Obesity and Weight Loss Strategies for Patients With Heart Failure

Amanda R. Vest, MBBS, MPH; Philip R. Schauer, MD; Jo E. Rodgers, PHARMD; Emily Sanderson, BA, MS; Courtney L. LaChute, MD; Jessica Seltz, MS, RD; Carl J. Lavie, MD; Stacy A. Mandras, MD; W.H. Wilson Tang, MD; Adrian daSilva-deAbreu, MD, MSC

Disclosures

JACC Heart Fail. 2024;12(9)

Abstract

Obesity is a common comorbidity among patients with heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF), with the strongest pathophysiologic link of obesity being seen for HFpEF. Lifestyle measures are the cornerstone of weight loss management, but sustainability is a challenge, and there are limited efficacy data in the heart failure (HF) population. Bariatric surgery has moderate efficacy and safety data for patients with preoperative HF or left ventricular dysfunction and has been associated with reductions in HF hospitalizations and medium-term mortality. Antiobesity medications historically carried concerns for cardiovascular adverse effects, but the safety and weight loss efficacy seen in general population trials of glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide/GLP-1 agonists are highly encouraging. Although there are safety concerns regarding GLP-1 agonists in advanced HFrEF, trials of the GLP-1 agonist semaglutide for treatment of obesity have confirmed safety and efficacy in patients with HFpEF.

Introduction

Heart failure (HF) remains a major public health challenge, imposing significant functional and quality of life (QoL) restrictions, economic burdens and persistently high rates of hospitalization and mortality.^[1] The management of obesity and HF interlinks on multiple levels. Obesity is a potential contributor to HF development and may also exacerbate symptoms, functional limitations, and hospitalization rates for adults with established HF. The presence of obesity can furthermore complicate HF treatment options, especially for patients with advanced heart failure with reduced ejection fraction (HFrEF) in whom heart transplantation (HT) is being considered, and the presence of HF often affects the safety profile of medical and surgical therapeutic options for obesity.^[2]

Historically, the presence of NYHA functional class II-IV HF has significantly limited opportunities to treat obesity across the lifestyle, metabolic and bariatric surgery (BSx), and pharmacologic domains of care. For example, earlier generations of pharmacotherapies approved for the treatment of obesity included stimulant medications with poor safety profiles for patients with HF. However, recent progress with the efficacy and safety of antiobesity medications (AOMs), as well as evolving experience with BSx in medically comorbid patient populations, are elevating standards of care for patients with both obesity and HF. Retrospective studies of BSx for the primary prevention and secondary treatment of HF are expanding our understanding of the obesity-HF relationship, and a heart failure with preserved ejection fraction (HFpEF)–specific AOM clinical trial confirms the appropriateness of obesity treatment in this population. However, fundamental questions remain regarding the optimal approach to obesity treatment within the HF population, with probable differences in these risk-benefit considerations between the HFrEF and HFpEF populations. This review summarizes currently published data regarding the epidemiology of obesity and HF, opportunities to prevent HF by treating obesity, the rationale and caveats regarding intentional weight loss for patients with HF across the lifestyle, surgical, and medication domains, and particularly the growing role of the AOMs for patients with obesity and HFrEF or HFpEF (Central Illustration).

(Enlarge Image)

Central Illustration. Treatment of Obesity Across the Lifestyle, Surgery, and Medication Domains for Primary Prevention and Secondary Treatment of HF

Visual summary of the best available current obesity treatment data from randomized clinical trials or nonrandomized cohort studies informing primary prevention of HF and secondary treatment of HF, further split into the HFpEF vs HFrEF phenotypes where available. Most relevant data from studies n ≥50. Made with BioRender.com. BMI = body mass index; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; NR = nonrandomized; RCT = randomized controlled trial; RYGB = Roux-en-Y gastric bypass; WL = weight loss, placebo-adjusted.

