Clinical Profile and Prognosis of Patients With Acute Decompensated Heart Failure Who Met the Obesity-Related Eligibility for Subcutaneous Semaglutide　― Findings From the CURE-HF Registry ―

Abstract

Background: Obesity is well-established risk factor of heart failure (HF); however, “obesity paradox” has been described in symptomatic HF patients. The STEP-HFpEF study suggested that once-weekly subcutaneous semaglutide might improve outcomes in patients with obesity-related HF. We explored the prevalence of obesity-related eligibility for semaglutide treatment among patients with acute decompensated heart failure (ADHF) and evaluated their prognoses.

Methods and Results: We analyzed data from 1,017 ADHF patients (median, 81 years; 44.2% female) enrolled in the CURE-HF registry. We assessed prevalence of obesity-related eligibility for semaglutide administration and examined the association between this eligibility and all-cause death over a median follow-up of 2.7 years. There were 73 patients (7.2%) who were semaglutide-eligible and they had a higher proportion of diabetes mellitus than patients who were semaglutide non-eligible (64.4% vs. 26.4%, P<0.001). Kaplan-Meier analysis indicated that semaglutide-eligible patients had a significantly lower all-cause mortality rate than non-eligible patients (log-rank P=0.005). After adjustment for demographic characteristics, there was no significant difference in mortality rate between the 2 groups (adjusted hazard ratio 0.63, 95% confidence interval (CI) 0.34–1.17, P=0.14). In the propensity score-matched cohort, we did not observe a significant difference in mortality rate (log-rank, P=0.79).

Conclusions: Almost 7.2% of the ADHF patients were semaglutide-eligible. Our findings did not affirm the “obesity paradox” in semaglutide-eligible HF patients after adjusting for demographic factors.

Over recent years, there has been a notable increase in the number of patients with heart failure (HF) in Japan,^1–4 which can be attributed to 2 main factors: an increase in ischemic cardiomyopathy resulting from adopting a westernized lifestyle and an increase in the prevalence of hypertension and valvular heart disease associated with an aging population.^5–7 Japan, one of the countries with the fastest aging populations, is expected to have a continual increase in number of patients with HF in the near future and so there is an urgent need for the development of new approaches to the treatment of HF.

In the general population, obesity is an independent risk factor of future development of HF, as shown in the Framingham heart study.⁸ On the other hand, an increase in weight is a good prognostic factor in patients with HF,⁹ a phenomenon known as the “obesity paradox”.¹⁰ The CHARM trial¹¹ in patients with chronic HF and the ADHERE registry¹² in acute HF both demonstrated that obese patients with HF had a better prognosis compared with their leaner counterparts. Nevertheless, other studies have reported conflicting results,^13,14 and the prognostic impact of obesity on cardiovascular (CV) outcomes in patients with symptomatic HF remains uncertain.

Semaglutide administration once a week in overweight or obese adults with or without type 2 diabetes in an East Asian population (the STEP 6 trial) demonstrated that the glucagon-like peptide-1 receptor agonist semaglutide improved body weight in patients with a body mass index (BMI) ≥35 kg/m² and those with BMI ≥27 kg/m² and accompanied by multiple obesity-related health problems.¹⁵ Further, another study showed that once a week administration of 2.4 mg semaglutide in patients with obesity-related HF with preserved ejection fraction (the STEP-HFpEF trial) reported improvements in HF symptoms in the obese patients.¹⁴ Due to the low prevalence of obesity in Japan,^16,17 there is a paucity of data on the association between obesity-associated HF and CV outcomes in Japanese patients with HF. Furthermore, the potential benefits of therapeutic interventions for weight management in patients with obesity-associated HF are not well understood. This study aimed to assess the prevalence of Japanese patients with HF eligible for subcutaneous weekly administration of semaglutide at a weight management dose of 2.4 mg and to evaluate their CV outcomes.

Methods

Patients and Study Design

This was a post hoc analysis of data collected from the Clue of Risk Stratification in Elderly Patients with Heart Failure (CURE-HF) registry, which was a prospective, multicenter, cohort study conducted in Nagano Prefecture, Japan.^18–20 The CURE-HF registry contains data of 1,036 consecutive patients who were hospitalized with a primary diagnosis of acute decompensated heart failure (ADHF) and discharged after treatment at 15 institutions between July 2014 and March 2019. The exclusion criteria were: age <20 years, unfeasible follow-up, failure to provide informed consent, in-hospital death, and acute coronary syndrome. After admission, medical treatment was initiated at the discretion of the investigators at each site. Baseline clinical data including demographics, medical history, laboratory data, and echocardiographic findings were evaluated during the compensatory phase of HF. Follow-up data were obtained from direct patient contact and hospital records of the referring physicians. To ensure accurate assessment of clinical events, additional information was obtained from visits or telephone contact with surviving patients or family members between June 2021 and August 2021, and from medical records obtained from other hospitals as needed. These events were completely anonymized prior to analysis by investigators who were blinded to the participants.

