Increased fat mass is an established risk factor for the cardiometabolic diseases type 2 diabetes and cardiovascular disease (CVD) and is associated with increased risk of all-cause and CVD ...mortality. However, also very low fat mass associates with such an increased risk. Whether impaired metabolic health, characterized by hypertension, dyslipidemia, hyperglycemia, insulin resistance, and subclinical inflammation, may explain part of the elevated risk of cardiometabolic diseases that is found in many subjects with very low fat mass, as it does in many obese subjects, is unknown. An important pathomechanism of impaired metabolic health is disproportionate fat distribution. In this article the risk of cardiometabolic diseases and mortality in subjects with metabolically healthy and unhealthy normal weight and obesity is summarized. Furthermore, the change of metabolic health during a longer period of follow-up and its impact on cardiometabolic diseases is being discussed. Finally, the implementation of the concept of metabolic health in daily clinical practice is being highlighted.
A BMI in the normal range associates with a decreased risk of cardiometabolic disease and all-cause mortality. However, not all subjects in this BMI range have this low risk. Compared to people who ...are of normal weight and metabolically healthy, subjects who are of normal weight but metabolically unhealthy (∼20% of the normal weight adult population) have a greater than 3-fold higher risk of all-cause mortality and/or cardiovascular events. Here we address to what extent major risk phenotypes determine metabolic health in lean compared to overweight and obese people and provide support for the existence of a lipodystrophy-like phenotype in the general population. Furthermore, we highlight the molecular mechanisms that induce this phenotype. Finally, we propose strategies as to how this knowledge could be implemented in the prevention and treatment of cardiometabolic diseases in different stages of adiposity in routine clinical practice.
Stefan et al. highlight that metabolically unhealthy normal weight (MUHNW) patients have an unexpectedly high risk of cardiometabolic mortality. Furthermore, they provide data indicating that the MUHNW class may represent a lipodystrophy-like phenotype in the general population and address implications of this phenotype for the prevention and treatment of cardiometabolic diseases.
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. In some patients with NAFLD, isolated steatosis can progress to advanced stages with non-alcoholic steatohepatitis ...(NASH) and fibrosis, increasing the risk of cirrhosis and hepatocellular carcinoma. Furthermore, NAFLD is believed to be involved in the pathogenesis of common disorders such as type 2 diabetes and cardiovascular disease. In this Review, we highlight novel concepts related to diagnosis, risk prediction, and treatment of NAFLD. First, because NAFLD is a heterogeneous disease, the advanced stages of which seem to be strongly affected by comorbidities such as insulin resistance and type 2 diabetes, early use of reliable, non-invasive diagnostic tools is needed, particularly in patients with insulin resistance or diabetes, to allow the identification of patients at different disease stages. Second, although the strongest genetic risk alleles for NAFLD (ie, the 148Met allele in PNPLA3 and the 167Lys allele in TM6SF2) are associated with increased liver fat content and progression to NASH and cirrhosis, these alleles are also unexpectedly associated with an apparent protection from cardiovascular disease. If consistent across diverse populations, this discordance in NAFLD-related risk prediction between hepatic and extrahepatic disease might need to be accounted for in the management of NAFLD. Third, drug treatments assessed in NAFLD seem to differ with respect to cardiometabolic and antifibrotic efficacy, suggesting the need to better identify and tailor the most appropriate treatment approach, or to use a combination of approaches. These emerging concepts could contribute to the development of a multidisciplinary approach for endocrinologists and hepatologists working together in the management of NAFLD.
Obesity and impaired metabolic health are established risk factors for the non-communicable diseases (NCDs) type 2 diabetes mellitus, cardiovascular disease, neurodegenerative diseases, cancer and ...nonalcoholic fatty liver disease, otherwise known as metabolic associated fatty liver disease (MAFLD). With the worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), obesity and impaired metabolic health also emerged as important determinants of severe coronavirus disease 2019 (COVID-19). Furthermore, novel findings indicate that specifically visceral obesity and characteristics of impaired metabolic health such as hyperglycaemia, hypertension and subclinical inflammation are associated with a high risk of severe COVID-19. In this Review, we highlight how obesity and impaired metabolic health increase complications and mortality in COVID-19. We also summarize the consequences of SARS-CoV-2 infection for organ function and risk of NCDs. In addition, we discuss data indicating that the COVID-19 pandemic could have serious consequences for the obesity epidemic. As obesity and impaired metabolic health are both accelerators and consequences of severe COVID-19, and might adversely influence the efficacy of COVID-19 vaccines, we propose strategies for the prevention and treatment of obesity and impaired metabolic health on a clinical and population level, particularly while the COVID-19 pandemic is present.
Among 20 leading global risk factors for years of life lost in 2040, reference forecasts point to three metabolic risks-high blood pressure, high BMI, and high fasting plasma glucose-as being the top ...risk variables. Building upon these and other risk factors, the concept of metabolic health is attracting much attention in the scientific community. It focuses on the aggregation of important risk factors, which allows the identification of subphenotypes, such as people with metabolically unhealthy normal weight or metabolically healthy obesity, who strongly differ in their risk of cardiometabolic diseases. Since 2018, studies that used anthropometrics, metabolic characteristics, and genetics in the setting of cluster analyses proposed novel metabolic subphenotypes among patients at high risk (eg, those with diabetes). The crucial point now is whether these subphenotyping strategies are superior to established cardiometabolic risk stratification methods regarding the prediction, prevention, and treatment of cardiometabolic diseases. In this Review, we carefully address this point and conclude, firstly, regarding cardiometabolic risk stratification, in the general population both the concept of metabolic health and the cluster approaches are not superior to established risk prediction models. However, both subphenotyping approaches might be informative to improve the prediction of cardiometabolic risk in subgroups of individuals, such as those in different BMI categories or people with diabetes. Secondly, the applicability of the concepts by treating physicians and communication of the cardiometabolic risk with patients is easiest using the concept of metabolic health. Finally, the approaches to identify cardiometabolic risk clusters in particular have provided some evidence that they could be used to allocate individuals to specific pathophysiological risk groups, but whether this allocation is helpful for prevention and treatment still needs to be determined.
Obesity has become a worldwide epidemic that poses substantial health problems for both individuals and society. However, a proportion of obese individuals might not be at an increased risk for ...metabolic complications of obesity and, therefore, their phenotype can be referred to as metabolically healthy obesity. This novel concept of metabolically healthy obesity might become increasingly important to stratify individuals in the clinical treatment of obesity. However, no universally accepted criteria exist to define metabolically healthy obesity. Furthermore, many questions have been raised regarding the biological basis of this phenotype, the transitory nature of metabolically healthy obesity over time, and predictors of this phenotype. We describe the observational studies that gave rise to the idea of metabolically healthy obesity and the key parameters that can help to distinguish it from the general form of obesity. We also discuss potential biological mechanisms underlying metabolically healthy obesity and its public health and clinical implications.
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