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Table 1. Randomized Trials of Dietary Interventions for Patients With HF and Obesity
First Author, Year	n	Key Inclusion Criteria	Intervention Group	Comparator Group	Weight Endpoint	Other Endpoints
Evangelista et al, 2009¹³⁹	14 HFrEF	NYHA functional class II-III, non– insulin-treated DM, BMI >27 kg/m²	HP hypocaloric diet (30% protein, 40% carbohydrate, 30% fat) or SP hypocaloric diet (15% protein, 55% carbohydrate, 30% fat) for 12 wks	Conventional normocaloric diet	HP diet group with greater weight loss compared with SP or conventional diet: -9.9 ± 2.0 kg vs-5.6 ± 0.8 kg, vs 1.5 ± 0.6 kg, respectively (P < 0.001)	HP diet group with greater reductions in waist circumference: -5.9 ± 1.4 cm vs -2.0 ± 1.6 cm vs 0.3 ± 1.5 cm (P < 0.001)
Kitzman et al, 2016⁷⁹	100 HFpEF	Age ≥60 y, BMI ≥30 kg/m²	Exercise (1 h 3x wk) vs diet (400 kcal/d deficit) vs exercise + diet (350 kcal/d deficit); diet included 1.2 g/kg ideal weight protein and not <1,000 kcal/d total	Attention control with 2 weekly telephone calls	Weight significantly decreased with both diet and exercise. Diet main effect: -7 kg (95% CI: -9 to -5; P < 0.001); within diet effect, decrease in both DXA lean and fat mass, percentage lean mass increased (2%; 95% CI: 1%-3%; P < 0.001); greatest weight loss in exercise plus diet group (-11 kg)	Both diet and exercise significantly increased peak VO₂; diet main effect: 1.3 mL/kg/min (95% CI: 0.8-1.8; P < 0.001); diet and exercise additive effect: 2.5 mL/kg/min
Gonzalez-Islas et al, 2017¹⁴⁰	88 HF, any EF	NYHA functional class I-III, 50% DM, 35% obesity	Low-carbohydrate normocaloric diet (40% carbohydrates, 20% protein, 40% fats) for 2 mo	Standard normocaloric diet (50% carbohydrates, 20% protein, 30% fats)	No significant weight loss	No significant differences in handgrip strength (P = 0.14)
Evangelista et al, 2021¹⁴¹	76 HF, any EF	NYHA functional class II-III, DM, and BMI >27 kg/m²	HP hypocaloric diet (30% protein, 40% carbohydrate, 30% fat) for 12 wks	SP hypocaloric diet (15%protein, 55% carbohydrate, 30%fat)	Equivalent weight loss (HP 3.6 kg vs SP 2.9 kg) and waist circumference change (HP 1.9 cm vs SP 1.3 cm)	Greater decreases in HbA1c (0.7 vs 0.1%; P = 0.002), TC (16.8 vs 0.9 mg/dL; P = 0.031), TG (25.7 vs 5.7 mg/dL; P = 0.032) in HP compared with SP
Brubaker et al, 2022¹⁴²	88 HFpEF (77 completed trial)	BMI ≥28 kg/m² and age ≥60 y	300 kcal/d deficit diet plus resistance and aerobic training for 20 wks	300 kcal/d deficit diet plus aerobic training alone	No significant differences in body weight mean (8 kg [95% CI: -9 to -7 kg] vs -9 kg [95% CI: -11 to -8 kg]; P = 0.21) and body fat (-6.5 kg [95% CI: -7.2 to -5.8 kg] vs -7.4 kg [95% CI: -8.1 to -6.7 kg]; P = 0.20)	Peak VO₂ increased in both groups (108 vs 80 mL/ min, respectively, or 7% and 5% improvement from baseline) with no significant between-group difference (44 mL/min [-25 to 112 mL/min]; P = 0.21)

BMI = body mass index; DM = diabetes mellitus; DXA = dual x-ray absorptiometry; EF = ejection fraction; HbA1c = hemoglobin A1c; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; HP = high-protein; SP = standard protein; TC = total cholesterol; TG = triglycerides; VO2 = oxygen consumption.

