Heart, liver, metabolism: the global CLM syndemic

Summary: Cardiovascular disease, fatty liver disease (MASLD), type 2 diabetes and obesity often occur together and reinforce each other. A review in Nature Reviews Cardiology calls this a “syndemic”: in 2021 alone it caused 21.2 million deaths and 435 million lost healthy life years. The authors propose a three-level framework: estimate risk more precisely, strengthen communities and tackle social causes.

State of the evidence: The review appeared in volume 23 (April 2026) of the journal. Its figures mostly come from 2021; projections run to 2050. The methods are in the paper's supplementary material. This article was written on 17 October 2026; newer studies are not included.

What is it about?

A syndemic is the interaction of several epidemics that reinforce each other and are driven by shared social causes. Here these are cardiovascular disease, MASLD (metabolic dysfunction-associated steatotic liver disease, formerly NAFLD), type 2 diabetes and obesity (the CLM syndemic, from “cardiovascular–liver–metabolic”). Shared pathways include inflammation, insulin resistance and excess belly fat.

How was it studied?

This is a review by Chew, Sperling and colleagues from Singapore and the USA, not a new patient study. It summarises epidemiological data on disease burden, shows projections to 2050 and proposes measures at three levels (micro: individuals, meso: communities, macro: policy and health systems).

What does the review show?

• Many people affected: In 2021, about one in three adults (32%) lived with MASLD, around 1.27 billion people. About one in four people had obesity, and 506 million had type 2 diabetes (10.5% of 20- to 79-year-olds).
• More common together: MASLD occurs in 65 to 70% of people with type 2 diabetes and in 75.3% of people with obesity. People with MASLD die more often from cardiovascular disease (4.20 deaths per 1,000 person-years) than from the liver (0.92) or from cancer outside the liver (2.83).
• Progress slowed: The decades-long fall in cardiovascular mortality has levelled off. In the USA, the linked diseases cost almost US$500 billion directly and US$1.2 trillion indirectly each year.
• Unequally spread: Age-standardised cardiovascular mortality is highest in Central and Eastern Europe and Central Asia (376.1 per 100,000), MASLD mortality highest in Latin America and the Caribbean (3.4 per 100,000). Social disadvantage such as poverty, low education and food insecurity worsens outcomes.
• Outlook to 2050: The number of people with cardiovascular disease is projected to rise by 90%, mainly through population growth and ageing. Per 100,000 people, lost healthy life years from heart attack fall by 41.6% and stroke mortality by 37.5%, while lost life years from type 2 diabetes rise by 22.3%.
• Recognised too late: In a global survey, 64% of primary-care physicians underestimated how common MASLD is; in a US study, only 46% of 250 primary-care physicians reported screening people with obesity and type 2 diabetes.
• Fibrosis test with weaknesses: The FIB-4 index detects advanced fibrosis with 98% specificity but only 33% sensitivity. For people aged 65 and over, a threshold of 2.0 is advised; in people up to 35 it performs poorly.
• Use available medicines: SGLT2 inhibitors, GLP-1 receptor agonists and PPAR agents can lower blood sugar, weight and liver fat together, but are prescribed too rarely.
• Trials leave out the liver: In the semaglutide heart trial named SELECT, only 8.2% of participants had MASLD. The authors call for liver disease to be included in heart trials.

Where are the limits?

• This is a review, not a systematic review; the authors chose the sources.
• Projections to 2050 are model calculations with large uncertainty.
• Whether MASLD causes cardiovascular disease or merely occurs with it is unsettled; genetic analyses do not prove a causal link.
• The definition of the CLM syndemic is not yet uniform; the proposed framework is a concept and not yet tested in practice.
• Knowledge of the course of MASLD comes mostly from liver-biopsy registries, which can skew the picture. In regions with little diagnostics, the burden may be underestimated.

What does this mean for me?

The review describes populations and says nothing about your personal risk. It does show that heart, liver, blood sugar and weight should be considered together. If you have obesity, type 2 diabetes or other cardiovascular risk factors, you can ask your family doctor to assess your risk of liver fibrosis. Discuss with your doctor which tests and treatments make sense for you.

This article does not replace medical advice.

Source and notes

• Citation: Chew NWS, Mehta A, Goh R, et al. The global cardiovascular–liver–metabolic syndemic: epidemiology, trends and challenges. Nat Rev Cardiol 2026;23:219–238. DOI: 10.1038/s41569-025-01220-4.
• Study type: Review article with epidemiological data and projections.
• Funding: Several authors receive funds from the National University Health System Seed Fund, the CSDU Clinician-Scientist Grant and the National Medical Research Council Singapore. The work is based on work supported by the CADENCE programme (Cardiovascular Disease Collaborative Enterprise).
• Conflicts of interest: Several authors report fees, consulting or research grants from pharmaceutical and medical technology companies, including Novo Nordisk, Eli Lilly and Boehringer Ingelheim; one author reports stock options. The other authors report no competing interests.