semaglutide once weekly in patients with type 2
15. Miyawaki K, Yamada Y, Ban N, Ihara Y, Tsukiyama K, Zhou H, et al. Inhibition diabetes. N Engl J Med. (2021) 385:503–15. doi: 10.1056/NEJMoa2107519
of gastric inhibitory polypeptide signaling prevents obesity. Nat Med. (2002) 8:738–42. 38. Colin IM. Endocrino-Diabetology Research Unit, Department of Internal
doi: 10.1038/nm727 Medicine, Centre Hospitalier Ré gional (CHR) Mons-Hainaut/Groupe Jolimont,
16. Dong C, Sanchez LE, Price RA. Relationship of obesity to depression: A family- Mons, Belgium; Gé rard, A.-C.; Endocrino-Diabetology Research Unit, Department
based study. Int J Obes. (2004) 28:790–5. doi: 10.1038/[Link].0802626 of Internal Medicine, Centre Hospitalier Ré gional (CHR) Mons-Hainaut/Groupe
Jolimont, Mons, Belgium; Group of Animal Molecular and Cellular Biology, Louvain
17. Colomba D, Duro G, Corrao S, Argano C, Di Chiara T, Nuzzo D, et al. Institute of Biomolecular Science and Technology (LIBST), Université catholique de
Endothelial nitric oxide synthase gene polymorphisms and cardiovascular damage in Louvain (UCLouvain), Louvain-La-Neuve, Belgium Once-Weekly 2.4 Mg Semaglutide
hypertensive subjects: an italian case-control study. Immun Ageing. (2008) 5:4. for Weight Management in Obesity: A Game Changer? Endocrinology. (2022) 18:35.
doi: 10.1186/1742–4933-5–4 doi: 10.17925/EE.2022.18.1.35
18. Scaglione R, Argano C, Duro G, Di Chiara T, Nuzzo D, Colomba D, et al. The 39. Wang L. Designing a dual GLP-1R/GIPR agonist from tirzepatide: comparing
relationship between the transforming growth factor b 1 T29C gene polymorphism and residues between tirzepatide, GLP-1, and GIP. DDDT. (2022) 16:1547–59. doi: 10.2147/
left ventricular geometry and function in hypertensive subjects. Int J Hypertension. DDDT.S358989
(2010) 2010:1–7. doi: 10.4061/2010/647147
40. Mayendraraj A, Rosenkilde MM, Gasbjerg LS. GLP-1 and GIP receptor signaling
19. Willard FS, Douros JD, Gabe MBN, Showalter AD, Wainscott DB, Suter TM, in beta cells – A review of receptor interactions and co-stimulation. Peptides. (2022)
et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI 151:170749. doi: 10.1016/[Link].2022.170749
Insight. (2020) 5:e140532. doi: 10.1172/[Link].140532
41. Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, et al.
20. Bulum T. Nephroprotective properties of the glucose-dependent insulinotropic
LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2
polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists.
diabetes mellitus: from discovery to clinical proof of concept. Mol Metab. (2018) 18:3–
Biomedicines. (2022) 10:2586. doi: 10.3390/biomedicines10102586
14. doi: 10.1016/[Link].2018.09.009
21. Di Chiara T, Argano C, Corrao S, Scaglione R, Licata G. Hypoadiponectinemia:
A link between visceral obesity and metabolic syndrome. J Nutr Metab. (2012) 2012:1– 42. Alam S, Hasan M, Neaz S, Hussain N, Hossain M, Rahman T. Diabetes mellitus:
7. doi: 10.1155/2012/175245 insights from epidemiology, biochemistry, risk factors, diagnosis, complications and
comprehensive management. Diabetology. (2021) 2:36–50. doi: 10.3390/diabetology2020004
22. Di Chiara T, Licata A, Argano C, Duro G, Corrao S, Scaglione R. Plasma
adiponectin: A contributing factor for cardiac changes in visceral obesity-associated 43. Borner T, Geisler CE, Fortin SM, Cosgrove R, Alsina-Fernandez J, Dogra M,
hypertension. Blood Pressure. (2014) 23:147–53. doi: 10.3109/08037051.2013.823767 et al. GIP receptor agonism attenuates GLP-1 receptor agonist–induced nausea and