The study was approved by the review and ethics committees of each participating institution. All study participants provided written informed consent prior to enrollment. The study was conducted in accordance with the principles of the Declaration of Helsinki and registered in the University Hospital Medical Information Network (UMIN 000024470).

Of the 1,036 patients with ADHF, we excluded 10 with missing follow-up data and 9 with missing height or weight data. We assessed a total of 1,017 patients (98.2%) (Figure 1). The eligibility criteria for once-weekly subcutaneous semaglutide 2.4 mg as a treatment for obesity-related health disorders and weight management (semaglutide-eligible) were: obese patient diagnosed with hypertension, dyslipidemia, or type 2 diabetes based on relevant criteria and who meets the criteria of BMI ≥27 kg/m² together with ≥2 obesity-related health conditions, or BMI ≥35 kg/m². The following 11 conditions were considered obesity-related health disorders: impaired glucose tolerance (type 2 diabetes, impaired glucose tolerance, etc.), dyslipidemia, hypertension, hyperuricemia/gout, coronary artery disease, cerebral infarction, non-alcoholic fatty liver disease, menstrual abnormalities/infertility, obstructive sleep apnea syndrome/obesity hypoventilation syndrome, musculoskeletal disorders, and obesity-related kidney disease (Supplementary Table 1).²¹ The primary outcomes were all-cause death, and the secondary outcomes were CV death, non-CV death, and HF rehospitalization. CV death was defined as due to HF, acute myocardial infarction, cerebral infarction, CV hemorrhage (non-stroke intracranial hemorrhage or non-traumatic vascular rupture), and sudden cardiac death.²² Non-CV death was defined as gastrointestinal, infectious, orthopedic/rheumatologic, cancer, renal, pulmonary, endocrine, neurological/psychiatric, or urologic/gynecologic cause.²³ Rehospitalization for HF was defined as documented worsening of HF requiring hospitalization (i.e., the patient had to show signs and symptoms of HF and require treatment with intravenous diuretics).²² Prior HF hospitalization was defined as a previous diagnosis of HF according to the Framingham criteria,²⁴ and history of hospitalization for worsening HF. Hypertension was defined as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or being treated for hypertension. Dyslipidemia was defined as serum total cholesterol level ≥220 mg/dL, low-density lipoprotein cholesterol level ≥140 mg/dL, or the need for treatment with lipid-lowering drugs. Diabetes mellitus was defined as hemoglobin (Hb) A1c ≥6.5%, fasting glucose ≥126 mg/dL, random plasma glucose ≥200 mg/dL, and clinical history of oral hypoglycemic and/or insulin use. The estimated glomerular filtration rate (eGFR) was calculated using the modification of diet and renal disease equation coefficient modified for Japanese patients.²⁵

Figure 1.

Study flowchart. ADHF, acute decompensated heart failure; BMI, body mass index.

Statistical Analysis

Continuous variables are presented as mean±standard deviation or median with interquartile range. Categorical variables are presented as frequencies and percentages. Clinical data were compared between semaglutide-eligible and semaglutide non-eligible patients using unpaired Student’s t test or Mann-Whitney’s U test. Poisson models were used to estimate incidence rates. Kaplan-Meier curves were calculated from baseline (date of discharge) to incidence of all-cause death, CV death, non-CV death or first HF hospitalization and compared using log-rank tests. A multivariable Cox proportional hazards regression analysis was performed to estimate associations between eligibility for semaglutide and subsequent clinical events using 10 covariates for clinical risk factors of HF (age, sex, left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) functional class at discharge, prior hospitalization for HF, atrial fibrillation, hemoglobin, albumin, eGFR, and B-type natriuretic peptide (BNP)), providing an estimated hazard ratio (HR) with 95% confidence interval (CI). Given the assumption of the Cox proportional hazards model of constant proportional hazard ratios over time, we utilized scaled Schoenfeld residuals to test each covariate. For the propensity score-matched analyses, we calculated the propensity scores for semaglutide eligibility using a logistic regression model that included age and sex. One-to-one nearest-neighbor matching without a replacement was performed for the estimated propensity scores of the patients using a caliper width set at 10% of the standard deviation of the propensity score. To assess the performance, patient characteristics before and after propensity score-matching were compared to one another using a standardized mean difference (SMD) ≤0.1, but this was negligible for age and sex. To assess nonlinear associations between BMI and the incidence of all-cause death, restricted cubic spline curves with the number of knots necessary to minimize the model Akaike Information Criteria (2–5 knots tested) were used. We also used Fine–Gray regression models to account for competing risks providing sub distribution HRs (SHRs). Specifically, competing risks were specified as non-CV death, CV death, and all-cause death when assessing the associations with semaglutide eligibility and CV death, non-CV death, and HF rehospitalization, respectively. All statistical analyses were performed using JMP version 14.2.0 (SAS Institute Inc., Cary, NC, USA) and STATA version 18.0 (Stata Corp, College Station, TX, USA).

