Obesity Paradox Questioned: Genetic Analysis Shows No Protective Effect in CVD Patients
China: A recent study published in Diabetes, Obesity and Metabolism has questioned the long-debated “obesity paradox” in patients with cardiovascular disease (CVD). The research, conducted by Fuzhong Xue from the Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China, and colleagues, suggests that excess body fat does not offer a protective effect against cardiovascular mortality and that previous observations may be due to confounding factors rather than genuine benefit.
The so-called obesity paradox has been reported in several observational studies, where individuals with CVD who were classified as overweight or mildly obese based on body mass index (BMI) appeared to have lower mortality rates compared to those with normal weight. However, these findings have often been criticized for relying solely on BMI, which does not distinguish between fat and lean mass or account for fat distribution.
To address these gaps, the researchers analyzed data from 85,926 participants with CVD enrolled in the UK Biobank. They assessed the relationship between cardiovascular mortality and three different measures: BMI, body fat percentage (BF%), and waist-to-hip ratio adjusted for BMI (WHRadjBMI), which reflects central obesity. In addition, they used Mendelian randomization with polygenic risk scores (PRSs) for BMI, BF%, and WHRadjBMI to evaluate potential causal links, reducing the risk of bias seen in traditional observational studies.
The study led to the following findings:
- During a median follow-up of 13.6 years, 5,432 participants died from cardiovascular causes.
- BMI in the overweight and class-I obesity ranges was linked to lower mortality rates.
- A clear linear association was observed between higher body fat percentage (BF%) and waist-to-hip ratio adjusted for BMI (WHRadjBMI) with increased cardiovascular mortality risk.
- Genetic analyses showed no evidence that higher BMI or body fat reduced mortality, challenging the concept of a protective effect.
- Findings remained consistent across analyses stratified by sex, age, and type of cardiovascular disease.
- Using a single variant from the FTO gene (rs1558902) as an instrumental variable produced similar results.
- The study suggests the obesity paradox may stem from residual confounding or reverse causation in earlier research.
According to the authors, these results indicate that focusing on body fat percentage and central obesity provides a more accurate picture of risk in patients with CVD than relying on BMI alone. The study highlights the importance of targeting fat reduction, particularly abdominal fat, to improve outcomes in this patient group rather than assuming mild obesity may be protective.
The large-scale genetic and observational analysis adds significant weight to the argument against the obesity paradox, suggesting that the association between higher BMI and lower CVD mortality is likely an artifact of study design rather than a true biological effect.
Reference: https://doi.org/10.1111/dom.16649
