Received: 6 March 2025 Revised: 27 May 2025 Accepted: 6 June 2025

DOI: 10.1111/dom.16549

REVIEW ARTICLE

Tirzepatide and cardiometabolic parameters in obesity:

Summary of current evidence

Naveed Sattar FMedSci 1 | Luis-Emilio García-Pérez MD 2 |

2 2
Angel Rodríguez MD | Richa Kapoor PhD | Adam Stefanski MD 2 |
2
Emily R. Hankosky PhD

1
School of Cardiovascular and Metabolic
Health, University of Glasgow, Glasgow, UK Abstract
2
Eli Lilly and Company, Indianapolis, Globally, cardiovascular diseases (CVDs) account for around one-third of all deaths.
Indiana, USA
Clinical trial evidence suggests that treatment of people with obesity or type 2 diabe-
Correspondence tes (T2D) and CVD with glucagon-like peptide-1 (GLP-1) receptor agonists reduces
Naveed Sattar, School of Cardiovascular and
Metabolic Health, Glasgow Cardiovascular
the risk of major adverse cardiovascular events, heart failure outcomes and all-cause
Research Centre, University of Glasgow, mortality. Tirzepatide is a once-weekly, dual glucose-dependent insulinotropic poly-
Glasgow G12 8TA, UK.
Email: [Link]@[Link]
peptide (GIP) and GLP-1 receptor agonist that has demonstrated dose-dependent
efficacy in people with obesity, T2D or both, in terms of glycaemic control and body-
Funding information
Eli Lilly and Company
weight reduction in clinical trials. This narrative review summarizes the current evi-
dence regarding the effects of tirzepatide treatment on cardiometabolic parameters,
including lipid profile, blood pressure and markers of renal function. Additionally, it
summarizes the reported impact of tirzepatide treatment on other relevant parame-
ters, such as body composition, liver fat, progression to T2D among individuals with
prediabetes, and incidence of heart failure events. Considering the changing land-
scape of clinical trial evidence of tirzepatide's effects, this review aims to compile the
available evidence, which suggests a promising outlook for the cardiometabolic bene-
fits of tirzepatide.

KEYWORDS
cardiometabolic factors, cardiovascular disease, obesity, tirzepatide

1 | I N T RO DU CT I O N The Semaglutide Effects on Cardiovascular Outcomes in People

with Overweight or Obesity trial (SELECT) was the first cardiovascular
Cardiovascular diseases (CVDs) present a considerable global public outcomes trial (CVOT) that provided evidence of a relationship
health issue, collectively accounting for one-third of all deaths in between an approved weight-reducing therapy (semaglutide 2.4 mg
2019.1 According to the American Heart Association, between 2017 administered subcutaneously once weekly) and atherosclerotic CVD
and 2020, 48.6% of the United States adult population had some form (ASCVD) risk reduction in people living with obesity.3 SELECT
2
of CVD (including hypertension). The economic burden is substantial; assessed the impact of semaglutide, a glucagon-like peptide-1 (GLP-1)
direct and indirect costs associated with CVD in the United States receptor agonist, on major adverse cardiovascular (MACE) outcomes
between 2019 and 2020 were estimated to be $422.3 billion.2 among people with obesity with preexisting CVD but without

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2025 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

5386 [Link]/journal/dom Diabetes Obes Metab. 2025;27:5386–5392.

