Weight loss and its influence on high-density lipoprotein cholesterol (HDL-C) concentrations: A noble clinical hesitation

Abstract

S u m m a r y

Background & aims: The relationship between obesity, weight loss, and high-density lipoprotein cholesterol (HDL-C) is poorly recognized and understood. Methods: Through an emphasis on current studies, in this viewpoint, we provide further scientific and medical considerations on the relationship between weight loss and the management of HDL-C levels. Results: Long-term adherence to a low-calorie diet is a determinant of weight loss, with weight loss and/ or normal weight being important clinical conditions to lower risk for the development of cardiometabolic dysregulations and cardiovascular diseases. These benefits appear to be independent of variations in serum lipids and lipoproteins. Indeed, there is a paradoxical link between weight loss and HDL-C levels, which can result in both increases and reductions in the concentrations of this recognized biomarker of cardiovascular health. Conclusions: Care should be exercised in order to avoid overvalued clinical recommendations in the management of HDL-C levels. Further hesitation is needed for health practitioners as well as skepticism surrounding science.

Full text

Opinion Paper
Weight loss and its influence on high-density lipoprotein cholesterol
(HDL-C) concentrations: A noble clinical hesitation
Heitor O. Santos
a
,
*
, Carl J. Lavie
b
a
School of Medicine, Federal University of Uberlandia (UFU), Uberlandia, Minas Gerais, Brazil
b
Ochsner Clinical School, The University of Queensland School of Medicine, New Orleans, LA, USA
article info
Article history:
Received 30 October 2020
Accepted 23 January 2021
Keywords:
HDL-C
Lipids
Nutrition
Weight loss
summary
Background &aims: The relationship between obesity, weight loss, and high-density lipoprotein
cholesterol (HDL-C) is poorly recognized and understood.
Methods: Through an emphasis on current studies, in this viewpoint, we provide further scientific and
medical considerations on the relationship between weight loss and the management of HDL-C levels.
Results: Long-term adherence to a low-calorie diet is a determinant of weight loss, with weight loss and/
or normal weight being important clinical conditions to lower risk for the development of car-
diometabolic dysregulations and cardiovascular diseases. These benefits appear to be independent of
variations in serum lipids and lipoproteins. Indeed, there is a paradoxical link between weight loss an
HDL-C levels, which can result in both increases and reductions in the concentrations of this recognized
biomarker of cardiovascular health.
Conclusions: Care should be exercised in order to avoid overvalued clinical recommendations in the
management of HDL-C levels. Further hesitation is needed for health practitioners as well as skepticism
surrounding science.
©2021 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights
reserved.
1. High-density lipoprotein (HDL) function vs. HDL-
cholesterol (HDL-C) levels
High-density lipoprotein cholesterol (HDL) has several impor-
tant cardiometabolic functions, such as cholesterol effluxdi.e.
transport of cholesterol from peripheral tissues to the liverd, anti-
inflammatory effects mediated by decreased expression and
adhesion of molecules in endothelial cells, improvement in endo-
thelial function, apoptotic effects, attenuation of low-density lipo-
protein cholesterol (LDL-C) oxidation and thus providing better
antioxidant status, among other atheroprotective actions [1e4]. In
light of these physiological aspects, particularly the anti-oxidative
function and endothelial protective effects of HDLs have been
proposed as determining features among measures of HDL-
cholesterol (HDL-C) levels [5,6].
HDL-C, which is specifically the HDL fraction aggregated to the
cholesterol content, does not seem to be the causal factor for cor-
onary heart disease and major vascular events [7]. So much so that
the cholesterol content of the HDL fraction is not mechanistically a
measure of HDL function and hence is not causally related to
vascular disease [7]. Employing Mendelian randomization study,
Voight et al. do not provide compelling evidence that HDL-C is
causally associated with the risk of atherosclerotic cardiovascular
disease (ASCVD) [8]. In this way, reverse cholesterol transport flux,
but not HDL-C, is a strong predictor marker for ASCVD, as supported
by the benchmark study by Khera et al. [7].
HDL particle concentration and apolipoprotein A1 are more
robust measures of HDL-C levels and HDL functional capacity,
showing a lesser extent of dependence on triglyceride (TG)-related
effects [9]. Additionally, it is no wonder that among the variety of
elements that impact the measurement of HDL-C, the particle
composition of TG-rich non-HDL lipoproteins, mainly the TG con-
tent, may affect the clinical measures of HDL-C. Indeed, most of the
HDL-C effects can be influenced by changes in metabolism and
transport of TG by TG-rich lipoproteins, as confirmed by a >1
million subject ultracentrifugation lipid database [10].
*Corresponding author. School of Medicine, Federal University of Uberlandia
(UFU), Para Street, 1720, Umuarama, Block 2H, Uberlandia, 38400-902, MG, Brazil.
E-mail address: heitoroliveirasantos@gmail.com (H.O. Santos).
Contents lists available at ScienceDirect
Clinical Nutrition ESPEN
journal homepage: http://www.clinicalnutritionespen.com
https://doi.org/10.1016/j.clnesp.2021.01.033
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Clinical Nutrition ESPEN xxx (xxxx) xxx
Please cite this article as: H.O. Santos and C.J. Lavie, Weight loss and its influence on high-density lipoprotein cholesterol (HDL-C)
concentrations: A noble clinical hesitation, Clinical Nutrition ESPEN, https://doi.org/10.1016/j.clnesp.2021.01.033

