- freely available
Nutrients 2013, 5(3), 928-948; doi:10.3390/nu5030928
Published: 18 March 2013
Abstract: Small, dense low density lipoprotein (sdLDL) represents an emerging cardiovascular risk factor, since these particles can be associated with cardiovascular disease (CVD) independently of established risk factors, including plasma lipids. Obese subjects frequently have atherogenic dyslipidaemia, including elevated sdLDL levels, in addition to elevated triglycerides (TG), very low density lipoprotein (VLDL) and apolipoprotein-B, as well as decreased high density lipoprotein cholesterol (HDL-C) levels. Obesity-related co-morbidities, such as metabolic syndrome (MetS) are also characterized by dyslipidaemia. Therefore, agents that favourably modulate LDL subclasses may be of clinical value in these subjects. Statins are the lipid-lowering drug of choice. Also, anti-obesity and lipid lowering drugs other than statins could be useful in these patients. However, the effects of anti-obesity drugs on CVD risk factors remain unclear. We review the clinical significance of sdLDL in being overweight and obesity, as well as the efficacy of anti-obesity drugs on LDL subfractions in these individuals; a short comment on HDL subclasses is also included. Our literature search was based on PubMed and Scopus listings. Further research is required to fully explore both the significance of sdLDL and the efficacy of anti-obesity drugs on LDL subfractions in being overweight, obesity and MetS. Improving the lipoprotein profile in these patients may represent an efficient approach for reducing cardiovascular risk.
A sedentary lifestyle and high energy diet increases the prevalence of being overweight, obesity, metabolic disorders (e.g., metabolic syndrome, MetS) and type 2 diabetes mellitus (T2DM) . Obesity and obesity-related co-morbidities, such as MetS and T2DM, are a major health problem worldwide . Each of these disorders, in addition to established vascular risk factors (e.g., dyslipidaemia, smoking and hypertension) increases the risk of cardiovascular disease (CVD). Therefore, the American Diabetes Association and the American College of Cardiology Foundation recommend a multifactorial risk reduction strategy targeting each risk factor and underlining both lifestyle and pharmacological treatment .
A commonly observed lipid abnormality in obese individuals (especially those with excess central adipose tissue), is an increased presence of small dense low-density lipoprotein (sdLDL) [4,5,6]. This predominance of sdLDL particles is associated with raised triglycerides (TG) and decreased high density lipoprotein cholesterol (HDL-C) levels, forming the so-called “atherogenic lipid triad” [7,8]. Adipose tissue also produces a diversity of adipokines that play a role in the pathogenesis of inflammation, dyslipidaemia and hypertension  that increase the rate of CVD morbidity and mortality linked to obesity, T2DM and the MetS . Excessive visceral adiposity enhances the availability of free fatty acids (FFA) that lead to TG accumulation in muscle and liver (fatty liver) and increase circulating TG levels, due to the enhanced hepatic production of very low density lipoprotein (VLDL) cholesterol [11,12,13]. Furthermore, the raised flux of FFA and TG to muscle and other tissues induces insulin resistance (IR) [14,15].
LDL varies in size, density and metabolic characteristics and comprises at least four distinct subclasses (large LDL-I, medium LDL-II, small LDL-III and very small LDL-IV (Table 1)), with sdLDL being associated with increased CVD risk . Although the association between IR and increased LDL-C levels is not typical, elevated sdLDL levels with lower large LDL concentrations are associated with reduced insulin sensitivity and increased adiposity [17,18,19]. Generally, two phenotypes have been described: pattern A, with a higher proportion of larger, more buoyant or medium-sized LDL, and pattern B, with a predominance of sdLDL . The difference in size and density among LDL subclasses is due to variations in surface lipid content and conformational changes in apoB-100, including increased exposure on the particle surface .
|Table 1. Physicochemical properties of low-density lipoprotein (LDL) subclasses (adapted from ).|
|Peak Sf||Density Peak||Diameter (Å)||Protein||Cholesteryl ester (%)||Unesterified cholesterol (%)||Triglycerides||Phospholipids|
|Pattern A||large LDL-1||7–12||1.019–1.023||272–285||18||43||9||7||22|
|medium LDL-2||5–7||a 1.023–1.028||265–272||19||45||10||4||23|
|Pattern B||small LDL-3||3–5||a 1.034–1.041||247–256||22||46||8||3||21|
|very small LDL-4||0–3||a 1.044–1.051||233–242||26||42||7||5||19|
Sf: Svedberg flotation.
Search Strategy: We searched PubMed and Scopus listings for relevant publications using combinations of the following keywords: “lipids”, “lipoproteins”, “small dense low density lipoprotein”, “high density lipoprotein”, “overweight”, “obesity”, “obesity treatment”, “anti-obesity drugs”, “lipid-lowering drugs” and “new anti-obesity drugs”.
2. The Clinical Relevance of sdLDL
sdLDL tend to coexist with elevated TG and low HDL-C levels and together comprise the “atherogenic dyslipidaemia” pattern, which appears to be heritable, but also several non-genetic factors, such as abdominal adiposity, influence the expression of this phenotype . However, it is still debated whether LDL particle size is an independent CVD risk factor after adjustment for TG and HDL-C levels .
In relation to large buoyant LDL, sdLDL particles are taken up more easily by arterial tissue, show lower affinity for the LDL receptor, have a longer half-life in plasma and greater oxidative and glycation susceptibility, suggesting a link between sdLDL particles and atherogenesis [22,23]. It has been shown that subjects with high levels of sdLDL particles have an approximately three- to seven-fold increase in the risk of developing coronary heart disease (CHD), independently of LDL-C concentration [24,25,26]. Some studies found that subjects at high CVD risk, such as those with peripheral arterial disease or abdominal aortic aneurysm, may also have higher levels of these particles [27,28]. Further, a significant relationship between LDL size and the occurrence of carotid atherosclerosis was reported [29,30,31]. In different metabolic diseases (e.g., polycystic ovary syndrome, growth hormone (GH) deficiency) [32,33,34] and in women with gestational diabetes , increased levels of sdLDL were also found.
sdLDL also represents a marker for diagnosis and severity of the MetS [36,37]. In this context, we confirmed that sdLDLs are increased in the MetS and showed an independent predictive role for future cardiovascular and cerebrovascular events . Additionally, it has been suggested that the sdLDL-C/LDL-C ratio correlates with various parameters associated with MetS rather than the LDL-C or sdLDL-C levels, thus possibly representing a more useful clinical indicator . Furthermore, an increased sdLDL-C/LDL-C ratio was an independent factor determining decreased adiponectin levels in MetS patients , but the mechanisms involved need to be elucidated.