emesis in preclinical models. Diabetes. (2021) 70:2545–53. doi: 10.2337/db21–0459
23. Di Chiara T, Argano C, Scaglione A, Corrao S, Pinto A, Scaglione R. Circulating
adiponectin: A cardiometabolic marker associated with global cardiovascular risk. Acta 44. Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin
Cardiologica. (2015) 70:33–40. doi: 10.1080/AC.70.1.3064591 hormone action. Cell Metab. (2013) 17:819–37. doi: 10.1016/[Link].2013.04.008
24. Scaglione R, Argano C, Di Chiara T, Colomba D, Parrinello G, Corrao S, et al. 45. Nauck MA, Quast DR, Wefers J, Pfeiffer AFH. The evolving story of incretins
Central obesity and hypertensive renal disease: association between higher levels of (GIP and GLP -1) in metabolic and cardiovascular disease: A pathophysiological
BMI, circulating transforming growth factor B1 and urinary albumin excretion. Blood update. Diabetes Obes Metab. (2021) 23:5–29. doi: 10.1111/dom.14496
Pressure. (2003) 12:269–76. doi: 10.1080/08037050310016484 46. Conlon JM, O’Harte FPM, Flatt PR. Dual-agonist incretin peptides from fish
25. Parrinello G, Licata A, Colomba D, Di Chiara T, Argano C, Bologna P, et al. Left with potential for obesity-related type 2 diabetes therapy – A review. Peptides. (2022)
ventricular filling abnormalities and obesity-associated hypertension: relationship with 147:170706. doi: 10.1016/[Link].2021.170706
overproduction of circulating transforming growth factor B1. J Hum Hypertens. (2005) 47. Gallwitz B, Witt M, Fölsch UR, Creutzfeldt W, Schmidt WE. Binding specificity
19:543–50. doi: 10.1038/[Link].1001864 and signal transduction of receptors for glucagon-like peptide-1(7–36)Amide and
26. Scaglione R, Argano C, Chiara TD, Parrinello G, Colomba D, Avellone G, et al. gastric inhibitory polypeptide on RINm5F insulinoma cells. J Mol Endocrinol. (1993)
Effect of dual blockade of renin–angiotensin system on TGFb1 and left ventricular 10:259–68. doi: 10.1677/jme.0.0100259
structure and function in hypertensive patients. J Hum Hypertens. (2007) 21:307–15. 48. Lupi R, Del Guerra S, D’Aleo V, Boggi U, Filipponi F, Marchetti P. The direct
doi: 10.1038/[Link].1002161 effects of GLP-1 and GIP, alone or in combination, on human pancreatic islets. Regul
27. Scaglione R, Argano C, Corrao S, Chiara TD, Licata A, Licata G. Transforming Peptides. (2010) 165:129–32. doi: 10.1016/[Link].2010.04.009
growth factor B1 and additional renoprotective effect of combination ACE inhibitor 49. Samms RJ, Christe ME, Collins KA, Pirro V, Droz BA, Holland AK, et al. GIPR
and angiotensin II receptor blocker in hypertensive subjects with minor renal agonism mediates weight-independent insulin sensitization by tirzepatide in obese
abnormalities: A 24-week randomized controlled trial. J Hypertension. (2005) mice. J Clin Invest. (2021) 131:e146353. doi: 10.1172/JCI146353
23:657–64. doi: 10.1097/[Link].0000160225.01845.26
50. Samms RJ, Zhang G, He W, Ilkayeva O, Droz BA, Bauer SM, et al. Tirzepatide
28. Argano C, Duro G, Corrao S, Di Chiara T, Nuzzo D, Colomba D, et al. induces a thermogenic-like amino acid signature in brown adipose tissue. Mol Metab.
Transforming growth factor B1 T29C gene polymorphism and hypertension: (2022) 64:101550. doi: 10.1016/[Link].2022.101550
relationship with cardiovascular and renal damage. Blood Pressure. (2008) 17:220–6.
51. Razzaki TS, Weiner A, Shukla AP. Tirzepatide: does the evidence to date show
doi: 10.1080/08037050802431416
potential for the treatment of early stage type 2 diabetes? TCRM. (2022) 18:955–64.