2. Non-medical strategies: focus on weight loss
In clinical practice, when low serum HDL-C concentrations are
detected, currently classified as <40 mg/dL for men and <50 mg/dL
for women according to international guidelines [11e14], health
professionals (e.g. physicians, dietitians, and physical education
instructors) typically recommend weight loss, physical exercise,
and dietary reductions in carbohydrates and increments of good
fats, including olive oil, avocado, and oilseeds. Undoubtedly, these
recommendations can provide cardiometabolic benefits; however,
they will not necessarily result in a substantial improvement in
HDL-C concentrations. For instance, in a systematic review of meta-
analyses, insufficient evidence was found to infer a significant in-
crease in HDL-C levels through aerobic, resistance, or combined
exercise training [15] while the consumption of oilseeds and olive
oil, in turn, has a modest effect in increasing HDL-C concentrations
(z[3e5 mg/dL) in the context of Mediterranean diet [16]. In
addition, meta-analyses of clinical trials show an ambiguous effect
of avocado consumption on HDL-C levels, only supporting a modest
increase ([2.84 mg/dL) [17] or even a small reduction (Y0.18 mg/
dL) [18].
On the other hand, some current guidelines for the management
of dyslipidemias (EAS/ESC 2019) do not provide specific goals for
HDL-C, such as the European Society of Cardiology and European
Atherosclerosis Society [19]. Moreover, among the setting of clinical
practice filled with unsubstantiated nutraceutical prescriptions and
overvaluation of physical activity programs, nothing more plausible
than focusing on the effects of weight loss. As a general rule, weight
loss per se provides metabolic amelioration regardless of several
medical factors (see Table 1), thus being an adjunct or protagonist
in the management of various diseases (e.g., obesity, diabetes,
dyslipidemia, metabolic syndrome, and arterial hypertension)
[20,21]. However, regarding HDL-C concentrations, weight loss can
either increase or decrease this considerably.
Recently, Hall et al. [28] cross-randomized 20 patients to ingest
ultra-processed or unprocessed foods for two weeks. Although the
sample number seems small from a medical point of view, it is
worth noting that the study was carried out in a well-controlled
scenario, in an infirmary. Concerning the main results of the
study by Hall et al. [28], when patients were submitted to the un-
processed food intervention, there was loss of body weight (Y
0.9 kg), improvement in the glycemic profiledreduced serum
levels of insulin, C-peptide, adiponectin, and resistindand
decreased serum TG levels of and total cholesterol. In contrast, a
point that was not discussed in the investigation, despite the fact
that typically HDL-C increases when TGs fall, there was the
reduction in HDL-C levels after unprocessed food intervention.
Remarkably, there was a z10 mg/dL reduction in HDL-C levels and,
therefore, not only statistical significance was noted (p <0.0001 for
both baseline period vs. end of the unprocessed food intervention
and the end of the unprocessed food vs. the end of the ultra-
processed food interventions) but also clinically this is a substan-
tial variation if analyzed in itself. Correspondingly, some evidence
suggests that for every 1 mg/dL increment in HDL-C, there is a 2e3%
change in CVD risk, especially coronary heart disease [29].
In a multicenter study [30], 2020 patients for eight weeks fol-
lowed a daily dietary protocol of only 810 kcal. As expected, loss of
body weight and improvement in insulin resistance were observed.
However, an average decrease of 4.6 mg/dL in HDL-C plasma levels
was detected as well. This multicenter study provides further ve-
