2025 ACC专家共识声明：优化心血管健康的医学体重管理

2025 Concise Clinical Guidance:An ACC Expert Consensus Statement on Medical Weight Management for Optimization of Cardiovascular Health

A Report of the American College of Cardiology Solution Set Oversight Committee

|Writing|Olivia Gilbert, MD, MSc, FACC, Chair|Michelle M. Kittleson, MD, PhD, FACC| |---|---|---| |Committee|Martha Gulati, MD, MS, FACC, Vice Chair|Rishi Rikhi, MD, MS| |Members|Ty J. Gluckman, MD, MHA, FACC|Joseph J.Saseen, PHARMD| |Solution Set|Gurusher S.Panjrath,MBBS,FACC,Chair|Beverly G.Tchang,MD| |Oversight|Nicole M. Bhave,MD,FACC,Immediate Past Chair*|Chayakrit Kittanawong,MD,FACC| |Committee||Dharam J.Kumbhani,MD,SM,FACC| |Niti R. Aggarwal, MD, FACC||Barbara Wiggins, Pharma, PHARMD, FACC| |Katie Bates, ARNPD, DNP|Megan Coeyright,wight,MD,MPH,FACC, Ex Officio|| |Eugene Chung, MD, MPH, FACC||*Former Committee members who also provided oversight for| |John P. Erwin, III, MD, FACC||this document|

TABLE OF CONTENTS

PREFACE 2

1.INTRODUCTION $\ldots$ 2

2. ASSUMPTIONS AND DEFINITIONS $\ldots$ 3

2.1. Assumptions and Definitions 3

2.2. Diagnosis $\boxed{3}$

2.3. Etiology and Pathophysiology of Obesity$\longdots$

Figure 1 Causes of Obesity and Its Association With Increased Cardiovascular Risk Factors

2.4. Risks Associated With Obesity.4

3.SUMMARY GRAPHIC•5

Figure 2. Obesity Management for Optimization of Cardiovascular Health

This document was approved by the American College of Cardiology Clinical Policy Approval Committee in May 2025.The American College of Cardiology requests that this document be cited as follows: Gilbert O, Gulati, M, Gluckman TJ, Kittleson MM, Rikhi R, Saseen JJ,Tchang BG.2025 concise clinical guidance: an ACC expert consensus statement on medical weight management for optimization of cardiovascular health: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. Published online June 20, 2025. https://doi.org/10.1016/j.jacc.2025.05.024

Copies: This document is available on the website of the American College of Cardiology(www.acc.org). For copies of this document, please contact Elsevier Inc Reprint Department via fax(1-212-633-3820) or e-mail(reprints@elsevier.com).

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4.DESCRIPTION,RATIONALE,AND IMPLICATIONS FOR MEDICAL THERAPIES 5

4.1. Rationale and Eligibility for NuSH Therapies$\longdots$

Figure 3A. Weight Loss Thresholds Associated With Comorbidity Improvements 6

Figure 3B. Achieving Clinically Significant Weight Reduction $\ldots$ 7

4.2. Evolution and Current Landscape of 6

4.3. Pharmacological Options $\ldots$ 7

4.4. Implications on Comorbidities $\ldots$ 10

4.5. General Treatment Considerations 11

4.5.1. General Principles That Apply to the Medical Management of Obesity.$$\text{ 11}$$

4.5.2. The Patient Experience $\ldots$ 12 Figure 4. Examples of Ways to Reduce Weight Stigma and More Optimally Deliver Care in Clinic and Hospital Settings $\ldots$ 11

Figure 5. General Overview of Patient's Weight Management Journey With NuSH Therap

4.6. Multidisciplinary Care Approaches $\ldots$ 12

Figure 6. Multidisciplinary Team Approach for Weight Management

4.7. Access Considerations $\ldots$ 13

4.8. Conclusions/Future Directions 14

REFERENCES 14

APPENDIX 1

Author Relationships with Industry and Other Entities(Relevant) $\ldots$ $18$

APPENDIX 2

Peer Reviewer Relationships with Industry and Other Entities(Comprehensive) $\ldots$ $19$

APPENDIX 3

Abbreviations $\ldots$ 20

PREFACE

The American College of Cardiology(ACC) has a long history of developing documents(eg, decision path-ways, appropriate use criteria) to provide clinicians with guidance on both clinical and nonclinical topics relevant to cardiovascular care. In most circumstances, these documents have been created to complement clinical practice guidelines and to inform clinicians about areas where evidence is new and evolving or where sufficient

<EndOfPara>data is more limited. Despite this, numerous gaps persist, highlighting the need for more streamlined and efficient processes to implement best practices in pa-tient care.

Central to the ACC's strategic plan is the generation of actionable knowledge-a concept that places emphasis on making clinical information easier to consume, share,integrate, and update. To this end, the ACC has shifted from developing isolated documents to creating inte-grated“solution sets.” These are groups of closely related activities, policy, mobile applications, decision-support tools, and other resources necessary to transform care and/or improve heart health. Solution sets address key questions facing care teams and offer practical guidance to be applied at the point of care. They use both estab-lished and emerging methods to disseminate information for cardiovascular conditions and their related manage-ment. The success of solution sets rests firmly on their ability to have a measurable impact on the delivery of care. Because solution sets reflect current evidence and ongoing gaps in care, the associated tools will be refined over time to match changing evidence and member needs.

Concise Clinical Guidance (CCG) documents are a key component of solution sets. Highly focused and limited in scope, CCGs provide recommendations where none currently exist and/or outline actions required for evi-dence to be implemented in practice for specific patient populations. Concise Clinical Guidance aim to illustrate clinical decision-making processes using tools (ie, figures,tables, and checklists) and are limited in scope, focusing on patient populations which share certain characteris-tics, such as conditions, subtypes, or lines of therapy. In some cases, covered topics will be addressed in subse-quent expert consensus decision pathways, appropriate use criteria, clinical practice guidelines, and other related ACC clinical policy as the evidence base evolves. In other cases, these will serve as stand-alone policy and represent best standards.

