The researchers examined heart cells from male mice with severe heart failure induced by transverse aortic constriction and male rabbits with chronic failure produced by combined pressure and volume overload. Healthy controls were included for both species. The mouse model produced an ejection fraction below 25%, while rabbit hearts with left ventricular end-systolic dimension above 1.4 cm and ejection fraction below 35% were classified as failing. Cells were randomly assigned to vehicle, 1 micromolar empagliflozin, or 1 micromolar cariporide, a selective inhibitor of the sodium-hydrogen exchanger NHE-1. Patch-clamp recordings were conducted at 37 degrees Celsius, and electrophysiological outcomes were compared using hierarchical analysis of variance.

Failing cardiomyocytes had prolonged action-potential duration at 90% repolarization, greater short-term variability, and, in the rabbit model, a more depolarized resting membrane potential. Mouse cells also showed a lower maximal action-potential upstroke velocity. Empagliflozin pretreatment attenuated these abnormalities in both models: it reduced action-potential prolongation and variability, improved resting potential in rabbit cells, and increased upstroke velocity in failing mouse cells. Three-hour treatment produced no significant electrophysiological changes in healthy controls, while three-minute exposure had no measurable effect in either healthy or failing cells. The delay between empagliflozin and its observed effects was a central feature of the results.

The drug also shifted the pacing threshold at which action-potential alternans appeared, a beat-to-beat oscillation linked with unstable repolarization. In failing mouse cells, alternans appeared at rates of at least 7 hertz; at 10 hertz it occurred in all 15 untreated failing cells but in only one of 10 cells after empagliflozin pretreatment. In rabbits, the alternans threshold was 3 hertz in failing cells and 5 hertz in controls. Pretreatment increased the threshold in failing rabbit cells and reduced the magnitude of alternans to control levels. These observations were made in isolated cells and therefore do not establish that the treatment prevents arrhythmias in a whole heart or in a patient.

Delayed afterdepolarizations, spontaneous depolarizations that can trigger abnormal beats, were also reduced. In failing mouse cells, empagliflozin lowered their incidence and prevented spontaneous action potentials. In failing rabbit cells, they occurred in 10 of 15 cells without pretreatment, compared with 2 of 12 after pretreatment, a statistically significant difference. Acute empagliflozin exposure did not reduce alternans or afterdepolarizations. Cariporide did not reproduce the broad effects of empagliflozin: it did not improve action-potential duration or alternans in either model and only modestly reduced afterdepolarizations in mouse cells. This comparison does not rule out NHE-1 as a contributor, because the experiments used normoxic conditions and an internal pH of 7.2, where NHE-1 activity is relatively low.

Strong buffering of intracellular calcium with 10 millimolar EGTA reproduced much of the electrical stabilization. It reduced action-potential prolongation and variability, prevented alternans in both failing models, and abolished delayed afterdepolarizations. The results identify disturbed intracellular calcium handling as a major component of the cellular phenotype, although they do not prove that every effect of empagliflozin is calcium-dependent. Calcium and sodium handling are closely coupled in failing hearts: increased late sodium current can promote intracellular sodium accumulation, alter calcium exchange, activate calcium/calmodulin-dependent protein kinase II, and reinforce abnormalities in calcium release. The study therefore supports a mechanistic link between improved sodium and calcium regulation and the observed electrical effects, without establishing a single molecular target.

Direct current measurements identified two ion currents consistent with the action-potential changes. Late sodium current was small in healthy cells but markedly increased in failing mouse and rabbit cardiomyocytes, by 126% and 93%, respectively, relative to healthy controls. Three-hour pretreatment with empagliflozin reversed this increase in both species. The inward rectifier potassium current, which supports resting membrane potential and repolarization, was reduced in failing cells. Empagliflozin increased its density in both models, including the physiologically relevant outward current in mouse cells, where it rose by 46%, compared with a 15% increase in inward current. As with the action-potential results, empagliflozin did not significantly change these currents in healthy control cells.