3. Overweight, Obesity and sdLDL
Visceral obesity and IR have been recognized as the main causes of raised levels of sdLDL, because these factors contribute to postprandial hypertriglyceridemia; an essential mechanism is increased FFA release from adipocytes, which stimulates hepatic TG output [11,13]. Additionally, if fatty liver is present, upregulated de novo synthesis of FFA may increase hepatic TG production and affect the hepatic metabolism of TG and/or LDL-C, resulting in increased sdLDL levels and rapid atherogenesis in patients with MetS or T2DM . In such metabolic conditions, fatty liver may enhance atherogenesis by raising the levels of sdLDL particles [41,42]. Hosoyamada et al. suggest that fatty liver may affect LDL particle size independently of both visceral obesity and IR . Thus, treatment of fatty liver might decrease atherogenesis in MetS or T2DM by reducing sdLDL-C levels.
Currently, there is renewed interest in the usefulness of measuring non-fasting TGs, as a more powerful and independent predictor of CVD risk than fasting levels . In this context, an expert panel provided a consensus statement on the classification of non-fasting TGs concentration and other related clinical recommendations . Standard reference values for post-prandial TG levels were suggested based on a recent meta-analysis .
Data from the Mima study  indicate that a polymorphism of the beta(3)-adrenergic receptor gene (the genetic marker for obesity-related traits) is correlated with the area percentage of sdLDL (p < 0.05), independently of age, gender, body mass index (BMI), smoking and IR index, suggesting a genetic predisposition to increased sdLDL in the presence of this polymorphism.
Weight loss in obese, non-diabetic women resulted in a significant reduction of the levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) (p < 0.01), a phospholipase primarily associated with LDL, especially with sdLDL, while neither the cholesterol levels of sdLDL particles nor the percentage of the sdLDL-cholesterol of the total LDL-C were changed [47,48]. This change in Lp-PLA2 activity correlated with the changes in VLDL levels (p < 0.05) and could be a potentially new predictor for atherosclerotic disease. Lp-PLA2 is also a marker of sdLDL in human plasma .
Alternate day modified fasting (ADMF) is a dietary restriction that could help overweight and obese individuals to lose weight and lower CHD risk . After eight weeks of ADMF, peak and integrated LDL particle size, as well as the proportion of large LDL particles increased, whereas the proportion of small and medium particles decreased (for all comparisons, p < 0.05). Cholesterol level in large particles did not alter, whereas this parameter was reduced within small- and medium-sized LDL particles (p < 0.05). Furthermore, LDL particle size was associated with reduced body weight (p = 0.04) and smaller waist circumference (p = 0.03). On the other hand, no association was observed between LDL particle size and plasma TGs (p = 0.11) or HDL-C concentrations (p = 0.65) , although reductions in plasma LDL and TGs concentrations were observed. However, given that the effect of weight loss on LDL particle size was not evaluated separately from the effect of fasting, it remains unclear whether these cardioprotective effects were due to reduced body weight or the prolonged fasting period. Future studies are needed to elucidate these effects on changes in lipoprotein subfractions.
The effects of glucose- or fructose-sweetened beverages have been investigated in overweight and obese subjects, and differential effects were shown on adipose distribution . Both total abdominal fat and visceral adipose tissue (VAT) volume were increased in individuals consuming fructose, while only subcutaneous adipose tissue volume was significantly increased in those consuming glucose. Fructose raised sdLDL, oxidized LDL (oxLDL) and postprandial remnant-like particle lipoprotein-cholesterol (RLP-C) and RLP-TG, whereas glucose consumption did not . Furthermore, sdLDL was mostly affected by pre-existing MetS risk factors (MSRF), and the increase in sdLDL levels during fructose consumption was more than two-fold greater in subjects with three MSRF than in those with zero to two MSRF . Finally, consumption of fructose at 25% of energy requirements with an ad libitum diet decreased glucose tolerance and insulin sensitivity (greater in women than in men) compared with glucose consumption.
A high prevalence of sdLDL in obese children, as well as a relationship between peak LDL diameter and abdominal fat accumulation, and the level of both HDL-C and TG was reported . When changes in LDL subfractions during a weight loss intervention for overweight and obese children were investigated, a reduction in cholesterol concentration of LDL III particles (54.1 vs. 40.4 mg/dL; p < 0.01), and shift in mean LDL-C peak particle density (1.041 vs. 1.035 g/mL) was found . These alterations were also positively and significantly correlated to changes in VLDL metabolism. In contrast, in a later study , statistical difference was reported in the LDL particle size between 26 obese and 27 healthy children (p = 0.575); the size of LDL particles was not correlated with BMI, homeostasis model assessment (HOMA)-IR or serum lipids, although obese children had increased TGs and low HDL levels. Based on these results, the authors suggested that LDL particle size measurement is not necessary in childhood obesity as a routine procedure. A potentially explanation for these different results might be genetic factors and age in different populations . Postprandial pro-atherogenic factors in obese boys were significantly improved after two different meals: moderate fat (MF: 61% carbohydrate, 27% fat) vs. high fat (HF: 37% carbohydrate, 52% fat). OxLDL concentration was raised after the HF, but not after the MF meal (9.3(2.2)% vs. 1.8(2.2)% from baseline, p < 0.02) and the densest LDL particles were associated positively (p < 0.05) with oxLDL levels. HDL-C concentration was lower (p < 0.05) at 300 min after HF vs. MF meal . These results indicate that an evaluation of postprandial lipids may be relevant in children, as suggested earlier .
Reduced GH secretion in obesity could be associated with atherogenic dyslipidaemia, including raised sdLDL particles, given that reduced peak-stimulated GH in obesity was independently associated with a more atherogenic lipoprotein profile defined in terms of particle size (p < 0.0001) [58,59]. In this study, obese patients with reduced GH secretion had a smaller mean LDL and HDL particle size in comparison with normal weight or obese subjects with sufficient GH (p < 0.0001).
In another study where the ethnic difference in lipid levels and LDL particle size and subclasses were investigated, obese black women had significantly more sdLDL (subclass IV) compared with obese white women .
In summary, the entities of MetS and obesity, with a clinical clustering of CV risk factors and underlying IR, are also associated with phenotypical changes in lipoprotein patterns that increase the atherosclerotic potential of circulating lipids and their interaction with the vessel wall and endothelium. LDL subfraction is positively correlated with higher waist circumference, higher serum TG, as well as older age and more statin usage in hypertensive patients. Thus, LDL size could represent a risk factor associated with endothelial dysfunction in hypertension . Further, in vitro studies, using cultured endothelial cells, have shown that LDL subfractions from hypercholesterolemic patients may deregulate endothelial function .
