Obesity in familial hypercholesterolaemia: when precision medicine should meet precision population health

This editorial refers to ‘Overweight, obesity, and cardiovascular disease in heterozygous familial hypercholesterolaemia: the EAS FH Studies Collaboration registry’, by A. Elshorbagy et al., https://doi.org/10.1093/eurheartj/ehae791.

Familial hypercholesterolaemia (FH) is an inherited dyslipidaemic state characterized by high levels of LDL-cholesterol in the blood.¹ Homozygous patients have very high LDL-cholesterol levels and develop atherosclerosis early in their childhood.² These homozygous FH patients must receive frequent plasma apheresis procedures in order to remove atherogenic apolipoprotein B (apoB)-containing lipoproteins from the blood.² Heterozygous (He) FH patients have variably elevated LDL-cholesterol levels depending upon their molecular defects, and they often display clinical signs of atherosclerosis before their mid-life.¹

HeFH: from molecular aspects to clinical practice and public health

With the discovery of the LDL receptor and of the molecular aspects related to its production, degradation, and activity, powerful pharmacological tools have been developed to substantially reduce LDL-cholesterol levels in patients with HeFH.¹ Clinical trials have shown that treatment with either statins or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors could substantially lower LDL-cholesterol levels in patients with HeFH.³

However, despite the availability of these effective lipid-lowering drugs, patients with HeFH obviously cannot benefit from such medications if clinicians do not recognize and diagnose FH in the first place. In this regard, international clinical organizations have contributed to streamline and standardize the diagnosis and management of patients with FH with the development of clinical guidelines.² The prevalence of HeFH has been reported to display regional variation but has been estimated to reach about 1:300 individuals.⁴ Thus, with the recognized impact of high LDL-cholesterol levels on the progression of atherosclerosis, HeFH is important not only at the individual/clinical standpoint but also from a public health perspective.

Lipids, atherosclerosis, and cardiovascular disease—abdominal obesity and features of the metabolic syndrome

Although LDL-cholesterol is well recognized as an important risk factor for accelerated atherosclerosis and cardiovascular disease (CVD), both large cohort studies and lipid-lowering trials have shown that, even in the absence of high LDL-cholesterol levels or even under high-intensity LDL-lowering therapy, other risk factors contribute to the development of CVD.⁵ Among these, behaviours such as smoking, lack of physical activity, overall dietary patterns of poor quality, and additional biological risk factors such as diabetes and hypertension also contribute to CVD risk. For more than two decades now, an agglomeration of metabolic and biological risk factors linked to abdominal obesity, named the ‘metabolic syndrome’, has also been reported to increase CVD risk at any given LDL-cholesterol level.⁶ Whether the metabolic syndrome increases CVD risk beyond its individual components remains debated. Nevertheless, in clinical practice, it is more and more recognized that among patients with overweight or obesity, the presence of a large waistline combined with features of the metabolic syndrome identifies a subgroup of patients at increased CVD risk requiring optimal management beyond LDL-lowering therapy.

Obesity also matters in HeFH!

With the development of international initiatives to build registries of patients living with FH such as the European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) Registry,⁷ not only has there been an opportunity to get a broader international perspective of issues relevant to HeFH and its management, but such a registry of individual patient data has provided very much needed data to better understand to what extent contemporary public health issues such as the worldwide epidemic of obesity may also impact the lives of patients living with HeFH.

In this issue of the European Heart Journal, Elshorbagy et al.⁸ report cross-sectional analyses conducted on an impressive sample of 35 540 patients with HeFH from 50 countries involved in the EAS-FH Studies-Collaboration Registry. World Health Organization (WHO)-defined overweight and obesity categories were used to investigate the frequency of these conditions in 29 265 adults and 6275 children/adolescents. Several interesting findings deserve discussion.

Firstly, 52% of adults and 27% of children with HeFH were in the overweight or obesity categories, respectively, with a higher prevalence noted in lower income countries, particularly in adults. Secondly, the prevalence of coronary artery disease (CAD) increased across body mass index (BMI) categories (from normal BMI to overweight to obesity), this relationship being observed not only in adult patients with FH but also among children. For instance, HeFH patients with overweight or obesity were respectively characterized by ∼1.5-fold and 2.3-fold higher odds of having CAD or premature CAD compared with HeFH patients with BMI values in the ‘normal’ range in the model adjusted for age, sex, lipid-lowering medication, LDL-cholesterol, HDL-cholesterol, triglycerides, and LDL-cholesterol × lipid-lowering medication interaction. Additional adjustment for diabetes, hypertension, and smoking attenuated but did not eliminate these associations. The authors conclude not only that overweight and obesity are common in patients living with HeFH, but that excess adiposity (at least as crudely estimated by the BMI) contributes to atherosclerotic CVD risk independent of LDL-cholesterol levels and lipid-lowering therapies.