Table 2. Nonrandomized Observational Reports of Bariatric Surgery in Subjects With Preoperative HFrEF or Left Ventricular Systolic Dysfunction
First Author, Year	n	Follow-Up, Mo	Mean Age, y	% Female	Study Procedures	Pre BMI, kg/m²	Post BMI, kg/m²	Pre LVEF, %	Post LVEF, %
McCloskey et al, 2007^143,a	14	6	46	29	RYGB, SG, AGB	50.8	36.8	23	32
Ramani et al, 2008^144,a	12	12	41	75	RYGB, SG, AGB	53	38	21.7	35
Vest et al, 2016¹⁰²	38	23	50	47	RYGB, AGB, SG	47.2	36.7	37.8	42.9
Yang et al, 2020¹⁴⁵	21	12	48.7	29	AGB, SG, BPD	46.2	38	32.5	42.5
Sarmiento-Cobos et al, 202¹⁷¹	19	18	56.6	57.9	SG, RYGB	41.3	30.9	38.8	48.5
Balakumaran et al, 2023^70,b	22	26	40.7	63.6	SG, RYGB	51.7	~38	32.2	~52
Weighted means (excluding McCloskey et al^a)	112	19.5	48.1	51.7		47.5	36.3	34.1	44.7

Only reports containing ≥10 subjects, without mechanical circulatory support, and with presurgery and postsurgery LVEFs included. Table adapted with permission from Supplemental Material in Vest et al.¹⁰² ^aTwo kin studies containing an overlapping population from the same institution; only Ramani et al¹⁴⁴ used for calculation of weighted means. ^bPost BMI and post LVEF are approximate values derived from Figure 2 of Balakumaran et al.⁷⁰

AGB = adjustable gastric band; BPD = biliopancreatic diversion; LVEF = left ventricular ejection fraction; RYGB = Roux-en-Y gastric bypass; SG = sleeve gastrectomy; other abbreviations as in Table 1.