Results

The baseline clinical characteristics of the 1,017 patients included in this study are listed in Table 1. The median age was 81 years, and 44.2% of the patients were female.

Table 1.

Baseline Characteristics of Patients Based on Semaglutide Eligibility for Obesity-Related Health Disorders and Weight Management

	Overall (N=1,017)	Semaglutide-eligible (N=73)	Semaglutide non-eligible (N=944)	P value
Age, years	81 [71, 87]	75 [57, 79]	82 [72, 87]	<0.001
Female, n (%)	450 (44.2)	36 (49.3)	414 (43.9)	0.37
Mean BMI (kg/m2)	21.6±4.3	30.8±4.3	20.9±3.4	<0.001
Median BMI (kg/m2)	21.0 [18.8, 23.8]	29.2 [27.9, 31.8]	20.6 [18.6, 23.1]	<0.001
BMI ≥27 (kg/m2), n (%)	106 (10.4)	73 (100)	33 (3.5)	<0.001
BMI ≥35 (kg/m2), n (%)	10 (1.0)	10 (13.7)	0 (0.0)	<0.001
Hypertension, n (%)	642 (63.1)	63 (86.3)	579 (61.3)	<0.001
Diabetes mellitus, n (%)	296 (29.1)	47 (64.4)	249 (26.4)	<0.001
Dyslipidemia, n (%)	261 (25.7)	33 (45.2)	228 (24.2)	<0.001
Smoker, n (%)	388 (38.2)	27 (37.0)	361 (38.3)	0.52
Hemodialysis, n (%)	8 (0.7)	0 (0.0)	8 (0.9)	0.43
CKD (eGFR <60 mL/min/1.73 m2), n (%)	774 (76.1)	53 (72.6)	721 (76.5)	0.45
Atrial fibrillation, n (%)	611 (60.1)	43 (58.9)	568 (60.2)	0.83
NYHA class III or IV, n (%)	217 (21.3)	15 (20.6)	202 (21.4)	0.86
History of hospitalization for HF, n (%)	320 (31.5)	21 (28.8)	299 (31.7)	0.60
Ischemic cardiomyopathy, n (%)	269 (26.5)	19 (26.0)	250 (26.5)	0.93
Stroke, n (%)	150 (14.7)	14 (19.2)	136 (14.4)	0.27
Albumin (g/dl)	3.5 [3.1, 3.8]	3.6 [3.4, 3.9]	3.4 [3.1, 3.8]	0.002
Hemoglobin (g/dl)	12.0 [10.5, 13.8]	13.6 [11.7, 15.4]	11.8 [10.4, 13.7]	<0.001
Uric acid (mg/dL)	6.9 [5.7, 8.2] (n=971)	6.7 [5.8, 8.1] (n=68)	6.9 [5.6, 8.2] (n=903)	0.92
LDL-C (mg/dL)	94 [75, 115] (n=848)	95 [72, 120] (n=58)	94 [75, 115] (n=790)	0.67
BNP (pg/mL)	290.1 [138.5, 527.0] (n=921)	126.1 [59.5, 289.5] (n=61)	305.7 [147.4, 540.6] (n=860)	<0.001
HbA1c (%)	6.0 [5.6, 6.5] (n=837)	6.5 [6.0, 7.2] (n=53)	6.0 [5.6, 6.4] (n=784)	<0.001
eGFR (mL/min/1.73 m2)	46.0 [33.0, 59.0]	45.6 [32.5, 64.0]	46.0 [33.0, 59.0]	0.57
CRP (mg/dL)	0.23 [0.10, 0.71] (n=943)	0.30 [0.11, 0.92] (n=73)	0.23 [0.10, 0.70] (n=870)	0.80
hs-CRP (ng/mL)	2,090 [718, 6,785] (n=702)	2,725 [1,086, 7,830] (n=48)	2,040 [693, 6,748] (n=654)	0.34
LVEF (%)	49.0 [34.8, 61.7]	51.0 [39.0, 62.0]	48.7 [34.7, 61.7]	0.72
HFrEF (LVEF <40%), n (%)	343 (33.7)	21 (28.8)	322 (35.1)	0.28
HFmrEF (40%≤LVEF<50%), n (%)	169 (16.6)	13 (17.8)	156 (17.0)	0.86
HFpEF (LVEF ≥50%), n (%)	468 (46.0)	39 (53.4)	429 (47.3)	0.31
LVDd (mm)	50.8 [44.0, 58.2] (n=996)	52.6 [46.2, 58.5] (n=73)	50.1 [44.0, 58.2] (n=923)	0.14
LVDs (mm)	36.7 [29.0, 47.1] (n=996)	37.2 [30.0, 45.4] (n=73)	36.5 [29.0, 47.1] (n=923)	0.39
Left atrial diameter (mm)	44.9 [39.9, 50.0]	47.0 [42.9, 51.4]	44.7 [39.6, 50.0]	0.051
E/e’ (av.)	13.6 [10.6, 18.1] (n=556)	13.8 [10.7, 16.7] (n=39)	13.6 [10.5, 18.2] (n=517)	0.40
Medications
Loop diuretic, n (%)	860 (84.6)	58 (79.5)	802 (85.0)	0.22
Thiazide, n (%)	71 (7.0)	5 (6.9)	66 (7.0)	0.96
β-blocker, n (%)	734 (72.2)	56 (76.7)	678 (71.9)	0.37
RASi, n (%)	725 (71.3)	63 (86.3)	662 (70.1)	0.003
MRA, n (%)	560 (55.1)	38 (52.1)	522 (55.3)	0.59
SGLT2i, n (%)	40 (3.9)	11 (15.1)	29 (3.1)	<0.001