Gurusher S. Panjrath, MBBS,FACC Chair,ACC Solution Set Oversight Committee

1. INTRODUCTION

Affecting>1 billion adults worldwide, obesity is a debili-tating, chronic disease with cardiovascular implications,including increased risk of heart failure, coronary artery disease, and stroke. ${}^{1,2}$ Across 3 decades, obesity rates in adults have doubled, and in children and adolescents,they have quadrupled internationally. ${}^{1}$ Within the United States, 40.3% of adults have obesity(body mass index $\left[\text{BMI}\right]\geq 30~kg/ m^{2}$ ), and 9.4% have severe obesity(BMI≥40 kg/m2).

As severe obesity is associated with significant reduc-tion in life expectancy of 9.1 years in men and 7.7 years in women, treatment is critical.4 Whereas specific BMI cut points are recommended for different races, controversy still exists as to which diagnostic criteria for obesity are most accurate.

Obesity therapeutics vary in effectiveness regarding weight loss and cardiovascular disease(CVD) mitigation.In general, weight loss thresholds for risk reduction are 10% to 15% for CVD and>15% for cardiovascular mortality and adverse outcomes in heart failure with preserved ejection fraction(HFpEF).5.6 Disappointingly, weight loss achieved with lifestyle interventions has not been asso-ciated with a reduction in adverse cardiovascular out-comes.7 Although bariatric surgery is able to achieve substantial weight loss and reduced CVD events, it may be less desirable for some patients.8

More effective than lifestyle interventions and with less risk than procedure-based interventions, modern obesity medications are increasingly relevant to cardiol-ogists for CVD modification. The intent of the current document is to provide the foundation for cardiologists to medically manage obesity using agents with proven CVD benefit.

In accordance with ACC's Relationships With Industry and Other Entities policy, relevant disclosures for the writing committee and comprehensive disclosures for external peer reviewers can be found in Appendices 1 and 2. A list of abbreviations relevant to this Concise Clinical Guidance can be found in Appendix 3. To ensure transparency, a comprehensive table of the writing com-mittee's relationships with industry, including those not pertinent to this document, has been created. This can be found in the online Supplemental Appendix.

2. ASSUMPTIONS AND DEFINITIONS

2.1. Assumptions and Definitions

As the newest generation of obesity medications,nutrient-stimulated hormone(NuSH) therapies represent a broad treatment category that acts on metabolic path-ways, while helping to control appetite. Current targets of U.S. Food and Drug Administration(FDA)-approved NuSH therapies include glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide(GIP)(Section 4.3).° For the purposes of the current document,we utilize the term NuSH therapies to encompass the GLP-1 receptor agonists liraglutide and semagulotide, as well as the GLP-1/GIP receptor agonist trizepatide.

2.2. Diagnosis

Overweight and obesity are defined as"abnormal or excessive fat accumulation that presents a risk to

TABLE 1 Obesity Threshold Classification Eurotopoid Asian BMI category,kg/m2

Waist-to-height ratio≥0.50

health."10,11 Obesity is often diagnosed using BMI, which is calculated using an individual's weight and height. As classified by the Centers for Disease Control and Preven-tion, weight thresholds based on BMI are summarized in Table 1.12-15

At a population level, BMI is a useful measure to assess excess weight; among individuals, however, BMI does not always correlate with adiposity. BMI cannot fully account for fat distribution or muscle mass in an individual.Additionally, it cannot account for sex or racial differ-ences in adiposity distribution and health risks. Classifi-cations may be inaccurate, particularly for South Asian and Chinese populations, where BMI cutoffs for over-weight and obesity have been proposed to be≥23 kg/m²and≥25 kg/m²,respectively. ${}^{16-21}$ Whereas other anthro-pometric measurements, such as waist circumference and waist-to-height ratio, may also be used to identify central adiposity and may better predict association with car-diovascular events, they require broader acceptance and definition of optimal thresholds across weight cate-gories.22 Combining these concepts, obesity is defined by excess adiposity in association with impaired organ and/or functional status where adiposity can be obtained by direct measurements of body fat(eg, dual-energy x-ray absorptiometry scan) or anthropometric measurements(Table 1) in addition to BMI.11,23

2.3. Etiology and Pathophysiology of Obesity

The etiology of obesity is complex. 24,25 Genetics, 26-29 neurological/psychological disorders,30,31 nutrient and hormonal imbalances,32 social determinants of health, the environment in which people live,33,34 medications 35-38 and medical conditions can all contribute to obesity(Figure 1). Its pathophysiology is defined by the

FIGURE 1 Causes of Obesity and its Association With Increased Cardiovascular Risk Factors

 development and defense of an elevated lipostat that is accompanied by dysregulated appetitive hormone signaling and abnormal adipose tissue, which promotes inflammation characteristic of weight-related car-diometabolic and mechanical diseases.39 Obesity has a strong impact on cardiovascular risk factors, including an increased risk of type 2 diabetes mellitus(T2DM),hypertension, hyperlipidemia, and obstructive sleep apnea,40-42 along with other disabilities that can contribute to physical inactivity(Figure 1).30,43 Obesity by itself is an independent risk factor for CVD.