SATTAR ET AL. 5387

diabetes.3 Semaglutide treatment significantly reduced the risk of SURMOUNT-4,15 and consistent results were reported for people
MACE-3 (non-fatal myocardial infarction, non-fatal stroke, cardiovas- with T2D in SURMOUNT-2.16 In post hoc analyses of a phase 2 study,
cular death) by 20% compared with placebo (hazard ratio: 0.80, 95% treatment with tirzepatide was shown to be associated with reduced
confidence interval [CI]: 0.72 to 0.90; p < 0.001), with nominally sig- circulating levels of biomarkers associated with cardiovascular risk,17
3
nificant reductions in heart failure outcomes and all-cause mortality. in addition to lowered hsCRP concentrations in participants with T2D
The results of this trial have increased interest in obesity management in SURPASS-4.18
medications in the cardiovascular and other scientific communities. Improvements in cardiometabolic parameters would be predicted
However, there remains a debate on the relative contribution of fac- to reduce the risk of metabolic and cardiovascular outcomes. A post
tors such as weight reduction, improvements in other cardiometabolic hoc analysis of the SURMOUNT-1 trial using a validated risk engine
parameters (including visceral fat, blood pressure and lipids), as well as that included modifiable risk factors as model inputs (SBP, total cho-
other mechanisms, to the reported MACE benefits associated with lesterol, HDL-C, presence of T2D, blood pressure treatments and cur-
incretin-based obesity management medications.4 rent smoking status) showed that following 72 weeks of tirzepatide
Tirzepatide is a once-weekly dual glucose-dependent insulinotro- treatment, the 10-year predicted risk of ASCVD was significantly
pic polypeptide (GIP) and GLP-1 receptor agonist, approved for the reduced compared with placebo.19 The predicted relative change in
treatment of adults with type 2 diabetes (T2D), for weight manage- risk of ASCVD from baseline to week 72 ranged from 23.5% to
ment in adults with obesity or overweight with at least one weight- 16.4% for tirzepatide versus 12.7% for placebo.19 Specifically,
related comorbid condition, and for obstructive sleep apnoea in adults tirzepatide-treated participants had 2.4 times greater odds (95%
with obesity.5–7 Tirzepatide exerts glucose-lowering effects by acti- CI: 1.7 to 3.5; p < 0.001) of improved ASCVD risk profiles from base-
vating both GIP and GLP-1 receptors, potentially in a synergistic or line to week 72 than those in the placebo group. The findings of ongo-
additive manner,8 thereby augmenting glucose-dependent insulin ing outcome trials (SURPASS-CVOT [NCT04255433]20 and
21
secretion and inhibiting glucagon release. Additionally, tirzepatide SURMOUNT-MMO [NCT05556512] ) will provide evidence of the
transiently delays gastric emptying, which may slow post-meal glucose effects of tirzepatide treatment on cardiovascular outcomes.
9
absorption and benefit postprandial glycaemia. Furthermore, by Increased heart rate has been associated with a higher risk of
increasing feelings of satiety and fullness, tirzepatide results in CVD and mortality.22,23 However, despite increases in heart rate,
decreased food intake and feelings of hunger, leading to appetite reg- GLP-1 receptor agonists were not associated with incident
ulation and bodyweight reduction.9 Tirzepatide also reduces the arrhythmias and did not increase the risk of cardiac arrhythmias.24 A
10
intensity of food cravings and preferences for high-calorie foods. In dose-dependent association was previously demonstrated between
clinical trials, tirzepatide has demonstrated dose-dependent efficacy tirzepatide treatment and increased heart rate, compared with GLP-1
in people with obesity, T2D or both, in terms of glycated haemoglobin receptor agonists and non-GLP-1 receptor agonists.25 Current evi-
(HbA1c) level reduction and bodyweight reduction compared with dence, however, does not indicate an adverse association between tir-
11,12
placebo, GLP-1 receptor agonists and basal insulin. In this narra- zepatide treatment and cardiovascular events. Rather, the hypothesis
tive review, we summarize current evidence on the effects of tirzepa- is that tirzepatide may lower such outcomes, with the results of ongo-
tide on cardiometabolic parameters. We do so as evidence is changing ing outcome trials expected shortly.
rapidly, and collating the totality of the effects of tirzepatide on cardi-
ometabolic parameters seen thus far is likely useful to some clinical
and research communities. 3 | E F F E C T S ON B O D Y F A T
DI S T R I B U T I O N , LI V E R F A T A N D C H R O N I C
KIDNEY DISEASE
2 | E F F E C T O F T I R Z E P A T I D E ON C V D A N D
C A RD I O M E TA B O L I C P A R A M E TE R S Sustained bodyweight reduction among people with obesity is associ-
ated with decreased cardiometabolic risk, as well as improved insulin
Results from clinical trials have indicated that tirzepatide treatment sensitivity, pancreatic β-cell function and hepatic triglycerides.26
improves cardiometabolic parameters among people with or without Recent evidence from the 3-year SURMOUNT-1 study demonstrated
T2D (Figure 1 and Table S1). For example, in SURMOUNT-1, a phase that participants with prediabetes and obesity or overweight achieved
3 randomized clinical trial that assessed the safety and efficacy of tir- up to 20% bodyweight reduction on average following tirzepatide
zepatide among people with obesity or overweight without T2D, par- treatment (15 mg), and maintained it over 3 years with sustained
ticipants showed significant placebo-adjusted improvements in improvements in waist circumference, blood pressure and lipid
systolic blood pressure (SBP), diastolic blood pressure (DBP), triglycer- levels.27 As blood pressure and lipids are impacted by weight, these
ides and waist circumference after 72 weeks of tirzepatide treat- findings further highlight the cardiometabolic benefits of sustained
ment.13 Similar improvements in SBP, DBP, high-density lipoprotein weight reduction.
cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and Additional evidence on the metabolic effects of tirzepatide treat-
triglycerides were reported for participants receiving tirzepatide com- ment comes from assessments of changes in body composition and
pared with placebo in the phase 3 clinical trials SURMOUNT-314 and fat distribution. The impact of tirzepatide on body fat distribution was
5388 SATTAR ET AL.