The main outcomes of discussed studies in this review are listed in Table 2.
|Table 2. Outcomes of the observed studies that have analysed small dense low density lipoprotein cholesterol (sdLDL) in overweight and obese subjects.|
|Study||Patients||sdLDL and measurement||Outcome of the study|
|Satoh N et al. ||214 subjects (97 men and 117 women)||↑||The ratio of sd-LDL-C/LDL-C is a more useful clinical indicator than sdLDL|
|Tsuzaki K et al. ||277 rural Japanese subjects||↑||Genetic predisposition to increased sdLDL in subjects with polymorphism of the beta(3)-adrenergic receptor gene|
|Tzotzas T et al. ||28 obese, non-diabetic women||↔||A low-calorie diet reduces the levels of Lp-PLA2; the levels of sdLDL particles were not changed|
|Varady KA et al. ||60 obese subjects||↓||ADMF is an efficient strategy for decreasing of sdLDL level and increasing LDL particle size|
|Stanhope KL et al. ||32 overweight and obese subjects||↑||Dietary fructose promotes dyslipidaemia|
|Miyashita M et al. ||30 obese children||↑||High prevalence of sdLDL in obese children; a relationship of peak LDL diameter with abdominal fat accumulation, HDL-C and TG levels|
|King RF et al. ||65 overweight and obese children||↓||Reduction in LDL-C, LDL-C III and LDL-C peak particle size|
|Tascilar ME et al. ||26 obese children (13 girls, 13 boys)||↔||Measurement of LDL particle size is not necessary in childhood obesity|
|Maffeis C et al. ||10 obese boys||↑||A change of ≈25% of energy load from fat to carbohydrate in a meal improves postprandial pro-atherogenic factors in obese boys|
|Makimura H et al. ||102 normal weight and obese men and women||↑||An independently association between reduced peak-stimulated GH and an atherogenic lipoprotein profile in obesity|
|Goedecke JH et al. ||15 normal-weight black; 15 normal-weight white; 13 obese black; 13 obese white South African women||↑||Obese black women had significantly more sdLDL compared to obese white women|
|Filippatos TD et al. ||89 overweight and obese patients||↓||Orlistat + fenofibrate led to a greater reduction in sdLDL-C levels and favourable effects on Lp-PLA2|
|Nakou ES et al. ||86 overweight and obese patients with hypercholesterolemia||↓||The combination orlistat and ezetimibe have a more favourable effect on LDL-C and sdLDL-C levels than either drug alone|
LDL-C—low density lipoprotein cholesterol; sdLDL—small dense LDL; HDL-C—high density lipoprotein cholesterol; TG—triglycerides; Lp-PLA2—lipoprotein-associated phospholipase A2; GH—growth hormone; ADMF—alternate day modified fasting, MetS—metabolic syndrome; HF—high fat; NMR—nuclear magnetic resonance; ↑: increased; ↓: decreased; ↔: no effect.
4. Treatment Options
Given that obese individuals with mixed dyslipidaemia have raised sdLDL-C levels, agents that have a potential beneficial effect on this LDL phenotype may be useful . In visceral obesity, drugs, such as statins, fibrates and insulin sensitizers , are often required to correct any associated dyslipidaemia ; cannabinoid receptor type 1 blockers (such as rimonabant) are not currently on the market . Furthermore, statins and other hypolipidemic agents (e.g., ezetimibe and fibrates), as well as weight-reducing agents were reported to favourably affect LDL subfractions [63,64]. Briefly, ezetimibe decreased the large and medium LDL particles and, to a lesser extent, the sdLDL particles, while it had no influence on LDL size; however, its sdLDL lowering capacity may be enhanced in individuals with elevated TG levels [65,68]. It seems that fenofibrate is equally or even more effective than statins in reducing sdLDL levels and increasing LDL size . Fibrates and niacin reduced sdLDL levels and shifted LDL size towards large, buoyant LDL particles .
It was shown that a normalization of adiposity could lead to conversion from pattern B to pattern A LDL phenotype ; weight loss through energy restriction also increased LDL particle size and, thus, reduced CHD risk in obese subjects . Several anti-obesity drugs were withdrawn from use over the past few years, due to adverse events, and currently, orlistat is available for long-term obesity management . Orlistat significantly reduced both LDL-C and sdLDL-C levels (−19% and −45%, respectively, all p < 0.01); however, the decrease in sdLDL-C levels (−76%; p < 0.01 vs. baseline) and the increase in LDL particle diameter (+1.4%; p < 0.01 vs. baseline) were greater with the combination of ezetimibe and orlistat compared with either monotherapy (p < 0.05) . These authors explained this greater fall in sdLDL-C levels by the greater decrease in TG in the combination group compared with monotherapy. In addition, orlistat, in both cases, alone or in combination with ezetimibe, improved anthropometric and metabolic variables (BMI, HOMA, serum uric acid, transaminase activities and plasma Lp-PLA2 ). In an earlier study, multiple regression analysis showed that the orlistat-induced reduction in sdLDL-C levels was significantly and independently correlated with the reduction in TG and HOMA ; orlistat raised sdLDL-C levels by 35% (p < 0.05 vs. baseline) and LDL particle diameter by 0.7% (non-significantly, p > 0.05). Furthermore, the combination treatment (orlistat + fenofibrate) was associated with decreases in VLDL-C (−36%; p < 0.01 vs. baseline) and sdLDL-C levels (−77%; p < 0.001 vs. baseline), as well as the proportion of the sdLDL-C of the total LDL-C (−68%; p < 0.01 vs. baseline) . Orlistat + fenofibrate led to a greater reduction in sdLDL-C levels (p <0.05), together with a greater increase in LDL particle diameter (p < 0.05) compared with the orlistat group. Lp-PLA2 activity was also significantly decreased . In addition, it was suggested that orlistat, alone or in combination with fenofibrate, may decrease LDL concentrations in obese MetS patients, confirming the findings that obese T2DM subjects with MetS orlistat + diet improved several CVD risk factors (fasting glucose, glycosylated haemoglobin (HbA1c), total cholesterol (TC) and LDL-C levels, systolic blood pressure (SBP), waist circumference and HOMA) compared with diet and exercise alone .