Values are presented as n (%), mean±standard deviation, or median [interquartile range]. BMI, body mass index; BNP, B-type natriuretic peptide; CKD, chronic kidney disease; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; HbA1c, hemoglobin A1c; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; hs-CRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; LVDd, left ventricular internal dimension in diastole; LVDs, left ventricular internal dimension in systole; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; RASi, renin-angiotensin system inhibitor; SGLT2i, sodium-dependent glucose transporter 2 inhibitor.

The 1,017 included patients were classified according to semaglutide eligibility, and 73 (7.2%) were semaglutide-eligible (Figure 1). The mean BMI was 21.6±4.3 kg/m², and the median was 21.0 kg/m² [interquartile range (IQR): 18.8–23.8 kg/m²]. Figure 2 is a scatter diagram of the BMI Of the 1,017 patients: 227 (22.3%) were underweight (<18.5 kg/m²), 606 (59.6%) were of normal weight (18.5–24.9 kg/m²), 144 (14.2%) were overweight (25–29.9 kg/m²), and 40 (3.9%) were obese (≥30 kg/m²). Compared with the semaglutide non-eligible patients, semaglutide-eligible patients were younger (75 years [IQR: 57–79] vs. 82 years [IQR: 72–87]; P<0.001), higher BMI (29.2 kg/m² [IQR: 27.9–31.8 kg/m²] vs. 20.6 kg/m² [IQR: 18.6–23.1 kg/m²]; P<0.01), had higher prevalence of hypertension, diabetes mellitus, and dyslipidemia, higher levels of serum albumin, hemoglobin, and lower BNP levels. Notably, none of the patients were being treated with glucagon-like peptide-1 receptor agonists. The differences in sex were not statistically significant between groups (female 49.3% vs. 43.9%; P=0.37), There were also no significant differences in the prevalence of chronic kidney disease, atrial fibrillation, NYHA functional class, history of hospitalization for HF, ischemic cardiomyopathy, history of stroke, HF with reduced EF, HF with preserved EF, or echocardiographic measures. Renin–angiotensin–aldosterone system inhibitors (RASi) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) were prescribed more frequently to semaglutide-eligible patients than to semaglutide non-eligible patients (RASi: 86.3% vs. 70.1%, P=0.003; SGLT2i: 15.1% vs. 3.1%, P<0.001, respectively).

Figure 2.

Histogram for body mass index. Red and blue lines have been drawn because the definition of semaglutide eligibility is body mass index (BMI) ≥27 kg/m² along with ≥2 health problems related to obesity or BMI ≥35 kg/m². Anything to the right of the red line indicates BMI ≥27 kg/m², and anything to the right of the blue line indicates BMI ≥35 kg/m².

