Biomarkers for cardiovascular–kidney metabolic syndrome: Clinical utility in diagnosis, screening, and treatment

Diabetes, metabolic disease, chronic kidney disease (CKD), and cardiovascular disease are tightly interlinked and result in significant morbidity globally. Accordingly, the term cardiovascular–kidney–metabolic (CKM) syndrome has now been coined to encompass these conditions and guide the use of preventive strategies.1 Biomarkers may serve an important role in CKM conditions and further inform the diagnosis, risk stratification, and treatment decisions.2 In this special issue of Diabetes, Obesity, Metabolism, an update on the use of four established biomarkers, such as albuminuria, N-terminal B-type natriuretic peptide, high-sensitivity troponin, and lipoprotein A or Lp(a), is discussed with a focus on their relevance to clinical practice. Albuminuria refers to the presence of albumin in the urine and is correlated with adverse kidney and cardiovascular outcomes. In clinical practice, measurement of albuminuria is commonly performed using a spot urine albumin-to-creatinine ratio (UACR), typically obtained from a first-morning void or early morning void, which accounts for the stochastic nature of urine concentration. However, variability in the UACR necessitates repeat measurements to confirm increased albuminuria. In this issue, Beernick et al. review the role of albuminuria in screening and guiding treatment for individuals with CKD.3 Presently, screening for albuminuria is recommended for at-risk populations including those with diabetes, hypertension and cardiovascular disease. The KDIGO 2024 guidelines further consider that screening may be extended to older individuals, those with a family history of kidney disease or genetic predisposition, and systemic autoimmune conditions.4 Given the global burden of CKD, population-wide screening remains under exploration. For example, the THOMAS study demonstrated that home-based screening with UACR was cost-effective.5 Whether this approach is feasible at a population-wide scale remains uncertain given that screening for albuminuria even in high-risk populations remains underutilized.6 From a prognostic perspective, reductions in albuminuria predict long-term benefit on kidney function.7 This has been demonstrated in trials of sodium-glucose cotransporter 2 inhibitors, non-steroidal mineralocorticoid receptor antagonists, and glucagon-like peptide 1 receptor agonists which not only reduce albuminuria but also have been shown to prevent CKD progression.7-11 Individuals with the highest degrees of albuminuria may obtain the greatest absolute benefit from these therapies,12 and residual albuminuria may identify individuals who warrant additional treatment. The benefit of combination therapy was recently observed in the CONFIDENCE trial which found that the combination of finerenone and empagliflozin resulted in greater reductions in UACR than either treatment alone.13 Thus, in clinical practice, monitoring the change in UACR with treatment may help to guide the use of additional medications which reduce cardiorenal risk. Additional therapies including soluble guanylate cyclase activators, aldosterone synthase inhibitors, and other incretin-based therapies remain under evaluation to determine whether further albuminuria lowering may be achieved with these medication classes and whether this translates into additional clinical benefit. Next in this series of articles, Jhund describes the role of using N-terminal pro-B-type natriuretic peptide (NT-proBNP) as an early biomarker to screen for left ventricular systolic dysfunction in at-risk individuals.14 Natriuretic peptides including BNP are released in response to left ventricular stretch from atrial granules and have been used for the diagnosis of heart failure for over two decades.15 While both active BNP and the inactive NT-proBNP may be measured, NT-proBNP is now preferred for clinical use due to its greater stability and longer half-life. The American Diabetes Association recommends NT-proBNP as a biomarker for the early detection of asymptomatic heart failure.16 Improved laboratory turnaround times have also enabled NT-proBNP testing at the point of care.17 Notably, NT-proBNP levels are increased in the setting of increased age, CKD, and atrial fibrillation. Sex and ethnicity may also influence levels, while obesity is associated with lower concentrations due to enhanced clearance of natriuretic peptides by adipose tissue. Furthermore, different thresholds are used in the acute setting versus the ambulatory setting. Thus, a challenge remains in incorporating these factors into clinical interpretation and in decision rules. Elevated levels of NT-proBNP are associated with a higher risk for adverse clinical outcomes including hospitalization and death. In people with diabetes, kidney disease or established cardiovascular disease, measurement of natriuretic peptides is recognized to provide prognostic information on the risk for heart failure and death, reflective of the role of cardiac neurohormonal activation as a risk factor for adverse outcomes.18-21 From a clinical trial perspective, NT-proBNP levels have been used to enrich for an at-risk population. For example, in the PONTIAC trial, 300 patients with type 2 diabetes mellitus without known cardiac disease but with an elevated NT-proBNP were selected to receive intensive initiation of renin-angiotensin-aldosterone system blockade and beta blockade versus controls who received usual diabetes care. Those in the intensive arm had a lower risk for hospitalization and death from cardiac causes than controls.22 Conversely, whether NT-proBNP levels can inform strategies to optimise cardiorenal therapies remains uncertain. In the STRONG-HF trial, high intensity rapid up-titration of goal-directed medical therapy (GDMT) was evaluated and changes in NT-proBNP were a component of the algorithm used.23 While the trial found that rapid institution of GDMT reduced the primary outcome of heart failure readmission and death, this occurred irrespective of the baseline NT-proBNP level.24 Thus, while NT-proBNP is used routinely to diagnose heart failure, more work is needed to elucidate whether NT-proBNP levels will have further clinical utility in optimising treatment. Alongside natriuretic peptides, troponin has emerged as an important biomarker in the clinical evaluation of chest pain or dyspnoea. Under conditions of myocardial ischemia, cardiac troponin is released from the myocardium into the circulation where it may be detected using high-sensitivity assays as evidence of cardiac injury.25 High-sensitivity cardiac troponin (hs-cTn) is now routinely used as a cardiac biomarker in the diagnosis of acute coronary syndrome (ACS). A newer area of focus discussed by