29. Meier JJ, Rosenstock J, Hincelin-Mé ry A, Roy-Duval C, Delfolie A, Coester H-V, doi: 10.2147/TCRM.S328056
et al. Contrasting effects of lixisenatide and liraglutide on postprandial glycemic
52. Urva S, Coskun T, Loghin C, Cui X, Beebe E, O’Farrell L, et al. The novel dual
control, gastric emptying, and safety parameters in patients with type 2 diabetes on
glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP -1)
optimized insulin glargine with or without metformin: A randomized, open-label trial.
receptor agonist tirzepatide transiently delays gastric emptying similarly to selective
Diabetes Care. (2015) 38:1263–73. doi: 10.2337/dc14–1984
LONG-ACTING GLP -1 receptor agonists. Diabetes Obes Metab. (2020) 22:1886–91.
30. Barre JL, Still EU. STUDIES ON THE PHYSIOLOGY OF SECRETIN: III. F doi: 10.1111/dom.14110
URTHER S TUDIES ON THE E FFECTS OF S ECRETIN ON THE B LOOD S UGAR. Am J Physiology-
53. Pratley RE. GIP: an inconsequential incretin or not? Diabetes Care. (2010)
Legacy Content. (1930) 91:649–53. doi: 10.1152/ajplegacy.1930.91.2.649
33:1691–2. doi: 10.2337/dc10–0704
31. Pankaj Modi. Diabetes beyond insulin: review of new drugs for treatment of
54. Wasada T, McCorkle K, Harris V, Kawai K, Howard B, Unger RH. Effect of
diabetes mellitus. CDDT. (2007) 4:39–47. doi: 10.2174/157016307781115476
gastric inhibitory polypeptide on plasma levels of chylomicron triglycerides in dogs.
32. Gutzwiller J-P, Tschopp S, Bock A, Zehnder CE, Huber AR, Kreyenbuehl M, J Clin Invest. (1981) 68:1106–7. doi: 10.1172/JCI110335
et al. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-
55. Oben J, Morgan L, Fletcher J, Marks V. Effect of the entero-pancreatic hormones,
resistant obese men. J Clin Endocrinol Metab. (2004) 89:3055–61. doi: 10.1210/jc.2003–
gastric inhibitory polypeptide and glucagon-like polypeptide-1(7–36) amide, on fatty
031403
acid synthesis in explants of rat adipose tissue. J Endocrinol. (1991) 130:267–72.
33. Vilsboll T, Christensen M, Junker AE, Knop FK, Gluud LL. Effects of glucagon- doi: 10.1677/joe.0.1300267
like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of
56. Kim S-J, Nian C, Karunakaran S, Clee SM, Isales CM, McIntosh CHS. GIP-
randomised controlled trials. BMJ. (2012) 344:d7771–1. doi: 10.1136/bmj.d7771
overexpressing mice demonstrate reduced diet-induced obesity and steatosis, and
34. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes improved glucose homeostasis. PloS One. (2012) 7:e40156. doi: 10.1371/
mellitus. Nat Rev Endocrinol. (2012) 8:728–42. doi: 10.1038/nrendo.2012.140 [Link].0040156

Frontiers in Endocrinology 11 [Link]

Corrao et al. 10.3389/fendo.2024.1402583

57. Pirro V, Roth KD, Lin Y, Willency JA, Milligan PL, Wilson JM, et al. Effects of 79. Rosenstock J, Frı́as JP, Rodbard HW, Tofé S, Sears E, Huh R, et al. Tirzepatide vs
tirzepatide, a dual GIP and GLP-1 RA, on lipid and metabolite profiles in subjects with insulin lispro added to basal insulin in type 2 diabetes: the SURPASS-6 randomized
type 2 diabetes. J Clin Endocrinol Metab. (2022) 107:363–78. doi: 10.1210/clinem/ clinical trial. JAMA. (2023) 330:1631. doi: 10.1001/jama.2023.20294
dgab722 80. Inagaki N, Takeuchi M, Oura T, Imaoka T, Seino Y. Efficacy and safety of
58. Forzano I, Varzideh F, Avvisato R, Jankauskas SS, Mone P, Santulli G. tirzepatide monotherapy compared with dulaglutide in Japanese patients with type 2
Tirzepatide: A systematic update. IJMS. (2022) 23:14631. doi: 10.3390/ijms232314631 diabetes (SURPASS J-mono): A double-blind, multicentre, randomised, phase 3 trial.