During the median follow-up of 2.7 years (IQR 1.7–3.6 years), 394 all-cause deaths (incidence 14.8/100 person-years), 225 CV deaths (incidence 8.5/100 person-years), 169 non-CV deaths (incidence 6.4/100 person-years), and 388 HF hospitalization events (incidence 18.4/100 person-years) occurred. Kaplan-Meier analysis showed that semaglutide-eligible patients had lower rates of all-cause death (log-rank: P=0.005) and non-CV death (log-rank P=0.04) than semaglutide non-eligible patients. There were no significant differences in CV death (log-rank P=0.055) or rehospitalization for HF (log-rank P=0.09) between groups (Figure 3). Table 2 presents the results for all-cause death, CV death, non-CV death, and rehospitalization for HF for semaglutide-eligible and non-eligible patients. In the crude model, semaglutide-eligible patients were associated with a lower risk of all-cause death (HR, 0.52; 95% CI, 0.32–0.85, P=0.01) compared with semaglutide non-eligible patients. There were no significant differences in CV death risk (HR, 0.58; 95% CI, 0.32–1.07, P=0.08), non-CV death (HR, 0.41; 95% CI, 0.17–1.004, P=0.051) or rehospitalization for HF (HR, 0.70; 95% CI, 0.46–1.09, P=0.11) between groups, although there was a trend towards a lower risk in patients who were semaglutide-eligible. After multivariable adjustment for clinical risk factors for HF, semaglutide-eligiblity was not associated with a lower risk of all-cause death (HR 0.63; 95% CI, 0.34–1.17, P=0.14), CV death (HR 0.78; 95% CI, 0.38–1.61, P=0.50), non-CV death (HR 0.48; 95% CI, 0.15–1.52, P=0.21), or rehospitalization for HF (HR 0.72; 95% CI 0.43–1.21, P=0.21). The Cox hypothesis of constant HRs over time was accepted, given that scaled Schoenfeld residuals were not rejected (P=0.09). Table 3 shows the baseline characteristics of patients according to semaglutide-eligibility after propensity score matching for age and sex. Semaglutide-eligible patients had significantly higher BMI (29.2 vs. 21.6 kg/m², SMD=0.53) and a higher prevalence of hypertension (SMD=0.89), diabetes (SMD=0.63), and dyslipidemia (SMD=0.47). Figure 4 shows the results of the Kaplan-Meier analysis after propensity matching by age and sex. Semaglutide-eligiblity was not significantly associated with an increased risk of all-cause death (log-rank P=0.79), CV death (log-rank P=0.89), non-CV death (log-rank P=0.82) or rehospitalization for HF (log-rank P=0.41). Higher BMI was significantly associated with a decreased risk of death. This association was nonlinear, and the relative plateau risk with BMI values of 22–25 kg/m² after adjusting for age and sex suggested that overweight or obese patients were not robustly related to a better outcome compared with normal weight (BMI 18.5–24.9 kg/m²) (Figure 5). Even when accounting for competing risk of non-CV death, semaglutide-eligiblity was not significantly associated with an increased risk of CV death (Supplementary Table 2; adjusted SHR, 0.60; 95% CI, 0.33–1.09; P=0.095). Consistent results were also observed when adjusted for clinical risk factors (adjusted SHR, 0.77; 95% CI, 0.36–1.63; P=0.49).

Figure 3.

Kaplan-Meier curves based on semaglutide eligibility created by comparing the 2 groups for all-cause death (Upper left), cardiovascular (CV) death (Upper right), non-CV death (Lower left) and rehospitalization due to heart failure (HF) exacerbation (Lower right). The incidence rate is plotted on the vertical axis, and the passage of time after enrolment is plotted on the horizontal axis. Event incidence was significantly lower in semaglutide-eligible patients than in semaglutide non-eligible patients.

Table 2.

Cox Proportional Hazards Analyses of Clinical Outcomes by Semaglutide Eligibility

	Overall (N=1,017)	Semaglutide non-eligible (N=944)	Semaglutide-eligible HR (95% CI) P value (vs. non-eligible) (N=73)
All-cause death	394 events	375 events	19 events
Event rate (per 100 patient-years, 95% CI)	14.8 (13.4–16.4)	15.4 (13.9–17.1)	8.5 (5.4–13.4)
Unadjusted		Ref.	0.52 (0.32–0.85) P=0.01
Adjusted		Ref.	0.63 (0.34–1.17) P=0.14
CV death	225 events	214 events	11 events
Event rate (per 100 patient-years, 95% CI)	8.5 (7.4–9.7)	8.8 (7.7–10.1)	4.9 (2.7–8.9)
Unadjusted		Ref.	0.58 (0.32–1.07) P=0.08
Adjusted		Ref.	0.78 (0.38–1.61) P=0.50
Non-CV death	169 events	161 events	8 events
Event rate (per 100 patient-years, 95% CI)	6.4 (5.5–7.4)	6.6 (5.7–7.7)	3.6 (1.8–7.2)
Unadjusted		Ref.	0.41 (0.17–1.004) P=0.051
Adjusted		Ref.	0.48 (0.15–1.52) P=0.21
HF hospitalization	388 events	363 events	25 events
Event rate (per 100 patient-years, 95% CI)	18.4 (16.7–20.3)	18.9 (17.1–20.9)	13.3 (9.0–19.6)
Unadjusted		Ref.	0.70 (0.46–1.09) P=0.11
Adjusted		Ref.	0.72 (0.43–1.21) P=0.21

