Series
Metabolically healthy obesity: the low-hanging fruit in obesity treatment?

https://doi.org/10.1016/S2213-8587(17)30292-9Get rights and content

Summary

Obesity increases the risk of several other chronic diseases and, because of its epidemic proportions, has become a major public health problem worldwide. Alarmingly, a lower proportion of adults have tried to lose weight during the past decade than during the mid-1980s to 1990s. The first-line treatment option for obesity is lifestyle intervention. Although this approach can decrease fat mass in the short term, these beneficial effects typically do not persist. If a large amount of weight loss is not an easily achievable goal, other goals that might motivate people with obesity to adopt a healthy lifestyle should be considered. In this setting, the concept of metabolically healthy obesity is useful. Accumulating evidence suggests that, although the risk of all-cause mortality and cardiovascular events might be higher in people with metabolically healthy obesity compared with metabolically healthy people of a normal weight, the risk is substantially lower than in individuals with metabolically unhealthy obesity. Therefore, every person with obesity should be motivated to achieve a normal weight in the long term, but more moderate weight loss sufficient for the transition from metabolically unhealthy obesity to metabolically healthy obesity might also lower the risk of adverse outcomes. However, how much weight needs to be lost for this transition to occur is under debate. This transition might be supported by lifestyle factors—such as the Mediterranean diet—that affect cardiovascular risk, independent of body fat. In this Series paper, we summarise available information about the concept of metabolically healthy obesity, highlight gaps in research, and discuss how this concept can be implemented in clinical care.

Introduction

The prevalence of overweight and obesity has increased globally during the past few decades, and increased fat mass promotes morbidity and mortality.1 In the USA, obesity is closely associated with several of the top ten leading causes of death, including heart disease, stroke, cancer, and type 2 diabetes.2, 3 Medical organisations are beginning to classify obesity, defined as a BMI of 30 kg/m2 or higher, as a disease.4 There is an ongoing debate about whether the lowest risk of mortality is found in the overweight state (defined by WHO as a BMI of 25·0 to <30·0 kg/m2).5, 6, 7 However, the largest study to date with the most rigorous criteria to account for confounding factors showed that a BMI in the normal weight range (defined by WHO as 18·5 to <25·0 kg/m2), and specifically a BMI of 20·0–25·0 kg/m2, was associated with the lowest all-cause mortality.8 These data suggest that maintaining BMI in this range or reducing an increased bodyweight to this range could effectively reduce the risk of early death.

Most clinical guidelines recommend an initial loss of 5–8% of total bodyweight for overweight and obese individuals, instead of the achievement of normal weight, to prevent cardiometabolic diseases.9, 10, 11, 12 Lifestyle intervention that targets eating behaviour and physical activity should always be the first option for weight management, because it is associated with relatively low costs and minimal risk of complications. Such lifestyle intervention programmes usually include intensive behavioural counselling with about 14 visits in 6 months; results show that 60–65% of patients lose 5% or more of their initial weight.9, 10, 11, 12 For example, 1 year after intensive lifestyle intervention in the Look AHEAD trial,13 which was done in patients with type 2 diabetes, of whom 85·1% also had obesity, 68% of participants lost 5% of their initial weight, and 37% lost 10%. After a median follow-up of 9·6 years, mean weight loss in the intensively treated participants in the Look AHEAD study was 6·0%, still within the range recommended by guidelines for reducing cardiovascular risk. However, mean BMI only declined from 35·9 kg/m2 (SD 6·0) at the start of the trial to 33·6 kg/m2 by the end.14 Therefore, although a decrease in bodyweight is achievable for obese people with lifestyle intervention, this intervention does not reduce BMI to the normal range in the long term. Similarly, in another large study (which included participants with elevated fasting and post-load plasma glucose concentrations in the prediabetic range, of whom 68% were obese, with a baseline BMI of 34·0 kg/m2 [SD 6·7]) that involved intensified lifestyle intervention—the Diabetes Prevention Program Outcomes Study15—weight loss after 10 years was about 1 kg in the control group and only 2 kg in the lifestyle intervention group. BMI at follow-up was greater than 33 kg/m2 in both groups.

