Obesity in Cardiorenal syndrome: Management Opportunities and Challenges

Abstract

Purpose of Review

The prevalence of obesity continues to increase globally. There is accumulating evidence of the complex interplay between obesity, cardiovascular disease, particularly heart failure with preserved ejection fraction, and chronic kidney disease (CKD). Here, we review the diagnostic and management considerations for these co-existent conditions and the current evidence regarding the impact of obesity treatments on long term health outcomes.

Recent Findings

Recent evidence suggests the pathophysiology of obesity, heart failure with preserved ejection fraction and CKD are inextricably linked as adipocytes appear to play a role in promoting renal sodium avidity and volume overload, which are the hallmarks of the cardiorenal syndrome. The clinical landscape of obesity management has changed significantly with the approval of glucagon-like peptide-1 receptor agonists, which have been shown to have cardiovascular and kidney benefit among patients with obesity and a range of comorbid conditions including diabetes, CKD, and heart failure.

Summary

Improved recognition, diagnosis and management of clinically consequential obesity is emerging as a key factor in improving outcomes for patients with comorbid conditions such as heart failure with preserved ejection fraction and CKD. The incorporation of comprehensive multi-disciplinary management, shared decision making with patients and broader access to therapies is critical to improving clinical outcomes.

Introduction

More than 1 in 5 adults in the US are obese, as defined by body mass index (BMI) of ≥30 kg/m². In some states, the rate of obesity among adults has risen to 40% or more.¹ While obesity historically has been viewed as a straightforward excess of caloric intake, or metabolic dysfunction,² more recently it has been conceptualized as a risk factor for disease arising from a milieu of psychosocial, socioeconomic and medical factors. ³ While much of the pre-clinical and epidemiologic evidence lies in examination of how obesity itself can lead to development of cardiovascular disease (CVD) and chronic kidney disease (CKD)—either through traditional metabolic risk factors such as hypertension and type 2 diabetes mellitus (T2DM) or independent of these co-morbid conditions—much of the trial evidence is focused on management of obesity among patients with prevalent cardiac and kidney disease. In this review, we will discuss clinical definitions of obesity and the cardiorenal syndrome (CRS), our pathophysiologic understanding of the pathways connecting obesity with CRS, diagnostic challenges, and evidence regarding treatment of obesity among those with prevalent CKD and heart failure (HF).

Clinical Definitions

Obesity

The World Health Organization has defined obesity as BMI ≥30 kg/m², a definition that has since been used widely. Importantly, while BMI can correlate with adiposity, it is not a direct measure of adiposity, nor does it indicate the severity of obesity in terms of medical sequalae.³ Elevated waist circumference, as an effort to capture central adiposity, has been incorporated into clinical research and tends to be more strongly associated with adverse clinical outcomes⁴ but has not been widely standardized or incorporated into clinical definitions of obesity. Similarly, elevated waist-to-height ratio has been examined as an alternative to BMI as providing a more objective metric of central adiposity yet also has not been standardized or incorporated into clinical definitions or clinical practice.

In 2022, the Lancet Commission on Obesity proposed a new classification system, differentiating between pre-clinical and clinical obesity, with the latter reflecting a disease state itself defined by obesity-related diseases.³,⁵ A potential limitation of this schema in the clinical setting is that it requires differentiation between conditions comorbid with obesity and those related to obesity itself. The commission defines the latter as “conditions for which there is a plausible cause-effect relationship, or at least a clear pathophysiological overlap or interaction”.³ Alternatively, the cardiovascular-kidney-metabolic (CKM) syndrome, proposed by the American Heart Association in 2023, encompasses the complex interplay between obesity, CVD and CKD, recognizing that multi-directional pathophysiology between these conditions may conspire to increase risk of poor health outcomes.⁶ The CKM paradigm also includes stages on the basis of metabolic factors and severity of CVD and/or CKD and thus facilitates risk stratification.

The Cardiorenal Syndrome

The CRS comprises a spectrum of complex syndromes centered around a bidirectional dysfunction in both the heart and the kidney. While the term CRS can be interpreted widely, for this review we will be referring to the clinical manifestation of a patient with HF plus reduced kidney function, sodium avidity and/or poor diuretic response. Figure 1 illustrates the interrelationship in concepts of clinical obesity, CKM and CRS.

Figure 1.