59. Finan B, Ma T, Ottaway N, Müller TD, Habegger KM, Heppner KM, et al. Lancet Diabetes Endocrinol. (2022) 10:623–33. doi: 10.1016/S2213–8587(22)00188–7
Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and 81. Bradley CL, McMillin SM, Hwang AY, Sherrill CH. Tirzepatide, the newest
humans. Sci Transl Med. (2013) 5(209):209ra151. doi: 10.1126/scitranslmed.3007218 medication for type 2 diabetes: A review of the literature and implications for clinical
60. Adriaenssens AE, Biggs EK, Darwish T, Tadross J, Sukthankar T, Girish M, et al. practice. Ann Pharmacother. (2023) 57:822–36. doi: 10.1177/10600280221134127
Glucose-dependent insulinotropic polypeptide receptor-expressing cells in the 82. Kadowaki T, Chin R, Ozeki A, Imaoka T, Ogawa Y. Safety and efficacy of
hypothalamus regulate food intake. Cell Metab. (2019) 30:987–996.e6. doi: 10.1016/ tirzepatide as an add-on to single oral antihyperglycaemic medication in patients with
[Link].2019.07.013 type 2 diabetes in Japan (SURPASS J-combo): A multicentre, randomised, open-label,
61. Kohnke S, Lam B, Buller S, Zhao C, Nuzzaci D, Tadross J, et al. Nutritional parallel-group, phase 3 trial. Lancet Diabetes Endocrinol. (2022) 10:634–44.
signals rapidly activate oligodendrocyte differentiation in the adult hypothalamic doi: 10.1016/S2213–8587(22)00187–5
median eminence. Neuroscience. (2019). doi: 10.1101/751198 83. Gao L, Lee BW, Chawla M, Kim J, Huo L, Du L, et al. Tirzepatide versus insulin
62. NamKoong C, Kim MS, Jang B-T, Lee YH, Cho Y-M, Choi HJ. Central glargine as second-line or third-line therapy in type 2 diabetes in the asia-pacific region:
administration of GLP-1 and GIP decreases feeding in mice. Biochem Biophys Res the SURPASS-AP-combo trial. Nat Med. (2023) 29:1500–10. doi: 10.1038/s41591–023-
Commun. (2017) 490:247–52. doi: 10.1016/[Link].2017.06.031 02344–1
63. Samms RJ, Coghlan MP, Sloop KW. How may GIP enhance the therapeutic 84. Nicholls SJ, Bhatt DL, Buse JB, Prato SD, Kahn SE, Lincoff AM, et al.
efficacy of GLP-1? Trends Endocrinol Metab. (2020) 31:410–21. doi: 10.1016/ Comparison of tirzepatide and dulaglutide on major adverse cardiovascular events in
[Link].2020.02.006 participants with type 2 diabetes and atherosclerotic cardiovascular disease: SURPASS-
CVOT design and baseline characteristics. Am Heart J. (2024) 267:1–11. doi: 10.1016/
64. Irwin N, McClean PL, Cassidy RS, O’Harte FPM, Green BD, Gault VA, et al. [Link].2023.09.007
Comparison of the anti-diabetic effects of GIP- and GLP-1-receptor activation in obese
85. Nauck MA, D’Alessio DA. Tirzepatide, a dual GIP/GLP-1 receptor co-agonist
diabetic (Ob/ob) mice: studies with DPP IV resistantN-acGIP and exendin(1–39)
for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic
Amide. Diabetes Metab Res Rev. (2007) 23:572–9. doi: 10.1002/dmrr.729
control and body weight reduction. Cardiovasc Diabetol. (2022) 21:169. doi: 10.1186/
65. Gault VA, Kerr BD, Harriott P, Flatt PR. Administration of an acylated GLP-1 s12933–022-01604–7
and GIP preparation provides added beneficial glucose-lowering and insulinotropic 86. DeVries JH, Desouza C, Bellary S, Unger J, Hansen OKH, Zacho J, et al.
actions over single incretins in mice with type 2 diabetes and obesity. Clin Sci. (2011) Achieving glycaemic control without weight gain, hypoglycaemia, or gastrointestinal
121:107–17. doi: 10.1042/CS20110006 adverse events in type 2 diabetes in the SUSTAIN clinical trial programme. Diabetes
66. Pathak NM, Pathak V, Gault VA, McClean S, Irwin N, Flatt PR. Novel dual Obes Metab. (2018) 20:2426–34. doi: 10.1111/dom.13396
incretin agonist peptide with antidiabetic and neuroprotective potential. Biochem 87. De Block C, Mathieu C, Sapin H, Kiljanski JI, Peleshok J. 727-P: glycemic effect
Pharmacol. (2018) 155:264–74. doi: 10.1016/[Link].2018.07.021 of tirzepatide by duration of diabetes. Diabetes. (2022) 71:727. doi: 10.2337/db22-727-P
67. Geisler CE, Antonellis MP, Trumbauer W, Martin JA, Coskun T, Samms RJ, 88. Chavda VP, Ajabiya J, Teli D, Bojarska J, Apostolopoulos V. Tirzepatide, a new
et al. Tirzepatide suppresses palatable food intake by selectively reducing preference for era of dual-targeted treatment for diabetes and obesity: A mini-review. Molecules.
