This randomized clinical trial evaluates if HU6, a controlled metabolic accelerator, reduces body weight, improves body composition, and increases exercise capacity in patients with obesity-related heart failure with preserved ejection fraction (HFpEF).
Key Points
Question
Does HU6, a novel controlled metabolic accelerator, reduce body weight, improve body composition, and increase exercise capacity in patients with obesity-related heart failure with preserved ejection fraction (HFpEF)?
Findings
In this randomized clinical trial, among 66 patients, short-term (19 weeks) oral administration of HU6 vs placebo led to modest but statistically significant reduction in body weight, total fat mass, and visceral adiposity while sparing skeletal muscle but did not significantly improve peak volume of oxygen consumption.
Meaning
These short-term results showing fat-specific weight loss support future, adequately powered trials of longer duration to determine whether longer-term HU6 will also improve functional status, quality of life, and clinical outcomes in patients with obesity-related HFpEF.
Abstract
Importance
Excess body fat plays a pivotal role in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). HU6 is a novel, controlled metabolic accelerator that enhances mitochondrial uncoupling resulting in increased metabolism and fat-specific weight loss.
Objective
To assess efficacy and safety of HU6 in reducing body weight, improving peak volume of oxygen consumption (VO2) and body composition among patients with obesity-related HFpEF.
Design, Setting, and Participants
The Exploratory Phase 2A, Double-Blind, Placebo-Controlled Dose Escalation Study of Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of HU6 for Subjects With Obese HFpEF (HuMAIN-HFpEF) trial was a multicenter, dose-escalation randomized clinical trial among patients with chronic stable HFpEF and obesity. Data were analyzed from July to October 2024.
Intervention
HU6 treatment for 19 weeks, starting at 150 mg per day and potentially up titrated to 450 mg per day based on safety and tolerability vs placebo.
Main Outcomes and Measures
The primary end point was change in body weight.
Results
Of 66 participants randomized (mean [SD] age, 64.5 [12] years; 38 female [58%]; mean [SD] weight, 110.9 [22.4] kg), 56 completed the trial. HU6 (vs placebo) significantly decreased weight (between-group difference, −2.86 kg; 95% CI, −4.68 to −1.04 kg; P = .003), total fat mass (between-group difference, −2.96 kg; 95% CI, −4.50 to −1.42 kg; P < .001), and percentage visceral fat (between-group difference,−1.3%; 95% CI, −2.1 to −0.5%; P = .003), with no significant loss of muscle mass. There were no statistically significant changes in peak VO2, 6-minute walk distance, Kansas City Cardiomyopathy Questionnaire score, high-sensitivity C-reactive protein level, N-terminal pro–brain natriuretic peptide level, or diastolic function. Serious adverse events were noted in 5 participants (4 in the HU6 group; 1 in the placebo group), including 1 death, all judged unrelated to treatment.
Conclusions and Relevance
Among patients with obesity-related HFpEF, treatment with HU6 for 19 weeks led to modest but statistically significant weight loss without significant changes in peak VO2. Larger trials of longer duration are warranted to determine whether longer-term administration of HU6 can improve exercise function, quality of life, and cardiovascular outcomes in this increasingly common disorder.
Trial Registration
ClinicalTrials.gov Identifier: NCT05284617
Introduction
Among patients with obesity-related heart failure with preserved ejection fraction (HFpEF), treatment with glucagonlike peptide-1 (GLP-1) agonist semaglutide significantly reduces body weight and improves patient-reported and clinical outcomes.1 However, GLP-1 agonists significantly lower lean muscle mass, which accounts for approximately 30% to 40% of the total weight loss achieved.2,3,4 Considering the high burden of sarcopenia and associated frailty in older patients with HFpEF,5,6 there is a need for novel weight loss therapies that selectively reduce adiposity while preserving skeletal muscle mass.
HU6 is a controlled metabolic accelerator that is metabolized to produce the controlled metabolite 2,4-dinitrophenol, an activator of the adenine nucleotide translocase channel, causing controlled mitochondrial uncoupling.7 In a phase 2 trial, HU6 led to significant fat-specific weight loss with preservation of lean mass among patients with steatotic liver disease,8 a disorder with multiple similarities to obesity-related HFpEF.9 However, the efficacy and safety of HU6 in obesity-related HFpEF is unknown. We conducted a randomized clinical trial to evaluate the efficacy and safety of HU6 in patients with obesity-related HFpEF.
Methods
The Exploratory Phase 2A, Double-Blind, Placebo-Controlled Dose Escalation Study of Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of HU6 for Subjects With Obese HFpEF (HuMAIN-HFpEF) trial was a multicenter, parallel-group, within-participant, dose-escalation randomized clinical trial of HU6 vs placebo (eFigure 1 in Supplement 1). The study design and rationale have been published.10 Patients were randomized 1:1 to either HU6 or placebo. This trial was approved by institutional review boards at each site and performed in accordance with International Council for Harmonization guidelines, the ethical principles of the Declaration of Helsinki, and applicable local or regional regulatory requirements. All participants provided written informed consent. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.