Interrelationship of obesity, cardiovascular disease and chronic kidney disease

Pathophysiology and Mechanisms

Pre-clinical animal models

The mechanistic pathways linking obesity with CKD, CVD and CRS can be considered either through traditional risk factors like hypertension, diabetes, or independent of these, although disentangling these pathways can be challenging. Adipocytes themselves have been shown to produce angiotensin II,⁷ contributing to renal sodium avidity, volume overload and potentially some contribution to activation of the renin angiotensin aldosterone system leading to the hypertensive, sodium avid and volume-overloaded clinical phenotype. In terms of insulin resistance, adipocytes have also been shown to contribute to elevated levels of inflammatory markers including C-reactive protein,^8,9 TNF-alpha^10,11 and interleukin 6,¹² leading to insulin resistance. Outside the risks of long-standing hypertension and T2DM leading to CVD, HF and CKD, there is also evidence linking visceral adipose tissue to incident CVD¹³ and perirenal fat deposition to CRS manifestations, including sodium avidity and abnormal cardiac hemodynamics.¹⁴ Whether there is something specific to the adipose tissue adjacent to the kidney that leads to CRS manifestations, or whether it is just associated with greater burden of visceral adiposity, is unclear. However, there is accumulating evidence that visceral fat is much more tightly associated with harmful metabolic derangements compared to peripheral subcutaneous fat, as suggested by lack of improvement in blood pressure control and insulin sensitivity in patients after removal of subcutaneous fat deposits via liposuction.¹⁵

Epidemiology of Obesity with Kidney and Cardiac Outcomes

In the general population, studies have shown an association between obesity and incident CKD,¹⁶ progression of CKD¹⁷ and risk of end stage kidney disease (ESKD).¹⁸ Among those with prevalent CKD or HF, the association between obesity, and CVD and CKD outcomes has been less consistent, likely given the frequent J-shaped association that is observed in epidemiologic studies. In other words, individuals who are underweight or with low BMI are often much sicker than their counterparts who are overweight and thereby more likely to experience adverse clinical outcomes and skew the association. Metrics of central adiposity, including elevated waist circumference and waist-to-height ratio, have been associated with lower eGFR among 123,629 adults in a Chinese cohort in a cross-sectional manner¹⁹ and associated with higher risk of incident CVD among 265,988 women from the UK Biobank.²⁰

Heart Failure with Preserved Ejection Fraction

One particular group of patients who have been a significant focus of research in relation to obesity are those with HF with preserved ejection (HFpEF). Upwards of 80% of patients with HFpEF meet the definition of obesity by BMI criteria,²¹ and obesity has been implicated as a key component in the pathogenesis of HFpEF. Among 1806 community participants in the Multi-Ethnic Study of Atherosclerosis with a mean age of 65 years and BMI of 28 kg/m², multiple measures of obesity including BMI, waist circumference and quantification of visceral adipose tissue by abdominal computed tomography (CT) scan were associated with significantly higher risk of incident HFpEF over an 11-year follow-up.²² These associations persisted even after adjustment for traditional risk factors including T2DM, smoking, hypertension and hyperlipidemia. In contrast, subcutaneous adipose tissue was not associated with development of HFpEF. Notably, measures of obesity also were not associated with development of HF with reduced ejection fraction (HFrEF).

Not only is obesity thought to be involved in the causal pathway to development of HFpEF, but it has also been shown to be a key comorbidity among patients with prevalent HFpEF. Among 99 patients with both HFpEF and obesity, multiple metrics of cardiac structure and function including plasma volume, biventricular remodeling and right ventricular dysfunction were significantly worse compared to a similar number of patients with HFpEF who were non-obese by BMI.²³ Similarly in terms of kidney function among patients with obesity and HFpEF, a post-hoc analysis of 332 patients with HFpEF pooled across several trials of acute decompensated heart failure suggested that those with BMI ≥30 kg/m² experienced a two-fold higher incidence of increase in serum creatinine by ≥0.3 mg/dl (28% vs 14%) during the course of diuresis in the hospital.²⁴ There are likely many complex and bidirectional pathways linking obesity with HFpEF and CKD that need further elucidation, but the data thus far supports that this represents an important and predominant clinical phenotype with high burden of mortality and morbidity and potential for therapeutic intervention.

