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Epidemiology and Population Health

Association between BMI, RFM and mortality and potential mediators: Prospective findings from the Moli-sani study

International Journal of Obesity volume 47, pages 697–708 (2023)Cite this article

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Abstract

Background

Body mass index (BMI) is the most frequently used adiposity measure, yet it is unable to differentiate fat mass from lean mass. Relative fat mass (RFM) has been proposed as an alternative. This paper aims to study RFM and BMI association with mortality in a general Italian population and potential mediators of such association.

Methods

20,587 individuals from the Moli-sani cohort were analysed (mean age = 54 ± 11, women = 52%, median follow up = 11.2 years, interquartile range = 1.96 years). Cox regressions were used to assess BMI, RFM, and their interactive association with mortality. Dose-response relationships were computed with spline regression, mediation analysis was performed. All analyses were separated for men and women.

Results

Men and women with BMI > 35 kg/m2 and men in the 4th quartile of RFM showed an independent association with mortality (HR = 1.71, 95% CI = 1.30–2.26 BMI in men, HR = 1.37, 95%CI = 1.01–1.85 BMI in women, HR = 1.37 CI 95% = 1.11–1.68 RFM in men), that was lost once adjusted for potential mediators. Cubic splines showed a U-shaped association for BMI in men and women, and for RFM in men. Mediation analysis showed that 46.5% of the association of BMI with mortality in men was mediated by glucose, C reactive protein, forced expiratory volume in 1 s (FEV1), and cystatin C; 82.9% of the association of BMI in women was mediated by HOMA index, cystatin C and FEV1; lastly, 55% of RFM association with mortality was mediated by glucose, FEV1 and cystatin C. Regression models including BMI and RFM showed that RFM drives most of the risk in men, but is not predictive in women.

Conclusions

The association between anthropometric measures and mortality was U shaped and it was largely dependent on sex. Associations were mediated by glucose metabolism, renal and lung function. Public health interventions should mainly focus on people with severe obesity or impaired metabolic, renal, or respiratory function.

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Fig. 1: Cubic splines of the associations between BMI and all-cause mortality.
Fig. 2: Cubic splines of the associations between RFM and all-cause mortality.

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Data availability

The data underlying this article will be shared on reasonable request to the corresponding author. The data are stored in an institutional repository (https://repository.neuromed.it) and access is restricted by the ethical approvals and the legislation of the European Union.

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Acknowledgements

We are grateful to the Moli-sani Study participants who enthusiastically joined the study, and wish to thank the Associazione Cuore Sano ONLUS (Campobasso, Italy) for its encouragement and support to our research activities.

Funding

The enrolment phase of the Moli-sani Study was supported by an unrestricted research grant from Pfizer Foundation (Rome, Italy), by the Italian Ministry of University and Research (MIUR, Rome, Italy–Programma Triennale di Ricerca, Decreto no.1588) and by Instrumentation Laboratory, Milan, Italy. The present analyses were partially supported by a grant to LI (AIRC Individual Grant - Project Code: 25942) and by the Italian Ministry of Health (Ricerca Corrente 2022–2024). Funders had no role in study design, collection, analysis, and interpretation of data, nor in the writing of the manuscript or in the decision to submit the article for publication. All Authors were and are independent from funders.

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Authors and Affiliations

  1. Research Center in Epidemiology and Preventive Medicine (EPIMED), Department of Medicine and Surgery, University of Insubria, Varese, Italy

    Anwal Ghulam, Francesco Gianfagna, Alessandro Gialluisi & Licia Iacoviello

  2. Mediterranea Cardiocentro, Napoli, Italy

    Francesco Gianfagna, Augusto Di Castelnuovo & Augusto Di Castelnuovo

  3. Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli, Italy

    Marialaura Bonaccio, Simona Costanzo, Amalia De Curtis, Alessandro Gialluisi, Chiara Cerletti, Maria Benedetta Donati, Giovanni de Gaetano, Licia Iacoviello, Giovanni de Gaetano, Americo Bonanni, Amalia De Curtis, Mariarosaria Persichillo, Teresa Di Prospero, Livia Rago, Teresa Panzera, Simona Esposito, Sabatino Orlandi, Emilia Ruggiero, Alfonsina Tirozzi, Sara Magnacca, Fabrizia Noro & Francesca Bracone

  4. Catholic University, Leuven, Belgium

    Jos Vermylen

  5. Pontificia Accademia per la Vita, Roma, Italy

    Renzo Pegoraro

  6. Università Cattolica del Sacro Cuore, Roma, Italy

    Antonio Spagnolo

  7. ASST Spedali Civili di Brescia, Brescia, Italy

    Deodato Assanelli

  8. Associazione Cuore Sano ETS, Campobasso, Italy

    Marco Olivieri

Authors
  1. Anwal Ghulam
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  6. Amalia De Curtis
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Consortia

for the Moli-sani Investigators

  • Steering Committee

    • Licia Iacoviello
    • , Giovanni de Gaetano
    •  & Maria Benedetta Donati

  • Scientific Secretariat

    • Marialaura Bonaccio
    • , Americo Bonanni
    • , Chiara Cerletti
    • , Simona Costanzo
    • , Amalia De Curtis
    • , Augusto Di Castelnuovo
    • , Alessandro Gialluisi
    • , Francesco Gianfagna
    • , Mariarosaria Persichillo
    •  & Teresa Di Prospero

  • Safety and Ethical Committee

    • Jos Vermylen
    • , Renzo Pegoraro
    •  & Antonio Spagnolo

  • External Event Adjudicating Committee

    • Deodato Assanelli
    •  & Livia Rago

  • Baseline and Follow-up Data Management

    • Simona Costanzo
    • , Marco Olivieri
    •  & Teresa Panzera

  • Data Analysis

    • Augusto Di Castelnuovo
    • , Marialaura Bonaccio
    • , Simona Costanzo
    • , Simona Esposito
    • , Alessandro Gialluisi
    • , Francesco Gianfagna
    • , Sabatino Orlandi
    • , Emilia Ruggiero
    •  & Alfonsina Tirozzi

  • Biobank, Molecular and Genetic Laboratory

    • Amalia De Curtis
    • , Sara Magnacca
    • , Fabrizia Noro
    •  & Alfonsina Tirozzi

  • Recruitment Staff

    • Mariarosaria Persichillo
    • , Francesca Bracone
    •  & Teresa Panzera

  • Communication and Press Office

    • Americo Bonanni

Contributions

AnG, FG, MB and LI conceived and designed the study. ADC managed the Moli-sani biobank and processed biological samples. SC managed the Moli-sani database. AnG and FG analysed the data. ADiC and AlG supervised the analysis. AnG and FG drafted the manuscript. CC, MBD, GdG and LI originally promoted the Moli-sani study; MB, ADiC, ADC, AlG, SC, MBD, GdG and LI critically revised this manuscript. All Authors gave final approval and agreed to be accountable for all aspects of the work ensuring integrity and accuracy.

Corresponding author

Correspondence to Francesco Gianfagna.

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Ghulam, A., Gianfagna, F., Bonaccio, M. et al. Association between BMI, RFM and mortality and potential mediators: Prospective findings from the Moli-sani study. Int J Obes 47, 697–708 (2023). https://doi.org/10.1038/s41366-023-01313-5

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