The study included participants older than 30 years with chronic HFpEF and obesity meeting inclusion and exclusion criteria as previously reported and detailed in eTable 1 in Supplement 1.10 The participants underwent procedures and assessments as previously described and detailed in eMethods 1 and eTables 2 and 3 in Supplement 1.10 This included standardized weight and body composition assessment performed at each study visit (InBody BWA) and cardiopulmonary exercise tests, transthoracic echocardiography, and magnetic resonance imaging (MRI, in a subset) at baseline and end of treatment. Participants self-identified with the following races and ethnicities: American Indian or Alaska Native, Asian, Black or African American, Latino or Hispanic, and White. Race and ethnicity data were included in this study as part of the demographic characteristics.
The primary efficacy end point was the change in body weight from baseline to day 134 (approximately 19 weeks, end of treatment). The key secondary end point was a change in peak volume of oxygen consumption (VO2). eTable 4 in Supplement 1 describes in detail additional secondary and exploratory end points.
Details about the sample size estimation have been reported previously and provided in eMethods 2 in Supplement 1. The intent-to-treat population included all randomized participants analyzed according to randomized treatment. The safety population included all participants who received at least 1 dose of study treatment. Treatment group differences were assessed using a mixed model for repeated measures, and least squares means were calculated for both within-group and between-group comparisons from this model as detailed in eMethods 3 in Supplement 1. Analysis of the primary and key secondary efficacy end points accounted for multiplicity and controlled for family-wise type I error rate at a 2-sided α level of .05 using a fixed sequence testing procedure as detailed in eMethods 4 in Supplement 1. Data were analyzed using SAS software, version 9.4 (SAS Institute), from July to October 2024.
Results
Baseline Characteristics
A total of 101 participants were screened between November 4, 2022, and June 21, 2024, of which 66 were randomized (mean [SD] age, 64.5 [12] years; 38 female [58%]; 28 male [42%]; mean [SD] weight, 110.9 [22.4] kg), 65 received at least 1 dose of the study drug, and 56 completed the trial (eFigure 2 in Supplement 1). Participants self-identified with the following races and ethnicities: 1 American Indian or Alaska Native (3.0%), 1 Asian (3.0%), 11 Black or African American (16.7%), 10 Latino or Hispanic (15.2%), and 53 White (80.3%). The prevalence of diabetes (14 of 33 [42.5%] vs 8 of 33 [24.2%]) was numerically higher and the baseline troponin I levels (median [range], 5.08 [2.50-11 714.44] ng/L vs 6.42 [2.50-16.05] ng/L; to convert to nanograms per milliliter and then to grams per liter, divide by 1000 and multiply by 1) numerically lower in the HU6 vs placebo arm (Table 1). There were no other meaningful differences in baseline characteristics across the 2 groups.
Table 1. Baseline Characteristics of the Study Participants.
| Characteristic | HU6 (n = 33) | Placebo (n = 33) |
|---|---|---|
| Demographics | ||
| Age, mean (SD), y | 63.8 (11.9) | 65.1 (12.3) |
| Female, No. (%) | 17 (51.5) | 21 (63.6) |
| Male, No. (%) | 16 (48.5) | 12 (36.4) |
| Race and ethnicity, No. (%) | ||
| American Indian or Alaska Native | 0 | 1 (3.0) |
| Asian | 1 (3.0) | 0 |
| Black or African American | 6 (18.2) | 5 (15.2) |
| Latino or Hispanic | 6 (18.2) | 4 (12.1) |
| White | 26 (78.8) | 27 (81.8) |
| Body composition | ||
| Weight, mean (SD), kg | 110 (17) | 111 (27) |
| Body mass index, mean (SD)a | 38.8 (5.1) | 40.0 (8.2) |
| 30 to <35, No. (%) | 9 (27.3) | 12 (36.4) |
| ≥35, No. (%) | 24 (72.7) | 21 (63.6) |