fat in rodents. Diabetes Obes Metab. (2023) 25:56–67. doi: 10.1111/dom.14843 (2022) 27:4315. doi: 10.3390/molecules27134315
68. Wilson JM, Lin Y, Luo MJ, Considine G, Cox AL, Bowsman LM, et al. The Dual 89. Kalavalapalli S, Bril F, Guingab J, Vergara A, Garrett TJ, Sunny NE, et al. Impact
Glucose-dependent Insulinotropic Polypeptide and Glucagon-like Peptide-1 Receptor of exenatide on mitochondrial lipid metabolism in mice with nonalcoholic
Agonist Tirzepatide Improves Cardiovascular Risk Biomarkers in Patients with Type 2 steatohepatitis. J Endocrinol. (2019) 241:293–305. doi: 10.1530/JOE-19–0007
Diabetes: A p OST HOC Analysis. Diabetes Obes Metab. (2022) 24:148–53. doi: 10.1111/ 90. Mantovani A, Byrne CD, Targher G. Efficacy of peroxisome proliferator-
dom.14553 activated receptor agonists, glucagon-like peptide-1 receptor agonists, or sodium-
69. Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, et al. IDF glucose cotransporter-2 inhibitors for treatment of non-alcoholic fatty liver disease:
diabetes atlas: global, regional and country-level diabetes prevalence estimates for 2021 A systematic review. Lancet Gastroenterol Hepatol. (2022) 7:367–78. doi: 10.1016/
and projections for 2045. Diabetes Res Clin Pract. (2022) 183:109119. doi: 10.1016/ S2468–1253(21)00261–2
[Link].2021.109119 91. Gastaldelli A, Cusi K. From NASH to diabetes and from diabetes to NASH:
70. Min T, Bain SC. The role of tirzepatide, dual GIP and GLP-1 receptor agonist, in mechanisms and treatment options. JHEP Rep. (2019) 1:312–28. doi: 10.1016/
the management of type 2 diabetes: the SURPASS clinical trials. Diabetes Ther. (2021) [Link].2019.07.002
12:143–57. doi: 10.1007/s13300–020-00981–0 92. Müller TD, Finan B, Bloom SR, D’Alessio D, Drucker DJ, Flatt PR, et al.
71. Marı́n-Peñalver JJ, Martı́n-Timó n I, Sevillano-Collantes C, Cañizo-Gó mez FJD. Glucagon-like peptide 1 (GLP-1). Mol Metab. (2019) 30:72–130. doi: 10.1016/
Update on the treatment of type 2 diabetes mellitus. WJD. (2016) 7:354. doi: 10.4239/ [Link].2019.09.010
wjd.v7.i17.354 93. Ferguson D, Finck BN. Emerging therapeutic approaches for the treatment of
72. Gallwitz B. Clinical perspectives on the use of the GIP/GLP-1 receptor agonist NAFLD and type 2 diabetes mellitus. Nat Rev Endocrinol. (2021) 17:484–95.
tirzepatide for the treatment of type-2 diabetes and obesity. Front Endocrinol. (2022) doi: 10.1038/s41574-021-00507-z
13:1004044. doi: 10.3389/fendo.2022.1004044 94. Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR, et al.