2.4. Risks Associated With Obesity

Obesity is associated with many different forms of CVD,including atherosclerotic CVD, heart failure(more commonly with HFPEF than reduced ejection fraction via inflammatory mechanisms), atrial fibrillation, sud-den cardiac death, venous thromboembolism, and valvular heart disease(Figure 2). ${}^{28,43-45}$ Obesity-related mechanisms result in hemodynamic, functional, and structural changes to the cardiovascular system, which contribute to the development of these disparate forms of CVD,41,43

3. SUMMARY GRAPHIC

FIGURE 2 Obesity Management for Optimization of Cardiovascular Health

 The presence of obesity is associated with multiple forms of CVD. The treatment of obesity with NuSH therapies has resulted in weight loss and proven beneficial in reducing CVD risk factors, cardiovascular endpoints, in addition to reduction in MASLD and CKD progression. AF= atrial fibrillation; ASCVD= atherosclerotic car-diovascular disease; CVD= cardiovascular disease; CKD= chronic kidney disease; HFpEF= heart failure with preserved ejection fraction; HFrEF= heart failure with reduced ejection fraction; MACE= major adverse cardiovascular event; MASLD= metabolic dysfunction-associated steatotic liver disease; NuSH= nutrient-stimulated hormone;SCD=sudden cardiac death;VTE/PE=venous thromboembolism/pulmonary embolism.

4. DESCRIPTION, RATIONALE, AND IMPLICATIONS FOR MEDICAL THERAPIES

4.1. Rationale and Eligibility for NuSH Therapies

NuSH therapies are a crucial component of comprehen-sive obesity care for three reasons:

1. NuSH therapies fill the treatment gap between lifestyle therapy and bariatric surgery(Figures 3A, 3B). Unfor-tunately, lifestyle therapy achieves insufficient long-term weight loss to resolve complications and comorbidities for a majority of patients.46 By contrast,bariatric surgery, while highly effective, is often undesired by patients. Pharmacotherapy strikes the balance between effectiveness and invasiveness.

2. NuSH therapies help to address the disease mecha-nisms of obesity by targeting the hormonal pathways that control appetite(eg, hunger, satiety, satiation, and cravings).

3. Because NuSH therapies are titratable, they allow dosing to minimize side effects and maximize weight loss, making them well suited to individualize care and address the obesity epidemic.

Eligibility for NuSH therapies may be determined by BMI thresholds, which other anthropometric data(Table 1) or direct measurement of excess adiposity, in combination with weight-related consequences. The BMI used to establish eligibility may be the patient's nonpregnant lifetime high, reflecting current under-standing around the“weight set point”49 and in concor-dance with managing obesity as a chronic disease. ${}^{23}$

Whereas prior guidelines suggested a trial of lifestyle intervention prior to pharmacotherapy,50 data from phase 3 trials evaluating semagulatide and tirzepatide show minimal additional weight loss when combined with intensive behavioral therapy/lifestyle intervention.51,52 Patients should not be required to"try and fail" lifestyle

FIGURE 3A Weight Loss Thresholds Associated With Comorbidity Improvements

changes prior to initiating pharmacotherapy; nonetheless,lifestyle interventions should always be offered in conjunction with NuSH therapies.

4.2. Evolution and Current Landscape of Obesity Medications

Obesity medications have a long history dating back to the early 19005,53,54 First-generation medications included thyroid hormone, dinitrophenol, and amphetaminens.Thyroid hormone stimulated metabolic rate but was accompanied by harmful cardiovascular side effects.Dinitrophenol, a mitochondrial uncoupler that increased metabolic rate, resulted in weight loss but increased hy-perthermia, tachycardia, diaphoresis, tachypnea, nausea,and vomiting.54 Ultimately, the FDA suspended use of dinitrophenol in 1938 due to the development of cata-racts. Amphetamines, that are still available today and

FDA-approved for short-term weight management(eg,phentermine, phendimetrazine, diethylpropion, benz-phytin), are effective appetite suppressants but lack data to support their long-term efficacy and safety with respect to cardiovascular and psychological effects.53

Second-generation medications were developed in accordance with the FDA clinical trial requirements seeking to prove long-term clinical efficacy and safety,and include oral therapies with novel mechanisms of ac-tion. 53,54 Some medications(ie, fenfluramine, dexfen-fluramine, sibutramine, and lorcaserin) have been withdrawn from the market due to safety concerns.53 Currently available second-generation agents approved for long-term weight management include orlistat,55 phentermine/topiramate,56 and naltrexone/bupropion.57 Each of these is limited by modest weight loss

$$\text{JACC}\,\text{VOL.}\,\text{.}\,\text{NO.}\,\text{.}\,\text{2025}$$■,2025:■

Medical Weight Management for Cardiovascular Health

 (5.9%-9.8%),55-57 side effects, and a lack of outcome data related to CVD.

Third-generation weight loss medications that target NuSH have changed the landscape of obesity manage-ment with robust long-term(up to 4 years) efficacy and safety data for the management of obesity in those with and without CVD.58 While all currently available medi-cations(liraglutide, semaglutide, and irztepatite) were initially approved by the FDA to treat T2DM, they are also approved for obesity. They share a similar side effect profile that includes primarily gastrointestinal side effects(eg, nausea, diarrhea, vomiting, abdominal pain, con-stipation) that can be mitigated with dose reductions or

behavioral modifications(eg, hydration). Liraglutide,semaglutide, and tirzepatide have been shown to reduce body weight by an average of 8.0%, 14.9%, and 20.9% on maximal doses, respectively(Figures 3A and 3B). ${}^{59-61}$

4.3. Pharmacological Options

Among FDA-approved obesity medications, NuSH thera-pies are most effective(Table 2). Liraglutide and sem-aglutide are GLP-1 receptor agonists. GLP-1 regulates blood glucose by stimulating glucose-dependent insulin secretion, slowing gastric emptying, and increasing satiety, collectively promoting weight loss. Tirzepatide is a dual-acting agent that is both a GLP-1 receptor and a GIP