Limitations

The study of Elshorbagy et al.⁸ provides relevant information with both clinical and public health implications. Hopefully, such a study should stimulate collection of additional data at the individual level in large cohorts of FH patients as several unanswered questions will require further investigation. For instance, although the BMI is useful to describe weight changes at the population level, this variable is a poor anthropometric index to assess adiposity at the individual patient level.⁹ In addition, many cardiometabolic imaging studies have also highlighted the fact that the BMI does not provide information about the substantial individual variation in visceral adiposity and related ectopic fat depots.⁹ Thus, it is likely that the association of visceral adiposity with CAD in patients with HeFH would even have been much stronger than the one reported with the BMI. Such a hypothesis remains to be tested in future studies.

It is also relevant to point out that even in the absence of imaging data, measuring waist circumference as a marker for abdominal adiposity¹⁰ would have probably provided a better discrimination of CAD risk within BMI categories in patients with HeFH. In the general population, large cohort studies have consistently shown that within any given BMI category, an increased waist circumference is predictive of an increased morbidity and mortality risk.¹¹ More than 25 years ago, Gaudet et al.¹² documented the associations between waist circumference, fasting insulin levels (as a crude marker of insulin resistance), and angiographically assessed CAD in a sample of patients without or with HeFH. Whereas the FH status was, as expected, predictive of an increased probability of being CAD positive, the combined presence of a high waist circumference and insulin levels was associated with CAD, the highest odds ratio for CAD being observed among patients with both HeFH and abdominal obesity–hyperinsulinaemia.¹² On that basis, it is suggested that the study by Elshorbagy et al.⁸ should pave the way to additional cardiometabolic imaging studies allowing us to further refine our understanding of the interaction between features of the metabolic syndrome (including visceral obesity, insulin resistance, and low-grade chronic inflammation) and LDL-cholesterol levels as drivers of CAD risk among patients living with HeFH.

Future directions

Considering that the molecular defect of HeFH patients already puts them at increased risk for premature CAD, the prevalence of overweight and obesity reported in these patients by Elshorbagy and colleagues is a source of concern. Another question arises: should we focus on weight loss to achieve a healthy body weight in patients with HeFH or should we rather target upstream behaviours associated with overweight or obesity known to affect CVD risk? For instance, it is very well documented that a low level of physical activity¹³ and a low cardiorespiratory fitness (CRF)¹⁴ are powerful discriminants of CVD risk irrespective of the BMI. Similar conclusions are reached when indices of overall diet quality are examined.¹⁵ Thus, if increasing the physical activity level in order to maintain an adequate level of CRF and improving dietary patterns are relevant objectives for the general population, to what extent measuring and targeting ‘lifestyle vital signs’ in clinical practice would contribute to optimize CAD risk management in patients with HeFH remains an unanswered question. Finally, because of the worldwide epidemic of obesity and of the social and economic determinants of this condition, population-based approaches aiming at reducing inequalities and improving environments and living conditions associated with obesity should also have an impact on the health trajectories of patients living with HeFH.

In conclusion, the study by Elshorbagy et al.⁸ provides a striking example of the power of registries (Graphical Abstract). Extension of this worldwide platform to include cardiometabolic imaging and lifestyle data should provide a wealth of information relevant to patients living with HeFH and to health professionals aiming at the optimal management of this condition.

Graphical Abstract.

Management of obesity in patients living with heterozygous familial hypercholesterolaemia (HeFH). (A) Current data indicate that overweight/obesity is associated with increased risk of premature coronary artery disease (CAD) in patients with HeFH. On that basis, a key remaining question is whether weight loss induced by a negative energy balance or by pharmacotherapy of obesity would lower CAD risk beyond pharmacologically reduced LDL particle concentration in these patients. (B) In the general population, cardiometabolic imaging studies have revealed that body mass index (BMI) is a black box that cannot properly assess individual variation in visceral adipose tissue accumulation and of fat deposition in normally lean tissues (e.g. heart, liver, and skeletal muscle), a phenomenon described as ectopic fat deposition. Waist circumference as a simple anthropometric index of abdominal adiposity has been shown to discriminate health risk at any BMI value. (B) Also highlights the fact that ‘lifestyle vital signs’ (cardiorespiratory fitness [CRF], physical activity [PA] and exercise, and overall diet quality) are also significant correlates of cardiovascular disease risk at any BMI value. Thus, whether going beyond BMI and weight-based strategies would be of value in the management of patients living with HeFH remains an important question to be addressed. Finally, as patients with HeFH are exposed to the same ‘chronic disease-promoting environment’ as the rest of the population, the illustration also emphasizes the need to target living/environmental/socioeconomic determinants of health.

Declarations

Disclosure of Interest

The author declares no disclosure of interest for this contribution.

Funding

The work of the author has been and is currently supported by the Canadian Institutes of Health Research (Foundation grant: FDN-16778) and by the Fondation de l'Institut universitaire de cardiologie et de pneumologie de Québec.