| Lean body mass, mean (SD), kg | 60.0 (11.3) | 57.0 (13.0) |
| Skeletal muscle mass, mean (SD), kg | 33.1 (6.4) | 31.2 (7.7) |
| Body fat, mean (SD), kg | 50.4 (10.5) | 54.5 (16.5) |
| Body fat, mean (SD), % | 45.6 (6.1) | 48.5 (5.9) |
| Visceral fat, mean (SD), % | 23.5 (4.2) | 24.3 (4.2) |
| Vital signs, mean (SD) | ||
| Systolic blood pressure, mm Hg | 124 (13) | 124 (13) |
| Diastolic blood pressure, mm Hg | 75 (7) | 74 (8) |
| Heart rate, bpm | 70 (11) | 71 (9) |
| Respiratory rate, breaths/min | 18 (2) | 18 (3) |
| Comorbidities, No. (%) | ||
| Hypertension | 30 (90.9) | 29 (87.9) |
| Atrial fibrillation | 7 (21.2) | 7 (21.2) |
| Myocardial infarction | 0 | 2 (6.1) |
| Coronary artery disease | 5 (15.2) | 4 (12.1) |
| Diabetes | 14 (42.5) | 8 (24.2) |
| Laboratory parameters | ||
| Glycated albumin, mean (SD), g/dL | 0.48 (0.13) | 0.42 (0.09) |
| Glycated hemoglobin, mean (SD), % | 6.1 (0.8) | 6.0 (0.8) |
| Glycated hemoglobin, No. (%) | ||
| <5.7% | 11 (33.3) | 13 (39.4) |
| ≥5.7% to ≤10% | 22 (66.7) | 20 (60.6) |
| eGFR, mean (SD), mL/min/1.73 m2 | 79 (21) | 78 (20) |
| C-reactive protein, mean (SD), mg/L | 6.3 (7.5) | 5.4 (5.4) |
| NT-proBNP, median (range), ng/L | 118 (22-4153) | 103 (30-1653) |
| Troponin I, median (range), ng/L | 5.08 (2.50- 11 714.44) |
6.42 (2.50-16.05) |
| Concomitant medications, No. (%) | ||
| SGLT2i | 16 (49) | 10 (31) |
| Loop diuretic | 21 (64) | 24 (75) |
| Thiazide diuretic | 4 (12) | 6 (19) |
| β-Blocker | 19 (58) | 19 (59) |
| ACEi, ARB, or ARNI | 19 (58) | 18 (56) |
| Mineralocorticoid receptor antagonists | 14 (42) | 14 (44) |
| Calcium channel blocker | 10 (30) | 7 (22) |
| Prior incretin-based weight loss therapy | 4 (12) | 3 (9) |
| Quality of life and symptom burden, mean (SD) | ||
| KCCQ score, overall summary score, mean (SD), points | 62.9 (19.3) | 59.6 (18.6) |
| EQ-5D-5L dimension index score, mean (SD) | 0.77 (0.21) | 0.70 (0.18) |
| NYHA class, No. (%) | ||
| II | 24 (72.7) | 23 (69.7) |
| III | 9 (27.3) | 10 (30.3) |
| Exercise performance, mean (SD) | ||
| 6-min Walk distance, m | 346 (120) | 341 (98) |
| Peak VO2, mL/kg/min | 13.6 (4.2) | 13.3 (3.2) |
| Peak VO2, mL/min | 1483 (477) | 1497 (552) |
| Peak workload, W | 103.3 (45.8) | 98.2 (35.9) |
| Exercise time, min | 11.9 (3.7) | 10.4 (2.8) |
| Echocardiographic parameters, mean (SD) | ||
| LV ejection fraction, % | 59.5 (4.4) | 61.6 (5.4) |
| LV mass, g | 181.6 (59.7) | 171.2 (52.9) |
| Relative wall thickness | 0.42 (0.07) | 0.39 (0.05) |
| LV end-diastolic volume, mL | 92.7 (27.6) | 88.1 (29.8) |
| LV end-systolic volume, mL | 38.4 (15.4) | 33.8 (11.9) |
| Stroke volume, mL | 84.9 (23.2) | 82.0 (25.0) |
| LA volume, mL/m2 | 30.5 (17.0) | 31.2 (15.0) |
| LA emptying fraction, % | 43.6 (13.5) | 42.2 (10.6) |
| LA reservoir strain, % | 26.7 (9.2) | 24.7 (8.2) |
| E/A ratio | 1.12 (0.62) | 0.98 (0.27) |
| Average E/e′ ratio | 10.0 (3.1) | 10.0 (2.9) |
| TAPSE, cm | 2.0 (0.42) | 2.1 (0.41) |
| RV S′ velocity, cm/s | 11.7 (2.9) | 13.2 (3.6) |
| LV Global strain (A4C), % | 19.4 (3.5) | 20.1 (3.4) |
Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor/neprilysin inhibitor; eGFR, estimated glomerular filtration rate; KCCQ, Kansas City Cardiomyopathy Questionnaire; LA, left atrial; LV, left ventricular; NT-proBNP, N-terminal pro–brain natriuretic peptide; NYHA, New York Heart Association; SGLT2i, sodium-glucose cotransporter 2 inhibitors; TAPSE, tricuspid annular plane systolic excursion; VO2, volume of oxygen consumption.
SI conversion factors: To convert glycated albumin to grams per liter, multiply by 10; C-reactive protein to milligrams per deciliter, divide by 10; NT-proBNP to picograms per milliliter, divide by 1; troponin I to nanograms per milliliter and then to grams per liter, divide by 1000 and multiply by 1.