F I G U R E 1 Summary of the treatment effects of tirzepatide relative to comparators on cardiometabolic parameters among people with
obesity or overweight with and without T2D: Evidence from randomized clinical trials. Ranges across studies for changes from baseline, or for
estimated treatment differences or absolute differences (regardless of efficacy estimand or treatment-regimen estimand) for tirzepatide (15 mg)
versus comparator groups are presented for the cardiometabolic parameters. Please note that ranges may vary depending on the characteristics
of the study population and treatment duration. Study-specific detailed results can be found in Table S1. Results are presented for the efficacy
estimand to provide clinicians with insights into what can be expected for patients who stay on treatment. 1For people with obesity and T2D,
changes from baseline in SBP and DBP values are presented for the treatment-regimen estimand. 2Reduction in risk of T2D in participants with
prediabetes in SURMOUNT-1 was assessed based on glycated haemoglobin and fasting serum glucose levels, and serum glucose levels in a 2-h
oral glucose tolerance test; diagnosis of diabetes was based on ADA guidelines. ADA, American Diabetes Association; CI, confidence interval;
DBP, diastolic blood pressure; diff, difference; eGFR, estimated glomerular filtration rate; HbA1c, glycated haemoglobin; HDL-C, high-density
lipoprotein cholesterol; HR, hazard ratio; KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire clinical summary score; LDL-C, low-density
lipoprotein cholesterol; SBP, systolic blood pressure; T2D, type 2 diabetes; UACR, urine albumin–creatinine ratio.

