Genetic evidence challenges the obesity paradox in cardiovascular-kidney-metabolic disease

The long-debated obesity paradox—the observation that people with overweight or obesity sometimes show lower mortality risk in certain diseases—may be an artefact of using body mass index as a measure of adiposity rather than a genuine protective effect of excess body fat, according to a study published in Cardiovascular Diabetology. The research, which examined mortality across the cardiovascular-kidney-metabolic (CKM) syndrome continuum, combined observational cohort data with genetic analyses to test whether the pattern holds up when inherited susceptibility to higher BMI is considered instead of measured weight.

The obesity paradox, generally defined by BMI, refers to the finding that individuals with overweight or obesity have lower mortality risk in certain conditions. The authors note that inherent observational confounding and reverse causation may bias such findings, and it has remained unclear whether genetic susceptibility to higher BMI shows the same pattern. To address this, the team conducted two-sample Mendelian randomization analyses to estimate potential causal effects of higher BMI on susceptibility to six CKM conditions, used Global Burden of Disease 2021 data to quantify the proportions of deaths from these conditions attributable to high BMI, and drew on genome-wide association studies to characterize genetic associations with CKM phenotypes.

The genetic and global-health analyses pointed consistently in one direction. Genetically predicted higher BMI was associated with greater susceptibility to all six CKM conditions, and the GBD analyses indicated a corresponding mortality burden attributable to high BMI. The CKM genome-wide association studies showed enrichment of lipid and lipoprotein metabolism pathways, reinforcing the metabolic links running through the continuum.

The observational side of the study drew on two large cohorts: the UK Biobank, with 488,656 participants, and NHANES, with 13,114. Using Cox regression, restricted cubic splines and two-piecewise Cox models, the researchers evaluated associations of measured BMI with all-cause and cardiovascular disease mortality across CKM stages. In both cohorts, measured BMI showed broadly U-shaped associations with mortality, and the fitted curve’s nadir generally shifted toward higher BMI as CKM stage advanced.

The magnitude of that shift was substantial. For all-cause mortality, the estimated breakpoint increased from 25.88 to 27.06 kg/m² across stages 2 to 4 in the UK Biobank, and from 22.10 kg/m² in stage 0 to approximately 30 kg/m² in stages 2 to 4 in NHANES, with similar trends observed for cardiovascular disease mortality. In other words, the BMI value associated with the lowest estimated mortality risk rose as disease progressed along the CKM continuum—the pattern conventionally described as the obesity paradox.

The picture changed markedly when the researchers turned to genetics. Using a BMI genetic risk score (BMI-GRS) in the UK Biobank, they examined whether inherited susceptibility to higher BMI exhibited mortality association patterns comparable to those seen for measured BMI. It did not. The BMI-GRS showed approximately linear adverse associations with all-cause mortality, with a hazard ratio of 1.05 per one-standard-deviation increment (95% CI 1.04–1.06), and with cardiovascular disease mortality, with a hazard ratio of 1.10 (95% CI 1.07–1.12). Moreover, mortality risk increased progressively with advancing CKM stage across BMI-GRS strata, with a trend P value below 0.001. There was no survival advantage at any stage for genetic susceptibility to higher BMI.

To probe the biology behind the measured-BMI association, the team conducted exploratory proteomic mediation analyses among participants with advanced CKM stages. These analyses highlighted FABP4, ADM, FSTL3 and LEP as candidate protein signals related to the BMI–mortality association in advanced CKM stages. The authors frame these as candidate signals from exploratory analyses rather than established mediators.

The study’s conclusion is direct: the apparent obesity paradox in observational studies may partly reflect the limitations of BMI as a proxy for adiposity, rather than a true protective effect of excess adiposity. Because measured BMI and genetically predicted BMI diverge so sharply in their mortality associations, the findings suggest that the U-shaped curves seen in cohort data may arise from characteristics of BMI itself as a crude measure rather than from any benefit of carrying more weight once disease is established.

The authors suggest the work may influence clinical practice by supporting the use of adiposity measures beyond BMI to assess prognostic risk. The study is published as open access research, and the version shared ahead of the final Version of Record is citable and carries a permanent DOI, subject to further edits. As with any observational and genetic analysis of this kind, the results describe associations and causal estimates within the studied populations and methods, and the proteomic findings remain exploratory pending further investigation.

Subject of Research: The relationship between body mass index and mortality across the cardiovascular-kidney-metabolic syndrome continuum

Article Title: Revisiting the BMI-based obesity paradox in mortality risk across the cardiovascular-kidney-metabolic syndrome continuum

Article References: Lu, J., Sun, S., Wang, S., Deng, Z., Wei, C., Jiang, S., & Li, W. (2026). Revisiting the BMI-based obesity paradox in mortality risk across the cardiovascular-kidney-metabolic syndrome continuum. Cardiovascular Diabetology. https://doi.org/10.1186/s12933-026-03419-2

Image Credits: AI Generated

DOI: 10.1186/s12933-026-03419-2

Keywords: obesity paradox, body mass index, cardiovascular-kidney-metabolic syndrome, Mendelian randomization, mortality, UK Biobank, NHANES, genetic risk score, Global Burden of Disease, proteomics, adiposity, Revisiting