Bariatric surgery is an effective treatment option in young obese patients with BMI > 40 kg/m2 or BMI > 35 kg/m2 in the presence of significant comorbidities [74,75]. A gender-dependent relationship between excess weight loss (EWL) and lipid subfractions (reduced TC, LDL-C, TG and HOMA-IR; p < 0.0005 for all) after laparoscopic Roux-en-Y gastric bypass (LRYGB) has been reported . Furthermore, a reduction of sdLDL with a rise in LDL relative flotation was observed after laparoscopic gastric banding (LAGB) (0.34 ± 0.04 vs. 0.38 ± 0.03; p < 0.001), but neither weight reduction nor changes in phospholipid fatty acid composition were found, despite a reduction in TG levels . In general, LRYGB seems to be more effective, safer and has lower mortality rates compared with LAGB .
Although rimonabant has been withdrawn from the market, monotherapy with this drug led to a decreased sdLDL proportion [79,80], whereas in combination with ezetimibe or fenofibrate, a non-significant reduction in sdLDL was observed . The effect of sibutramine, which has also been withdrawn from the market, on the sdLDL profile has not been described. Recently, a meta-analysis reported that orlistat and rimonabant could lead to an improvement in CVD risk factors (reduced SBP, diastolic BP, TC, LDL, fasting glucose, as well as body weight), whereas sibutramine might increase CVD risk factors (i.e., hypertension); future studies should fully elucidate the effects of any similar drugs on cardiovascular risk factors, if they are marketed .
5. Effects of New Anti-Obesity Drugs on Lipids
In the field of anti-obesity drugs, the U.S. Food and Drugs Administration (FDA) has recently (June–July 2012) approved two new agents, namely lorcaserin (Belviq; a selective 5-hydroxytryptamine receptor 2c agonist)  and qsymia (formerly named qnexa, a combination of phentermine with controlled release topiramate) . Of note, lorcaserin is contraindicated in combination with drugs for migraine and depression, as well as agents that can activate serotonin receptors or increase serotonin . Patients with valve abnormalities should be carefully monitored, as serotonin receptors may induce valvular heart disease . With regard to qsymia, heart rate should be monitored regularly during treatment, whereas patients with hyperthyroidism, glaucoma, recent (within the last six months) or unstable heart disease and stroke should not receive it . Both drugs should be discontinued if <5% of initial body weight is lost within three months of treatment.
Contrave (naltrexone sustained-release (SR) combined with bupropion SR) was rejected by the FDA in 2011, due to concerns on CVD risk; however, the FDA agreed to consider the results of a currently running cardiovascular outcomes . These anti-obesity drugs were shown not only to reduce weight, but also to beneficially affect the cardiometabolic profile of obese patients (e.g., waist circumference, lipids, fasting glucose and insulin sensitivity) [86,87,88]. With regard to lipids, these drugs were reported to significantly reduce TC, LDL and TG and increase HDL [86,88,89,90]. However, these data are scarce and, even more, no data exist regarding sdLDL. Future larger studies are needed to establish the effect of these anti-obesity drugs on lipids.
6. Effects of Lipid-Lowering and Anti-Obesity Drugs on HDL Subfractions
HDL-C also circulates in several subclasses with different properties, composition, metabolism and pathophysiological significance [91,92]. The HDL subfraction distribution may potentially affect the multiple actions of HDL with clinical consequences [93,94], but the role of each individual HDL subfraction on CVD risk remains inconclusive [95,96].
MetS has been linked to increased small HDL-3 particles and reduced large HDL-2 levels . Patients with acute ischemic stroke were reported to have smaller HDL size with less HDL 2b and more HDL 3a, 3b and 3c subclasses .
Interestingly, atorvastatin was shown to increase HDL particle size in hyperlipidemic patients . Similarly, rosuvastatin alone or in combination with ω-3 fatty acids raised larger HDL subfractions, whereas rosuvastatin with fenofibrate increased small HDL levels .
Gemfibrozil was found to increase small HDL subclasses in the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) . In contrast, when combined with niacin, gemfibrozil raised large HDL-2 levels .
Niacin treatment was associated with increases in large HDL particles in both type 2 diabetics  and hyperlipidemic patients . Interestingly, the beneficial effects on HDL particles (i.e., increase in large HDL and reduction in small HDL) were numerically greater following niacin plus simvastatin combination therapy compared with atorvastatin monotherapy in a post-hoc analysis of 137 hyperlipidemic patients of the SUPREME study . In another study, niacin monotherapy, as well as its combination with simvastatin raised both HDL-3 and HDL-2 levels, the latter in a relatively greater degree, in dyslipidemic individuals .
Pioglitazone and metformin were shown to beneficially affect both LDL and HDL subclasses in type 2 diabetic patients [106,107]. In contrast, rosiglitazone was found to increase smaller HDL and reduce larger HDL particles in patients with T2DM , as was troglitazone . Of note, both rosiglitazone and troglitazone were withdrawn from the market, due to severe adverse effects (cardiovascular and hepatic disorders, respectively).
Cilostazol, a selective inhibitor of phosphodiesterase 3A used in patients with intermittent claudication to improve their walking distance, was also shown to beneficially affect HDL subclasses . This may be relevant if obese patients have peripheral artery disease.
In obese hyperlipidemic patients, orlistat and ezetimibe, alone or in combination, although not affecting HDL quantity, led to significant changes in HDL quality . In detail, orlistat raised HDL-2 and decreased HDL-3 subclasses, whereas ezetimibe and their combination reduced HDL-3 subfraction. Similarly, in another study with obese MetS patients, orlistat increased large HDL and decreased small HDL subclasses, whereas fenofibrate raised small HDL particles . Ezetimibe was also reported to reduce small HDL subfractions in patients with primary dyslipidaemia .
With regard to the new anti-obesity drugs (i.e., lorcaserin, qsymia and contrave), no data exist on their impact on HDL subclasses; future studies are required to evaluate any possible effect.
Small HDL3c particles in MetS subjects failed to protect endothelial cells from oxLDL-induced apoptosis, and a negative correlation between HDL3c-mediated protection from apoptosis and waist circumference, plasma TG, TC/HDL-C ratio and oxLDL were found . This deficiency in anti-apoptotic activity of small HDL was associated with altered apolipoprotein and lipid composition.