Table 3. Summary of Medications Approved for Chronic Treatment of Obesity
Medication and Approval Date(s)	Mechanism of Action	Mean Weight Loss, Placebo/Drug, and Mean Weight Loss at >1 y	Dose and Monitoring	Contraindications and Precautions	Serious Drug Interactions	Adverse Reactions	HF Considerations	Cost
Pancreatic lipase inhibitor Orlistat FDA 1999, EMA 1998 (overthe- counter product available at lower doses)	Gastrointestinal and pancreatic lipase inhibitor: decrease lipid absorption	10.2%, -3 kg	60 or 120 mg 3x per d during or within 1 h of a fat-containing meal; monitor hepatic and renal function.	Contraindications: pregnancy or breastfeeding, cholestasis, chronic malabsorption syndrome	Pancreatic lipase inhibitor Amiodarone cyclosporine, warfarin, fat-soluble drugs	Abdominal pain, steatorrhea, fecal urgency or incontinence, hepatotoxicity, oxalate nephropathy, deficiency in vitamins A, D, E, and K	Monitor for reduced amiodarone efficacy, monitor coagulation parameters (eg, international normalized ratio) closely with warfarin	$681-$832^b,c
Sympathomimetic/anticonvulsant Phentermine–topiramate ER^a FDA 2012 Phentermine alone	NE agonist (phentermine)/GABA agonist, glutamate antagonist (topiramate): suppress appetite	-1.2%/-7.8% to -9.3% (dose dependent), -7.4 to -10.8 kg	3.75/23 mg daily for 14 d, then 7.5/46 mg daily. If <3% weight loss at 12 wks, increase to 11.25/69 mg daily for 14 d, followed by 15/92 mg/d thereafter. Gradually discontinue if <5% weight loss at 12 wks on highest dose (avoid abrupt withdraw). Pregnancy test at baseline and monthly for women of childbearing age (REMS Program). Adjust for renal impairment (schedule IV).	Contraindications: pregnancy or breastfeeding, hyperthyroidism, glaucoma, agitation, MAO inhibitor within 14 d Use with caution: uncontrolled HTN, CVD, CKD, history of drug abuse, depression	Sympathomimetic/anticonvulsant MAO inhibitors (contraindicated), opioid or other central nervous system depressants, CYP3A4 and CYP1A2 inducers	Dysgeusia, dizziness, dry mouth, constipation, paresthesia, insomnia, anxiety, depression, suicidal ideation, memory loss, nephrolithiasis, increased HR, CV events, angle-closure glaucoma, acute myopia, abrupt withdrawal of topiramate increases the risk of seizures	Minimal increase in HR, minor decrease in BP (when used for weight loss); no safety data in patients with HFpEF or HFrEF	$190-$234^b,c
Opioid receptor antagonist/ dopamine and noradrenaline reuptake inhibitor Naltrexone SR–bupropion SR FDA 2014 EMA 2015	Opioid receptor antagonist (naltrexone)/dopamine agonist and NE reuptake inhibitor (bupropion): increase satiety, suppress appetite	-1.3%/-5% to -6.1% (dosedependent), -2.7 to 4.9 kg	8/90 mg for 7 d, then twice a day for 7 d, then 2 tablets in morning and 1 tablet in the evening for 7 d, followed by 2 tablets twice a day thereafter. Discontinue if <5% weight loss at 12 wks. Adjust for renal and hepatic impairment.	Contraindications: pregnancy or breastfeeding, end-stage renal failure, severe hepatic impairment, uncontrolled HTN, seizure disorder, eating disorder (anorexia, bulimia nervosa), drug addiction, abrupt discontinuation of alcohol, any opioid use MAO inhibitor within 14 d	Opioid receptor antagonist/ dopamine and noradrenaline reuptake inhibitor MAO inhibitors (contraindicated), chronic opioid use or opiate agonists (contraindicated), acute opiate withdrawal, benzodiazepines, barbiturates, antiepileptic drugs, bupropion, linezolid, CYP2B6 inhibitors	Nausea, vomiting, diarrhea, constipation, dry mouth, headache, dizziness, insomnia, seizures, palpitations, increased HR, increased BP	Minor increases in HR and BP; cardiovascular safety study excluded patients with NYHA functional class III-IV HF¹¹¹	$515^c,d
GLP-1 agonist Liraglutide FDA 2014 EMA 2015	GLP-1 agonist: slow gastric emptying, increase satiety, decrease food reward	-2.6%/-8%, -4 to -5.9 kg	0.6 mg subcutaneously daily. Increase by 0.6 mg/wk to a target dose of 3 mg/d. Discontinue if <4% weight loss at 16 wks.	Contraindications: pregnancy or breastfeeding, personal or family history of medullary thyroid cancer or MEN type 2 syndrome, moderate to severe renal impairment Use with caution: history of pancreatitis, severe renal insufficiency; In patients with type 2 DM, monitor blood glucose before starting and during treatment	GLP-1 agonist Other hypoglycemic agents; delays gastric emptying—may affect absorption of concomitantly administered oral medications	Nausea, vomiting, diarrhea, constipation, dyspepsia, hypoglycemia, pancreatitis, gallbladder disease, renal impairment, suicidal thoughts	May alter absorption of GDMT. Monitor renal function when initiating or escalating dose in patients reporting severe adverse gastrointestinal reactions In advanced HFrEF (FIGHT trial¹¹⁷). Nonsignificant increase in hospitalization and mortality. In stable HFrEF (86% NYHA functional class I-II, LIVE trial¹¹⁶), no difference in LVEF but increase in serious cardiac events. In type 2 DMand high CV risk (LEADER trial¹¹³), no difference in HF hospitalization.	$1,629-$1,332^b,c
Semaglutide FDA 2021 EMA 2021	GLP-1 agonist: slow gastric emptying, increase satiety, decrease food reward	-2.4%/-14.9%, -6.5 to -16.8 kg	0.25 mg once/wk for 4 wks. In 4-wk intervals, increase the dose until 2.4 mg is reached. Maintenance dose is 2.4 mg/wk.	Contraindications: pregnancy or breastfeeding, personal or family history of medullary thyroid carcinoma or MEN type 2 syndrome Use with caution: history of pancreatitis; in patients with type 2 DM, monitor blood glucose before starting and during treatment	Other hypoglycemic agents; delays gastric emptying—may affect absorption of concomitantly administered oral medications	Nausea, vomiting, diarrhea, constipation, dyspepsia, dizziness, headache, eructation, hypoglycemia, pancreatitis, gastroenteritis, gastroesophageal reflux disease	May alter absorption of GDMT. Monitor renal function when initiating or escalating dose in patients reporting severe adverse gastrointestinal reactions. In overweight/obesity and CVD (SELECT trial³⁸), reduction in combined CV death and HF hospitalizations and serious adverse events. In HFpEF and obesity (STEP-HFpEF trial⁶¹), improved functional capacity and quality of life with reduced adverse effects.	$1,935-$1,332^b,c
Glucose-dependent insulinotropic polypeptide receptor/GLP-1 agonist Tirzepatide FDA 2022 for type 2 DM, 2023 for obesity EMA 2022	Glucose-dependent insulinotropic polypeptide receptor agonist and GLP-1 agonist: enhance first- and second-phase insulin secretion, reduce glucagon levels, slow gastric emptying, increase satiety, decrease food reward	-3.1%/-15 to 20.9% (dose dependent), -11.9 to -17.8 kg	2.5 mg once/wk for 4 wks, then increase by 2.5 mg increments up to 15 mg once/wk. Note: above dose is per the SURMOUNT-1 trial, which compared dosing at 5, 10, and 15 mg once/wk;¹³³ this dosing is similar to the current FDA-approved dosing for DM	Contraindications: personal or family history of medullary thyroid carcinoma or MEN type 2 syndrome Use with caution: history of pancreatitis; in patients with type 2 DM, monitor blood glucose before starting and during treatment	Glucose-dependent insulinotropic polypeptide receptor/GLP-1 agonist Other hypoglycemic agents; delays gastric emptying—may affect absorption of concomitantly administered oral medications	Nausea, vomiting, diarrhea, constipation, indigestion, decreased appetite, hypoglycemia, pancreatitis, acute kidney injury	May alter absorption of GDMT. Monitor renal function when initiating or escalating dose in patients reporting severe adverse gastrointestinal reactions. No CV safety data currently available. SUMMIT study in patients with HFpEF and obesity currently ongoing.	$980- $1,017^b,c

