Guideline-recommended preventive management in metabolic and renal disease: a paradigm shift for all healthcare professionals to maintain ‘normal’ cardiac function

This editorial refers to ‘Benefit of early initiation of disease-modifying therapy in community-based patients with suspected heart failure’, by K.F. Docherty et al., https://doi.org/10.1093/eurheartj/ehaf675. Metabolic diseases—particularly diabetes mellitus (DM), chronic kidney disease (CKD), and obesity—often exert a profound negative impact on cardiac structure and function.1 They accelerate processes such as myocardial fibrosis, endothelial dysfunction, and neurohormonal activation, leading from subtle impairment to overt heart failure (HF) if untreated. Conversely, HF aggravates metabolic disease via systemic inflammation, insulin resistance, renal hypoperfusion, and catabolic states, creating a vicious cycle. Other frequent contributors include severe dyslipidaemia. HF is common in DM, CKD, and obesity, reflecting strong pathophysiological links. In type 2 DM (T2D), large cohorts and consensus statements from the American Diabetes Association (ADA) and American College of Cardiology (ACC) report HF prevalence up to 22% and incidence as high as 11.9 per 1000 patient-years, a two- to four-fold excess risk vs non-diabetics.2 In type 1 DM (T1D), population studies suggest a three- to five-fold higher risk, probably due to early microvascular damage, autonomic neuropathy, and chronic hyperglycaemia. In CKD, KDIGO data show that 17%–21% develop new-onset HF, and ∼44% of haemodialysis patients have HF, most often HF with preserved ejection fraction (HFpEF).3,4 Conversely, at least half of HF patients have CKD.5 In obesity, longitudinal studies show a two- to three-fold increased risk of incident HF, mediated by inflammation, haemodynamic overload, and metabolic dysregulation.1 These findings underscore the bidirectional and mutually amplifying relationship between metabolic, renal, and cardiac dysfunction, highlighting the need for systematic screening to detect and assess heart dysfunction in populations at high risk of cardiovascular disease (CVD). However, despite clear recommendations from several international societies,6,7 recent evidence, published in this issue of the European Heart Journal8 and presented as a late-breaking trial at the 2025 Annual Meeting of the European Society of Cardiology (ESC) by K.F. Docherty et al., confirms that nationwide implementation of systematic screening and assessment of HF remains suboptimal. Docherty et al. studied a cohort of 74 945 adults in the UK with no prior documented diagnosis of HF, in whom community-measured N-terminal probrain natriuretic peptide (NT-proBNP), performed for suspected de novo HF, was ≥400 pg/mL—the threshold recommended by the National Institute for Health and Care Excellence (NICE) to prompt referral for echocardiography and specialist assessment within 2–6 weeks. It should be noted, however, that European and North American guidelines consistently recommend a threshold of 125 pg/mL for NT-proBNP to raise suspicion of HF. It would have been informative, despite NICE guidance adopting a higher value, if the authors had also examined outcomes in patients with NT-proBNP levels above the internationally recognized 125 pg/mL threshold, who might have derived substantial benefit from earlier referral and appropriate management. Among individuals who underwent echocardiography, one-third had HF, while two-thirds did not. As expected, many of these patients with so-called elevated NT-proBNP had established metabolic comorbidities: diabetes (23%), estimated glomerular filtration rate (eGFR) <60 mL/min (38%), and/or hypertension (78%). The authors further reported that, among individuals with suspected de novo HF and elevated NT-proBNP, only about half underwent echocardiography within 12 months, while the other half never received imaging; the median delay from initial substantiated clinical suspicion to echocardiography was 7 weeks. Although no data were provided on changes in management following a confirmed diagnosis of HF, it is plausible that patients in whom HF was validated by echocardiography received some degree of guideline-directed medical therapy (GDMT), as 1 year all-cause mortality was lower than in patients who never underwent echocardiography. International societies9,10 recommend introducing therapies to prevent the occurrence of heart dysfunction in patients at high risk of cardiovascular disease (CVD), even in the case of no signs and symptoms of HF. Recently, a few agents traditionally used as disease-modifying therapies in established HF—most notably, sodium–glucose co-transporter-2 (SGLT2) inhibitors and a non-steroidal mineralocorticoid receptor antagonist (MRA), namely finerenone—have demonstrated significant benefits when initiated earlier, effectively acting as disease-preventing therapies for heart dysfunction in patients with high risk of CVD. The European Society of Cardiology 2023 update of the 2021 HF guidelines9 recommended an SGLT2 inhibitor (class I, level A) for the prevention of HF hospitalization or cardiovascular death and finerenone for the prevention of HF hospitalization (class I, level A) in patients with T2D and CKD based on several studies.4,11–14 Recently, a glucagon-like peptide-1 receptor agonist was added to prevent HF.1 This growing body of evidence supports a paradigm shift in which early pharmacological intervention can interrupt or delay the pathological cascade from metabolic or renal disease to overt heart dysfunction, thereby challenging conventional treatment timelines and enabling preventive cardiology strategies before the onset of advanced or irreversible myocardial damage. Faced with the delay between the