Values are presented as HR (95% CI). The multivariable model was adjusted for age, sex, LVEF, NYHA functional class at discharge, prior hospitalization for HF, atrial fibrillation, hemoglobin level, albumin level, eGFR, and BNP level (10 covariates). CI, confidence interval; CV death, cardiovascular death; non-CV death, non-cardiovascular death; HF hospitalization, heart failure rehospitalization; HR, hazard ratio. Other abbreviations as in Table 1.

Table 3.

Baseline Characteristics of Patients According to Semaglutide Eligibility After Propensity Score-Matching Analysis

	Semaglutide-eligible (N=73)	Semaglutide non-eligible (N=73)	P value	Standardized mean differences
Age, years	75 [57, 79]	75 [59, 79]	0.78	0.003
Female, n (%)	36 (49.3)	33 (45.2)	0.50	0.10
Mean BMI (kg/m2)	29.2±4.3	21.6±3.9	<0.001	0.53
Median BMI (kg/m2)	29.2 [27.8, 31.9]	21.5 [19.3, 24.2]	<0.001	0.53
BMI ≥27 (kg/m2), n (%)	73 (100)	5 (6.9)	<0.001	0.52
BMI ≥35 (kg/m2), n (%)	10 (13.7)	0 (0.0)	<0.001	0.56
Hypertension, n (%)	63 (86.3)	35 (48.0)	<0.001	0.89
Diabetes mellitus, n (%)	47 (64.4)	25 (34.3)	<0.001	0.63
Dyslipidemia, n (%)	33 (45.2)	17 (23.3)	0.005	0.47
Smoker, n (%)	27 (37.0)	26 (35.6)	0.91	0.02
CKD (eGFR <60 mL/min/1.73 m2), n (%)	53 (72.6)	50 (68.5)	0.59	0.09
Atrial fibrillation, n (%)	43 (58.9)	43 (58.9)	1.00	0.00
NYHA III or IV, n (%)	15 (20.6)	16 (21.9)	0.84	0.03
History of hospitalization for HF, n (%)	21 (28.8)	25 (34.3)	0.48	0.11
Ischemic cardiomyopathy, n (%)	19 (26.0)	12 (16.4)	0.15	0.24
Stroke, n (%)	14 (19.2)	11 (15.1)	0.50	0.11
Alb (g/dL)	3.6 [3.4, 3.9]	3.6 [3.2, 3.9]	0.69	0.04
Hemoglobin (g/dL)	13.6 [11.7, 15.4]	12.4 [10.9, 14.3]	0.02	0.13
Uric acid (mg/dL)	6.7 [5.7, 8.2] (n=68)	6.9 [5.5. 8.1] (n=69)	0.88	0.01
LDL-C (mg/dL)	95 [70, 122] (n=58)	94 [76, 111] (n=63)	0.88	<0.001
BNP (pg/mL)	126.1 [59.5, 289.5] (n=61)	221.1 [115.7, 402.2] (n=68)	0.008	0.002
HbA1c (%)	6.5 [6.0, 7.2] (n=54)	5.9 [5.5, 6.6] (n=63)	0.001	0.48
eGFR (mL/min/1.73 m2)	45.6 [32.5, 64.0]	49.0 [37.0, 65.0]	0.24	0.009
CRP (mg/dL)	0.30 [0.11, 0.94] (n=73)	0.20 [0.08, 0.60] (n=67)	0.17	0.02
hs-CRP (ng/mL)	2,725 [999, 7,870] (n=48)	1,610 [560, 3,785] (n=47)	0.10	<0.001
LVEF (%)	51.0 [39.0, 62.0]	46.0 [34.9, 60.0]	0.43	0.008
HFrEF (LVEF <40%), n (%)	21 (28.8)	24 (32.9)	0.59	0.09
HFmrEF (40%≤LVEF<50%), n (%)	13 (17.8)	19 (26.0)	0.23	0.20
HFpEF (LVEF ≥50%), n (%)	39 (53.4)	30 (41.7)	0.16	0.24
LVDd (mm)	52.6 [46.1, 58.6]	51.7 [44.0, 58.2]	0.41	0.12
LVDs (mm)	37.2 [30.0, 47.1]	39.8 [29.2, 48.0]	0.84	0.03
Left atrial diameter (mm)	47.0 [42.8, 51.5]	45.2 [38.0, 48.4]	0.06	0.37
E/e’ (av.)	13.8 [10.6, 16.9] (n=39)	13.1 [10.5, 18.5] (n=60)	0.40	0.03
Medications
Loop diuretic, n (%)	58 (79.5)	57 (78.1)	0.84	0.03
Thiazide, n (%)	5 (6.9)	2 (2.7)	0.24	0.19
β-blocker, n (%)	56 (76.7)	53 (72.6)	0.57	0.09
RAS inhibitor, n (%)	63 (86.3)	49 (67.1)	0.006	0.47
MRA, n (%)	38 (52.1)	40 (54.8)	0.74	0.05
SGLT2i, n (%)	11 (15.1)	1 (1.4)	0.001	0.52