TABLE 2 FDA-Approved NuSHO Obesity Medications

|Medication (Brand Name)|FDA-Approved Indication for|Dosage/Titration/ Storage|Clinical Efficacy for Weight Loss|Contraindications/Cautions|Most Common Side Effects||| |---|---|---|---|---|---|---|---| |Weight Management|Gasage|Contraindications/Cautions|||||| |GLP-1 receptor agonists|||||||| |Liraglutide (Victoza,*|Adults with an initial|■ Start 0.6 mg subcuta-|SCALE Obesity and Prediabetes|56-week double-blind trial|Contraindicated if:|Nausea, diarrhea,|| |Xaxsendae)*|BMI≥30 kg/m²|or≥27 kg/m² with|neously daily|56-week double-blind trial|(n=3,731)|ity of family history of medullary|constipation, vomiting,| ||a weight-related comorbidity|dose of 3 mg for adults|beased of 30 days at controlled room temperature and|↓ weight:8.0% liraglutide, 2.6% placebo|(n=3,731)|innealasine syndrome type 2|bypermasine without molecules| |Semaglutide (Ozmpic, *|Adults with obesity or overweight and a|Ons at controlled longer with refrigeration#|down at controlled room temperature and|↓ weight≥5%:63.2%-liraglutide, 27.1% placebo|allaglutide, 27.1% placebo|Cautions: Acute hepatitis, acute gallbladder dis- ease, hypoglycemia, renal impairment/|| |increase every 4 weeks up to a maintenance|STEP-160 (n=1,961): ↓ weight:14.9% semaglutide, 2.4% placebo||||||| |Wogovyit)*|overweight and a comorbidity|Increase every 4 weeks up to a maintenance|↓ weight≥5%:86.4% sem- aglutide, 31.5% placebo||||| |Ozempic can be stored for 56 days and|↓ weight≥5%:86.4% sem- aglutide, 31.5% placebo||||||| |Dual GLP-1 and GIP receptor agonist||||||||

Dual GLP-1 and GIP receptor agonist

Tirzpatite(Mounjaro,*67 Zepboundt)+68

- Can be stored for 21 days at controlled room temperature and longer with refrigeration#

*Victoza, Ozempic, and Mounjaro are FDA-approved for T2DM regardless of weight status.

tSaxenda, Wegovy, and Zepbound are FDA-approved for weight loss with or without T2DM.

\#Frigerator storage:36°F to 46°F(2°C to 8°C), controlled room temperature: 59°F to 86°F(15°C to 30°C).

BMI=body mass index;FDA=U.S.Food and Drug Administration;GIP=glucose-dependent insulinotropic polypeptide;GLP-1=glucagon-like peptide-1;NuSH=nutrient-stimulated hormone;SCALE=Sathy and Clinical Adiposity-Liragluide Evidence;STEP=1=Semagulide Treatment Effect in People with Obesity-1; SURMOUNT-1= Study of Tirzepatide in Participants With Obesity or Overweight-1; T2DM= type 2 diabetes mellitus.

receptor agonist. GIP is a potent gut-derived NuSH that stimulates glucose-dependent insulin secretion in response to food, contributing to endogenous post-prandial insulin release. IP GIP regulates energy balance through cell-surface receptor signaling in the brain to suppress appetite and in adipose tissue to modify lipid metabolism.62 This dual mechanism likely explains the greater weight loss achieved with tirzepatide compared with that of GLP-1 receptor agonists. Several novel agents with dual and triple mechanisms of action that target other NuSH therapies(eg, glucagon, amylin) are in development.

Among the NuSH therapies, semaglutide and tirzepa-tide have the highest efficacy and are the obesity medi-cations of choice. Clinical trial and real-world observational data support slightly greater weight loss with tirzepatide.58,63 Insurance coverage,availability, and affordability are likely to dictate agent selection.

Both GLP-1 and GIP receptor agonists are contra-indicated in patients who have a personal or family history of medullary thyroid carcinoma, multiple endo-crinene neoplasia syndrome type 2, or known hypersensi-tivity to an individual product or any excipients(Table 2). In contrast with liraglutide, which is dosed

TABLE 3 Cardiovascular Outcomes of FDA-Approved NuSH Obesity Medications

|Trial|Medication|Population|Size/Duration (Participants)/ (Years)|Average Baseline BMI and Weight Change in Treatment Group|Effect on Primary Outcome (Composite of Cardiovascular Health Outdhi,AMI, or CVA Unless Specified)|Effect on HF Hospitalization| |---|---|---|---|---|---|---| |Obesity with diabetes and high cardiovascular risk or CVD||||||| |LEADER59|Liraglutide 1.8 mg|T2DM and high cardiovascular risk or disease(81.3% with CVD)|9,340 participants/ 3.8 years|32.5 kg/m2 -2.3 kg|Reduction HR:0.87;95% CI, 0.78-0.97|No difference HR:0.87;95% CI,0.73-1.05| |SUSTAIN-67|Semaglutide 1.0 mg|T2DM and high cardiovascular risk (83.0% with CVD)|3,297 participants/ 2.1 years|33.0 kg/m2 -4.3 kg|Reduction HR:0.74;95% CI, 0.58-0.95|No difference HR:1.11;95% CI,0.77-1.61)| |SURPASS-CVOT86 (NCTO4255433)|Tirzepatide up to 15 mg vs dulaglutide 1.5 mg|CVD,T2DM,BMI≥25 kg/m2|13,299 participants enrolled|Trial fully recruited and ongoing|Estimated completion date 2025|Not available| |Obesity without diabetes||||||| |SELECT79|Semaglut 2.4 mg|CVD and BMI>27 kg/m2|17,604 participants/ 3.3 years|33.4 kg/m2-9.1 kg|Reduction HR:0.80;95% CI: 0.72-0.90|No difference HR:0.80;95% CI:0.60-1.03| |STEP-HFpEF32|Semaglutide 2.4 mg|Hf with EF≥45% and BMI≥30 kg/m2|529 participants/ 12 months|37.0 kg/m2 -13.9 kg|Improvement in KCCQ|No difference (exploratory endpoint)| |SUMMIT85|Tirzeputide 15 mg|HF with EF≥50% and BMI≥30 kg/m2|731 participants/ 2.3 years|38.2 kg/m2-13.9% weight change of -13.9%|Reduction in cardiovascular death, worsening HC 0.41-0.95|Reduction HR:Reduction: 0.44;95% CI:0.22-0.87| |SURMOUNT-MMO (NCTO5556512)|Tirzepatide 15 mg|CVD or risk, BMI≥27 kg/m2|15,374 participants|Trial fully recruited and ongoing|Estimated; 2027|Not available|

Weight changes represent placebo-subtracted outcomes from intention-to-treat analyses. Shaded cells indicate that the trials are ongoing.