Although modest weight loss of 5–8%, which is in the range recommended by most clinical guidelines, improves measures of diabetes, hypertension, and disability without major risks, its effect on cardiovascular outcomes remains unclear.16, 17, 18, 19, 20, 21 In the Look AHEAD trial,14 intensive lifestyle intervention did not reduce the risk of cardiovascular morbidity or mortality compared with a control programme of diabetes support and education among overweight or obese patients with type 2 diabetes. Notably, the subgroup of individuals who lost at least 10% of their bodyweight (mean weight loss 15·4% [SD 5·0], mean BMI at follow-up close to overweight range, estimated as approximately 30·5 kg/m2) over a median follow-up of 10·2 years had a 21% lower risk of cardiovascular morbidity or mortality than did individuals with stable weight or weight gain.16

In this Series paper, we address the question of how much weight loss might be necessary to protect from cardiometabolic diseases in people with obesity; in effect, how much weight loss is necessary to move from a state of metabolically unhealthy obesity to metabolically healthy obesity. Furthermore, we discuss whether the concept of metabolically healthy obesity could help to stratify people with obesity as low or high cardiometabolic risk despite similar weight loss. Finally, we highlight future research approaches that could help to better understand the mechanisms underlying the transition from metabolically unhealthy to metabolically healthy obesity, and discuss how this knowledge can be implemented in clinical care.

Section snippets

Relevance for the patient

For clinicians, the goals of a structured lifestyle intervention in addition to weight loss are well defined. These goals include normalisation of the parameters that are used to define metabolic syndrome (table), such as hypertension (systolic/diastolic blood pressure ≥130/85 mm Hg), low HDL cholesterol levels (<40 mg/dL in men and <50 mg/dL in women), hyperglycaemia (fasting glucose level ≥100 mg/dL), visceral obesity (waist circumference ≥102 cm in men and ≥88 cm in women), and insulin

Metabolic health and risk of cardiometabolic disease

Although the concept of metabolically healthy obesity has been widely studied in research settings, its relevance to clinical practice is still unclear.28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42 The lack of a consensus on its relevance is not only due to the absence of an established definition of the phenotype of metabolically healthy obesity, but also because epidemiological evidence that link obesity with cardiometabolic risk is heterogeneous. In a meta-analysis,22 we

Weight loss

Because people with metabolically healthy obesity have a lower risk of cardiometabolic diseases than people with metabolically unhealthy obesity do, the question arises: how can a transition from metabolically unhealthy to healthy obesity be achieved? Lifestyle intervention-induced weight loss should always be the first target in the treatment of obesity, irrespective of metabolic health phenotypes.9, 10, 11, 12 Weight loss reduces cardiometabolic risk and provides other health benefits, such

Implications for doctor–patient communication

To understand how the concept of metabolically healthy obesity can be used to treat obesity, the take-home message from the literature from weight-loss interventions needs to be clarified. In the study by Ruiz and colleagues53 and in our TULIP study,52 only about a quarter of individuals with metabolically unhealthy obesity converted to metabolically healthy obesity, despite losing more than 5% of their bodyweight. Although this outcome could be discouraging for health-care providers and most

Conclusions

Lifestyle intervention in people with obesity to reduce bodyweight is considered safe and effective at decreasing cardiometabolic risk. However, results from several studies, especially from the Look AHEAD trial13 and the Diabetes Prevention Program Outcomes Study,15 showed that it is very difficult to reach and maintain a bodyweight in the normal or overweight range with lifestyle intervention alone. As was shown in the SOS studies,44, 45, 46 for many people with obesity, only bariatric

Search strategy and selection criteria

We searched PubMed for full-text original studies and review articles published in English between Jan 1, 1990, and Aug 31, 2017, to identify reports on metabolic parameters and mortality in people with obesity. Search terms were “metabolically healthy obesity” OR “metabolically unhealthy obesity” OR “metabolically benign obesity” OR “metabolic syndrome” OR “insulin sensitivity” OR “insulin resistance” OR “bariatric surgery” AND “lifestyle intervention” AND “mortality”. The reference lists of

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