The move towards a holistic approach is advancing at pace
The increasing recognition of biological and clinical interconnection between cardiovascular, renal, and metabolic (CVRM) diseases is clear to see. A shift away from siloed, stepwise treatment approaches towards mechanistic, holistic management of risk is advancing at pace. This is in part driven by the emergence of cornerstone therapies such as SGLT2 inhibitors and GLP-1 receptor agonists, but also reflects a more integrated understanding of patient health; one that recognizes the close interplay between cardiovascular disease, kidney impairment, and metabolic function. Emerging frameworks make the case for a unified, system-level approach to cardiometabolic disease. They outline the case for treatment of ‘CKM syndrome’ (cardiovascular-kidney-metabolic syndrome) and holistic staging of risk with a goal of preventing overall cardiovascular risk and, ultimately, morbidity1.
But isn’t there an important (liver-shaped) piece missing?
Despite growing recognition of the interconnected nature of chronic disease, the liver is surprisingly absent from many of the frameworks shaping cardiometabolic care. Metabolic dysfunction-associated steatohepatitis (MASH) remains secondary within the broader CVRM narrative. Where it is considered, the move towards a more integrated approach to managing risk may actually detract focus from disease-specific interventions in MASH in favor of broader, often lifestyle-focused, comorbidity-directed approaches.
Is MASH the overlooked pillar of cardiometabolic risk?
MASLD (metabolic dysfunction-associated steatotic liver disease) has an estimated global prevalence of over 16·1% and affects approximately 1.3 billion people. With approximately 1 in 5 of these patients progressing to MASH (Metabolic dysfunction-associated steatohepatitis), this is a major global chronic disease2,3.
MASH management has historically been centered around lifestyle intervention: weight loss, dietary change, and management of upstream metabolic drivers. In practice, liver disease was often viewed as a downstream consequence of obesity or Type 2 Diabetes, rather than a distinct clinical priority requiring targeted intervention. That framing persists today.
MASH is frequently positioned as part of a broader metabolic picture rather than a condition requiring independent attention, with an apparent lack of appetite to medicalize and target underlying disease processes. While understandable given the close relationship between obesity, insulin resistance, and liver disease, this mindset shapes clinical behavior in subtle but important ways:
- prioritizing glycaemic or cardiovascular management ahead of liver-specific assessment
- viewing liver disease improvement as an indirect consequence of weight reduction alone
- reinforcing focus on lifestyle-only interventions, and consequently stigma around the condition
- delaying disease-specific intervention(s) until fibrosis progression or advanced disease becomes clinically unavoidable
Emerging understanding of MASH also raises broader questions around the liver’s role within cardiometabolic risk itself. Growing evidence suggests liver pathology may also contribute to systemic inflammation and long-term cardiovascular risk, operating as an independent risk factor for cardiovascular morbidity4.
A shifting MASH treatment landscape moves closer to a disease modification mindset
However, the treatment landscape is beginning to shift. Disease-specific therapies targeting liver pathology are now emerging – the launch of Rezdiffra (resmetirom) paves the way for MASH-specific therapies. Developmental therapies targeting hepatic lipid reduction and anti-fibrotic action (such as FGF21 (fibroblast growth factor 21) analogue/fusion proteins, FASN inhibition, dual GLP-1/glucagon agonists) will advance the ability to treat MASH further, thus reducing reliance on lifestyle and incretin -based pharmacological approaches. This redefines the situation.
Now is the time to put the ‘L’ in CVRM
Now MASH is increasingly treatable in its own right, earlier identification of liver disease is more clinically meaningful. Monitoring can no longer be viewed solely through the lens of obesity or diabetes management, but as part of a broader effort to identify patients at risk of progressive liver damage before irreversible disease develops.
‘L’ is the missing piece in the CVRM jigsaw – the absence of the liver from broader CVRM frameworks is becoming increasingly significant.
CVRM frameworks need to rapidly evolve to support the shift to targeted treatment of MASH – with a focus on recognition of the disease in its own right and operationalizing disease-specific care early enough to meaningfully reduce risk. That’s why we believe it’s time to put the L in CVRM.
References:
- Ndumele, C. E., Rangaswami, J., Chow, S. L., Neeland, I. J., Tuttle, K. R., Khan, S. S., Coresh, J., Mathew, R. O., Baker-Smith, C. M., Carnethon, M. R., Després, J.-P., Ho, J. E., Joseph, J. J., Kernan, W. N., Khera, A., Kosiborod, M. N., Lekavich, C. L., Lewis, E. F., Lo, K. B., Ozkan, B., Palaniappan, L. P., Patel, S. S., Pencina, M. J., Powell-Wiley, T. M., Sperling, L. S., Virani, S. S., Wright, J. T., Rajgopal Singh, R., & Elkind, M. S. V. (2023).
Cardiovascular-kidney-metabolic health: A presidential advisory from the American Heart Association. Circulation, 148(20), 1606–1635.
https://doi.org/10.1161/CIR.0000000000001184 - Miao, L., Targher, G., Byrne, C. D., Cao, Y.-Y., & Zheng, M.-H. (2024).
Current status and future trends of the global burden of MASLD. Trends in Endocrinology & Metabolism, 35(8), 697–707.
https://doi.org/10.1016/j.tem.2024.02.007 - GBD 2023 MASLD Collaborators. (2026).
Global burden of metabolic dysfunction-associated steatotic liver disease, 1990–2023, and projections to 2050: A systematic analysis for the Global Burden of Disease Study 2023. The Lancet Gastroenterology & Hepatology, 11(6), 463–494.
https://doi.org/10.1016/S2468-1253(26)00011-7 - Eslam, M., Sanyal, A. J., George, J., & International Consensus Panel. (2024).
Systemic impacts of metabolic dysfunction-associated steatotic liver disease (MASLD). Frontiers in Cell and Developmental Biology, 12, Article 1433857.
https://doi.org/10.3389/fcell.2024.1433857