The time dependence is compatible with several non-acute mechanisms discussed by the authors. Empagliflozin may suppress post-translational changes that enhance late sodium current in heart failure, potentially involving altered CaMKII-dependent phosphorylation. It might also act as a pharmacological chaperone, changing the trafficking or functional membrane expression of cardiac sodium channels. Previous studies have reported both direct inhibition of Nav1.5, generally at concentrations above the 1 micromolar used here, and increased functional expression of peak sodium current after longer exposure. The present experiments did not directly distinguish these mechanisms or test whether changes in late sodium and inward rectifier currents caused the action-potential improvements.

Several boundaries constrain the findings. The study used only male animals and deliberately excluded diabetes and ischemic disease, isolating a glucose-independent effect in chronic non-ischemic failure; whether responses differ by sex or in ischemic heart failure remains unknown. The work also examined isolated cells rather than intact hearts, animals, or people. Although empagliflozin improves clinical outcomes in heart failure, these experiments do not show that the electrophysiological changes observed here explain its clinical benefits or predict reduced arrhythmias in patients. The next steps would include tissue and organ-level studies using whole-heart optical mapping and in-vivo arrhythmia testing, alongside experiments designed to identify the relevant molecular targets and determine whether the effects are specific to empagliflozin or shared by other SGLT2 inhibitors.

Subject of Research: Cellular electrophysiological effects of empagliflozin in non-ischemic HFrEF cardiomyocytes

Article Title: Complex antiarrhythmic effects of empagliflozin in non-ischemic HFrEF cardiomyocytes

Article References: Hegyi, B., & Bers, D. M. (2026). Complex antiarrhythmic effects of empagliflozin in non-ischemic HFrEF cardiomyocytes. Frontiers in Pharmacology, 17, Article 1955044. https://doi.org/10.3389/fphar.2026.1955044

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1955044

Keywords: empagliflozin, heart failure, HFrEF, cardiac arrhythmias, action potential, ion channels, intracellular calcium, late sodium current, IK1, SGLT2 inhibitors, cardiomyocytes, Complex

Chronic heart failure is far more than a problem of a failing pump. The condition disrupts the delicate interplay between the heart and the lungs, producing pulmonary congestion, altered gas exchange, and impaired lung mechanics. As a result, the work and energy cost of every breath rises, and even modest physical effort becomes exhausting. This physiological burden explains why patients with heart failure often experience profound breathlessness and fatigue, and why rehabilitation programs that target only the legs and arms may miss a crucial piece of the therapeutic puzzle. The Bialystok team designed their intervention with this cardiopulmonary coupling in mind, pairing conventional endurance training with structured breathing exercises and inspiratory muscle training.

The evidence base for exercise training in heart failure is already strong. Large randomized trials and meta-analyses have shown that regular exercise improves physical endurance and quality of life, reduces all-cause and heart failure-related hospitalizations, and may even lower long-term mortality. The European Society of Cardiology currently recommends supervised exercise training and rehabilitation for all patients with chronic heart failure who are able to participate. Yet in practice, cardiac rehabilitation remains dramatically underused, with participation rates estimated at only 10 to 30 percent. Distance, cost, frailty, and simple logistics keep many patients from ever setting foot in a center-based program, creating an urgent need for models that work beyond the clinic walls.

To test whether rehabilitation could be safely and effectively moved into patients’ homes, the researchers enrolled 63 patients with stable heart failure with reduced ejection fraction, meaning their hearts pumped at less than 40 percent of normal capacity. Participants were randomized in a 3:2 ratio to an intervention or control group. The intervention group received detailed instruction in a tailored home program: physical training performed once daily, at least five times per week, at an intensity of 4 to 5 points on a 10-point Borg scale of perceived exertion, building toward sessions of 45 to 60 minutes. Each patient also received a Pulmogain RespiTrain device for resistance training of the respiratory muscles, along with an illustrated booklet, a pedometer, and a self-monitoring diary to record heart rate, blood pressure, breathlessness, and step counts.