assessed in a subgroup of SURMOUNT-1 trial participants who 0.93 at baseline to 0.70 at week 72) than with placebo (from 0.95 to
underwent dual-energy x-ray absorptiometry.13 The mean total body 0.88), suggesting an improvement in overall body composition.13
fat mass reduction was 33.9% with tirzepatide and 8.2% with placebo While magnetic resonance imaging (MRI) data on body composi-
(estimated treatment difference [ETD]: 25.7%; 95% CI: 31.4 to tion and fat distribution are not yet available among tirzepatide-
20.0 for the efficacy estimand). The decrease in the ratio of total fat treated people with obesity without T2D, data from people with T2D
mass to total lean mass was numerically greater with tirzepatide (from might highlight potential benefits of tirzepatide on relevant
SATTAR ET AL. 5389

parameters. The SURPASS-3 MRI sub-study characterized changes in 176-week period, tirzepatide treatment was associated with a 94%
liver fat content (LFC), volume of visceral adipose tissue (VAT) and reduction in the risk of developing T2D compared with placebo (1.2%
abdominal subcutaneous adipose tissue (ASAT) following 52 weeks of vs. 12.6%, respectively, for the efficacy estimand; hazard ratio: 0.06;
tirzepatide or insulin degludec treatment among a subgroup 95% CI: 0.0 to 0.10; p < 0.001).27 Furthermore, 92% of the
28
of SURPASS-3 participants. The study reported significant LFC tirzepatide-treated participants with prediabetes had sustained rever-
reduction for pooled tirzepatide groups compared with the insulin sion to normoglycaemia. Glycaemic benefits were reported even
degludec group (ETD: 4.71%; 95% CI: 6.72 to 2.70; p < 0.0001). among tirzepatide-treated participants who lost less than 5% body-
In addition, tirzepatide treatment significantly reduced the volumes of weight, in keeping with known incretin effects on glycaemia.27 These
VAT and ASAT from baseline, while both significantly increased fol- results are consistent with a post hoc risk prediction modelling study
lowing insulin degludec treatment at 52 weeks. LFC reduction was demonstrating that tirzepatide treatment was associated with reduced
significantly correlated with baseline LFC and VAT, ASAT and body- 10-year predicted risk of developing T2D (either among people with
weight reductions in the tirzepatide groups.28 Further studies evaluat- prediabetes at baseline or regardless of prediabetes status at
ing these outcomes among people with obesity will provide additional baseline).36
insights into the effects of tirzepatide on body composition and fat
distribution.
Obesity is an independent risk factor for chronic kidney disease 5 | E F F E C T S ON C A R D I O V A S C U L A R
(CKD) and can increase CKD risk by elevating the risk of T2D, hyper- S A F E T Y A N D M A C E A M ON G P E O P L E
tension and atherosclerosis.29 Weight reduction-induced mitigation of WITH T2D
these risk factors could potentially have a protective effect on
obesity-related CKD.4 Preliminary post hoc analyses on surrogate Considerable evidence of the effects of tirzepatide in terms of
measures of kidney function from SURPASS-4 suggest that tirzepatide improved lipid levels, SBP, DBP, HbA1c and bodyweight comes from
may be associated with improved albuminuria and slow the rate of clinical trials for T2D, summarized in Table S1 and Figure 1. Addition-
estimated glomerular filtration rate (eGFR) decline among people with ally, in SURPASS-4, tirzepatide treatment demonstrated safety in