7. Lifestyle as the First-Line Therapeutic Option
Changes in the HDL profile were reported in overweight diabetic men and women following weight reduction . Weight loss has been suggested as an effective method in reversing the decrease in HDL levels in obesity, and weight loss achieved through exercise is more effective than weight loss achieved by diet . In a study with 46 obese subjects , only the combination of alternate day fasting plus exercise resulted in decreased LDL-C (p < 0.05) and increased HDL-C (p < 0.05) with a decreased proportion of small HDL particles (p < 0.01) compared with each intervention alone. Several recent meta-analyses [118,119,120] have also reported beneficial effects of exercise on lipids and lipoproteins in patients with MetS, in accordance with the results of many studies that have reported that exercise could have an important role in increasing HDL-C level [117,121,122]. Interestingly, when associations of all-cause mortality, adiposity and fitness were examined in older adults, fitness was inversely associated with mortality, and results were changed a little by adjustments for adiposity or fat distribution . Thus, the authors have found that both fitness and BMI are independent predictors of all-cause mortality in adults 60 years old or older, emphasizing that further studies are needed to confirm if total adiposity per se may be the factor that increases mortality risk. The same authors have shown that lower levels of fitness are also associated with a higher risk of all-cause and CVD mortality in younger and middle-aged men [124,125].
In a six-month randomized study  performed in 78 severely obese subjects (86% of them had either diabetes or MetS), the authors found a favourable effect of a low carbohydrate diet on lipoprotein subfractions compared with a conventional diet, while both diets similarly decreased LDL particles and increased large HDL. In addition, both diets significantly decreased postprandial lipemia and led to similar (but non-significant) alterations in the total cholesterol/HDL-C ratio, fasting triacylglycerols, oxLDL and LDL subclasses distribution . However, a very low carbohydrate diet prevents a decrease in HDL-C, although it did not lower LDL-C compared with a low-fat weight loss diet . Similar results were also achieved when both diets were consumed for weight maintenance rather than weight loss, thereby reducing the effect of change in body weight on lipids . In a study that compared the effects of pioglitazone vs. diet/exercise on body fat, glucose and lipid metabolism in obese, insulin-resistant individuals , only diet/exercise reduced total cholesterol, TG and LDL-C concentrations, whereas both treatment increased large LDL and decreased sdLDL particles. Furthermore, a Mediterranean-style diet rich in fruits and vegetables and with high polyunsaturated fats reduced cardiovascular events and decreased LDL-C with a concomitant increase in HDL-C .
Increased physical activity may improve sdLDL in hyperlipidemic subjects . In general, lifestyle modification is the first-line therapy , with smoking cessation, exercise, mild-to-moderate alcohol consumption and weight loss increasing HDL-C in patients with levels <40 mg/dL . In summary, first-line therapy in obese patients should be a healthy diet and physical activity. Lipid-lowering therapies should be prescribed only after or together with lifestyle modifications, unless the risk of a vascular event is so high that the prescribing clinician elects not to delay effective pharmacological intervention. If after statins therapy, HDL-C remains low, then niacin should be prescribed.
It is known that increased LDL-C (including decreased HDL-C) is one of several factors that are linked with high cardiovascular risk. However, the exact mechanisms by which LDL particle size may act as an independent CVD risk factor remains unclear. Currently, there is no strong clinical evidence to show that targeting lipoprotein subfractions is useful or recommended. Further large studies are needed to elucidate the clinical implications of lipoprotein subfractions, as well as to establish the effect of the here mentioned anti-obesity drugs on lipoproteins.
In overweight and obese hypercholesterolemic subjects, statins are the first treatment choice. Orlistat and ezetimibe coadministration had a more favourable effect on LDL-C and sdLDL-C levels than either drug alone . This combination also exhibited favourable effects on Lp-PLA2 activity and LDL phenotype in overweight and obese patients with MetS, but positive effects on the LDL distribution profile should be replicated in larger studies. ADMF may increase LDL particle size, thus decreasing the sdLDL proportion, and ADMF could be a suitable alternative to traditional energy restriction for lowering CVD risk in obese individuals.
Anti-obesity medications, either as monotherapy or in combination with other drugs, presented encouraging results in terms of weight loss, safety and improvement of cardiometabolic risk factors. Combinations of drugs targeting different pathways in low doses may have better results than strategies that modify one pathway alone; this might represent the future strategy in obesity treatment.
Improving the quantity and the quality of lipoproteins in obesity and the MetS may represent an effective approach to reduce cardiovascular risk.
This work is part of collaboration between the Department of Clinical Biochemistry, Royal Free Hospital campus, University College of London (UCL), UK, Department of Internal Medicine and Medical Specialties, University of Palermo, Italy, Euro-Mediterranean Institute of Science and Technology, Italy, Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece, and Institute Vinca, University of Belgrade, Serbia, and is supported by the grant No.173033 (to E.R.I) from the Ministry of Science, Republic of Serbia.
Declaration of Interest
DN has no conflict of interest. NK has given talks and attended conferences sponsored by Genzyme, Pfizer and Novartis. GM and ERI have no conflict of interest. DPM has given talks, attended conferences and participated in trials and advisory boards sponsored by MSD, Genzyme and Abbott. MR has given talks and participated in conferences sponsored by Astra-Zeneca, Bracco, Bromatech, Chiesi Farmaceutici, Novartis, Novo-Nordisk, Rikrea and Servier.
- Rosolova, H.; Nussbaumerova, B. Cardio-metabolic risk prediction should be superior to cardiovascular risk assessment in primary prevention of cardiovascular diseases. EPMA J. 2011, 2, 15–26, doi:10.1007/s13167-011-0066-1.
- Charakida, M.; Finer, N. Drug treatment of obesity in cardiovascular disease. Am. J. Cardiovasc. Drugs 2012, 12, 93–104, doi:10.2165/11599000-000000000-00000.
- Brunzell, J.D.; Davidson, M.; Furberg, C.D.; Goldberg, R.B.; Howard, B.V.; Stein, J.H.; Witztum, J.L. Lipoprotein management in patients with cardiometabolic risk: Consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation. J. Am. Coll. Cardiol. 2008, 51, 1512–1524, doi:10.1016/j.jacc.2008.02.034.
- Despres, J.P. Cardiovascular disease under the influence of excess visceral fat. Crit. Pathw. Cardiol. 2007, 6, 51–59, doi:10.1097/HPC.0b013e318057d4c9.
- Magkos, F.; Mohammed, B.S.; Mittendorfer, B. Effect of obesity on the plasma lipoprotein subclass profile in normoglycemic and normolipidemic men and women. Int. J. Obes. (Lond.) 2008, 32, 1655–1664.
- Rizzo, M.; Mikhailidis, D.P. There is more to predicting vascular disease than just established risk factors. Curr. Pharm. Des. 2011, 17, 3608–3610, doi:10.2174/138161211798220990.