Crucially, the program did not abandon patients to their own devices. Scheduled clinic visits at one and three months allowed the team to verify exercise technique and adjust the training plan, while weekly telephone support reinforced adherence. Family members or caregivers were trained to supervise sessions at home. This hybrid of autonomy and remote oversight proved remarkably effective: adherence to the recommended protocol, defined as completing at least 120 sessions over 24 weeks, averaged an impressive 91.5 percent, and 82.8 percent of patients who started the program completed the full six-month assessment. Patients logged an average of more than 9,000 steps per day, including roughly 3,300 steps within each dedicated training session.

The physiological results were striking. After six months, the distance patients could walk in six minutes, a standard measure of functional capacity, increased by an average of 37.86 meters, a change the authors describe as clinically meaningful. Maximal inspiratory pressure, the force the diaphragm and other inspiratory muscles can generate, rose by 20.21 centimeters of water, while maximal expiratory pressure climbed by 20.75 centimeters of water, both highly statistically significant gains. Fatigue, measured with the validated Fatigue Severity Scale, fell by an average of 0.68 points. Notably, the magnitude of the inspiratory pressure improvement closely matches results from meta-analyses of supervised inspiratory muscle training, which reported gains of roughly 16 to 25 centimeters of water, suggesting that home-based delivery can achieve comparable physiological effects.

The respiratory component of the program deserves particular attention. Heart failure impairs ventilation and the matching of airflow to blood perfusion in the lungs, and previous research has shown that breathing exercises and inspiratory muscle training can improve not only respiratory mechanics but also exercise tolerance and quality of life. Meta-analytic data indicate that patients with inspiratory muscle weakness benefit most from this form of training, and the baseline inspiratory pressure of the Bialystok cohort, around 63 centimeters of water, was consistent with substantial respiratory muscle impairment. The study’s combined approach, pairing endurance walking with targeted respiratory resistance training, produced gains consistent with the best results reported in the supervised literature.

Safety, often the central concern when prescribing unsupervised exercise to cardiac patients, was reassuring. No serious adverse events related to training were reported, and no deaths occurred in the heart failure group. The few exercise-related complaints were minor: one case each of excessive fatigue, breathlessness, and calf cramps, and two episodes of chest pain. The researchers attribute this safety profile to careful patient selection, thorough instruction in contraindications and safe exercise principles, and the structured self-monitoring system that kept the study team informed of each patient’s status week by week.

The study was not without limitations, and the authors are candid about them. The COVID-19 pandemic disrupted the original design, and the control group could not be assessed after six months because most participants were unwilling to attend hospital visits during lockdowns. This means the analysis effectively became a single-arm before-and-after comparison, so some of the observed improvement could reflect natural variability, regression to the mean, or the motivating effect of increased attention. The sample was also small, dominated by men, and enrolled before newer heart failure drugs such as SGLT2 inhibitors became standard. These caveats temper the strength of the conclusions, though they do not erase the consistency of the physiological gains with the broader supervised-rehabilitation literature.

Even with those qualifications, the implications are considerable. Prior systematic reviews have found home-based cardiac rehabilitation to be non-inferior to center-based programs in clinical outcomes, with marginally higher completion rates, and the landmark HF-ACTION trial struggled to keep long-term adherence above 30 percent even with intensive support. Against that benchmark, an adherence rate above 90 percent in an unsupervised, home-delivered program is remarkable, and the authors suggest that simple tools such as pedometers, diaries, and weekly phone calls may offer a viable, cost-effective alternative to high-tech telemonitoring, especially in low-resource settings. For the vast majority of heart failure patients who never receive rehabilitation today, a program that requires little more than a pair of legs, a breathing device, a booklet, and a telephone line could bring the benefits of the clinic directly into the home.