Clinical Management

While treatment of kidney disease, cardiac disease and obesity has traditionally been siloed, with primary care physicians, obesity medicine specialists and endocrinologists prescribing medications for weight loss and glycemic control, and cardiologists and nephrologists, respectively, managing HF and CKD, the introduction of glucagon-like peptide-1 receptor agonists (GLP-1 RA), and to a lesser degree sodium-glucose cotransporter 2 (SGLT2) inhibitors, has streamlined and unified treatment goals across specialties and additionally has engaged an expanded group of specialists and sub-specialists in obesity management. Here we aim to consolidate diagnostic and management considerations for all three—obesity, HF, and CKD. We summarize current obesity treatment guidelines and recent trials regarding medical and surgical treatments for obesity within the context of HF, CVD and CKD. We focus our discussion on GLP-1 RA and bariatric surgery as these are obesity treatment options for which the most is known about long-term kidney and CV outcomes. We briefly discuss other medical treatments for obesity but a nuanced discussion of these is outside the scope of this review.

Diagnostic considerations

Given the increased number of available therapeutic options, greater recognition of obesity, HF, and CKD alone, and as important overlapping comorbid conditions, is needed (Figure 1). The diagnostic criteria for HF can be complex and include signs and symptoms resulting from structural or functional impairment of ventricular filling or forward ejection of blood. Particularly for the diagnosis of HFpEF, in which ejection fraction is ≥50%, there should be evidence of spontaneous or provokable increased ventricular filling either by biomarker criteria such as elevated B-type natriuretic peptide (BNP) or hemodynamic assessment. Signs of volume overload, such as lower extremity edema or jugular venous distention can be more difficult to assess among patients with obesity. Relatedly, volume overload in either HF or advanced CKD may contribute to inaccuracies in BMI estimation. Among patients with obesity, BNP may be falsely low due to unknown reasons, although proposed mechanisms include increased clearance from receptors on adipocytes,²⁵ decreased production related to insulin resistance,²⁶ and decreased wall stretch from mechanical compression due to epicardial fat.²³

Diagnosis of CKD may also be confounded by obesity. The Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for the Evaluation and Management of CKD recommend use of eGFR creatinine-cystatin to estimate GFR in patients with BMI ≥40.²⁷ Among individuals with CKD, particularly those with comorbid HF, sarcopenia, including in the setting of obesity, is prevalent and may confound measures of GFR and BMI, potentially leading to inaccuracy in obesity and CKD diagnoses.^28–31 Individuals with sarcopenia may have increased adiposity relative to muscle mass and are therefore at risk for underdiagnosis of obesity and lower creatinine generation, which may result in overestimation of GFR.^29,31 Patients suspected of sarcopenic obesity may benefit from more direct estimation of adiposity. The European Society of Cardiology (ESC) clinical consensus statement on obesity and CVD notes that with increased availability and utilization of imaging modalities—such as dual-energy X-ray absorptiometry, CT, magnetic resonance imaging and positron emission tomography scanning—more consistent measurements of adiposity could be attained.³²

Many questions remain regarding appropriate and accurate assessment of kidney function among patients with obesity. Among 731 participants in the Study of Terzepatide in Participants with Heart Failure with Preserved Ejection Fraction and Obesity (SUMMMIT) trial, baseline eGFR based on cystatin C was about 9 ml/min/1.73 m² lower than the eGFR based on creatinine across the range of kidney function (eGFR-cystatin C of 55.3 ± 22.4 ml/min/1.73 m² vs eGFR-creatinine of 64.4 ± 22.4 ml/min/1.73 m²).³³ Of note, adipocytes themselves have been shown to produce cystatin C, which may contribute to the appearance of lower eGFR,³⁴ and there is also evidence that inflammation and glucocorticoid use can both increase cystatin C levels.^35,36 Weight loss, in particular with GLP-1-RA may result in reduction in both muscle mass and adiposity,³⁷ with the former potentially impacting creatinine-based estimates of GFR independent of any changes to glomerular filtration. Despite all the questions surrounding best approaches for GFR estimation among patients with obesity, however, general management decisions can still be pursued by following general KDIGO definitions for CKD based on eGFR < 60 ml/min/1.73 m² for greater than 3 months, or presence of kidney damage including abnormalities in urine such as presence of albuminuria, proteinuria, hematuria or other structural kidney abnormalities for greater than 3 months.³⁸

