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Definitions of metabolic health

Clinical value of defining metabolic health is limited

The meta-analysis was conducted in 140,845 individuals from 14 cohort studies in which participants were classified as being either metabolically healthy or unhealthy

Definitions of metabolic health that have been proposed to help explain differences in the risk of developing type 2 diabetes between people of different weight may be less helpful than was thought, according to a meta-analysis of data from over 140,000 individuals published in Diabetes Care (‘Definitions of Metabolic Health and Risk of Future Type 2 Diabetes in BMI Categories: A Systematic Review and Network Meta-analysis‘). The analysis was undertaken by scientists at the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge, together with colleagues from the European Federation of Pharmaceutical Industries and Associations.

The observation that several risk factors for type 2 diabetes and cardiovascular disease, such as obesity, high fasting blood sugar or triglyceride levels and high blood pressure, often coexist gave rise to the notion of a ‘metabolic syndrome’ in which obesity is a central feature. However, not all obese individuals have these metabolic risk factors and thus more recently, the concept of metabolically healthy obesity has gained currency. It has also been suggested that there is an opposite phenotype of people who are not obese but have metabolic risk factors, a group sometimes referred to as the metabolically unhealthy lean.

Luca Lotta

“As the proportion of people who are obese continues to increase, it is important to identify those who are at greatest risk of developing type 2 diabetes and who may therefore benefit most from focused preventive actions,” said Dr Luca Lotta of the MRC Epidemiology Unit, who led the analysis. “However, there are several different definitions of metabolic health in use, and it has not been shown that these definitions are useful in identifying individuals at a high risk of developing type 2 diabetes in a clinical setting.”

In order to assess this, the authors reviewed the literature on the definitions of metabolic health, and undertook a meta-analysis of the relative risk of developing type 2 diabetes in lean, overweight and obese individuals.

The meta-analysis was conducted in 140,845 individuals from 14 cohort studies in which participants were classified as being either metabolically healthy or unhealthy. In the course of the follow up of these studies, 5,963 cases of type 2 diabetes were diagnosed. The authors found that individuals classified as metabolically unhealthy had a higher relative risk (RR) of type 2 diabetes compared with individuals classified as healthy in all categories of BMI, a measure of adiposity [RR (95% confidence interval, CI)]: lean individuals, 4.0 (95% CI: 3.0 – 5.1); overweight individuals, 3.4 (95% CI: 2.8 – 4.3); obese individuals, 2.5 (95% CI: 2.1 – 3.0).

The authors used this data to estimate the absolute risk of developing type 2 diabetes at five and ten years in each of the six BMI and metabolic health categories. This showed that metabolically healthy obese individuals had a cumulative incidence of type 2 diabetes over ten years of 3.1% (95% CI: 2.6 – 3.5%), which was lower than that of metabolically unhealthy obese individuals, who had a cumulative incidence of type 2 diabetes over ten years of 7.6% (95% CI: 7.3 – 8.0%).

However, it was still greater than that observed in metabolically unhealthy lean individuals, who had a cumulative incidence of type 2 diabetes over ten years of 2.2% (95% CI: 1.9 – 2.5%).

“This work indicates that current simplistic definitions of obesity and metabolic health are of limited value in a clinical setting and that the notion of metabolically health obesity is a misnomer as this category of people,” added Lotta. “While at lower risk than people who had metabolically unhealthy obesity, still had a higher absolute risk of developing type 2 diabetes than people who are lean but apparently metabolic unhealthy.”

Further analysis revealed that current definitions of metabolic health were not able to accurately predict future cases of type 2 diabetes. In lean individuals, testing metabolic health was not sensitive 40% (95% CI: 31 – 49%), but was specific 88% (95% CI: 84 – 91%) while in obese individuals, sensitivity was satisfactory 81% (95% CI: 76 – 86%) but specificity was low 42% (95% CI: 35 – 49%).

Nick Wareham

“It is important that we continue research to identify biological markers that will allow us to better predict the metabolic health consequences of obesity so that individual-level interventions can be targeted at those at highest risk,” said Professor Nick Wareham, Director of the MRC Epidemiology Unit. “As all the obese categories were at increased risk, these data support population-level interventions aimed at reducing the prevalence of obesity.”

The meta-analysis was supported by the Innovative Medicines Initiative, a joint undertaking between the European Union and the European Federation of Pharmaceutical Industries and Associations, the Netherlands Organization for Scientific Research, and the UK Medical Research Council.

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