racity in reducing HDL-C levels under caloric restriction. A biolog-
ical plausibility for such a fact may be the metabolism related to fat
intake, as fatty acids are substrates for HDL-C particles and increase
their actions [31e33]. Hence, taking into account that adherence to
most low-calorie diets naturally results in decreased fat intake,
decreased HDL-C levels may be clinically contemplated.
3. Take-home message
HDL-C does not appear to be a reliable surrogate marker or in-
termediate phenotype for CVD risk. Accordingly, health practi-
tioners who work with lipid profile requests, such as physicians and
dietitians, need not be concerned about reductions in serum HDL-C
concentrations when the patient is in the process of losing weight,
especially when physical activity and exercise is not a main mo-
dality for the weight loss program, as the body weight decline,
mainly from fat mass, is metabolically essential for the patients
with obesity and thus being the cornerstone of this wisdom [34,35].
A myriad of improvements in cardiometabolic biomarkers
associated with chronic low-grade inflammation [22,23,36e38]
overcome the mere reduction in HDL-C levels found in the afore-
mentioned nutritional interventions [28,30]. Paradoxically how-
ever, the detection of raised HDL-C concentrations under weight-
loss interventions is also a circumstance to be expected in clinical
practice as well as in research.
In other words, care should be exercised in order to avoid
overvalued clinical recommendations in the management of HDL-C
levels. Further hesitation is needed for health practitioners as well
as skepticism surrounding science.
Author's contributions
Heitor O. Santos: wrote the manuscript. Carl J. Lavie: reviewed
the manuscript.
Table 1
Cardioprotective effects of weight loss through obesity-associated diseases.
Diseases Mechanisms Reference
Atherosclerotic cardiovascular
disease and dyslipidemia
Decreased fasting plasma levels of triglycerides, lipoprotein(a), LDL-cholesterol and total cholesterol, while
increasing levels of HDL-cholesterol and sdLDL-particles. Decreased lipoprotein oxidation as well.
[20,22,23]
Hypertension Decreased uric acid levels and insulin resistance while modulating the sympathetic nervous and renin
eangiotensinealdosterone systems and hence preserving the structures and functions of the heart, kidney, and
vasculature.
[24]
Fatty liver disease and non-
alcoholic fatty liver disease
Improved insulin resistance and reduction in liver de novo lipogenesis, continuous lipolysis within visceral fat
depots, and release of fatty acids into the portal circulation, i.e., the substrates for the production of hepatic
triglycerides. These effects, alongside decrease in reactive oxygen species generated by fatty acid oxidation, can
prevent the development of the non-alcoholic fatty liver disease.
[25]
Type 2 diabetes mellitus Positive modulation in islet
b
-cell and insulin-sensitive tissues, increasing glucose uptake in musculoskeletal
and adipose tissue and hence preventing chronic hyperglycemia and higher levels of advanced glycation end
products. Decreased hypothalamic inflammation and central leptin resistance as well.
[26]
Respiratory disorders Decreased accumulation of fat in the thoracic and abdominal regions improves the downward movement of the
diaphragm and chest wall properties, thus increasing cardiopulmonary performance by raising maximal oxygen
uptake per kilogram
[27]
H.O. Santos and C.J. Lavie Clinical Nutrition ESPEN xxx (xxxx) xxx
2

Financial Support
None.
Declaration of competing interest
The authors declared they do not have anything to disclose
regarding conflict of interest with respect to this manuscript.
Acknowledgments
None.
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