Values are presented as n (%), mean±standard deviation, or median [interquartile range]. Abbreviations as in Table 1.

Figure 4.

After propensity score-matching by age and sex, Kaplan-Meier curves were created by comparing the 2 groups for all-cause death (Upper left), cardiovascular (CV) death (Upper right), non-CV death (Lower left) and rehospitalization due to heart failure (HF) exacerbation (Lower right). The incidence rate is plotted on the vertical axis, and the passage of time after enrolment is plotted on the horizontal axis. After propensity score-matching for age and sex, no significant differences were found between groups for the endpoints.

Figure 5.

Associations between BMI and incidence rate of all-cause death using restricted cubic spline curves. (A) unadjusted, (B) adjusted for age and sex, and (C) adjusted for age, sex, and BNP values. The incidence rate of all-cause death (events per 100 person-years) is shown on the left y-axis and BMI values on the x-axis. The solid curves depict the incidence with 95% confidence intervals for the estimates. Poisson models were used to estimate incidence rates. Histograms show the population distribution of BMI. BMI, body mass index; BNP, B-type natriuretic peptide.

Discussion

In this post hoc analysis of the CURE-HF database, 7.2% of post-ADHF patients were identified as semaglutide-eligible for obesity-related health disorders and weight management. In the crude model, patients with HF and obesity who were semaglutide-eligible had a significantly better prognosis for all-cause death and non-CV death and a trend towards better prognosis for CV death and rehospitalization for HF than patients who were semaglutide non-eligible. However, in the multivariable analysis and by propensity score-matching by age and sex, semaglutide eligibility was not significantly associated with a favorable prognosis, suggesting that the protective effect of overweight or obesity in patients with HF might not correlate with better clinical outcomes.

Prevalence of overweight (BMI ≥25 kg/m²) in the general population in Japan is reported to be 33.0% in men and 22.3% in women.²⁶ In the Framingham study, approximately one-third of women and nearly 50% of men are overweight and approximately 16% of individuals are obese (BMI ≥30 kg/m²), indicating a higher prevalence of obesity than in Japan.¹¹ The ESC Heart Failure Long-Term Registry reported a median BMI of 28 kg/m² [IQR: 25–31 kg/m²].²⁷ In addition, J-ROAD reported that 6.0% of patients with HF in Japan had a BMI ≥30 kg/m².^28,29 In this study, 40 patients (3.9%) had a BMI ≥30 kg/m², and we examined obese patients who were candidates for treatment with semaglutide and found that 7.2% of them met the eligibility criteria. The mean BMI of the CURE-HF registry used in this study was 21.6 kg/m², which is lower than that of overseas HF registries; however, the mean BMI in the Kyoto Congestive Heart Failure registry (a Japanese observational study) was 22.8 kg/m². Those findings are consistent with our results, suggesting a low possibility of selection bias between other Japanese data and our findings.^30–32