AMI= acute myocardial infarction; BMI= body mass index;CVA= cerebrovascular accident;CVD= cardiovascular disease;EF= ejection fraction;FDA= U.S. Food and Drug Administration;HF= heart failure; HR= hazard ratio; KCQK= Kansas City Cardiomyopathy Questionnaire; LEADER= Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results;NuSH= nutrient-stimulated hormone;SELECT= Semagulide Effects on Cardiovascular Outcomes in People With Overweight or Obesity;STEP-HFpEF= Semagulite Treatment Effect in People with Obesity and Heart Failure with Preserved Ejection Fraction; SUMMIT= Study Comparing the Efficacy and Safety of Tirzepatide Verus Placebo in Patients With Heart Failure With Preserved Ejection Fraction and Obesity; SURMOUNT-MMO(NCT05556512)= Study of Tirzepatide in Participants With Obesity or Overweight Metabolic and Mobility Outcomes; SURPASS-CVOT= Effect of Tirzepatide Versus Dulagulide on Major Adverse Cardiovascular Events in Patients With Type 2 Diabetes; SUSTAIN-6= Semagulite Unated Sustainability in Treatment of Type 2 Diabetes-6;T2DM= type 2 diabetes mellitus.

daily, both semaglutide and tirzepatide are dosed once weekly. All agents require dose titration to minimize adverse effects, which are largely gastrointestinal. Slow titration(Table 2) mitigates intolerance. For patients with adverse effects, decreasing the dose to a previously tolerated dose is recommended. ${}^{64}$ In clinical trials, 4.3%to 7.1% of participants discontinued therapy due to adverse events. ${}^{59-61}$

Among published clinical trials, the longest duration of treatment with a NuSH(liragltide) was 3.8 years.69 Observational data across 5 years, however, suggest that GLP-1 receptor agonists are safe and effective. ${}^{70}$ This is an important issue, given that obesity is a chronic disease,

and weight regain after discontinuation of therapy is expected.71 Nonetheless, this highlights the importance of long-term medication persistence and maintaining life-style modifications if pharmacotherapy is discontinued.

In addition to tolerance, major challenges with contemporary obesity medications, especially semaglu-tide and tirzeidepatic, include limited access(related to payer denial and supply shortages) and affordability.Should a patient miss dosages due to lack of access,published strategies to address this exist and also guide therapeutic interchanges. ${}^{72}$ For example, if≥3 missed dosages of once-weekly semaglutide or tirzepatide occur,a dose reduction may be considered. Semaglutide and

TABLE 4 Multidisciplinary Considerations for Patients on NuSH Theries

|Specialty Topic|Obesity-Related Condition|Medication|Procedure| |---|---|---|---| |Cardiology|ASCD Vatrial fibrillation Heart failure Hypertension Hyperterglyceridemia/dyslipidemia|De-escalate antihypertensives to avoid low blood pressure De-escalate diurets in heart failure to avoid intravascular depletion|| ||||| |Endocrinology|T2DM|Consider repeat TSH at 10% weight loss as levothyroxine dose may be weight-based95 Reduce medications for T2DM to avoid|Screening thyroid ultrasound is not required prior to NuSH therapy initiation| |Nephrology|■Chronic kidney disease|■AKI may occur in the setting of gastrointestinal side effects|Adjust hemodialysis protocol for weight or body surface area ${}^{100}$ Adjust dry weight in hemodialysis in patients undergoing active obesity treatment101| |Gastroenterology/ hepatology|MASLD GER Gallbladder disorders|■Because NuSH therapies are associated with a higher risk of gallbladder disorders, there could be a low threshold to consider urosdiol in patients with choleliithiasis ${}^{64,102}$ Adjust antireflux medications, given known improvement with weight loss but common side effects of NuSH therapies ${}^{66,68}$ |There are no data to support stopping a GLP-1 receptor agonist prior to elective upper endoscopy 104,105 Consider adjusting bowel preparation regimen for patients on NuSH therapy 106| |Obstetrics/gynecology|PCOS Infertility|■Tirzepatide may reduce the efficacy of some contraceptive agents68 Weekly NuSH therapies should be discontinued≥2 months prior to conception107|| |Psychiatry|■ Eating disorders Depression|■ Consider re-evaluating medication dosages after significant weight loss, as the therapeutic window of some psychotropic medications may depend on body weight108|| |Hematology/oncology|■ Some cancers Venous thromboembolism|■ Consider re-evaluating medication dosages after significant weight loss, as the chemotherapy or anticoagulant dosing may be weight-based109|| |Surgery/ anesthesiology|||GLP-1 receptor agonist therapy may be proper-atively continued in patients without elevated risk of delayed gastric emptying and aspiration. If the decision to hold semagulotide or tirazepatide is made, there is a lack of evidence to inform duration, but 1 week may be considered ${}^{110,111}$ | |Pulmonary/critical care|■OSA||Adjust CPAP settings or repeat OSA assessment after significant weight loss(≥79) ${}^{88}$ | |Geriatrics||■Caution with excess weight loss and higher risk of sarcopenia and frailly in this age group Re-evaluate medications and dosages after significant weight loss to reduce the risk of polypharmacy||