Subject of Research: Home-based exercise and respiratory rehabilitation for chronic heart failure

Article Title: Beyond the clinic: a six-month home-based exercise and respiratory rehabilitation program improves functional capacity, respiratory muscle strength, and fatigue in chronic heart failure

Article References: Ciołkiewicz, M., Wojciuk, M., Kuryliszyn-Moskal, A., Dakowicz, A., Sawicka-Śmiarowska, E., & Kamiński, K. (2026). Beyond the clinic: a six-month home-based exercise and respiratory rehabilitation program improves functional capacity, respiratory muscle strength, and fatigue in chronic heart failure. Frontiers in Rehabilitation Sciences, 7, Article 1958027. https://doi.org/10.3389/fresc.2026.1958027

Image Credits: AI Generated

DOI: 10.3389/fresc.2026.1958027

Keywords: heart failure, cardiac rehabilitation, home-based exercise, respiratory muscle training, inspiratory muscle training, six-minute walk test, fatigue, functional capacity, HFrEF, adherence, telemonitoring, pilot study

The biological problem at the heart of the trial is well known to cardiologists and nephrologists alike. Renin-angiotensin-aldosterone system inhibitors, or RAASi, which include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and mineralocorticoid receptor antagonists, are cornerstones of treatment for heart failure with reduced ejection fraction. They reduce mortality, slow disease progression and improve quality of life. Yet these drugs suppress aldosterone, the hormone that drives potassium excretion by the kidneys. In patients whose kidneys are already impaired, potassium clearance is compromised, and RAASi therapy can push serum potassium above the normal range. Hyperkalaemia is not a trivial side effect: levels of 5.6 mmol/L or higher can destabilise the cardiac rhythm and, in severe cases, trigger fatal arrhythmias. As a result, clinicians frequently down-titrate or discontinue these life-prolonging medications, leaving patients under-protected.

Sodium zirconium cyclosilicate belongs to a newer class of non-absorbed, inorganic crystalline agents designed to solve exactly this problem. Taken orally, the compound acts as a selective trap in the gastrointestinal tract, binding potassium ions throughout the intestinal lumen in exchange for hydrogen and sodium. Because it is not absorbed into the bloodstream, its effect is confined to the gut, where it lowers the amount of dietary and secreted potassium that would otherwise be absorbed. This mechanism effectively gives the gut a role as an auxiliary route of potassium elimination, compensating for the reduced renal excretion that characterises advanced chronic kidney disease. Earlier studies established that SZC can normalise serum potassium and maintain it in the normal range, but questions remained about whether that pharmacological effect would translate into genuine, sustained up-titration of RAASi therapy in real patients.

The new trial was designed to answer that question directly. The investigators enrolled 112 adults with heart failure with reduced ejection fraction and chronic kidney disease stages 3 to 5, all of whom had mildly elevated serum potassium between 5.0 and 5.5 mmol/L, a range high enough to make clinicians hesitant to intensify RAASi therapy. Participants were randomised in a one-to-one ratio to receive either SZC or a matching placebo. The trial ran for 14 weeks, during which the clinical team attempted to optimise each patient’s RAASi regimen toward guideline-recommended target doses. The primary outcome was deliberately stringent: a patient was counted as a success only if they achieved the target dose of RAAS inhibition without ever crossing the hyperkalaemia threshold of 5.6 mmol/L during the 14-week period. Failing either criterion, whether through under-dosing or through a potassium excursion, counted as not meeting the endpoint.

The results were striking. In the per-protocol analysis, which included the 43 of 53 participants in the SZC arm and 53 of 59 in the placebo arm who completed the protocol, 24 of 43 patients in the SZC group, or 56 percent, achieved target RAASi dosing without developing hyperkalaemia, compared with 15 of 53 patients, or 28 percent, in the placebo group. That difference was statistically significant, with a p value of 0.006. The intention-to-treat analysis, which included all 112 randomised participants regardless of protocol adherence, produced a nearly identical picture, with a p value of 0.007. Expressed as an odds ratio, patients receiving SZC were 3.16 times more likely to reach the target dose without their potassium climbing to 5.6 mmol/L or above, with a 95 percent confidence interval of 1.35 to 7.39 and a p value of 0.008.