- Vinik, A.I. The metabolic basis of atherogenic dyslipidemia. Clin. Cornerstone 2005, 7, 27–35, doi:10.1016/S1098-3597(05)80065-1.
- Rizzo, M.; Kotur-Stevuljevic, J.; Berneis, K.; Spinas, G.; Rini, G.B.; Jelic-Ivanovic, Z.; Spasojevic-Kalimanovska, V.; Vekic, J. Atherogenic dyslipidemia and oxidative stress: A new look. Transl. Res. 2009, 153, 217–223, doi:10.1016/j.trsl.2009.01.008.
- Athyros, V.G.; Tziomalos, K.; Karagiannis, A.; Anagnostis, P.; Mikhailidis, D.P. Should adipokines be considered in the choice of the treatment of obesity-related health problems? Curr. Drug Targets 2010, 11, 122–135, doi:10.2174/138945010790030992.
- Athyros, V.G.; Tziomalos, K.; Karagiannis, A.; Mikhailidis, D.P. Dyslipidaemia of obesity, metabolic syndrome and type 2 diabetes mellitus: The case for residual risk reduction after statin treatment. Open Cardiovasc. Med. J. 2011, 5, 24–34, doi:10.2174/1874192401105010024.
- Paradis, M.E.; Badellino, K.O.; Rader, D.J.; Tchernof, A.; Richard, C.; Luu-The, V.; Deshaies, Y.; Bergeron, J.; Archer, W.R.; Couture, P.; et al. Visceral adiposity and endothelial lipase. J. Clin. Endocrinol. Metab. 2006, 91, 3538–3543, doi:10.1210/jc.2006-0766.
- Chapman, M.J.; Sposito, A.C. Hypertension and dyslipidaemia in obesity and insulin resistance: Pathophysiology, impact on atherosclerotic disease and pharmacotherapy. Pharmacol. Ther. 2008, 117, 354–373, doi:10.1016/j.pharmthera.2007.10.004.
- Adiels, M.; Taskinen, M.R.; Packard, C.; Caslake, M.J.; Soro-Paavonen, A.; Westerbacka, J.; Vehkavaara, S.; Hakkinen, A.; Olofsson, S.O.; Yki-Jarvinen, H.; Boren, J. Overproduction of large VLDL particles is driven by increased liver fat content in man. Diabetologia 2006, 49, 755–765, doi:10.1007/s00125-005-0125-z.
- Bugianesi, E.; Gastaldelli, A.; Vanni, E.; Gambino, R.; Cassader, M.; Baldi, S.; Ponti, V.; Pagano, G.; Ferrannini, E.; Rizzetto, M. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: Sites and mechanisms. Diabetologia 2005, 48, 634–642, doi:10.1007/s00125-005-1682-x.
- Avramoglu, R.K.; Basciano, H.; Adeli, K. Lipid and lipoprotein dysregulation in insulin resistant states. Clin. Chim. Acta 2006, 368, 1–19, doi:10.1016/j.cca.2005.12.026.
- Berneis, K.K.; Krauss, R.M. Metabolic origins and clinical significance of LDL heterogeneity. J. Lipid Res. 2002, 43, 1363–1379, doi:10.1194/jlr.R200004-JLR200.
- Nieves, D.J.; Cnop, M.; Retzlaff, B.; Walden, C.E.; Brunzell, J.D.; Knopp, R.H.; Kahn, S.E. The atherogenic lipoprotein profile associated with obesity and insulin resistance is largely attributable to intra-abdominal fat. Diabetes 2003, 52, 172–179, doi:10.2337/diabetes.52.1.172.
- Goff, D.C., Jr.; D’Agostino, R.B., Jr.; Haffner, S.M.; Otvos, J.D. Insulin resistance and adiposity influence lipoprotein size and subclass concentrations. Results from the Insulin Resistance Atherosclerosis Study. Metabolism 2005, 54, 264–270, doi:10.1016/j.metabol.2004.09.002.
- Rizzo, M.; Rini, G.B.; Berneis, K. The clinical relevance of LDL size and subclasses modulation in patients with type-2 diabetes. Exp. Clin. Endocrinol. Diabetes 2007, 115, 477–482, doi:10.1055/s-2007-980179.
- Segrest, J.P.; Jones, M.K.; De Loof, H.; Dashti, N. Structure of apolipoprotein B-100 in low density lipoproteins. J. Lipid Res. 2001, 42, 1346–1367.
- Carmena, R.; Duriez, P.; Fruchart, J.C. Atherogenic lipoprotein particles in atherosclerosis. Circulation 2004, 109, III2–III7.
- Rizzo, M.; Berneis, K. Low-density lipoprotein size and cardiovascular risk assessment. QJM 2006, 99, 1–14, doi:10.1093/qjmed/hci154.
- Superko, H.R.; Gadesam, R.R. Is it LDL particle size or number that correlates with risk for cardiovascular disease? Curr. Atheroscler. Rep. 2008, 10, 377–385, doi:10.1007/s11883-008-0059-2.
- Koba, S.; Yokota, Y.; Hirano, T.; Ito, Y.; Ban, Y.; Tsunoda, F.; Sato, T.; Shoji, M.; Suzuki, H.; Geshi, E.; Kobayashi, Y.; Katagiri, T. Small LDL-cholesterol is superior to LDL-cholesterol for determining severe coronary atherosclerosis. J. Atheroscler. Thromb. 2008, 15, 250–260, doi:10.5551/jat.E572.
- Mikhailidis, D.P.; Elisaf, M.; Rizzo, M.; Berneis, K.; Griffin, B.; Zambon, A.; Athyros, V.; de Graaf, J.; Marz, W.; Parhofer, K.G.; et al. “European panel on low density lipoprotein (LDL) subclasses”: A statement on the pathophysiology, atherogenicity and clinical significance of LDL subclasses: Executive summary. Curr. Vasc. Pharmacol. 2011, 9, 531–532.
- Mikhailidis, D.P.; Elisaf, M.; Rizzo, M.; Berneis, K.; Griffin, B.; Zambon, A.; Athyros, V.; de Graaf, J.; Marz, W.; Parhofer, K.G.; et al. “European panel on low density lipoprotein (LDL) subclasses”: A statement on the pathophysiology, atherogenicity and clinical significance of LDL subclasses. Curr. Vasc. Pharmacol. 2011, 9, 533–571.
- Rizzo, M.; Krayenbuhl, P.A.; Pernice, V.; Frasheri, A.; Battista Rini, G.; Berneis, K. LDL size and subclasses in patients with abdominal aortic aneurysm. Int. J. Cardiol. 2009, 134, 406–408, doi:10.1016/j.ijcard.2007.12.082.
