Heart failure, a condition long recognized as a formidable challenge in cardiovascular medicine, is becoming even more prevalent as the world’s population ages and the rates of obesity and metabolic disorders continue to climb. According to Nature Reviews Cardiology, this growing epidemic has shifted the landscape of heart failure, forcing clinicians and researchers to rethink both its underlying mechanisms and the strategies used to treat it. The statistics are sobering: heart failure is now a leading cause of morbidity and mortality globally, with millions affected and the numbers only expected to rise in coming decades.
At the core of this complex condition lies a fundamental disruption in the heart’s ability to generate and utilize energy efficiently. The heart, after all, is a muscle that never rests—its relentless pumping relies on a steady supply of energy, primarily produced by mitochondria within cardiac cells. But in heart failure, this finely tuned system goes awry. Mitochondrial function falters, and the process of excitation–contraction coupling—essentially how electrical signals translate into muscle movement—becomes impaired. The result? An energy deficit that undermines the heart’s contractile strength and leaves it struggling to meet the body’s demands.
This breakdown in energy management is not uniform across all cases of heart failure. Researchers have identified two major subtypes, each with its own distinct profile: heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). In HFrEF, the heart’s pumping ability is diminished, often due to defects in excitation-contraction coupling. These defects disrupt the signaling pathways and calcium handling necessary for robust contractions, leading to a downward spiral of energy depletion and worsening function.
HFpEF, on the other hand, presents a different challenge. Here, the heart’s pumping function appears normal, but the muscle is stiff and less able to relax between beats. This form is increasingly common among older adults and those with obesity or hypertension. In HFpEF, the heart faces increased mechanical workload—thanks to higher preload and afterload pressures—yet the mitochondria’s tricarboxylic acid cycle can’t keep up with the demand for ATP, the energy currency of cells. As Nature Reviews Cardiology explains, this mismatch between energy supply and demand propels the heart toward dysfunction, even when the ejection fraction remains technically within the normal range.
One thread unites both forms of heart failure: oxidative stress. As the heart’s antioxidative defenses are depleted, reactive oxygen species (ROS) accumulate, causing damage to cardiac cells and promoting maladaptive remodeling. This oxidative burden not only worsens contractile dysfunction but also initiates a vicious cycle of further energy depletion and structural deterioration.
Given these insights, it’s no surprise that new therapeutic strategies are focusing on the “mechano-energetic uncoupling” at the heart of the disease. Efforts are underway to develop treatments that enhance mitochondrial function, improve energy delivery to heart muscle, and ultimately restore the delicate balance between mechanical work and bioenergetic supply. According to Nature Reviews Cardiology, both established and emerging therapies—including gene therapy and regenerative medicine—are being explored with the hope of reversing or halting the progression of heart failure.
But the search for effective treatments doesn’t stop with basic science. At the 2025 European Society of Cardiology (ESC) Congress, a team of German and US cardiologists presented striking new evidence: patients with HFpEF who were treated with the weight-loss drugs semaglutide or tirzepatide experienced a more than 40% reduction in hospitalization risk. These findings, published by Medscape, have already prompted the American College of Cardiology to recommend these GLP-1 receptor agonists as possible therapies for HFpEF—a significant shift in clinical practice.
Professor Dr. Ulrich Laufs, chief of cardiology at Leipzig University Hospital, explained the significance in an interview with Medscape: “We have seen two large study programs that enrolled patients with heart failure and preserved pump function. This is a large patient group in Germany characterized by a high symptom burden and reduced life expectancy, and until now, we have had relatively few evidence-based pharmacologic treatment options for them.”
The STEP-HFpEF trial, for example, enrolled obese patients (BMI ≥ 30) with HFpEF and treated them with semaglutide, a GLP-1 receptor agonist. Similarly, the SUMMIT trial tested tirzepatide, a dual GIP and GLP-1 receptor agonist, in a comparable patient population. Both studies documented clear symptomatic benefits, including improved functional capacity and lower hospitalization rates.
These advances are particularly meaningful because, until recently, the mainstays of HFpEF treatment were SGLT2 inhibitors and nonsteroidal mineralocorticoid receptor antagonists. As Dr. Laufs noted, “So far, we have not had positive trials for other drugs.” The arrival of new options like semaglutide and tirzepatide offers hope to a patient group that has long faced limited choices.
Yet, questions remain. While the benefits of GLP-1 receptor agonists are now well documented in obese HFpEF patients, their utility in other heart failure populations is less clear. Dr. Laufs emphasized, “For patients with heart failure and markedly reduced pump function (ie, reduced ejection fraction), we cannot make as many statements yet because that population has not been fully investigated.” There are hints of benefit, but definitive data are lacking.
The issue of which patients should receive these drugs is also evolving. Current guidance, according to Medscape, supports the use of GLP-1 receptor agonists in patients with type 2 diabetes and atherosclerosis, as well as those with HFpEF. The evidence is strongest for obese individuals, but there are ongoing debates about whether overweight or even normal-weight patients with HFpEF might also benefit. The SELECT trial, for instance, found no significant difference in outcomes between patients with BMI under 30 and those over 30, suggesting that benefits may extend beyond the severely obese—though data for those with BMI below 25 remain sparse.
Regulatory and reimbursement hurdles add another layer of complexity. While semaglutide and tirzepatide are authorized for obesity treatment (for BMI over 30, or 27-30 with comorbidities), insurance coverage varies widely. In Germany, for example, statutory health insurance reimburses these drugs only for patients with type 2 diabetes in addition to metformin. For others, including those with HFpEF and obesity but without diabetes, the medications are typically available only on a self-pay basis.
As the science advances, so too does the conversation about prevention. Experts stress the importance of public health initiatives aimed at curbing obesity and metabolic disorders—key drivers of heart failure. Engaging communities in lifestyle changes, nutrition education, and preventive care could help stem the tide of new cases and improve outcomes for those already affected.
Ultimately, the fight against heart failure demands a holistic approach—one that bridges the gap between cutting-edge research, innovative therapies, and population-level prevention. With continued collaboration between clinicians, scientists, and public health leaders, the hope is that this persistent burden may one day be lifted, restoring heart health and quality of life for millions worldwide.