Just as important as the efficacy signal was the safety profile. The investigators observed no significant differences in adverse events between the two groups, an encouraging finding given that the trial deliberately pushed RAASi doses upward in patients with substantially impaired kidney function. In a population where both under-treatment and potassium toxicity carry real risks, the absence of a safety penalty is what transforms a statistically significant result into a clinically actionable one. The trial was double-blind and placebo-controlled, meaning neither participants nor the treating team knew who was receiving the active binder, which protects the results from the placebo effects and ascertainment biases that can distort open-label potassium studies.

The trial’s design choices deserve attention because they reflect the practical realities of modern cardiology and nephrology. By setting the entry potassium range at 5.0 to 5.5 mmol/L, the investigators targeted the exact grey zone in which clinicians most often hesitate: potassium is technically above normal, but not yet at an emergency level. By requiring both dose optimisation and potassium safety within a 14-week window, the trial tested whether rapid optimisation, rather than slow, cautious titration over many months, is feasible. Speed matters in heart failure with reduced ejection fraction, because patients spend the intervening months at elevated risk of hospitalisation and death while their medication regimen remains incomplete. A strategy that compresses optimisation into weeks rather than quarters could meaningfully change the trajectory of the disease.

The implications extend beyond the individual patient. Under-prescription of RAASi therapy in patients with coexisting kidney disease is a widespread and persistent quality-of-care gap, documented across health systems worldwide. If a potassium binder can be deployed as a routine companion to RAASi up-titration, it gives clinicians a concrete tool to close that gap rather than simply an aspiration to prescribe better. The findings also feed into a broader shift in thinking about hyperkalaemia: rather than treating elevated potassium as an automatic stop sign for cardioprotective drugs, the field is increasingly exploring whether binders can convert hyperkalaemia from a barrier into a manageable laboratory abnormality. The trial’s primary endpoint, which demanded both full dosing and potassium safety, was constructed to test precisely that proposition.

Some caveats are worth bearing in mind. The trial enrolled 112 participants, a sample size that provides confidence in the primary endpoint but leaves room for uncertainty about rarer adverse events and about subgroups such as patients at different CKD stages within the 3-to-5 spectrum. The per-protocol populations were smaller still, with 43 and 53 participants respectively, and some participants did not complete the protocol. The study was funded by AstraZeneca through an Externally Sponsored Scientific Research grant, ESR-19-20174, although the funder had no contribution to the trial design, data collection, analysis or interpretation, and the study was conducted with independent trial steering and data safety monitoring committees. The corresponding author has disclosed speaker fees from AstraZeneca and Vifor Pharma. These disclosures are standard for industry-sponsored trials of an approved agent, but readers should weigh them when interpreting the results.

Nevertheless, the trial, registered as NCT05004363 on ClinicalTrials.gov and 2020-002946-18 in the EudraCT database, adds a rigorous randomised data point to a question that has long been answered only by observational evidence and expert opinion. For the large population of patients whose heart failure and kidney disease coexist, the message is concrete: with a modern potassium binder, full-dose RAAS inhibition appears achievable in a matter of weeks, with roughly double the success rate of placebo and no excess adverse events. The work, published open access under a Creative Commons licence and partially supported by the National Institute for Health and Care Research, points toward a future in which the kidneys’ limitations no longer dictate the ceiling of heart failure therapy. Confirmatory studies in larger and more diverse cohorts will determine how broadly this strategy should be adopted, but for now the trial offers a compelling proof of concept that the potassium barrier to optimal heart failure care can, in fact, be lowered.