McDermott et al. is the potential for point of care troponin testing to meet the analytical criteria for high-sensitivity assays performed at central laboratories, enabling incorporation into additional clinical settings, including primary care, ambulance/emergency medical services, and emergency departments.26 However, in the WESTCOR trial, point of care testing evaluated in the emergency setting demonstrated only a very modest reduction in length of stay.27 This question is being further explored in the POB HELP trial, which will evaluate whether incorporating point of care hs-cTn into a decision rule will reduce hospital referrals for ACS.28 Beyond ACS, it is possible that hs-cTn elevation may have utility in guiding therapy in those with chronic coronary syndromes, which include microvascular disease resulting in reversible transient myocardial ischaemia. However, this remains underexplored, and more evidence is required in this domain.29 While serial troponins were previously considered essential to exclude ACS, studies with hs-cTn assays have now demonstrated that a single reading may be sufficient to exclude ACS.30 While this may improve efficiency in excluding ACS, it is important to recognize that serial levels may remain necessary when the timing of symptom onset is under 3 hours. Outside of the acute setting, elevated hs-cTn measurement in stable individuals with cardiometabolic disease is associated with an increased long-term risk of cardiovascular events,31 and may improve risk stratification, particularly for heart failure.32 Prospective studies are needed to more firmly establish how the outpatient measurement of hs-cTn can inform the selection and use of available preventive treatments. A relatively newer biomarker which has entered clinical practice is Lp(a) which has been found to predict increased cardiovascular risk independent of traditional risk factors and is discussed in the article by Razavi et al.33 Despite studies demonstrating that 20% of the population have elevated Lp(a) levels, rates of screening remain low.34 Lp(a) is a lipoprotein which possesses atherogenic properties as it facilitates the accumulation of oxidized phospholipids and competitively inhibits plasminogen activity. The causative role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) has garnered attention given an accumulating body of epidemiologic evidence correlating elevated Lp(a) with increased risk of ASCVD, death, and calcific aortic disease in multi-ethnic populations.35 A unique aspect of Lp(a) is that levels are predominantly (>90%) genetically pre-determined and thus levels remain stable over the course of an individual's lifespan. Given this, a single measurement at this time is presently considered sufficient for screening. Current measurement of Lp(a) typically employs immunoassays. Presently, heterogeneity in the size of Apo(a) poses a challenge in measurement and ongoing efforts are being made to standardise testing and reporting. Given limitations in assay availability and cost, screening is currently only recommended for selected high-risk populations, although there is interest in exploring a single lifetime measurement in the general population. The paradigm by which Lp(a) informs treatment is evolving. Unlike lipids, Lp(a) levels are not modified by lifestyle interventions. Statins modestly increase Lp(a) but remain important for reduction in overall ASCVD risk. PCKS9 inhibitors have been shown to lower Lp(a) by 25–30% with greater reduction in ASCVD observed in those with the highest Lp(a) levels.36, 37 Given the pro-thrombotic properties of Lp(a), aspirin may be considered in those with elevated Lp(a) although this has not been confirmed prospectively.38 More recently, specific potent Lp(a) lowering therapies have been developed which include subcutaneous antisense oligonucleotides (pelcarsen) and silencing interfering RNA based agents (olpasiran, lepodisiran, zerlasiran) which inhibit hepatic production.39 Oral small molecules such as muvalaplin are also under evaluation.40 Lp(a) specific therapies are now being studied in several cardiovascular outcome trials (HORIZON, OCEAN and ACCLAIM) and the results of these studies will be pivotal in informing our understanding of whether Lp(a) lowering constitutes a modifiable cardiac risk factor. Furthermore, should these trials demonstrate the clinical benefit of Lp(a) directed therapies, the role of monitoring serial Lp(a) levels will warrant further exploration. There is a growing burden of CKM syndrome, and the use of biomarkers including albuminuria, NT-proBNP, hs-cTn and Lp(a) may be used to aid in diagnosis and inform therapy. A commonality amongst these biomarkers is the greater need for standardization in measurement and reporting. Ongoing work is underway to determine whether disease screening efforts in broader populations are warranted, and how biomarker levels may inform personalized treatment in an era of precision medicine. Furthermore, technological advances may allow for greater opportunity to measure these biomarkers from home or at the point-of-care. KY, DZIC and AO all contributed to the writing of the manuscript and provided critical edits, reviewed and approved the final manuscript. This Guest Editorial was commissioned by the Editor as part of a themed issue on Biomarkers made possible by funding from Roche Diagnostics. Sponsor identity was not disclosed to the authors prior to publication KY and AO are supported by KRESCENT New Investigator Awards. The KRESCENT program is co-sponsored by the Kidney Foundation of Canada, the Canadian Society of Nephrology, and the Canadian Institute of Health Research. DZIC is supported by a Department of Medicine, University of Toronto Merit Award and receives support from the Canadian Institute of Health Research, Diabetes Canada and the Heart and Stroke Richard Lewar Centre of Excellence. He is also the Gabor Zellerman Chair in Nephrology Research, University of Toronto, and is also supported by a CIHR-Kidney Foundation of Canada Team Grant Award, with additional support from Breakthrough-T1D. AO is also supported by the Black Research Network and the Canadian Institute for Health Research, Research Excellence, Diversity, and Independence (REDI) Grant. DZIC has received honoraria from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, AMGEN, Bayer, Prometic, BMS, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon, Inversago, GSK, Biobridge, Vantage, Altimmune and Novo-Nordisk and has received operational funding for clinical trials from Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring, Lexicon, Novo-Nordisk and Bayer. KY and AO declare no conflicts of interest. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.70044. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.