Treatment Considerations

GLP-1 Receptor Agonists and dual GLP-1/GIP Receptor Agonists

Glucagon like peptide −1 and glucose-dependent insulinotropic polypeptide (GIP) are the two primary incretin hormones that are secreted from the intestines in response to food. GLP-1 RAs and dual GLP-1/GIP RAs work by activating the receptors throughout the body, including the pancreas, gastric mucosa, kidney, heart, and hypothalamus. The effects of these agents include the stimulation of insulin release and slowed gastric emptying, leading to improved glycemic control, appetite suppression and weight loss. The FDA first approved semaglutide for glycemic control for patients with T2DM in 2017, though they tend to have only modest impact on reductions in hemoglobin A1c and subsequently were found to have substantial protection against CV outcomes and kidney outcomes. Of note, per FDA medical review, pivotal trials of semaglutide showed no increased exposure of the drug in patients with CKD, including ESKD, with the implication that they do not need to be renally dose adjusted.³⁹ In a 2021 meta-analysis of 8 large GLP-1 RA trials, randomization to GLP-1 RA versus placebo was associated with a significant reduction in the risk for all-cause mortality (HR 0.88 [0.82, 0.94]), and hospitalization for HF (HR 0.89 [0.82, 0.98]).⁴⁰ Overall, all the evidence led to additional FDA approval for the indication of reducing risk of adverse CV outcomes in patients with T2DM.

Recent trials comparing GLP-1 RA to placebo have expanded beyond patients with diabetes and were designed to assess CV and CKD primary outcomes (Table 1). Both SUMMIT and the Effect of Semaglutide 2.4 mg Once Weekly on Function and Symptoms in Subjects with Obesity-related Heart Failure with Preserved Ejection Fraction (STEP-HFpEF) trials examined GLP-1 RA in patients with HF. The SUMMIT trial showed that participants treated with the dual GLP-1/GIP RA tirzepatide had a lower risk of death from CV causes or worsening HF.⁴¹ A secondary analysis indicated that tirzepatide was also associated with a decrease in albuminuria, blood pressure, BNP and other clinical markers.⁴² Important to keep in mind that the STEP-HFpEF trial examined the impact of GLP-1 RA on functional outcomes and was not powered for primary CV outcomes.⁴³

Table 1.

Select landmark trials of GLP-1 RAs and dual GLP-1/GIP RAs with particular focus on cardiovascular and kidney study populations and outcomes