Subject of Research: Use of the potassium binder sodium zirconium cyclosilicate to enable optimisation of renin-angiotensin-aldosterone system inhibitor therapy in patients with chronic kidney disease and heart failure with reduced ejection fraction

Article Title: Rapid Renin Angiotensin Aldosterone System inhibitor optimisation in patients with chronic kidney disease and heart failure with reduced ejection fraction using potassium binder: a randomised, double-blinded, placebo-controlled trial

Article References: Banerjee, D., Ali, M., Tumelty, E., Murphy, D., Warrens, H., Parmar, S., McNally, T., Lopez, T., Abat, S., Paul, R., Hussain, S., Mookerjee, S., Chung, I., Ster, I. C., & Anderson, L. (2026). Rapid Renin Angiotensin Aldosterone System inhibitor optimisation in patients with chronic kidney disease and heart failure with reduced ejection fraction using potassium binder: a randomised, double-blinded, placebo-controlled trial. Nature Communications. https://doi.org/10.1038/s41467-026-78377-0

Image Credits: AI Generated

DOI: 10.1038/s41467-026-78377-0

Keywords: heart failure, chronic kidney disease, hyperkalaemia, sodium zirconium cyclosilicate, RAAS inhibitors, randomised controlled trial, potassium binder, cardiology, nephrology, drug titration, HFrEF, clinical trial

The study drew on two prospective, multicenter Korean registries: the Korea Heart Failure Registry, which enrolled 3,200 patients hospitalized for acute heart failure at 24 tertiary centers between 2004 and 2009, and the Korean Acute Heart Failure Registry, which captured 5,625 patients across 10 tertiary centers between 2011 and 2014. After excluding 442 patients with missing body mass index or diabetes data, the researchers analyzed 8,383 individuals with a mean age of 68.2 years, 52 percent of whom were men. Importantly, the team applied an Asian-specific threshold for overweight, classifying patients as lean if their body mass index fell below 23 kilograms per square meter and overweight if it met or exceeded that value—a cutoff grounded in evidence that cardiometabolic risk rises at lower body weights in Asian populations than in Western ones. Roughly a third of the cohort had diabetes, and the patients were sorted into four groups: overweight non-diabetic, overweight diabetic, lean non-diabetic, and lean diabetic.

The baseline profiles of these groups told a striking story before any outcome data were even examined. Overweight patients without diabetes had the most favorable characteristics: they were younger, less likely to have ischemic heart disease, and displayed lower creatinine, C-reactive protein, and natriuretic peptide levels, along with better echocardiographic measures of cardiac function. At the opposite extreme, lean patients with diabetes carried the heaviest burden of disease, with more advanced heart failure symptoms, greater renal dysfunction, and a higher prevalence of ischemic etiology. That gradient—healthiest at the heavier, non-diabetic end of the spectrum and sickest at the lean, diabetic end—set the stage for outcome differences that were as dramatic as they were consistent.

During the index hospitalization, 5.3 percent of all patients died, with in-hospital mortality peaking at 6.9 percent among lean diabetic patients and falling as low as 4.2 percent among overweight diabetic patients. But it was the post-discharge picture that revealed the paradox in its sharpest form. Over one year of follow-up, 14.9 percent of patients died overall, yet the mortality gradient across the four groups was steep: 9.3 percent among overweight non-diabetic patients, 12.7 percent among overweight diabetic patients, 16.4 percent among lean non-diabetic patients, and a sobering 20.7 percent among lean diabetic patients. Diabetes alone raised the one-year mortality rate from 13.8 to 17.1 percent, but leanness exerted an even larger penalty, lifting mortality from 11.1 to 18.8 percent.

After multivariable adjustment for age, sex, systolic blood pressure, symptom severity, hemoglobin, renal function, ejection fraction, ischemic etiology, and other confounders, the survival advantage of overweight status remained statistically robust for one-year mortality. Overweight diabetic patients faced a 35 percent lower risk of death within a year compared with their lean diabetic counterparts, with an adjusted hazard ratio of 0.65 and a 95 percent confidence interval of 0.53 to 0.79. The same directional benefit appeared among overweight patients without diabetes. Critically, when the researchers tested for an interaction between body mass index and diabetes status, none was found—the protective association held with equal force whether or not a patient had diabetes. When body mass index was modeled as a continuous variable, each single-unit increase was associated with a 7 percent reduction in one-year mortality risk, and restricted cubic spline analysis revealed a smooth, monotonic decline in hazard across the entire observed range of body weight.