- Rizzo, M.; Pernice, V.; Frasheri, A.; Berneis, K. Atherogenic lipoprotein phenotype and LDL size and subclasses in patients with peripheral arterial disease. Atherosclerosis 2008, 197, 237–241, doi:10.1016/j.atherosclerosis.2007.03.034.
- Watanabe, T.; Koba, S.; Kawamura, M.; Itokawa, M.; Idei, T.; Nakagawa, Y.; Iguchi, T.; Katagiri, T. Small dense low-density lipoprotein and carotid atherosclerosis in relation to vascular dementia. Metabolism 2004, 53, 476–482, doi:10.1016/j.metabol.2003.11.020.
- Berneis, K.; Jeanneret, C.; Muser, J.; Felix, B.; Miserez, A.R. Low-density lipoprotein size and subclasses are markers of clinically apparent and non-apparent atherosclerosis in type 2 diabetes. Metabolism 2005, 54, 227–234, doi:10.1016/j.metabol.2004.08.017.
- Wallenfeldt, K.; Bokemark, L.; Wikstrand, J.; Hulthe, J.; Fagerberg, B. Apolipoprotein B/apolipoprotein A–I in relation to the metabolic syndrome and change in carotid artery intima-media thickness during 3 years in middle-aged men. Stroke 2004, 35, 2248–2252, doi:10.1161/01.STR.0000140629.65145.3c.
- Rizzo, M.; Trepp, R.; Berneis, K.; Christ, E.R. Atherogenic lipoprotein phenotype and low-density lipoprotein size and subclasses in patients with growth hormone deficiency before and after short-term replacement therapy. Eur. J. Endocrinol. 2007, 156, 361–367, doi:10.1530/EJE-06-0652.
- Rizzo, M.; Berneis, K.; Hersberger, M.; Pepe, I.; Di Fede, G.; Rini, G.B.; Spinas, G.A.; Carmina, E. Milder forms of atherogenic dyslipidemia in ovulatory versus anovulatory polycystic ovary syndrome phenotype. Hum. Reprod. 2009, 24, 2286–2292, doi:10.1093/humrep/dep121.
- Berneis, K.; Rizzo, M.; Hersberger, M.; Rini, G.B.; di Fede, G.; Pepe, I.; Spinas, G.A.; Carmina, E. Atherogenic forms of dyslipidaemia in women with polycystic ovary syndrome. Int. J. Clin. Pract. 2009, 63, 56–62, doi:10.1111/j.1742-1241.2008.01897.x.
- Rizzo, M.; Berneis, K.; Altinova, A.E.; Toruner, F.B.; Akturk, M.; Ayvaz, G.; Rini, G.B.; Spinas, G.A.; Arslan, M. Atherogenic lipoprotein phenotype and LDL size and subclasses in women with gestational diabetes. Diabet. Med. 2008, 25, 1406–1411, doi:10.1111/j.1464-5491.2008.02613.x.
- Gazi, I.; Tsimihodimos, V.; Filippatos, T.; Bairaktari, E.; Tselepis, A.D.; Elisaf, M. Concentration and relative distribution of low-density lipoprotein subfractions in patients with metabolic syndrome defined according to the National Cholesterol Education Program criteria. Metabolism 2006, 55, 885–891, doi:10.1016/j.metabol.2006.02.015.
- Rizzo, M.; Berneis, K. Small, dense low-density-lipoproteins and the metabolic syndrome. Diabetes Metab. Res. Rev. 2007, 23, 14–20, doi:10.1002/dmrr.694.
- Rizzo, M.; Pernice, V.; Frasheri, A.; di Lorenzo, G.; Rini, G.B.; Spinas, G.A.; Berneis, K. Small, dense low-density lipoproteins (LDL) are predictors of cardio- and cerebro-vascular events in subjects with the metabolic syndrome. Clin. Endocrinol. (Oxf.) 2009, 70, 870–875.
- Satoh, N.; Wada, H.; Ono, K.; Yamakage, H.; Yamada, K.; Nakano, T.; Hattori, M.; Shimatsu, A.; Kuzuya, H.; Hasegawa, K. Small dense LDL-cholesterol relative to LDL-cholesterol is a strong independent determinant of hypoadiponectinemia in metabolic syndrome. Circ. J. 2008, 72, 932–939, doi:10.1253/circj.72.932.
- Hosoyamada, K.; Uto, H.; Imamura, Y.; Hiramine, Y.; Toyokura, E.; Hidaka, Y.; Kuwahara, T.; Kusano, K.; Saito, K.; Oketani, M.; et al. Fatty liver in men is associated with high serum levels of small, dense low-density lipoprotein cholesterol. Diabetol. Metab. Syndr. 2012, 4, 34, doi:10.1186/1758-5996-4-34.
- Toledo, F.G.; Sniderman, A.D.; Kelley, D.E. Influence of hepatic steatosis (fatty liver) on severity and composition of dyslipidemia in type 2 diabetes. Diabetes Care 2006, 29, 1845–1850, doi:10.2337/dc06-0455.
- Sugino, I.; Kuboki, K.; Matsumoto, T.; Murakami, E.; Nishimura, C.; Yoshino, G. Influence of fatty liver on plasma small, dense LDL-cholesterol in subjects with and without metabolic syndrome. J. Atheroscler. Thromb. 2011, 18, 1–7, doi:10.5551/jat.5447.
- Kolovou, G.D.; Mikhailidis, D.P.; Nordestgaard, B.G.; Bilianou, H.; Panotopoulos, G. Definition of postprandial lipaemia. Curr. Vasc. Pharmacol. 2011, 9, 292–301.
- Kolovou, G.D.; Mikhailidis, D.P.; Kovar, J.; Lairon, D.; Nordestgaard, B.G.; Ooi, T.C.; Perez-Martinez, P.; Bilianou, H.; Anagnostopoulou, K.; Panotopoulos, G. Assessment and clinical relevance of non-fasting and postprandial triglycerides: An expert panel statement. Curr. Vasc. Pharmacol. 2011, 9, 258–270.
- Mihas, C.; Kolovou, G.D.; Mikhailidis, D.P.; Kovar, J.; Lairon, D.; Nordestgaard, B.G.; Ooi, T.C.; Perez-Martinez, P.; Bilianou, H.; Anagnostopoulou, K.; Panotopoulos, G. Diagnostic value of postprandial triglyceride testing in healthy subjects: A meta-analysis. Curr. Vasc. Pharmacol. 2011, 9, 271–280.