Calculated as weight in kilograms divided by height in meters squared.
Effect of HU6 on Body Weight (Primary End Point) and Body Composition
By 19 weeks, HU6 (vs placebo) led to a significantly greater reduction in total body weight (between-group difference, −2.86 kg; 95% CI, −4.68 to −1.04 kg; P =.003) and percentage body weight (between-group difference, −2.72%; 95% CI, −4.49% to −0.95%; P =.003) (Figure). Among body composition parameters, total lean body mass or dry lean mass did not change significantly with HU6 (vs placebo). However, HU6 led to a significant reduction in total fat mass (between-group difference, −2.96 kg; 95% CI, −4.50 to −1.42 kg; P <.001), percentage of fat mass (between-group difference, −1.77%; 95% CI, −2.71% to −0.84%; P <.001), and percentage visceral fat (between-group difference,−1.3%; 95% CI, −2.1% to −0.5%; P = .003) as assessed by InBody Scale (InBody BWA) (Table 2 and Figure). Among participants with MRI-based body composition assessment (eTable 3 in the Supplement), HU6 (vs placebo) was associated with a significantly greater reduction in abdominal visceral adipose tissue volume (between-group difference, −0.19 L; 95% CI, −0.34 to −0.05 L; P =.01) and thigh subcutaneous adipose tissue volume (between-group difference, −0.18 L; 95% CI, −0.33 to −0.03 L; P =.02) but not thigh muscle volume or other regional adiposity measures (Table 2 and eFigure 3 in the Supplement).
Figure. Changes in Body Weight and Body Composition With HU6 vs Placebo From Baseline.
A, Mean change in body weight. B, Percentage change in body weight. C, Percentage change in total body fat. D, Percentage change in visceral fat. E, Percentage change in dry lean mass. Body composition parameters were assessed by InBody Scale (InBody BWA). Data presented as least square means and SEs for the 2 study groups at each time point.
Table 2. Within and Between-Group Changes From Baseline to 19 Weeks for Body Weight, Body Composition, Exercise Performance, and Quality-of-Life Measures.
| Variable | LSM (95% CI) | ||
|---|---|---|---|
| Within-group change from baseline to day 134 | Between-group difference | ||
| HU6 | Placebo | HU6 vs placebo | |
| Body weight and composition (in-body scale) | |||
| Weight, kg (primary end point) | −3.1 (−4.46 to −1.72) | −0.23 (−1.56 to 1.11) | −2.9 (−4.68 to −1.04) |
| Weight change, % | −2.9 (−4.21 to −1.57) | −0.17 (−1.47 to 1.12) | −2.7 (−4.49 to −0.95) |
| Body mass indexa | −1.13 (−1.64 to −0.63) | −0.11 (−0.60 to 0.38) | −1.02 (−1.69 to −0.36) |
| Lean body mass, kg | 0.34 (−0.35 to 1.03) | 0.29 (−0.38 to 0.96) | 0.05 (−0.85 to 0.96) |
| Skeletal muscle mass, kg | 0.15 (−0.21 to 0.52) | 0.14 (−0.21 to 0.50) | 0.01 (−0.47 to 0.49) |
| Body fat, kg | −3.36 (−4.51 to −2.21) | −0.40 (−1.51 to 0.72) | −2.96 (−4.50 to −1.42) |
| Body fat, % | −2.01 (−2.70 to −1.32) | −0.23 (−0.90 to 0.44) | −1.77 (−2.71 to −0.84) |
| Visceral fat, % | −1.5 (−2.1 to −0.8) | −0.2 (−0.8 to 0.4) | −1.3 (−2.1 to −0.5) |
| Body composition (MRI) | |||
| Abdominal volume | |||
| Visceral adipose tissue, L | −0.16 (−0.29 to −0.03) | 0.04 (−0.09 to 0.16) | −0.19 (−0.34 to −0.05) |
| Subcutaneous adipose tissue, L | −0.15 (−0.34 to 0.032) | −0.05 (−0.23 to 0.13) | −0.11 (−0.32 to 0.11) |
| Thigh volume | |||
| Muscle, L | −0.06 (−0.12 to 0.005) | −0.015 (−0.08 to 0.05) | −0.04 (−0.12 to 0.03) |
| Contractile muscle, L | −0.06 (−0.12 to 0.002) | −0.014 (−0.08 to 0.05) | −0.04 (−0.11 to 0.03) |
| Intramuscular fat fraction, % | 0.42 (−0.01 to 0.84) | 0.30 (−0.12 to 0.73) | 0.11 (−0.33 to 0.56) |
| Intramuscular fat, mL | 6.10 (−4.92 to 17.11) | 4.89 (−5.63 to 15.41) | 1.21 (−10.37 to 12.78) |