Obesity is a good prognostic factor in patients with HF, a phenomenon widely known as the “obesity paradox”. Several factors have been postulated to explain improved outcomes observed in patients with obesity and concomitant HF. One is that obese patients often exhibit increased blood pressure, which may enhance their tolerance to higher doses of medications that would otherwise increase hypotension risk in non-obese patients, particularly if HF is mediated by hyperactivation of the renin-angiotensin-aldosterone system. Furthermore, obese patients might also present with symptoms that resemble those of HF such as dyspnea and exercise intolerance, which are commonly associated with both conditions. This overlap in symptomatology can prompt clinicians to perform earlier diagnostic evaluations, facilitating timely identification of HF and earlier initiation of guideline-directed medical therapy, which might contribute to the improved clinical outcomes described in obese patients with HF. In our study, semaglutide-eligible patients had a higher prevalence of hypertension and diabetes mellitus. Additionally, semaglutide-eligible patients had more prescriptions of RASi and SGLT2i than semaglutide non-eligible patients. Our findings did not indicate that obesity was not a significant prognostic factor of HF after adjusting for age and sex, which suggests that obese individuals were not robustly associated with a better prognosis in this population. Patients with HF with reduced EF enrolled in the PARADIGM-HF study did not exhibit a BMI-related “obesity paradox” after comprehensive adjustment for multiple factors, which is consistent with our findings.³³ There are fewer obese patients in Japan than in Western countries; however, we found a certain number of patients with obesity-related health disorders and concomitant HF. These findings underscore the existence of a certain group of obese patients and suggest the need to reexamine interventions for obese patients with HF. In the STEP-HFpEF trial program (which included STEP-HFpEF and STEP-HFpEF-DM trials), once-weekly semaglutide administration improved HF-related symptoms and suggested a potentially decreased risk of worsening HF.^14,34 Tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, also led to a lower risk of a composite of CV death or worsening HF than placebo in patients with HF with preserved EF.³⁵ Further validation of the efficacy and safety of semaglutide in patients with obesity-associated HF and its implementation in the real world in Japan is warranted.

Study Limitations

First, it was not a prespecified analysis, and there was no information regarding the duration from initial HF diagnosis or HF medications at admission in the CURE-HF registry. Regardless of multivariable adjustment, unmeasured confounding factors might have affected the results. Second, BMI was only evaluated at discharge, and changes in body weight during follow-up were not assessed. Third, alternative anthropometric indices such as waist circumference, waist-to-hip ratio, and weight-adjusted weight index might be better indicators of intra-abdominal fat (central obesity); therefore, a precise comprehensive assessment of the “obesity paradox” in patients with HF was not available. In addition, the obesity paradox itself may include selection bias, survivor bias and multiple other confounding factors, and there is also a possibility of reverse causality. Fourth, there is a possibility of potential selection bias in the CURE-HF registry, and it is not possible to evaluate causality due to the retrospective observational study design. Finally, the sample size was relatively small and there was a small number of events in the semaglutide-eligible group, so it would be difficult to simply conclude regarding the validity of obesity paradox and to assess the effects of semaglutide on CV outcomes; thus, our exploratory findings should be considered hypothesis generating.

In conclusion, once-daily subcutaneous semaglutide eligibility for obesity was observed in 7.2% of ADHF patients (64% with comorbidity of diabetes mellitus). An “obesity paradox”, assessed by semaglutide eligibility and associated with lower mortality risk, was observed in patients after ADHF; however, these associations were not significant after adjustment for demographic factors. These exploratory findings might underscore the need for future studies to evaluate the implementation of semaglutide in obese patients with HF, focusing on its efficacy and safety in the Japanese population.

Acknowledgments

The authors thank all the participants (patients, caregivers, and staff) in the CURE-HF registry and Minako Aono and Mebae Kobayashi for their invaluable contributions.

Disclosures

M.M. has received consulting fees from Alexion Pharma GK, payment or honoraria for lectures from Pfizer Japan Inc., Nippon Boehringer Ingelheim Co. Ltd., and Alnylam Japan, and is a member of the advisory boards for Pfizer Japan Inc. and Alexion Pharma GK. K. Kuwahara is a member of Circulation Reports’ Editorial Team and has received research grants or contracts from Kowa Co., Ltd., AstraZeneca K.K., Daiichi Sankyo Co., Ltd., Novo Nordisk Pharma Ltd., Amgen, Janssen Pharmaceutical K.K., Parexel International Inc., Astellas Pharma Inc., Otsuka Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corp., Nippon Boehringer Ingelheim Co., Ltd., and Kyowa Kirin Co., Ltd. Medtronic Japan Co. Ltd., Boston Scientific Japan K.K., Abbott Japan LLC, Japan Lifeline Co., Ltd., Biotronik Japan, Terumo Corporation, Nipro Corporation, Cordis Japan G.K and has consulted for Astellas Pharma Inc., AstraZeneca, MSD, Otsuka Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Kowa Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd. (Sumitomo Pharma Co., Ltd.), Mitsubishi Tanabe Pharma Corp., Eli Lilly Japan, Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma, Novo Nordisk Pharma Ltd., Bayer Yakuhin, Ltd., Pfizer Japan Inc., Janssen Pharmaceutical. Other authors have nothing to declare.

IRB Information

The study was approved by the Institutional Review Board of the Shinshu University School of Medicine (approval no.: 4237)

Data Availability

The de-identified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circrep.CR-25-0041

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