T2D.30,31 Furthermore, a post hoc analysis of a pooled population terms of adjudicated MACE-4 events (cardiovascular death, myocar-
from the SURPASS 1–5 studies showed that tirzepatide was associ- dial infarction, stroke, hospitalization for unstable angina) relative to
ated with a clinically meaningful decrease in the urine albumin- insulin glargine (hazard ratio: 0.74, 95% CI: 0.51 to 1.08) at
to-creatinine ratio relative to comparators, suggesting potential 104 weeks.37 Furthermore, a pre-specified meta-analysis of 7 SUR-
kidney-related benefits among people with T2D, with or without PASS randomized controlled trials found that tirzepatide treatment
CKD.32 Additionally, a post hoc analysis of the SURMOUNT-2 trial did not increase the risk of MACE relative to controls.38 The overall
demonstrated that among participants with obesity or overweight hazard ratios comparing tirzepatide (at an estimated average dose of
with T2D and preserved eGFR at baseline, tirzepatide was associated 9 mg per week) with a range of different controls (placebo, insulin
with reduced albuminuria without adversely affecting eGFR.33 Further degludec, insulin glargine, semaglutide 1 mg) for MACE-4, cardiovas-
studies are needed to understand the potential association between cular death and all-cause death were 0.80 (95% CI: 0.57 to 1.11;
the effects of tirzepatide on the kidney and its impact on the risk of p = 0.183), 0.90 (95% CI: 0.50 to 1.61) and 0.80 (95% CI: 0.51 to
34
CVD among people with obesity. TREASURE-CKD (NCT05536804) 1.25), respectively.38 Cumulatively, these findings support a potential
is a randomized, placebo-controlled study of the effects of tirzepatide association between tirzepatide and improved cardiovascular safety,
on kidney oxygenation and perturbed renal energetics, kidney inflam- though outcomes trials will report soon to give the best evidence.
mation, fibrosis and renal blood flow, in participants with overweight
or obesity and CKD, with or without T2D. In addition, assessments of
kidney function among people with obesity are ongoing for tirzepa- 6 | TIRZEPATIDE AND HEART FAILURE
tide in the SURMOUNT-MMO (NCT05556512)21 trial.
The impact of tirzepatide in terms of improved bodyweight reduction,
glycaemic control and blood pressure reduction is likely to translate to
4 | R I S K O F D E V E L O P M E N T OF T 2 D protective effects against heart failure. These effects were examined
in the SUMMIT trial, a phase 3, placebo-controlled, randomized clini-
Tirzepatide treatment exerts concurrent benefits on adiposity and gly- cal trial evaluating the safety and efficacy of tirzepatide in adults with
caemia, which may prevent progression to T2D and induce normogly- heart failure with preserved ejection fraction and obesity, with or
caemia, potentially lessening the risk of CVD among people with without T2D.39 Tirzepatide demonstrated a 38% reduction (95% CI:
prediabetes, as hyperglycaemia is an additional cardiovascular risk fac- 5% to 59%; p = 0.026) in the relative risk of time-to-first occurrence
tor once diabetes develops.35 of adjudicated death from cardiovascular causes or a worsening heart
The 3-year SURMOUNT-1 study among adults with prediabetes failure event compared with placebo, though event numbers were
and obesity or overweight evaluated tirzepatide for long-term weight modest.39 Tirzepatide-treated participants also reported improved
27
management and delay in progression to diabetes. Over a health status and exercise tolerance and decreased high-sensitivity
5390 SATTAR ET AL.