| Intermuscular fat, mL | −13.21 (−27.21 to 0.78) | 0.33 (−14.20 to 14.85) | −13.54 (−29.55 to 2.48) |
| Subcutaneous adipose tissue, L | −0.13 (−0.25 to −0.01) | 0.05 (−0.08 to 0.17) | −0.18 (−0.33 to −0.03) |
| Paracardial volume | |||
| Paracardial adipose tissue, mL | −3.70 (−14.97 to 7.57) | −6.47 (−18.63 to 5.70) | 2.76 (−9.94 to 15.46) |
| Pericardial adipose tissue, mL | −7.82 (−21.19 to 5.54) | −6.56 (−21.12 to 8.0) | −1.26 (−16.30 to 13.77) |
| Epicardial adipose tissue, mL | −4.48 (−11.75 to 2.78) | 0.53 (−7.39 to 8.45) | −5.02 (−12.96 to 2.93) |
| Exercise performance | |||
| Peak VO2, mL/kg/min (key secondary end point) | 0.10 (−0.61 to 0.80) | −0.04 (−0.69 to 0.62) | 0.13 (−0.73 to 0.99) |
| Peak VO2, mL/min | −37.5 (−118.2 to 43.2) | −13.5 (−88.0 to 61.0) | −24.0 (−123.0 to 75) |
| Exercise time, min | −0.21 (−0.73 to 0.30) | 0.16 (−0.29 to 0.61) | −0.37 (−0.98 to 0.23) |
| 6-min Walk test, m | 23.4 (−10.00 to 56.74) | 10.8 (−20.02 to 41.6) | 12.6 (−27.4 to 52.6) |
| Quality of life | |||
| KCCQ overall summary | 4.3 (−1.5 to 10.2) | 4.8 (−0.9 to 10.6) | −0.5 (−8.2 to 7.2) |
| EQ-5D-5L index score | −0.009 (−0.09 to 0.07) | 0.011 (−0.07 to 0.09) | −0.02 (−0.128 to 0.088) |
| Echocardiography | |||
| LV ejection fraction, % | 1.40 (−0.45 to 3.25) | −2.36 (−3.95 to −0.76) | 3.76 (1.67 to 5.84) |
| LV mass, g | 6.7 (−5.9 to 19.3) | 8.0 (−3.6 to 19.6) | −1.3 (−16.0 to 13.4) |
| Relative wall thickness | 0.009 (−0.02 to 0.04) | 0.0008 (−0.03 to 0.03) | 0.008 (−0.03 to 0.05) |
| LV end-diastolic volume, mL | −3.25 (−10.28 to 3.77) | 1.91 (−4.64 to 8.46) | −5.17 (−13.35 to 3.01) |
| LV end-systolic volume, mL | −2.38 (−5.93 to 1.16) | 3.25 (−0.03 to 6.54) | −5.64 (−9.80 to −1.47) |
| Stroke volume, mL | −2.30 (−10.08 to 5.47) | −2.53 (−9.87 to 4.80) | 0.23 (−8.91 to 9.37) |
| LA volume, mL/m2 | 1.20 (−1.29 to 3.69) | 1.87 (−0.42 to 4.15) | −0.67 (−3.45 to 2.12) |
| LA emptying fraction, % | −2.39 (−6.46 to 1.69) | −2.71 (−6.60 to 1.19) | 0.32 (−4.28 to 4.92) |
| LA reservoir strain, % | 1.44 (−0.97 to 3.85) | 0.90 (−1.45 to 3.25) | 0.54 (−2.15 to 3.23) |
| Mitral E/A ratio | −0.06 (−0.29 to 0.17) | −0.06 (−0.27 to 0.15) | 0.0005 (−0.20 to 0.20) |
| Average E/e′ ratio | −0.89 (−1.91 to 0.14) | −0.31 (−1.23 to 0.61) | −0.58 (−1.75 to 0.60) |
| TAPSE, cm | −0.03 (−0.18 to 0.13) | −0.10 (−0.25 to 0.04) | 0.08 (−0.10 to 0.25) |
| RV S’ velocity, cm/s | 1.52 (0.27 to 2.78) | −0.58 (−1.78 to 0.62) | 2.10 (0.67 to 3.54) |
| LV global strain (A4C), % | 0.38 (−0.57 to 1.33) | −0.14 (−0.98 to 0.71) | 0.52 (−0.55 to 1.58) |
| Resting blood pressure, respiratory rate, and heart rate | |||
| Systolic BP, mm Hg | −6.0 (−10.9 to −1.1) | 2.7 (−1.9 to 7.3) | −8.7 (−15.0 to −2.3) |
| Diastolic BP, mm Hg | −3.7 (−7.0 to −0.48) | 1.2 (−1.9 to 4.2) | −4.9 (−9.0 to −0.8) |
| Respiratory rate, breaths/min | 1.0 (−0.8 to 2.8) | 0.7 (−0.9 to 2.4) | 0.3 (−1.9 to 2.4) |
| Heart rate, beats/min | 1.5 (−3.0 to 6.0) | 4.6 (0.3 to 8.8) | −3.0 (−8.8 to 2.7) |
Abbreviations: A4C, apical 4 chamber; BP, blood pressure; E/A, ratio of peak velocity blood flow from left ventricular relaxation in early diastole (the E wave) to peak velocity flow in late diastole caused by atrial contraction (the A wave); E/e′, ratio of early diastolic mitral inflow velocity to early diastolic mitral annulus velocity; KCCQ, Kansas City Cardiomyopathy Questionnaire; LA, left arial; LSM, least squares mean; LV, left ventricular; MRI, magnetic resonance imaging; RV, right ventricular; S′, peak systolic velocity of the lateral tricuspid annulus; TAPSE, tricuspid annular plane systolic excursion; VO2, volume of oxygen consumption.