73. Syed YY. Tirzepatide: first approval. Drugs. (2022) 82:1213–20. doi: 10.1007/ Randomized controlled trial testing the effects of weight loss on nonalcoholic
s40265–022-01746–8 steatohepatitis. Hepatology. (2010) 51:121–9. doi: 10.1002/hep.23276
74. Ludvik B, Giorgino F, Jó dar E, Frias JP, Ferná ndez Landó L, Brown K, et al. 95. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-
Once-Weekly Tirzepatide versus Once-Daily Insulin Degludec as Add-on to Oramas B, Gonzalez-Fabian L, et al. Weight loss through lifestyle modification
Metformin with or without SGLT2 Inhibitors in Patients with Type 2 Diabetes significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. (2015)
(SURPASS-3): A Randomised, Open-Label, Parallel-Group, Phase 3 Trial. Lancet. 149:367–378.e5. doi: 10.1053/[Link].2015.04.005
(2021) 398:583–98. doi: 10.1016/S0140–6736(21)01443–4
96. Lee J, Hong S-W, Rhee E-J, Lee W-Y. GLP-1 receptor agonist and non-alcoholic
75. Del Prato S, Kahn SE, Pavo I, Weerakkody GJ, Yang Z, Doupis J, et al. fatty liver disease. Diabetes Metab J. (2012) 36:262. doi: 10.4093/dmj.2012.36.4.262
Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular
risk (SURPASS-4): A randomised, open-label, parallel-group, multicentre, phase 3 trial. 97. Lee J, Hong S-W, Kim M-J, Moon SJ, Kwon H, Park SE, et al. Dulaglutide
Lancet. (2021) 398:1811–24. doi: 10.1016/S0140–6736(21)02188–7 ameliorates palmitic acid-induced hepatic steatosis by activating FAM3A signaling
pathway. Endocrinol Metab. (2022) 37:74–83. doi: 10.3803/EnM.2021.1293
76. Battelino T, Bergenstal RM, Rodrı́guez A, Ferná ndez Landó L, Bray R, Tong Z,
et al. Efficacy of once-weekly tirzepatide versus once-daily insulin degludec on 98. Lee Y-S, Park M-S, Choung J-S, Kim S-S, Oh H-H, Choi C-S, et al. Glucagon-like
glycaemic control measured by continuous glucose monitoring in adults with type 2 peptide-1 inhibits adipose tissue macrophage infiltration and inflammation in an obese
diabetes (SURPASS-3 CGM): A substudy of the randomised, open-label, parallel- mouse model of diabetes. Diabetologia. (2012) 55:2456–68. doi: 10.1007/s00125–012-
group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol. (2022) 10:407–17. 2592–3
doi: 10.1016/S2213–8587(22)00077–8 99. Kannt A, Madsen AN, Kammermeier C, Elvert R, Klöckener T, Bossart M, et al.
77. Dahl D, Onishi Y, Norwood P, Huh R, Bray R, Patel H, et al. Effect of Incretin combination therapy for the treatment of non-alcoholic steatohepatitis.
subcutaneous tirzepatide vs placebo added to titrated insulin glargine on glycemic Diabetes Obes Metab. (2020) 22:1328–38. doi: 10.1111/dom.14035
control in patients with type 2 diabetes: the SURPASS-5 randomized clinical trial. 100. Gastaldelli A, Cusi K, Ferná ndez Landó L, Bray R, Brouwers B, Rodrı́guez Á .
JAMA. (2022) 327:534. doi: 10.1001/jama.2022.0078 Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose
78. Tall Bull S, Nuffer W, Trujillo JM. Tirzepatide: A novel, first-in-class, dual GIP/ tissue in people with type 2 diabetes (SURPASS-3 MRI): A substudy of the randomised,
GLP-1 receptor agonist. J Diabetes its Complications. (2022) 36:108332. doi: 10.1016/ open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol.
[Link].2022.108332 (2022) 10:393–406. doi: 10.1016/S2213–8587(22)00070–5

Frontiers in Endocrinology 12 [Link]

Corrao et al. 10.3389/fendo.2024.1402583

101. Patel Chavez C, Cusi K, Kadiyala S. The emerging role of glucagon-like peptide- 110. Karlsson C, Lindell K, Ottosson M, Sjöström L, Carlsson B, Carlsson LMS. Human
1 receptor agonists for the management of NAFLD. J Clin Endocrinol Metab. (2022) adipose tissue expresses angiotensinogen and enzymes required for its conversion to
107:29–38. doi: 10.1210/clinem/dgab578 angiotensin II 1. J Clin Endocrinol Metab. (1998) 83:3925–9. doi: 10.1210/jcem.83.11.5276
102. Malhotra A, Bednarik J, Chakladar S, Dunn JP, Weaver T, Grunstein R, et al. 111. Maenhaut N, Van de Voorde J. Regulation of vascular tone by adipocytes. BMC
Tirzepatide for the treatment of obstructive sleep apnea: rationale, design, and sample Med. (2011) 9:25. doi: 10.1186/1741–7015-9–25
baseline characteristics of the SURMOUNT -OSA phase 3 trial. Contemp Clin Trials. 112. El Meouchy P, Wahoud M, Allam S, Chedid R, Karam W, Karam S.
