Body mass index versus surrogate measures of central adiposity as independent predictors of mortality in type 2 diabetes
Authors: Orsi Emanuela , Solini Anna , Penno Giuseppe , Bonora Enzo , Fondelli Cecilia , Trevisan Roberto , Vedovato Monica , Cavalot Franco , Lamacchia Olga , Haxhi Jonida , Nicolucci Antonio , Pugliese Giuseppe ,   for the Renal Insufficiency And Cardiovascular Events (RIACE) Study Group, Laviola Luigi , Bollanti Lucilla , Alessi Elena , Vitale Martina , Cirrito Tiziana , Cavallo-Perin Paolo , Gruden Gabriella , Lorenzati Bartolomeo , Trovati Mariella , Di Martino Leonardo , Mazzaglia Fabio , Zerbini Giampaolo , Martina Valentina , Maestroni Silvia , Capuano Valentina , Palmieri Eva , Lunati Elena , Grancini Valeria , Resi Veronica , Pontiroli Antonio , Veronelli Annamaria , Zecchini Barbara , Arosio Maura , Montefusco Laura , Rossi Antonio , Adda Guido , Corsi Anna , Albizzi Mascia , Zoppini Giacomo , Avogaro Angelo , Pucci Laura , Lucchesi Daniela , Russo Eleonora , Garofolo Monia , Dotta Francesco , Nigi Laura , Morano Susanna , Filardi Tiziana , Turinese Irene , Rossetti Marco , Buzzetti Raffaella , Foffi Chiara , Cignarelli Mauro , Pinnelli Sabina , Monaco Lucia , Giorgino Francesco , Natalicchio Annalisa , Sesti Giorgio , Andreozzi Francesco , Baroni Marco Giorgio , Frau Giuseppina , Boi Alessandra 
Published: December 2022

Abstract
Background
An “obesity paradox” for mortality has been shown in chronic disorders such as diabetes, and attributed to methodological bias, including the use of body mass index (BMI) for obesity definition. This analysis investigated the independent association of BMI versus surrogate measures of central adiposity with all-cause mortality in individuals with type 2 diabetes.

Methods
The Renal Insufficiency And Cardiovascular Events Italian Multicentre Study is a prospective cohort study that enrolled 15,773 patients in 19 Italian centres in 2006–2008. Exposures were BMI and the surrogate measures of central adiposity waist circumference (WC), waist-to-height ratio (WHtR), and A Body Shape Index (ABSI). Vital status was retrieved on 31 October 2015 for 15,656 patients (99.3%),

Results
Age- and sex-adjusted hazard ratios and 95% confidence intervals were significantly higher in BMI-based underweight (1.729 [1.193–2.505), P = 0.004), moderately obese (1.214 [1.058–1.392), P = 0.006) and severely obese (1.703 [1.402–2.068), P < 0.0001), lower in overweight (0.842 [0.775–0.915), P < 0.0001) and similar in mildly obese (0.950 [0.864–1.045), P = 0.292), compared to normal-weight individuals. When further adjusting for smoking, physical activity (PA), and comorbidities, risk was lower also in mildly obese versus normal-weight patients. The BMI-mortality relationship did not change after sequentially excluding ever smokers, individuals with comorbidities, and those died within two years from enrollment and when analyzing separately participants below and above the median age. Conversely, a paradox relationship was observed among inactive/moderately inactive, but not moderately/highly active patients. Mortality risk adjusted for age, gender, smoking, PA and comorbidities was significantly higher in the highest tertile of WC (1.279 [1.089–1.501], P = 0.003), WHtR (1.372 [1.165–1.615], P < 0.0001), and ABSI (1.263 [1.067–1.495], P = 0.007) versus the lowest tertile. However, risk was lower in the intermediate versus lowest tertile for WC (0.823 [0.693–0.979], P = 0.028), similar for WHtR, and higher, though not significantly, for ABSI.

Conclusions
An “overweight paradox” remained after controlling for age, smoking, and comorbidities, arguing against a collider bias or reverse causation. However, it could be partly explained by confounding from PA level, possibly through its impact on lean mass and cardiorespiratory fitness. No obesity paradox was observed with WHtR and especially ABSI, which predicted mortality risk associated with central adiposity better than WC.
Trial registration ClinicalTrials.gov, NCT00715481, 15 July, 2008