C-reactive protein levels relative to placebo ( 38.8% vs. 5.9%, We also recognize this article does not discuss mechanisms and
respectively; between-group difference: 34.9%; 95% CI: 45.6 to pathways by which tirzepatide mediates its actions for benefit.
39
22.2; p < 0.001). Moreover, the pre-specified meta-analysis of SURPASS-CVOT (NCT04255433)20 and SURMOUNT-MMO
21
7 SURPASS trials demonstrated that tirzepatide had a similar point (NCT05556512) are phase 3 trials evaluating the effects of tirze-
estimate for the risk of hospitalization for heart failure (hazard ratio: patide on the prevention of major cardiovascular events among peo-
0.67, 95% CI: 0.26 to 1.70) as the SUMMIT trial, accepting wide CIs ple with T2D and morbidity and mortality in adults living with
38
due to smaller total event numbers. obesity, respectively. These ongoing clinical trials will address the
gap in hard evidence of the potential cardioprotective benefits of
tirzepatide.
7 | SUMMARY OF SAFETY DATA
THUS FAR AUTHOR CONTRIBU TIONS
Design: Naveed Sattar, Luis-Emilio García-Pérez and Emily
Tirzepatide use is associated with gastrointestinal symptoms, most R. Hankosky. Conduct/data collection/interpretation: Naveed Sattar,
commonly nausea, diarrhoea, vomiting, constipation, abdominal pain Luis-Emilio García-Pérez, Angel Rodríguez, Richa Kapoor, Adam Ste-
6
and dyspepsia, among other adverse effects. Results from the SUR- fanski and Emily R. Hankosky. Writing/critical review of manuscript:
MOUNT and SURPASS trials indicate that the gastrointestinal symp- Naveed Sattar, Luis-Emilio García-Pérez, Angel Rodríguez, Richa
toms following tirzepatide treatment were typically transient and of Kapoor, Adam Stefanski and Emily R. Hankosky.
mild-to-moderate severity, with the majority of adverse events occur-
ring at treatment initiation and dose escalation. The frequencies of AC KNOW LEDG EME NT S
serious adverse events between tirzepatide- and placebo-treated par- The authors thank Gayathri Ashok of Eli Lilly Services India Pvt. Ltd.
ticipants were generally comparable. Furthermore, the SURMOUNT-1 for medical writing support, which was funded by Eli Lilly and Com-
3-year study reported decreased incidence of gastrointestinal adverse pany, Indianapolis, USA.
events with tirzepatide use over time, supporting the long-term use of
tirzepatide among people with obesity or overweight, with or without FUNDING INF ORMATI ON
T2D.27 A meta-analysis of 12 randomized controlled trials of tirzepa- Eli Lilly and Company, Indianapolis, USA, sponsored this narrative
tide demonstrated that the total incidence of adverse events following review article.
tirzepatide treatment was similar to GLP-1 receptor agonists (dulaglu-
tide and semaglutide) and expectedly higher than placebo and insulin CONFLIC T OF INTER E ST STATEMENT
groups.40 Naveed Sattar has consulted for and/or received speaker honoraria
Among adverse events of special interest, clinical trials have from Abbott Laboratories, AbbVie, Amgen, AstraZeneca, Boehringer
assessed pancreatitis, cholecystitis, hypoglycaemia, MACE and Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Menarini-
neoplasms (including medullary thyroid cancer). According to a meta- Ricerche, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics and
analysis of 12 randomized clinical trials, the risk of pancreatitis, chole- Sanofi and grant funding paid to his university from AstraZeneca,
cystitis, MACE-4 and neoplasms following tirzepatide treatment Boehringer Ingelheim, Novartis and Roche Diagnostics. Luis-Emilio
appears to be comparable to GLP-1 receptor agonists, placebo or García-Pérez, Angel Rodríguez, Richa Kapoor, Adam Stefanski and
insulin. Tirzepatide is associated with significantly lower hypoglycae- Emily R. Hankosky are employees and stockholders of Eli Lilly
mic risk compared with insulin (p < 0.01).40 and Company, IN, USA.

PE ER RE VIEW
8 | D I S C U S S I O N A N D F U TU R E The peer review history for this article is available at [Link]
DIRECTIONS [Link]/api/gateway/wos/peer-review/10.1111/dom.
16549.
Accumulating evidence shows that treatment with tirzepatide con-
fers sustained (up to 3 years) and clinically meaningful weight reduc- DATA AVAILABILITY STAT EMEN T
tion, alongside improvements in cardiometabolic parameters Data sharing not applicable to this article as no datasets were gener-
(including lipids, blood pressure and markers of kidney function), ated or analysed during the current study.
improvements in body composition and liver fat, a significant reduc-
tion in the progression to T2D among people with prediabetes and a OR CID
reduction in the incidence of heart failure events, all of which offer a Naveed Sattar [Link]
degree of optimism for the potential cardiovascular benefits of tirze- Luis-Emilio García-Pérez [Link]
patide (Figure 1). We recognize the limitation that this article is not a Angel Rodríguez [Link]
systematic review. Rather, the work is a narrative review of the Richa Kapoor [Link]
headline cardiometabolic results reported to date with tirzepatide. Emily R. Hankosky [Link]
SATTAR ET AL. 5391

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