AKI= acute kidney injury; ASCVD= atherosclerotic cardiovascular disease; CPAP= continuous positive airway pressure; GERD= gastroesophageal reflux disease; GLP-1= glucagon-like peptide-1; MASLD= metabolic dysfunction-associated steatotic liver disease; NuSH= nutrient-stimulated hormone; OSA= obstructive sleep apnea; PCOS= polycystic ovarian syndrome; T2DM= type 2 diabetes mellitus; TSH= thyroid-stimulating hormone.

tirzepatide can also be interchanged based on clinical judgment. Use of compounded NuSH therapies is discouraged due to the potential for dosing errors and concern regarding counterfeit agents, which may contain impurities. 73-75

4.4. Implications on Comorbidities

A summary of the effects of NuSH therapies on cardio-vascular outcomes is shown in Table 3. NuSH therapies have been shown to reduce weight along with the risk of

cardiovascular death, myocardial infarction, or stroke in patients with T2DM76 at increased cardiovascular risk or with established CVD. ${}^{69,77,78}$

The benefits of NuSH therapies extend beyond T2DM.In patients without T2DM but with atherosclerotic CVD and a BMI>27 kg/m2,semaglutide resulted in significant weight loss as well as a reduction in a composite of car-diovascular death, myocardial infarction, and stroke.79 Whether this benefit is also observed with tirzeatide is being tested in a similar population(NCT05556512)80 as

FIGURE 4 Examples of Ways to Reduce Weight Stigma and More Optimally Deliver Care in Clinic and Hospital Settings

 Sources for this figure: Beavers and Bagai115; Bianchettin et al116; Gerstein et al117; Madder et al118; Plourde et al119; Powell-Wiley et al43;Refahiyat et al120;Singh et al.Lreducing weight stigma should be built into clinics and hospitals, improving the care of patients with excess weight. Some examples are listed in this figure.CT computed tomography; MRI= magnetic resonance imaging.

well as in patients with CVD and T2DM with a lower BMI threshold of 25 kg/m2(NCT04255433).

In patients with HFpEF, semaglutblqmed resulted in improvement in symptoms, physical limitation, and ex-ercise function. ${}^{82}$ Whereas the magnitude of benefit was directly related to the extent of weight loss, ${}^{83}$ there may be weight-independent mechanisms of benefit. ${}^{84}$ In a separate study that evaluated ziratepine in patients with obesity and HFpEF, a significant reduction in the com-posite outcome of cardiovascular death and worsening heart failure was observed,85 which may further extend the role of these agents to patients with HFpEF. ${}^{85}$

4.5. General Treatment Considerations

4.5.1. General Principles That Apply to the Medical Management of Obesity

Comprehensive treatment of obesity is multimodal. Life-style interventions support overall weight manage-ment, ${}^{50,60,61}$ and their utility alongside highly effective obesity medications is evolving. ${}^{51,52,87}$

Obesity treatment is multidisciplinary. The use of NuSH therapies may necessitate adjustments in the management of obesity-related comorbidities; as such,these patients benefit from coordination of care(Table 4).5,88-90 Patients should be guided toward evidence-based interventions whenever possible and be

educated regarding nonevidence-based options(eg,compounded peptides, over-the-counter supplements)that may pose potential harm. 91,92

Clinicians should incorporate shared decision-making into their treatment approach to best balance risks and benefits. Off-label, but evidence-based, strategies may be considered to mitigate potential harms and optimize health outcomes(eg, lowest therapeutic dose for weight loss maintenance, ${}^{93}$ combination therapies). ${}^{88,94}$

4.5.2. The Patient Experience

Obesity care should include attention to reducing weight bias and stigma. Person-first language should be used. In addition, the clinical space should be designed to appro-priately welcome and treat patients(Figure 4).113,114 Cli-nicians should make every effort to validate the lifelong journey that patients experience with this chronic disease.

The initial encounter should elicit potential contributors to and consequences of obesity, identify contraindications to obesity medications, and obtain anthropometric and clinical data to aid in the diagnosis and staging of obesity. ${}^{23}$ Blood work is unlikely to change the decision to pursue NuSH therapies, given that these medications'contraindications cannot be detected by laboratory re-sults, but may be helpful for insurance coverage,however, if T2DM is diagnosed. ${}^{122}$ Published resources

FIGURE 5 General Overview of Patient's Weight Management Journey With NuSH Therapes

Diagnose and stage patients with obesity(Table 1)

Assess if treatment goals are met(eg,≥5% weight loss)

Escalate NuSH therapy dose if there are no significant side effects and if treatment goals are not yet met

Consider monthly assessments(proactively or as needed) to monitor weight loss effectiveness and presence of side effects such as acute kidney injury

Consider alternative NuSH therapy or referral to an obesity medicine specialist if side effects limit dose escalation

Evaluate status of other treatment goals

Schedule annual appointments(at a minimum) to guide the weight management plan Continue standard health care maintenance

Continue NuSH therapy

Consider alternative NuSH therapy or referral to an obesity medicine specialist if<5% weight loss at the maximum tolerated dose or functional weight functions are beneficial for weight loss

Continue lifestyle strategies that are beneficial for weight loss

Continue NuSH therapy

Continue lifestyle strategies that are beneficial for weight loss

Laboratory monitoring specific to long-term NuSH treatment is not routinely required

An overview of a patient's journey when undergoing treatment with NuSH therapies. Source for this figure: Rubino et al.113 NuSH= nutrient-stimulated hormone.

may guide clinicians in establishing an obesity care practice. ${}^{50,114,123}$

Frequency of follow-up depends on the stage of the patient's journey and the practice's capabilities(Figure 5).More frequent interactions with a weight management team have been associated with greater weight loss and weight loss maintenance success. ${}^{7,71,124}$ Given a paucity of data, practitioners should use their clinical judgment to best manage situations that might be concerning for un-intentional or rapid weight loss, signs or symptoms of vitamin/mineral deficiencies, signs or symptoms of disordered eating behaviors, or excess weight loss asso-ciated with frailty. ${}^{71}$

The goals of obesity treatment should be tailored to the individual. A reasonable initial goal is achievement of clinically significant weight loss, defined as≥5% from baseline, which is associated with improvement in tri-glycerides, fasting blood glucose, and systolic blood pressure as well as the prevention of incident dis-ease. ${}^{50,125}$ Individuals who seek to resolve weight-related comorbidities(eg, CVD, sleep apnea, metabolic dysfunction-associated steatotic liver disease) should aim

for≥10% weight loss.5 Patient quality of life, functional status, and psychosocial health should also be considered as part of one's treatment goals, supporting a holistic approach to obesity care.