Calculated as weight in kilograms divided by height in meters squared.
Effect of HU6 on Peak VO2, Quality of Life, and Cardiac Parameters
HU6 (vs placebo) was not associated with significant changes in peak VO2, exercise time, 6MWD, or quality of life (KCCQ score or EQ-5D-5L score) (Table 2 and eFigure 4 in Supplement 1). Among echocardiographic measures, HU6 (vs placebo) led to significant improvement in left ventricular systolic function (increased left ventricular EF: between-group difference, 3.8%; 95% CI, 1.7%-5.8% and decreased left ventricular end-systolic volume: between-group difference, −5.46 mL; 95% CI, −9.80 to −1.47 mL) and right ventricular function (right ventricular S′ increase: between-group difference, 2.10 cm/s; 95% CI, 0.67-3.54 cm/s; S′ represents the peak systolic velocity of the lateral tricuspid annulus) with no significant change in other cardiac parameters (Table 2 and eFigure 5 in Supplement 1). Among participants with cardiac MRI, (eTable 5 in Supplement 1), there were no significant differences in the changes in cardiac parameters between the HU6 vs placebo group (eFigure 5 and eTable 6 in Supplement 1).
Effects of HU6 on Blood Pressure, Heart Rate, and Biomarkers
HU6 (vs placebo) significantly reduced resting systolic (between-group difference, −8.7 mm Hg; 95% CI, −15.0 to −2.3 mm Hg) and diastolic (between-group difference, −4.9 mm Hg; 95% CI, −9.0 to −0.8 mm Hg) blood pressure that was observed early and persisted throughout the study (Table 2 and eFigure 6 in Supplement 1). HU6 was not associated with significant change in resting heart rate or respiratory rate (Table 2). Among biomarkers, HU6 was not associated with significant changes in NT-proBNP level, troponin I level, hs-CRP level, and other glycemic or lipid parameters (eTable 7 in Supplement 1).
Safety
Dose de-escalation, dose interruption, and premature discontinuation were numerically more frequent in HU6 vs placebo (eTable 8 in Supplement 1). At least 1 adverse event (AE) while receiving treatment was reported in 69% of participants (45 of 65 participants) with no between-group difference (eTable 8 in Supplement 1). Dyspnea was reported in 4 participants in the HU6 group, 3 of whom were deemed not to be study drug related. One participant had pyrexia that was related to septic arthritis (eTable 9 in Supplement 1). Serious AEs were reported in 4 participants in the HU6 group and 1 participant in the placebo group, and all were deemed unrelated to the study drug by blinded investigators. One participant died in the HU6 group due to worsening comorbidity while not receiving the study drug. The death was deemed not related to the study treatment.
Discussion
Among patients with obesity-related HFpEF, HU6 led to a significant reduction in body weight and favorable changes in body composition. The weight loss achieved by HU6 over 19 weeks was smaller in magnitude than that observed with semaglutide over the same period. However, it was primarily driven by significant loss of fat mass and visceral adiposity with preservation of lean mass. This is particularly relevant as loss of lean mass may be detrimental in the long-term among older patients with HFpEF and could worsen sarcopenia and lead to worse frailty and disability.11,12 Preserving lean muscle mass may be a more desirable and safer strategy for weight loss among older patients with obesity-related HFpEF. Moreover, HU6-mediated fat-specific weight loss and reduction in visceral adiposity may be advantageous as it directly targets the key pathophysiologic mechanisms pivotal to the progression of HFpEF.11,13
Despite favorable effects on body weight and composition, HU6 did not significantly improve exercise capacity or HF-specific quality of life. This may be related to the small sample size combined with relatively short treatment duration at the therapeutic dose (450 mg), which likely led to lack of power to observe changes in functional and quality of life parameters. Among cardiac parameters, HU6 was associated with a suggestion of improvement in left ventricular and right ventricular systolic function, with no changes in other echocardiographic parameters, or biomarkers of myocardial injury and neurohormonal stress. These observations suggest that the mitochondrial uncoupling associated with HU6 did not impair and instead may have favorably affected myocardial contractility. Blood pressure was also favorably lowered by HU6, an effect that preceded weight loss, suggesting that it may be related to the favorable effects of mitochondrial uncoupling on arterial compliance through reduction in mitochondrial reactive oxygen species production.14,15 Finally, there were numerical imbalances in the rates of treatment discontinuation and serious AEs between the 2 groups. However, the overall rates of serious AEs were low. Future studies with longer-term treatment in larger cohorts of patients are needed to evaluate the efficacy of HU6 to improve functional outcomes and quality of life and assess the clinical relevance of its effects on body composition, cardiac function, and blood pressure. The present study findings provide the rationale and critical preliminary data needed for design and conduct of such trials.