Trial name (year)	Intervention	Pertinent Eligibility Criteria			Cohort Description						CV outcome(s)	Kidney outcome(s)	Other outcomes	Pertinent sub-group analysis	Commentary
		BMI	Kidney	HF or CV disease	Overall	N	Mean or Median Age	Mean or Median BMI	Mean GFR (ml/min/1.73 m2)	Urine protein (g/day) or urine albumin to creatinine ratio (UACR) (mg/g)
ELIXA (2015)62	10 to 20 mcg SC daily lixisenatide or placebo	N/A	CrCl ≥ 30 ml/min/1.73 m2 by Cockroft and Gault	ACS event within the prior 12 weeks	≥30yo with T2DM with recent ACS event	6068	59.9 (treatment); 60.6 (placebo)	30.1 (treatment); 30.2 (placebo)	76.7 (treatment); 75.2 (placebo)	10.2 mg/g (treatment); 10.5 mg/g (placebo)	Primary composite of CV death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina: HR 1.02 (0.89–1.17); p-value 0.81	Reduced risk of new-onset UACR > 300mg/g: HR 0.81 (0.66, 0.99) for lixisenatide vs placebo over median 108 week follow-up63	Secondary composite of the primary end point or hospitalization for HF: HR 0.97 (0.85–1.10)		Few kidney events, and only 23% of participants had eGFR of < 60 ml/min/1.73m2 at baseline
LEADER (2016)64	1.8 mg liraglutide SC daily or placebo	N/A	Non ESKD and not receiving renal replacement therapy	Prior CVD or subclinical evidence of CVD	T2DM and high CVD risk	9340	64	32	Not reported. 23% with eGFR<60 ml/min/1.73 m2	10.5% with UACR > 300 mg/g	Primary composite of CV death, nonfatal MI, nonfatal stroke: HR 0.87 (0.78, 0.97) for liraglutide vs placebo	Kidney composite of new onset UACR > 300 mg/g, doubling of SCr, ESKD or death due to kidney disease: HR 0.78 (0.67, 0.92) for liraglutide vs placebo over median 3.8 years65			More patients in the placebo group received sulfonylurea agents, potentially leading to imbalance of CV events
SUSTAIN-6 (2016)66	0.5 or 1 mg semaglutide SC weekly or placebo for 104 weeks	N/A	Non ESKD and not receiving renal replacement therapy	Prior CVD or subclinical evidence of CVD	≥ 50 yo, with T2DM and CVD	3297	65	32.8	28.5% with eGFR<60 ml/min/1.73 m2	N/A	Primary composite of CV death, nonfatal MI, nonfatal stroke: HR 0.74 (0.58, 0.95) for semaglutide vs placebo	Kidney composite of new onset UACR>300 mg/g, doubling of SCr ESKD or death due to kidney disease: HR 0.64 (0.46, 0.88)			Potential risk of worsening diabetic retinopathy
EXSCEL (2017)67*	2mg exenatide or placebo SC weekly	N/A	eGFR ≥30 ml/min/1.73m2	Designed for some with and without CVD	T2DM with and without CVD	14,752	62	32	76	N/A	Primary composite of CV death, nonfatal MI, nonfatal stroke: HR 0.91 (0.83, 1.00) for exenatide vs placebo	Kidney composite of >40% eGFR decline, ESKD, death due to kidney reasons or new UACR>300 mg/g: HR 0.88 (0.76, 1.01)68 *		Subgroup with HF (16.2%): benefits of exenatide were attenuated for the primary composite of CV death, nonfatal MI, nonfatal stroke (HR 0.97 [0.81, 1.16]), and for the outcome of CV death or HF hospitalization (HR of 1.05 [0.86, 1.29])69	High rate of participants stopping regimen early (up to 45% in each arm)
REWIND (2019)70	1.5mg dulaglutide SC weekly or placebo	N/A	eGFR ≥30 ml/min/1.73m2	CVD or CVD risk factors	≥ 50 yo, with T2DM and CVD or CVD risk factors	9901	66	32.3	11% with eGFR <60 ml/min/1.73m2	35% with UACR > 300 mg/g	Primary composite of first occurrence of non-fatal MI, non-fatal stroke or death from CV causes: HR 0·88, 95% CI 0·79–0·99; p=0·026;	Kidney composite of new UACR >300 mg/g, >30% eGFR decline, or ESKD: HR 0.85 (0.77, 0.93) over median of 5.4 years of follow-up		Among subgroup with BMI ≥32, dulaglutide was associated with decreased risk of primary outcome HR 0.82 (0.69, 0.96)	Less than 25% of study cohort had eGFR <60
PIONEER 6 (2019)71	Target of 14 mg PO daily semaglutide or placebo	N/A	eGFR ≥30 ml/min/1.73m2	CVD or CVD risk factors	≥ 50 yo, with T2DM and CVD or CVD risk factors	3183	66	32.3	74		Primary composite of CV death, nonfatal MI, nonfatal stroke: HR 0.79 {0.57, 1.11]) over median 15.9 months	Annual eGFR slope was lower in semaglutide than placebo (estimated treatment difference of 0.55 [0.04, 1.06]) ml/min/1.73m2/year72			Relatively short follow-up period
SELECT (2023)44	2.4mg semaglutide SC weekly vs placebo for 104 weeks	≥27	Non ESKD and not receiving renal replacement therapy	CVD (prior MI, prior stroke, or symptomatic peripheral arterial disease)	≥ 45 yo, overweight, and CVD, without T2DM	17604	61.6	33.3	84	N/A	Primary composite of CV death, nonfatal MI, or non- fatal stroke: HR 0.80; 95% CI 0.72 to 0.90 for semaglutide vs placebo; P<0.001	Kidney composite end point of death from renal causes, initiation of long-term renal replacement therapy, eGFR <15 ml/min/1.73 m2, >50% reduction in eGFR, or onset of urinary albumin-to-creatine ratio >300 mg/g: HR 0.78 (95% CI 0.63–0.96) for semaglutide vs placebo73	HF composite outcome of CV death or HF hospitalization: HR 0.82 (0.71, 0.96) for semaglutide vs placebo44
STEP-HFpEF (2023)74	2.4mg semaglutide SC weekly vs placebo for 52 weeks	≥30	Non ESKD and not receiving renal replacement therapy	HFpEF (>45%)	≥ 18 years with HF and obesity, excluded patients with T2DM	529	69	37.0	Not reported	N/A	Fewer HF events in the semaglutide arm (1/263) vs placebo arm (12/266)	N/A	Greater improvement in KCCQ-CSS score with semaglutide vs placebo: difference of 7.8 [4.8, 10.9] points		Not powered for CV outcomes.
FLOW (2024)75	1 mg SC semaglutide weekly or placebo	N/A	eGFR 50– 75 ml/min/1.73 m2 and UACR >300–<5000 OR eGFR 25– <50 mL/min/1.73 m2 and UACR >100–<5000	N/A	T2DM with high-risk CKD; excluded patients with NYHA functional class IV HF	3533	66.6	32	45	557.8 mg/g (median UACR)	Secondary outcome of major CV events including CV death, nonfatal MI, nonfatal stroke: HR 0.82 (95% CI 0.68 to 0.98) for semaglutide vs placebo, p-value 0.029	Primary outcome of major adverse kidney events including kidney failure, sustained eGFR <15 ml/min/1.73 m2, sustained ≥50% eGFR decline, or death from kidney-related or cardiovascular causes: HR 0.76; 95% CI 0.66, 0.88 for semaglutide vs placebo; P=0.0003			only 24% of participants had a diagnosis of HF. Only 11% of participants had eGFR <30.
SUMMIT (2025)76	2.5mg-15mg terzepatide SC weekly vs placebo for at least 52 weeks	≥30	eGFR≥15 and not receiving renal replacement therapy	HFpEF (EF≥50%)	≥ 40 yo with HF and obesity, with and without T2DM	731	65.2	38.3	64	N/A	1) Primary composite endpoint of CV death or worsening HF event: HR 0.62; 95% CI 0.41 to 0.95 among those randomized to terzepatide vs placebo; P = 0.026. Death from CV cause alone HR 1.58; 95% CI 0.52 to 4.83. Death from any cause HR 1.25; 95% CI 0.63 to 2.45	N/A	Greater improvement in KCCQ-CSS score with terzepatide vs placebo: difference of 6.9 (3.3, 10.3) points	Similar results among those with and with CKD: HR 0.67 (0.41. 1.05) among those with CKD, HR 0.58 (0.24, 1.32) among those without CKD; p-interaction of 0.7733

Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; CrCl, creatinine clearance; UACR, urine albumin:creatinine ratio; T2DM, type 2 diabetes mellitus; HF, heart failure; ACS, acute coronary syndrome; MI, myocardial infarction; CVD, cardiovascular disease; CKD, chronic kidney disease; ESKD, end stage kidney disease; NYHA, New York Heart Association; HFpEF, heart failure with preserved ejection fraction; KCCQ-CSS, Kansas City Cardiomyopathy Questionnaire – Clinical Summary Score

The Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) trial was unique in that it examined primary CV outcomes in non-diabetic patients with overweight and obesity (BMI ≥27 kg/m²).⁴⁴ It showed reduced risk of CV adverse events in individuals treated with semaglutide compared to placebo. There was a possible reduction in adverse kidney events, although this did not meet statistical significance. The FLOW trial examined primary kidney outcomes among patients with T2DM and CKD and showed a reduction in kidney disease events in participants treated with semaglutide. Of note, however, fewer than one quarter of participants in the trial had a diagnosis of HF. Given the benefits demonstrated in these trials, there is strong evidence that GLP-1 RAs are efficacious in improving CV outcomes in diabetic patients. In patients with pre-existing kidney disease or severe GI symptoms, FDA guidance suggest close monitoring of GFR given post-marketing reports of AKI, including AKI requiring dialysis.³⁹

Kidney and CV considerations for additional medical obesity treatments

Evidence regarding use of non-GLP-1 RA medical obesity treatments in CKD and CVD is limited.⁴⁵ By and large, these drugs have not been studied in CKD. Naltrexone combined with buproprion is FDA approved for weight loss in patients with BMI ≥30 kg/m² or BMI ≥27 kg/m² with comorbid conditions. ⁴⁶ Per FDA drug labeling, this medication requires renal dose adjustment, has not been studied in patients with ESKD and is not recommended in this population. CV outcomes associated with use of this medication are not known. A 2016 trial evaluating major adverse cardiovascular events with this medication was terminated early due to release of confidential interim results.⁴⁷ Orlistat, which reduces absorption of free fatty acids via inactivation of gastric and pancreatic lipases, was not studied in patients with kidney disease. Of note, it may cause increased urinary oxalate levels and has been associated with oxalate nephropathy.⁴⁸ Furthermore, its mechanism of action results in reduced absorption of many medications, including cyclosporine. Phentermine and topiramate should also be used with caution. Phentermine acts to suppress appetite and the exact mechanism of topiramate in weight loss is not fully known.⁴⁹ Post-marketing reports suggest phentermine may be associated with increased blood pressure and ischemic events, although data on this is lacking. Potential kidney-related adverse effects from topiramate include metabolic acidosis and increased risk of hypokalemia with loop or thiazide diuretics. Renal dosing is required and the drug was not studied in patients requiring dialysis.