Intriguingly, the same pattern did not survive scrutiny for in-hospital mortality. Although the raw death rates favored heavier patients during the admission itself, the association weakened and lost statistical significance once the fully adjusted model accounted for the less favorable baseline profiles of lean patients—including their more advanced heart failure and greater comorbidity burden. This divergence suggests that body mass index carries greater prognostic weight over the months following discharge than during the acute phase, when illness severity and body composition may dominate short-term outcomes more than adiposity itself. In other words, the obesity paradox appears to be primarily a phenomenon of medium-term survival rather than of immediate peri-hospitalization risk.

The research team took considerable care to test whether their findings could be an artifact of statistical fragility. Sensitivity analyses using the World Health Organization overweight cutoff of 25 kilograms per square meter produced nearly identical results, with mortality falling monotonically across body mass index strata from 26.9 percent in the underweight range to just 7.0 percent among those with a body mass index of 30 or higher. Excluding patients with a body mass index below 20—who are most likely to suffer from cardiac cachexia, frailty, or severe malnutrition—did not erase the survival advantage of overweight status, arguing against reverse causality as the sole explanation. Registry-stratified analyses showed consistent associations in both cohorts, with no significant registry-by-body-mass-index interaction, and the pattern held across all three heart failure phenotypes: reduced, mildly reduced, and preserved ejection fraction. Only the smaller mid-range ejection fraction subgroup failed to reach statistical significance, most likely due to insufficient sample size.

Still, the investigators are careful to emphasize the limits of what an observational study can prove. Reverse causality—the idea that leanness reflects advanced disease rather than causing poor outcomes—cannot be dismissed entirely, and the registries lacked longitudinal weight trajectories, body composition data, nutritional markers, and measures of skeletal muscle mass that might distinguish protective adiposity from simply the absence of wasting. The cohort was also exclusively Korean, with a low mean body mass index of 23 kilograms per square meter, raising questions about generalizability to Western populations with very different body composition distributions. HbA1c data were missing in more than three-quarters of patients, diabetes type and duration were not captured, and the cohort predates the widespread use of sodium-glucose cotransporter-2 inhibitors, so the interplay between modern weight-lowering drugs and the paradox remains unresolved. The authors frame their conclusions explicitly as associations, not evidence of a causal protective effect of being overweight.

Yet the clinical implications are difficult to ignore, particularly at a moment when guideline-directed heart failure therapy increasingly includes drugs that cause weight loss. Sodium-glucose cotransporter-2 inhibitors can reduce body weight by 3 to 5 percent, and while trial-level evidence from DAPA-HF and EMPEROR-Reduced suggests these therapies benefit patients across the body mass spectrum without modifying the paradox, the new findings add urgency to the question of whether aggressive weight reduction is appropriate for lean patients with heart failure. Notably, a prespecified analysis of the STEP-HFpEF trial showed that semaglutide improved symptoms and function in overweight patients with preserved ejection fraction in proportion to the weight they lost—hinting that there may be a therapeutic sweet spot, a window of body weight beyond which the prognostic advantage of adiposity diminishes. For now, the message from Korea is unambiguous: among patients hospitalized with heart failure, low body weight—especially when combined with diabetes—identifies a strikingly vulnerable phenotype, and the obesity paradox is no respecter of diabetes status.

Subject of Research: The obesity paradox in heart failure patients with and without diabetes mellitus

Article Title: Obesity paradox in heart failure with and without diabetes mellitus: a retrospective cohort study

Article References: Kwon, O., Yoon, M., & Park, J. J. (2026). Obesity paradox in heart failure with and without diabetes mellitus: a retrospective cohort study. Clinical Research in Cardiology. https://doi.org/10.1007/s00392-026-03007-0

Image Credits: AI Generated

DOI: 10.1007/s00392-026-03007-0

Keywords: obesity paradox, heart failure, diabetes mellitus, body mass index, mortality, KorHF, KorAHF, prognosis, HFrEF, HFpEF, SGLT2 inhibitors, cardiology