Limitations
Certain limitations to our study are noteworthy. The trial was relatively small and short in duration. Thus, all analyses other than the primary and key secondary outcomes should be considered hypothesis generating. Second, there were some baseline imbalances between the 2 study groups (eg, higher prevalence of diabetes in HU6 arm). However, the analysis of the primary and key secondary efficacy end points accounted for diabetes status in the adjusted models. Third, body composition was assessed using bioelectrical impendence analysis and the criterion standard whole-body MRI was only conducted in a subset of participants. Thus, adequately powered comparison of the effects of HU6 on regional adiposity depots cannot be performed. However, the consistent favorable effects of HU6 on body composition assessed using the InBody Scale (InBody BWA) in the overall cohort and confirmed by the MRI-based assessments of regional lean and fat mass highlight the robustness of the observed treatment effects.
Conclusions
In conclusion, in this randomized clinical trial, among patients with obesity-related HFpEF, treatment with HU6 over 19 weeks was associated with modest but statistically significant reductions in fat-specific body weight but no improvements in peak VO2, with overall low rates of serious adverse events and treatment discontinuation.
eMethods 1.
eMethods 2.
eMethods 3.
eMethods 4.
eTable 1. Key Selection Criteria for the HuMAIN-HFpEF Trial
eTable 2. Cardiopulmonary Exercise Testing Parameters Assessed
eTable 3. Echocardiographic and MRI Parameters Assessed During the Study
eTable 4. HuMAIN-HFpEF Trial End Points
eTable 5. Baseline Magnetic Resonance Imaging Characteristics
eTable 6. Within and Between Group Changes From Baseline to 19 Weeks for Measures of Cardiac Structure and Function by Cardiac MRI
eTable 7. Within and Between Group Changes From Baseline to 19 Weeks for Biomarkers and Cardiometabolic Parameters
eTable 8. Treatment Interruptions, Discontinuation, and On-Treatment Adverse Events by Treatment Group
eTable 9. Description of Key Adverse Events of Dyspnea and Pyrexia With HU6 During the Study
eFigure 1. Study Design
eFigure 2. CONSORT Diagram
eFigure 3. Percent Change From Baseline in Body Composition Parameters Measured With MRI
eFigure 4. Scatterplot of Percent Change From Baseline for Peak Exercise Oxygen Uptake, Exercise Time, 6-Minute Walk Distance, and Kansas City Cardiomyopathy Questionnaire Overall Score for Individual Patients
eFigure 5. Percent Change From Baseline for Measures of Cardiac Structure and Function
eFigure 6. Mean Change in Resting Systolic Blood Pressure and Diastolic Blood Pressure From Baseline
Data Sharing Statement
References
- 1.Butler J, Shah SJ, Petrie MC, et al. ; STEP-HFpEF Trial Committees and Investigators . Semaglutide vs placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomized trials. Lancet. 2024;403(10437):1635-1648. doi: 10.1016/S0140-6736(24)00469-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Wilding JPH, Batterham RL, Calanna S, et al. ; STEP 1 Study Group . Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989-1002. doi: 10.1056/NEJMoa2032183 [DOI] [PubMed] [Google Scholar]
- 3.McCrimmon RJ, Catarig AM, Frias JP, et al. Effects of once-weekly semaglutide vs once-daily canagliflozin on body composition in type 2 diabetes: a substudy of the SUSTAIN 8 randomized controlled clinical trial. Diabetologia. 2020;63(3):473-485. doi: 10.1007/s00125-019-05065-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Pandey A, Patel KV, Segar MW, et al. Effect of liraglutide on thigh muscle fat and muscle composition in adults with overweight or obesity: Results from a randomized clinical trial. J Cachexia Sarcopenia Muscle. 2024;15(3):1072-1083. doi: 10.1002/jcsm.13445 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Pandey A, Kitzman D, Reeves G. Frailty is intertwined with heart failure: mechanisms, prevalence, prognosis, assessment, and management. JACC Heart Fail. 2019;7(12):1001-1011. doi: 10.1016/j.jchf.2019.10.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Upadhya B, Haykowsky MJ, Eggebeen J, Kitzman DW. Sarcopenic obesity and the pathogenesis of exercise intolerance in heart failure with preserved ejection fraction. Curr Heart Fail Rep. 2015;12(3):205-214. doi: 10.1007/s11897-015-0257-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Portell F, Eaton S, Dennis J, et al. FRI-338-mitochondrial uncoupler HU6 reduces hepatic oxidative stress in the DIAMOND (TM) mouse model, thus abrogating NASH development. J Hepatol. 2019;70(1)(suppl):e544. doi: 10.1016/S0618-8278(19)31077-1 [DOI] [Google Scholar]
