Principal findings
The current study demonstrated that people with MHO were at a substantially higher risk of diabetes, ASCVD, HF, respiratory diseases and all-cause mortality compared with people with MHN. Particularly worth noting is that people with MHO were at an even higher risk than those with MUN of HF and respiratory disease. Among people with MHO at baseline who remained obese, over one-third became metabolically unhealthy within 3 to 5 years. These people acquired an even higher risk of ASCVD. In addition, there were weak or non-significant interactions of obesity and metabolic health factors with health outcomes. The key point therefore is that the risk of many important outcomes, such as HF and respiratory disease, is elevated in people with obesity even if they have a normal metabolic profile. Using the label ‘metabolically healthy’ to describe this group in clinical medicine is misleading and therefore should be avoided.
Strengths and limitations of this study
This study has several strengths over the previous evidence. First, we were able to investigate emerging outcomes such as HF and respiratory diseases that have often been omitted in MHO studies. In fact, the associations with these outcomes, along with the instability of the MHO status, highlight that MHO is not a healthy state. Furthermore, this study conducted a 5 year landmark analysis which indicated that the findings were unlikely to simply reflect reverse causation. We also adjusted for a wide range of potential confounders, including individual- and area-level socioeconomic status and lifestyle factors. Using mediation analysis, the current study also found that individuals with MHO may develop ASCVD and HF outcomes through diabetes-independent pathways. However, as with any observational study, residual confounding, such as from excess energy intake and family history of diabetes and ASCVD, is possible. Furthermore, whilst the UK Biobank cohort broadly reflects the general population in terms of sociodemographic characteristics, it is not representative in terms of lifestyle [25]. Therefore, whilst relative risk should be generalisable, as shown in a previous analysis [26], summary statistics and estimates of absolute risk should not be generalised. In addition, fasting glucose and insulin resistance were not measured, which limited how well we could define metabolically healthy states. However, HbA 1c is a well-established measure to reflect the mean blood glucose level in the last 2–3 months, and predicts relevant outcomes with similar efficacy to other blood glucose level measures [27]. This study also did not consider alternative definitions of MHO, e.g. by using the absence of hospitalisation [28, 29], or by using other genetics and omics data, which could be explored in future studies. Factors associated with MHO transitioning to MUO (or lack thereof) could also be explored.
Strengths and limitations compared with other studies
Some of the results of our study are consistent with the results of previous studies, lending external validity. In a study of 5269 adults aged 39–62 years followed up for 17.7 years, MHO was associated with high risk of all-cause mortality (HR 1.81, 95% CI 1.16 to 2.84) compared with MHN [7]. The same results were found in a prospective study of 1758 middle-aged men from Sweden followed up over 30 years [12]. The long-term relationship between MHO and CVD has been explored in several existing studies [7, 12]. Consistent with our findings, a multi-national European study found those with MHO to have a higher CVD risk than MHN but lower than MUN and MUO [30]. Conversely, there have been studies showing no association between MHO and CVD, such as a UK study that followed 22,203 participants over 12.7 years [11]. However, the effect size reported in that study was similar to our current study, suggesting that their lack of statistical significance could be due to insufficient power. It is worth noting that this previous literature has mostly focused on ASCVD, including ischaemic heart disease and stroke, and often omitted HF. Importantly, we found that MHO was associated with substantially higher risk of HF even compared with those with MUN. This could be related to a range of mechanistic factors beyond the usual metabolic aspect, such as haemodynamic perturbances, that likely link obesity to HF risk [31]. Notably, others have shown that obesity may be more strongly linked to incident HF than to MI [32].
To our knowledge, no previous study has directly examined the association between MHO and respiratory diseases, including COPD. However, it is well recognised that obesity is generally associated with lower respiratory function and a wide range of respiratory diseases, such as COPD, obstructive sleep apnoea and obesity hypoventilation syndrome [33]. There have been several hypotheses as to why obesity may be associated with COPD, including fat oxidative capacity, inflammation and insulin resistance [34]. However, as shown in this study, having a normal metabolic profile, and HbA 1c , did not guarantee lower risk of respiratory diseases among obese people. Of note, chronic respiratory diseases account for considerable morbidity and mortality worldwide and are estimated to have been the third leading cause of death in 2017 [35].
Implications of this study
Although our results suggested that people with MHO may have lower cardiovascular and respiratory risk compared with MUO, their risk was still higher than those who were metabolically healthy without obesity, especially with respect to HF and respiratory diseases. These findings, as well as the unstable nature of MHO, suggest that weight management could be beneficial for people with obesity even if they do not currently show abnormalities in their metabolic profile. Weight management strategies include lifestyle changes, such as diet and physical activity, concomitant pharmacotherapies upon risk assessment [36, 37] or bariatric surgery in severe obesity [38].
It is worth noting that half of the participants remained with MHO after 4.4 years of follow-up. We could not detect any significant elevated risk among them compared with people who were metabolically healthy and non-obese throughout the study. It is likely that this group of people are at lower risk than people with other MHO trajectories. However, since there were not sufficient numbers of events, we cannot conclude whether they were at the same risk as people with MHN, or were at a modestly elevated risk. Future prospective studies should consider this research question.
This study also showed that people with obesity are a heterogenous group, and there is a potential to risk stratify based on prognosis. For example, people with MUO were at a higher risk of mortality and morbidity than everyone else, and thus they should be prioritised for intervention. However, it should be noted that using a single binary label (i.e. ‘MHO’) for clinical management may have questionable utility. Obesity is associated with a wide range of diseases and using a single label (or categorical risk algorithm) is unlikely to be effective compared with prediction algorithms based on disease-specific and continuous risk markers. It has been shown that the metabolic syndrome, a similar categorical risk criterion to MHO, predicted neither ASCVD nor diabetes satisfactorily [39].
Conclusions
People with MHO are not ‘healthy’ as they are at higher risk of ASCVD, HF and respiratory diseases compared with non-obese people with a normal metabolic profile. As such, weight management could be beneficial to all people with obesity irrespective of metabolic profile. We suggest the term ‘MHO’ should be avoided in clinical medicine as it is misleading, and different strategies for risk stratification should be explored.