Surgical management

For some patients, medical management of obesity is not a viable option, either due to patient preference, underlying conditions that exclude use of medical therapies, or ineffectiveness of these therapies at helping patients achieve and maintain weight loss. For these patients, metabolic bariatric surgery (MBS) is a treatment option that has been shown in largely observational studies to result in sustained weight loss and modification of metabolic comorbidities. With observational data emerging that anywhere from ~40 to 60% of patients discontinue GLP-1 RA within the first year of starting,^50,51 for patients in whom large, sustained weight loss is critical, alternative options such as MBS may be more appropriate. However, the decision of pursuing medical versus surgical options is complex and needs to balance many factors including patient preferences, financial costs,⁵² up-front surgical risks and anatomical considerations, and ultimately needs to be a patient-centered decision. Much of the evidence regarding MBS compares different surgical approaches and to date, there are no randomized control trials comparing weight loss and long-term outcomes in patients undergoing MBS versus those prescribed GLP-1 RA.

A chief concern in patients with CKD and HF for any surgical procedure is peri-operative risk. Among 302 patients with CKD who underwent Roux-en-Y gastrectomy (RYGB) or sleeve gastrectomy (SG), overall rates of acute post-operative complications were low (6.2 percent for SG and 4.8 percent for RYGB).⁵³ The majority (92%) of patients with CKD Stage 4 and CKD Stage 5 underwent SG. Notably, 45% of patients who underwent SG were receiving maintenance dialysis pre-operatively. Total percent weight loss was higher among the RYGB cohort and maintained at 60 months post-operatively. In terms of kidney outcomes, more than 40 percent of patients with CKD Stage 3 pre-operatively had apparent improvement to CKD Stage 2 following surgery, albeit based on GFR estimates utilizing serum creatinine. In contrast, CKD stage did not improve in patients with CKD Stage 4 and 23.5% progressed to CKD Stage 5. A total of 63 patients underwent kidney transplantation following MBS, and 40 were post-operatively deemed to be transplant candidates, suggesting that elevated BMI was the primary barrier for kidney transplantation. The authors point out that RYGB may be high risk for potential transplant candidates given risk for anastomotic leaks and other infectious concerns, and they recommend SG if the surgical route is pursued.

Metabolic bariatric surgery also appears to improve albuminuria, as indicated in a recent meta-analysis examining impact of MBS on diabetic nephropathy.⁵⁴ Of note, sub-group analysis showed that albuminuria reduction was significant only for patients who underwent RYGB. MBS has also been shown to lower risk of conditions comorbid with obesity, CKD and HF. Among patients undergoing RYGB versus lap adjustable banding (LABG), weight loss was variable but prevalence of T2DM and hypertension were lower in both groups at 7-year follow up, although greater for patients who underwent RYGB.⁵⁵ Among patients with baseline T2DM, diabetic regression or resolution was more common among those who underwent RYGB. With regard to CVD impact, MBS was shown in the prospective Swedish Obese Subjects intervention study to be associated with a reduction in incident CV events as well as CV death.⁵⁶ A recent cohort study using data from claims and electronic medical records suggests that MBS may be associated with more weight loss and lower costs at 2 years.⁵²

Current guidelines for treatment of obesity in the setting of CVD and/or CKD

Current guidelines on obesity management in patients with comorbid conditions provide important recommendations for subspeciality clinicians who may be relatively new or inexperienced in managing obesity. Management of obesity has gained a prominent position among guidelines and position statements from national and international cardiology and kidney societies, all of which have broad and resolute recommendations for use of GLP-1 RA for several patient populations in order to aid weight loss.

The 2025 American College of Cardiology Scientific Statement On the Management of Obesity in Adults with Heart Failure recommends semaglutide or tirzepatide, respectively, for patients with obesity and HF with mildly reduced EF (≥45%) or preserved EF (≥50%) to improve symptoms and functional status.⁵⁷ These recommendations caution that there is not sufficient evidence at this point to recommend these medication for reduction in HF events for patients with HFpEF and obesity. They recommend consideration of MBS for potential reduction in risk of HF events, based on observational evidence, though risks of GLP-1 RA must be weighed against risk of peri-operative adverse cardiovascular events.