Information sources: Bersoux et al,¹⁴⁶ Tak et al,¹⁴⁷ Gjermeni et al,¹²¹ Muller et al,¹⁴⁸ Williams et al,¹⁴⁹ Son et al,¹⁵⁰ Liraglutide package insert,¹⁵¹ Semaglutide package insert,¹⁵² Tirzepatide package insert,¹⁵³ and Jastreboff et al.¹³³ ^aPrescribers must complete Healthcare Provider Training Program and HCP Registration Form before they can prescribe this medication (www.qsymiarems.com). ^bPrice listed includes lowest price available and actual retail price according to GoodRx.com. ^cManufacturer assistance may be available. However, if private or commercial insurance exists, the maximal savings is often capped, eg, $200 per 30-day * supply; cash payers: save up to $200 per 30-day supply. ^dPrice listed includes only lowest price available according to GoodRx.com; no actual retail price provided.

BP = blood pressure; CKD = chronic kidney disease; CV = cardiovascular; CVD = cardiovascular disease; CYP = cytochrome; EMA = European Medicines Agency; ER = extended release; FDA = U.S. Food and Drug Administration; GABA = gamma-aminobutyric acid; GDMT = guideline-directed medical therapy; GLP = glucagon-like peptide; HR = heart rate; HTN = hypertension; IV = intravenous; MAO = monoamine oxidase; MEN = multiple endocrine neoplasia; NE = norepinephrine; SR = sustained release; REMS = risk evaluation and mitigation strategy; other abbreviations as in Table 1.