Therages for weight-related comorbidities and weight-based medications should be de-escalated as needed(Table 4). As a patient achieves their weight management goals, actively reduce or discontinue interventions to avoid harm from overtreatment, mitigate polypharmacy,and reinforce progress.96-99,126,127

Long-term treatment should be the default plan. As such, obesity medications should not be discontinued unless determined by the patient and/or treating clini-cian, as this commonly results in weight regain. ${}^{71,124}$

4.6. Multidisciplinary Care Approaches

Weight management is best optimized using a team-based approach to create personalized health assessments and identify contributing factors, modifiable risk factors, and comorbid conditions(Figure 6). ${}^{128}$ Early involvement with behavioral therapists can be beneficial to recognize indi-vidual stressors, encourage social support systems,

FIGURE 6 Multidisciplinary Team Approach for Weight Management

Behavioral Therapists

Multidisciplinary Care in Obesity

Registered

Dietitian Nutritionists

Exercise Physiologists

Pharmacists

A multidisciplinary team-based approach to weight management is recommended, creating a personalized approach for individual patients. This integrated model will allow for comprehensive and tailored weight management.

identify long-term patient goals, and set reasonable ex-pectations.129 Additionally, health coaching with regis-tered dietians and exercise physiologists has been shown to improve weight loss, physical activity, and metabolic markers.130,131 Finally, a team of clinicians with pharmacy support is integral for monitoring medication side effects, therapeutic goals, and improving access to care.132 Thus, a multidisciplinary team approach allows for comprehensive and tailored weight management. ${}^{128}$

4.7. Access Considerations

Despite profound cardiovascular and weight loss benefits with NuSH therapies, medication coverage serves as a major barrier for patients.133 Whereas the average yearly cost for semagulide, liraglutide, and tiratepetine in the United States is$14,080, $15,738, and$8,126,

respectively, cost is significantly lower in other countries(eg,$2,066 for liraglutide, Switzerland).133 NuSH thera-pies are covered by Medicare Part D for patients with obesity and other comorbid conditions, including T2DM and specific CVD diagnoses; however, these medications are not covered for obesity alone.134 Initial strategies to improve access to NuSH therapies include identifying individuals most likely to benefit, close monitoring of treatment outcomes, and price negotiations. ${}^{133}$ There is ongoing need to improve access to NuSH therapies in the United States, acknowledging that this may be delayed by current price points limiting its cost-effectiveness. ${}^{133}$ It should also be noted that until prices are further adjusted,individuals may seek unregulated routes to access, such as compounding, which can be associated with increased risk of complications. ${}^{135,136}$ Advocacy efforts on behalf of

Gilbert et al Medical Weight Management for Cardiovascular Health

patients and health care professionals are ongoing with a focus on increasing access to comprehensive obesity care.137

4.8. Conclusions/Future Directions

In this new era of obesity management, there exists an ever-expanding set of adults to assist patients in diagnosis,weight reduction, and CVD risk mitigation. With more precisely ways of identifying adipose tissue on the horizon,care will be further personalized. Beyond improvement of CVD risk factors, third-generation obesity medications(NuSH therapies) have been shown to reduce adverse events events among those with obesity and established atherosclerotic CVD and/or HFpEF. In addi-tion, a growing number of therapies are in development.Obesity management by the cardiovascular community needs to be embraced, given both the prevalence of obesity and the impact it has on many forms of CVD.

Several questions remain that will need to be resolved to ouation of these therapies in the treatment of this chronic disease.

PRESIDENT AND STAFF

Christopher M. Kraimer, MD, FACC Cathec L.Cates,Chief Executive Officer Richard J. Kovacs, MD, MACC, Chief Medical Officer Brendan Mullen, Executive Vice President Joseph M. Allen, MA, Team Leader, Science& Quality Amy Dearborn, Team Leader, Decision Science Ashleigh M. Covington, MA, Team Leader, Decision Science Science

Grace and Ronol Production and Operations Manager, Clinical Policy Publication

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KEY WORDS GIP, GLP-1, NuSH, obesity,weight management

APPENDIX 1. AUTHOR RELATIONSHIPS WITH INDUSTRY AND OTHER ENTITIES(RELEVANT)-2025 CONCISE CLINICAL GUIDANCE: AN ACC EXPERT CONSENSUS STATEMENT ON MEDICAL WEIGHT MANAGEMENT FOR OPTIMIZATION OF CARDIOVASCULAR HEALTH

|Committee Member|Employment|Consultant|Speakers Bureau|Ownership/ Partnership/ Principal|Personal Research|Institutional, Organizational, or Other Financial Benefit|Expert Witness|| |---|---|---|---|---|---|---|---|---| |Olivia Gilbert (Chair)|Wake Forest University School of Medicine- Associate Professor|None|None|None|None|None|None|None| |Martha Gulati (Vice Chair)|Smid Heart Institute,Cedars-Sinai Medical Center-Director of the Barbra Streisand Women's Heart Center|■ Esperia Retapeutics NewAmsterdam Pharma ■ Medtronic|None|None|None|Merck& Co.(DSMB)|None|None| |Ty J.Gluckman|Providence Heart Institute-Medical Director, Center for Cardiovascular Analytics, Research, and Data Science|None|None|None|None|None|None|None| |Michelle M. Kittleson|Smid Heart Institute,Cedars-Sinai Medical Center-Professor of Medicine|None|None|None|None|None|None|None| |Rishi Rikhi|Wake Forest University School of Medicine- Cardiology Fellow|None|None|None|None|None|None|None| |Joseph J.saseen|University of Colorado Anschutz-Professor and Associate Dean|None|None|None|■ Amgen (DSMB)|None|None|None| |Beverly G. Tchang|Weill Cornell Medical College, Cornell University- Assistant Professor of Clinical Medicine|None|None|None|■ KVK TECH (DSMB)|None|None|None|