(2024) 141:107516. doi: 10.1016/[Link].2024.107516 Hypertension related to obesity: pathogenesis, characteristics and factors for control.
103. Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, et al. IJMS. (2022) 23:12305. doi: 10.3390/ijms232012305
Tirzepatide once weekly for the treatment of obesity. N Engl J Med. (2022) 387:205–16. 113. Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest. (2000) 106:473–
doi: 10.1056/NEJMoa2206038 81. doi: 10.1172/JCI10842
104. Garvey WT, Frias JP, Jastreboff AM, Le Roux CW, Sattar N, Aizenberg D, et al. 114. da Silva AA, do Carmo JM, Li X, Wang Z, Mouton AJ, Hall JE. Role of
Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes hyperinsulinemia and insulin resistance in hypertension: metabolic syndrome revisited.
(SURMOUNT-2): A double-blind, randomised, multicentre, placebo-controlled, phase Can J Cardiol. (2020) 36:671–82. doi: 10.1016/[Link].2020.02.066
3 trial. Lancet. (2023) 402:613–26. doi: 10.1016/S0140–6736(23)01200-X
115. Horita S, Seki G, Yamada H, Suzuki M, Koike K, Fujita T. Insulin resistance,
105. Wadden TA, Chao AM, Machineni S, Kushner R, Ard J, Srivastava G, et al.
obesity, hypertension, and renal sodium transport. Int J Hypertens. (2011) 2011:391762.
Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the
doi: 10.4061/2011/391762
SURMOUNT-3 phase 3 trial. Nat Med. (2023) 29:2909–18. doi: 10.1038/s41591-023-
02597-w 116. Vitari AC, Deak M, Collins BJ, Morrice N, Prescott AR, Phelan A, et al. WNK1,
106. Aronne LJ, Sattar N, Horn DB, Bays HE, Wharton S, Lin W-Y, et al. Continued the kinase mutated in an inherited high-blood-pressure syndrome, is a novel PKB (Protein
treatment with tirzepatide for maintenance of weight reduction in adults with obesity: kinase B)/akt substrate. Biochem J. (2004) 378:257–68. doi: 10.1042/BJ20031692
the SURMOUNT-4 randomized clinical trial. JAMA. (2024) 331:38. doi: 10.1001/ 117. Heise T, Mari A, DeVries JH, Urva S, Li J, Pratt EJ, et al. Effects of subcutaneous
jama.2023.24945 tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin
107. Bucheit J, Ayers J, Pamulapati L, Browning A, Sisson EA. Novel dual incretin sensitivity in adults with type 2 diabetes: A multicentre, randomised, double-blind,
agent, tirzepatide (LY3298176), for the treatment of type 2 diabetes mellitus and parallel-arm, phase 1 clinical trial. Lancet Diabetes Endocrinol. (2022) 10:418–29.
cardiometabolic health. J Cardiovasc Pharmacol. (2022) 80:171–9. doi: 10.1097/ doi: 10.1016/S2213–8587(22)00085–7
FJC.0000000000001299 118. Heise T, DeVries JH, Urva S, Li J, Pratt EJ, Thomas MK, et al. Tirzepatide
108. De Block C, Bailey C, Wysham C, Hemmingway A, Allen SE, Peleshok J. reduces appetite, energy intake, and fat mass in people with type 2 diabetes. Diabetes
Tirzepatide for the treatment of adults with type 2 diabetes: an endocrine perspective. Care. (2023) 46:998–1004. doi: 10.2337/dc22–1710
Diabetes Obes Metab. (2023) 25:3–17. doi: 10.1111/dom.14831 119. Thomas MK, Nikooienejad A, Bray R, Cui X, Wilson J, Duffin K, et al. Dual GIP and
109. Mertens IL, Van Gaal LF. Overweight, obesity, and blood pressure: the effects of GLP-1 receptor agonist tirzepatide improves beta-cell function and insulin sensitivity in type
modest weight reduction. Obes Res. (2000) 8:270–8. doi: 10.1038/oby.2000.32 2 diabetes. J Clin Endocrinol Metab. (2021) 106:388–96. doi: 10.1210/clinem/dgaa863

Frontiers in Endocrinology 13 [Link]