detection of elevated natriuretic peptides and the performance of echocardiography—which may confirm or exclude a diagnosis of HF—Docherty et al. took the reverse approach. They modelled the potential benefits of initiating preventive treatment for cardiac dysfunction, namely an SGLT2 inhibitor and an MRA, in patients at high risk of CVD, as an early-phase introduction of disease-modifying HF therapy. To this end, they applied treatment effect estimates for SGLT2 inhibitors and MRAs derived from meta-analyses of randomized, placebo-controlled trials in patients with established HF across the left ventricular ejection fraction (LVEF) spectrum.15,16 Their analysis suggested that, in at-risk individuals with a pre-existing indication for these therapies, initiating both at the time of detecting NT-proBNP ≥400 pg/mL could prevent roughly 80–90 HF hospitalizations or deaths per 1000 treated per year. The study has several limitations, many acknowledged in the Discussion. It highlights a shortcoming in the HF diagnostic pathway within the UK healthcare system, potentially relevant to other settings, but remains descriptive, as the modelling approach is only partially accurate when extrapolated to a population differing substantially from those enrolled in pivotal randomized trials. The hazard ratios used to project benefits came from studies including patients with confirmed HF—often younger, with different comorbidity profiles and systematically documented LVEF—whereas in the present cohort LVEF data were unavailable. The absence of echocardiographic information precludes stratification by HF phenotype and prevents exploration of interactions with other foundational therapies, which were not evaluated but may contribute to prognosis. Extrapolations also provide no information on the specific drugs used (particularly MRAs), their dosing, or titration. Although the supporting meta-analyses suggest a consistent effect across subgroups, applying these estimates to a dissimilar population introduces the risk of spectrum bias. The reliance on routinely collected healthcare data (CPRD) further compounds uncertainty, as eligibility variables (blood pressure, potassium, renal function, and diabetes) were extracted within a wide 12 month window, which may not reflect the status at the clinically relevant timepoint. Symptom burden and clinical presentation were incompletely captured, making it difficult to distinguish between patients who should have been prescribed therapy and those who, despite formally meeting criteria, were judged unlikely to benefit. The analysis was deliberately restricted to individuals with a pre-existing indication for an SGLT2 inhibitor and/or an MRA under current guidelines, excluding those with NT-proBNP ≥400 pg/mL but no other qualifying criteria. While this avoids unnecessary exposure in those without confirmed HF, it also excludes a subset who might benefit from earlier intervention. Comparing these groups would help disentangle drug effects on HF risk from their benefits in treating comorbidities. The hypothesized additive benefit of combining an SGLT2 inhibitor and an MRA—which implies a potentially greater, synergistic impact—remains biologically plausible yet unproven, as this has not been tested in outcome trials with hard endpoints. Finally, the absence of sensitivity analyses—testing alternative NT-proBNP thresholds (as recommended in European and North American guidelines), different follow-up durations, or safety and discontinuation outcomes—further limits the robustness and applicability of the finding. In summary, as described in the Graphical Abstract, applying international cardiology guidelines, including the correct thresholds for cardiac biomarkers, for all at-risk patients must be considered non-negotiable. A tiered strategy—preventing dysfunction in at-risk individuals and, when prevention fails, detecting NT-proBNP exceeding 125 pg/mL, prompt imaging, and rapid GDMT initiation—offers a far more effective and cost-efficient alternative to our current late-stage, treatment-focused paradigm. Embedding this approach within the 5P framework—Predictive, Preventive, Personalized, Participatory, and Population-based—and operationalizing it through precise multidisciplinary and interprofessional recommendations is essential to curb the growing burden of HF and to maintain normal cardiac function for as long as possible in high-risk populations. This effort should be recognized as a major national health priority, comparable with other leading public health challenges, in order to achieve meaningful and sustained impact. Importantly, embedding a ‘Keep the Heart Healthy’ strategy within public health policies would also enable systematic action on broader determinants of risk, including the disproportionate burden of disease in socioeconomically disadvantaged populations, the growing challenge of obesity, as well as the persistent delays and difficulties in implementing guideline-recommended care among women and older patients. To achieve these goals, more trials in prevention are urgently needed, supported by strong political commitment. Thanks to James Januzzi, MD, PhD for his great input. JB has nothing to declare. KGS has served on advisory board for Sanofi and received travel support for congress participation from AstraZeneca. AM received research contracts from 4TEEN4, Roche, Sphingotec, Abbott Diagnostics, Windtree; consultation fee from Roche, Corteria, Adrenomed, Fire, Johnson honorarium for lecture from Merck, Novartis, Roche, Bayer; is co-inventor of patent on combined therapies to treat dyspnea, owned by S-Form Pharma; member of Committee of trials for Secret-HF, sponsored by the French Government, for S-Form Pharma, for 4TEEN4, Echosens and Implicity.