This table represents the relationships of committee members with industry and other entities that were determined to be relevant to this document. These relationships were reviewed and updated in conjunction with all meetings and/or conference calls of the writing committee during the document development process. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of≥5% of the voting stock or share of the business entity or ownership of=$5,000 of the fair market value of the business entity, or if funds received by the person from the business entity exceed 5% of the person's gross income for the previous year.Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. According to the ACC, a person has a relevant relationship IF: a) the relationship or interest relates to the same or similar subject matter, intellectual property or asset, topic, or issue addressed in the document; b) the company/entity(with whom the relationship exists) makes a drug, drug class, or device addressed in the document or makes a competing drug or device addressed in the document; or c) the person or a member of the person's household, has a reasonable potential for financial, professional or other personal gain or loss as a result of the issues/content addressed in the document.*No financial benefit.

$$\text{ACC}=\text{American College of Cardiology; DSMB}=\text{Data Safety Monitoring Board.}$$

APPENDIX 2. PEER REVIEWER RELATIONSHIPS WITH INDUSTRY AND OTHER ENTITIES(COMPREHENSIVE)-2025 CONCISE CLINICAL GUIDANCE: AN ACC EXPERT CONSENSUS STATEMENT ON WEIGHT MANAGEMENT FOR OPTIMIZATION OF CARDIOVASCULAR HEALTH

|Peer Reviewer|Representation|Employment|Consultant|Speakers Bureau|Ownership/ Principal|Personal Research|Institutional, Organizational, or Other Financial Benefit|Expert Witness| |---|---|---|---|---|---|---|---|---| |Craig Beavers|Content Reviewer-ACC Expert|University of Kentucky- Assistant Adjunct Professor|None|None|None|None|None|None| |Nicole Bhave|Content Reviewer-ACC Expert|University of Michigan-Clinical Professor|None|None|Doximity|None|None|None| |Robert Kushner|Content Reviewer-ACC Expert|Northwestern University- Medical Director, Wellness Institute|Antag Medical Director, Wellness Institute|None|None|None|None|None| ||||Boehringer Ingelheim Pharmaceuticals|||||| ||||Currax* Eli Lilly and Company* Novo Nordisk* Regeneron Structure|||||| ||||Novo Nordisk* Regeneron|||||| ||||Structure|||||| |Michael Shapiro|Content Reviewer-ACC Expert|Wake Forest University of Medicine-Professor of Cardiology and Molecular Medicine|0 Aidoc Novartis Corporation* Amgen Arrowhead Merck& Co. Ionis Regeneron|None|None|None|American Society of Pre- ventive Cardiology ACCCLAIM,Eli Lilly and Company¥|None| |||||||||| |||||Amgen Arrowhead Merck& Co.|||BROOKLYN, New Amsterdam|| ||||| ■ Merck& Co. Ionis|||CLEAR-PATH,Esperion|| |||||1 Ionis|||MUR-3, Arrowhead|| |||||Regeneron*|||0 OCEAN(a),Amgen ORION-16, Novartis Corporation|| ||||||||0 ORION-16, Novartis Corporation|| ||||||||0 PREVENTABLE, National Institutes of Health+ TRANSFORM, Clelyer|| |Barbara Wiggins|Official Reviewer- Solution Set Oversight880 Committee|scPharmaceuticals- Regional Medical Lead|None|None|None|None|Victorion 1-PREVENT, Novartis Corporation|| ||||||||None|None|

|Barbara Wiggins|Official Reviewer-Solution Set Oversight Committee|scPharmaceuticals-Regional Medical Lead|None|None|None|None|None|None| |---|---|---|---|---|---|---|---|---| |||||||||| |||||||||| |||||||||| |||||||||| |||||||||| |||||||||| |||||||||| |||||||||| ||||||||||

This table represents all relationships of reviewers with industry and other entities that were reported by reviewers, including those not deemed to be relevant to this document, at the time this document was under development. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of≥5% of the voting stock or share of the business entity, or ownership of≥5,000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person's gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency.Relationships in this table are modest unless otherwise noted. Please refer to https://www.acc.org/Guidelines/About-Guidelines-and-Clinical-Documents/Relationships-with-Industry-Policy for definitions of disclosure categories or additional information about the ACC Disclosure Policy for Writing Committees.

*Significant relationship.

tNo financial benefit.

Relationship with this company is limited to enrolling patients in clinical trials. This disclosure was entered under the Clinical Trial Enroller category in the ACC's disclosure system. To appear in this category, the author acknowledges that there is no direct or institutional relationship with the trial sponsor as defined in the ACC Disclosure Policy for Writing Committees.

ACC=American College of Cardiology.

APPENDIX 3. ABBREVIATIONS

ACC= American College of Cardiology BMI= body mass index CVD= cardiovascular disease FDA= U.S. Food and Drug Administration GIP= glucose-dependent insulinotropic polypeptide GLP-1= glucagon-like peptide-1 HFpEF= heart failure with preserved ejection fraction NuSH= nutrient-stimulated hormone T2DM= type 2 diabetes mellitus