The ESC clinical consensus statement on obesity and CVD also recommend use of GLP-1 RAs for: 1) patients with obesity and T2DM to aid in weight loss (Class IIa, level of evidence B); 2) in patients with T2DM and atherosclerotic CVD to reduce CV outcomes regardless of hemoglobin A1c or concomitant use of glucose lowering medications (Class 1, level of evidence A); 3) in overweight or obese patients with “chronic coronary syndrome” without diabetes to reduce CV outcomes including CV death, MI and stroke (Class IIa, level of evidence B). The diabetes, cardiorenal, and/or metabolic disease task force recently revised their recommendations and include GLP-1RA in the treatment algorithm for individuals with HF with moderately reduced EF and obesity, those with HFpEF and obesity and those with CKD and diabetes.⁵⁸

The KDIGO 2024 CKD treatment guidelines recommend the use of GLP-1 RA in treatment of patients with CKD and T2DM who have not met glycemic goals with metformin or SGLT2 inhibitor, or for whom these medications are contraindicated or not tolerated (1B recommendation).²⁷ These recommendations suggest use of GLP-1 RA agents with known CV benefit. The American Society of Nephrology Kidney Health Guidance provides specific guidance for managing obesity in patients with kidney disease.⁴⁵ In addition to GLP-1 RA, there is discussion of use of naltrexone-buproprion, orlistat and phentermine-topiramate for weight loss in obesity. The guidance suggests a limited use of these medications for treating obesity in kidney disease given data on CV and kidney outcomes is lacking. In addition, naltrexone-buproprion and phentermine-topiramate both require dose adjustment for decreased eGFR and orlistat is associated with increased urine oxalate levels.

Multi-disciplinary management and shared decision making

Implicit in any discussion of obesity management is the need for shared decision-making with the patient regarding approach to weight loss in the context of their overall health.⁵⁹ Perception of body weight and its associated risks may be influenced by psychosocial and cultural factors, in addition to personal beliefs. Moreover, patients may experience food insecurity which limits their ability to alter their nutritional habits, or circumstances that limit their ability to exercise. For this reason, a multi-disciplinary approach to obesity care is needed to ensure ongoing management of comorbid conditions, to help identify and address underlying barriers to safe weight loss, including social risks or mental health conditions (e.g. disordered eating) that may be contributing to obesity, and to support patients in navigating weight loss in the setting of HF and CKD. This team could include, but is not limited to, nurses, dietitians and social workers, psychologists and pharmacists, in addition to a multi-specialty medical team, including primary care physicians, surgeons, cardiologists, nephrologists, endocrinologists and psychiatrists.

The American Heart Association has recommended multidisciplinary care models for patients with two or more CKM conditions as a component of high-quality care.⁶ These models include the role of a CKM care coordinator who can help support interdisciplinary communication and coordination. The American College of Lifestyle Medicine, the American Society for Nutrition, the Obesity Medicine Association, and The Obesity Society, in a joint statement regarding nutritional priorities for patients receiving GLP-1 RA for obesity, identify group-based visits, nutrition counseling by registered dietitians, telehealth and Food is Medicine (FIM) initiatives as potential tools for supporting patients undergoing treatment for obesity.⁵⁹ Insurance coverage for these supports is variable, although several states are now piloting FIM, or other food-based initiatives.⁶⁰

Conclusion

Addressing obesity in the setting of HF and CKD is a complex and clinically nuanced topic, yet critically important for improving clinical outcomes including candidacy for kidney and heart transplant. The evidence to date shows that GLP-1 RA are potent agents for improving obesity related outcomes including CKD and CVD. While much of the evidence regarding GLP-1 RA focuses on patients with T2DM, there is also evidence suggesting these medications improve outcomes in patients with obesity in the absence of T2DM. Of note however, access to these medications is not equitable. As of 2024, only 13 state Medicaid programs provided coverage for GLP-1 RA for obesity treatment.⁶¹ With the enthusiasm of GLP-1 agonists and combined GLP-1/GIP agonists, and the recognition that obesity exists with a complex ecosystem of comorbid conditions and social determinants of health, a number of new questions need to be addressed including 1) how to optimally and efficiently measure adiposity to diagnose clinically excess adiposity for patients with CKD and/or HF, 2) how to treat sarcopenic obesity for patients with CKD and HF, and 3) how to ensure equitable access to obesity treatment for patients with complex comorbidities. A more uniform and widely accepted set of clinical guidelines with widespread stakeholder engagement from various medical subspecialties (primary care, endocrinology, cardiology, nephrology) as well as regulatory groups, payers and patient advocacy groups is critical to ensure high quality care and improved outcomes.