Table 4. Example Eligibility Criteria for an Antiobesity Medication Protocol Embedded in a HF Clinic
Patients with HFpEF or HFrEF and BMI ≥30 kg/m² with comorbidities, symptoms, or functional limitations anticipated to benefit from weight loss; or BMI ≥35 kg/m²
Already engaged in a lifestyle intervention for obesity management and ideally working with a registered dietitian-nutritionist
HF syndrome clinically stable, especially for patients with HFrEF, and an implantable cardiac defibrillation already in place if indicated, without recent ventricular tachycardia¹¹⁹
No history of hypoglycemia
No personal or family history of MEN 2
No history of pancreatitis
No prior adverse reactions to GLP-1 agonists
No type 1 DM or history of diabetic ketoacidosis

Abbreviations as in Tables 1 and 3.

Authors and Disclosures

Amanda R. Vest, MBBS, MPH^a; Philip R. Schauer, MD^b; Jo E. Rodgers, PHARMD^c; Emily Sanderson, BA, MS^d; Courtney L. LaChute, MD^e; Jessica Seltz, MS, RD^f; Carl J. Lavie, MD^g,h; Stacy A. Mandras, MDⁱ; W.H. Wilson Tang, MD^j; Adrian daSilva-deAbreu, MD, MSC^j,k

From the ^aDepartment of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Kaufman Center for Heart Failure Treatment and Recovery, Cleveland Clinic, Cleveland, Ohio, USA; ^bMetamor Metabolic Institute, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA; ^cDivision of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA; ^dFriedman School of Nutrition Science and Policy at Tufts University, Boston, Massachusetts, USA; ^eDepartment of Medicine, Louisiana State University, Baton Rouge, Louisiana, USA; ^fFrances Stern Nutrition Center, Tufts Medical Center, Boston, Massachusetts, USA; ^gDepartment of Cardiology, Ochsner Medical Center, New Orleans, Louisiana, USA; ^hUniversity of Queensland Ochsner Clinical School, University of Queensland, New Orleans, Louisiana, USA; ⁱTransplant Institute, AdventHealth Orlando, Orlando, Florida, USA; ^jDoctoral School, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain; and the ^kDepartment of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA.

ADDRESS FOR CORRESPONDENCE: Dr Amanda R. Vest, Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, Desk J3-230, Cleveland, Ohio 44195, USA. E-mail: vesta2@ccf.org.

FUNDING SUPPORT AND AUTHOR DISCLOSURES Dr Schauer has consultancy agreements with GI Dynamics; Keyron; Persona; Mediflix, Metabolic Health International, Lilly, Ethicon, Medtronic, Novo Nordisk, and Heron; ownership interest in SE Healthcare, Mediflix, and Metabolic Health International; and has received research funding from Ethicon and Medtronic. Dr Lavie has been a speaker and consultant for AstraZeneca on an SGLT2i; and has served on a data and safety monitoring board for Novo Nordisk. Dr Mandras has been a consultant and has served on the Speakers Bureaus for Bayer, CVRX, and United Therapeutics. Dr Tang has served as a consultant for Sequana Medical, Cardiol Therapeutics, Genomics, Zehna Therapeutics, Renovacor, WhiteSwell, Kiniksa Pharmaceuticals, Boston Scientific, CardiaTec Biosciences, and Intellia; and has received honoraria from Springer Nature and American Board of Internal Medicine. Dr daSilva-deAbreu owns stocks of TransMedics Group. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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Obesity and Weight Loss Strategies for Patients With Heart Failure

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Central Illustration. Treatment of Obesity Across the Lifestyle, Surgery, and Medication Domains for Primary Prevention and Secondary Treatment of HF

Central Illustration. Treatment of Obesity Across the Lifestyle, Surgery, and Medication Domains for Primary Prevention and Secondary Treatment of HF

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