- 8.Noureddin M, Khan S, Portell F, et al. Safety and efficacy of once-daily HU6 vs placebo in people with nonalcoholic fatty liver disease and high BMI: a randomized, double-blind, placebo-controlled, phase 2a trial. Lancet Gastroenterol Hepatol. 2023;8(12):1094-1105. doi: 10.1016/S2468-1253(23)00198-X [DOI] [PubMed] [Google Scholar]
- 9.Capone F, Vettor R, Schiattarella GG. Cardiometabolic HFpEF: NASH of the heart. Circulation. 2023;147(6):451-453. doi: 10.1161/CIRCULATIONAHA.122.062874 [DOI] [PubMed] [Google Scholar]
- 10.Kitzman DW, Lewis GD, Pandey A, et al. A novel controlled metabolic accelerator for the treatment of obesity-related heart failure with preserved ejection fraction: rationale and design of the phase 2a HuMAIN trial. Eur J Heart Fail. 2024;26(9):2013-2024. doi: 10.1002/ejhf.3305 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Pandey A, Shah SJ, Butler J, et al. Exercise intolerance in older adults with heart failure with preserved ejection fraction: JACC state-of-the-art review. J Am Coll Cardiol. 2021;78(11):1166-1187. doi: 10.1016/j.jacc.2021.07.014 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Haykowsky MJ, Kouba EJ, Brubaker PH, Nicklas BJ, Eggebeen J, Kitzman DW. Skeletal muscle composition and its relation to exercise intolerance in older patients with heart failure and preserved ejection fraction. Am J Cardiol. 2014;113(7):1211-1216. doi: 10.1016/j.amjcard.2013.12.031 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Sorimachi H, Obokata M, Takahashi N, et al. Pathophysiologic importance of visceral adipose tissue in women with heart failure and preserved ejection fraction. Eur Heart J. 2021;42(16):1595-1605. doi: 10.1093/eurheartj/ehaa823 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Bailey SR, Mitra S, Flavahan S, Flavahan NA. Reactive oxygen species from smooth muscle mitochondria initiate cold-induced constriction of cutaneous arteries. Am J Physiol Heart Circ Physiol. 2005;289(1):H243-H250. doi: 10.1152/ajpheart.01305.2004 [DOI] [PubMed] [Google Scholar]
- 15.Kakarla M, Puppala VK, Tyagi S, et al. Circulating levels of mitochondrial uncoupling protein 2, but not prohibitin, are lower in humans with type 2 diabetes and correlate with brachial artery flow-mediated dilation. Cardiovasc Diabetol. 2019;18(1):148. doi: 10.1186/s12933-019-0956-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eMethods 1.
eMethods 2.
eMethods 3.
eMethods 4.
eTable 1. Key Selection Criteria for the HuMAIN-HFpEF Trial
eTable 2. Cardiopulmonary Exercise Testing Parameters Assessed
eTable 3. Echocardiographic and MRI Parameters Assessed During the Study
eTable 4. HuMAIN-HFpEF Trial End Points
eTable 5. Baseline Magnetic Resonance Imaging Characteristics
eTable 6. Within and Between Group Changes From Baseline to 19 Weeks for Measures of Cardiac Structure and Function by Cardiac MRI
eTable 7. Within and Between Group Changes From Baseline to 19 Weeks for Biomarkers and Cardiometabolic Parameters
eTable 8. Treatment Interruptions, Discontinuation, and On-Treatment Adverse Events by Treatment Group
eTable 9. Description of Key Adverse Events of Dyspnea and Pyrexia With HU6 During the Study
eFigure 1. Study Design
eFigure 2. CONSORT Diagram
eFigure 3. Percent Change From Baseline in Body Composition Parameters Measured With MRI
eFigure 4. Scatterplot of Percent Change From Baseline for Peak Exercise Oxygen Uptake, Exercise Time, 6-Minute Walk Distance, and Kansas City Cardiomyopathy Questionnaire Overall Score for Individual Patients
eFigure 5. Percent Change From Baseline for Measures of Cardiac Structure and Function
eFigure 6. Mean Change in Resting Systolic Blood Pressure and Diastolic Blood Pressure From Baseline
Data Sharing Statement