- Tsuzaki, K.; Kotani, K.; Fujiwara, S.; Sano, Y.; Matsuoka, Y.; Domichi, M.; Hamada, T.; Shimatsu, A.; Sakane, N. The Trp64Arg polymorphism of the beta3-adrenergic receptor gene is associated with increased small dense low-density lipoprotein in a rural Japanese population: The Mima study. Metabolism 2007, 56, 1689–1693, doi:10.1016/j.metabol.2007.07.012.
- Tzotzas, T.; Filippatos, T.D.; Triantos, A.; Bruckert, E.; Tselepis, A.D.; Kiortsis, D.N. Effects of a low-calorie diet associated with weight loss on lipoprotein-associated phospholipase A2 (Lp-PLA2) activity in healthy obese women. Nutr. Metab. Cardiovasc. Dis. 2008, 18, 477–482, doi:10.1016/j.numecd.2007.04.004.
- Tselepis, A.F.; Rizzo, M.; Goudevenos, I.A. Therapeutic modulation of lipoprotein-associated phospholipase A2 (Lp-PLA2). Curr. Pharm. Des. 2011, 17, 3656–3661, doi:10.2174/138161211798220936.
- Gazi, I.; Lourida, E.S.; Filippatos, T.; Tsimihodimos, V.; Elisaf, M.; Tselepis, A.D. Lipoprotein-associated phospholipase A2 activity is a marker of small, dense LDL particles in human plasma. Clin. Chem. 2005, 51, 2264–2273, doi:10.1373/clinchem.2005.058404.
- Varady, K.A.; Bhutani, S.; Church, E.C.; Klempel, M.C. Short-term modified alternate-day fasting: A novel dietary strategy for weight loss and cardioprotection in obese adults. Am. J. Clin. Nutr. 2009, 90, 1138–1143, doi:10.3945/ajcn.2009.28380.
- Varady, K.A.; Bhutani, S.; Klempel, M.C.; Lamarche, B. Improvements in LDL particle size and distribution by short-term alternate day modified fasting in obese adults. Br. J. Nutr. 2011, 105, 580–583, doi:10.1017/S0007114510003788.
- Stanhope, K.L.; Schwarz, J.M.; Keim, N.L.; Griffen, S.C.; Bremer, A.A.; Graham, J.L.; Hatcher, B.; Cox, C.L.; Dyachenko, A.; Zhang, W.; et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J. Clin. Invest. 2009, 119, 1322–1334, doi:10.1172/JCI37385.
- Miyashita, M.; Okada, T.; Kuromori, Y.; Harada, K. LDL particle size, fat distribution and insulin resistance in obese children. Eur. J. Clin. Nutr. 2006, 60, 416–420, doi:10.1038/sj.ejcn.1602333.
- King, R.F.; Hobkirk, J.P.; Cooke, C.B.; Radley, D.; Gately, P.J. Low-density lipoprotein sub-fraction profiles in obese children before and after attending a residential weight loss intervention. J. Atheroscler. Thromb. 2008, 15, 100–107, doi:10.5551/jat.E490.
- Tascilar, M.E.; Ozgen, T.; Cihan, M.; Abaci, A.; Yesilkaya, E.; Eker, I.; Serdar, M. The effect of insulin resistance and obesity on low-density lipoprotein particle size in children. J. Clin. Res. Pediatr. Endocrinol. 2010, 2, 63–66, doi:10.4274/jcrpe.v2i2.63.
- Maffeis, C.; Pinelli, L.; Surano, M.G.; Fornari, E.; Cordioli, S.; Gasperotti, S.; Vianello, D.; Corradi, M.; Zambon, A. Pro-atherogenic postprandial profile: Meal-induced changes of lipoprotein sub-fractions and inflammation markers in obese boys. Nutr. Metab. Cardiovasc. Dis. 2012, 22, 959–965, doi:10.1016/j.numecd.2010.12.009.
- Nzekwu, M.M.; Ball, G.D.; Jetha, M.M.; Beaulieu, C.; Proctor, S.D. Apolipoprotein B48: A novel marker of metabolic risk in overweight children? Biochem. Soc. Trans. 2007, 35, 484–486, doi:10.1042/BST0350484.
- Makimura, H.; Feldpausch, M.N.; Stanley, T.L.; Sun, N.; Grinspoon, S.K. Reduced growth hormone secretion in obesity is associated with smaller LDL and HDL particle size. Clin. Endocrinol. (Oxf.) 2012, 76, 220–227.
- Rizzo, M.; Mikhailidis, D.P. Lipoprotein alterations and reduced growth hormone secretion: Relationships with obesity and cardiovascular risk. Clin. Endocrinol. (Oxf.) 2012, 76, 177–178.
- Goedecke, J.H.; Utzschneider, K.; Faulenbach, M.V.; Rizzo, M.; Berneis, K.; Spinas, G.A.; Dave, J.A.; Levitt, N.S.; Lambert, E.V.; Olsson, T.; Kahn, S.E. Ethnic differences in serum lipoproteins and their determinants in South African women. Metabolism 2010, 59, 1341–1350, doi:10.1016/j.metabol.2009.12.018.
- Kim, Y.K.; Seo, H.S.; Lee, E.M.; Na, J.O.; Choi, C.U.; Lim, H.E.; Kim, E.J.; Rha, S.W.; Park, C.G.; Oh, D.J. Association of hypertension with small, dense low-density lipoprotein in patients without metabolic syndrome. J. Hum. Hypertens. 2012, 26, 670–676, doi:10.1038/jhh.2011.86.
- Tai, M.H.; Kuo, S.M.; Liang, H.T.; Chiou, K.R.; Lam, H.C.; Hsu, C.M.; Pownall, H.J.; Chen, H.H.; Huang, M.T.; Yang, C.Y. Modulation of angiogenic processes in cultured endothelial cells by low density lipoproteins subfractions from patients with familial hypercholesterolemia. Atherosclerosis 2006, 186, 448–457, doi:10.1016/j.atherosclerosis.2005.08.022.
- Filippatos, T.D.; Gazi, I.F.; Liberopoulos, E.N.; Athyros, V.G.; Elisaf, M.S.; Tselepis, A.D.; Kiortsis, D.N. The effect of orlistat and fenofibrate, alone or in combination, on small dense LDL and lipoprotein-associated phospholipase A2 in obese patients with metabolic syndrome. Atherosclerosis 2007, 193, 428–437, doi:10.1016/j.atherosclerosis.2006.07.010.
- Nakou, E.S.; Filippatos, T.D.; Georgoula, M.; Kiortsis, D.N.; Tselepis, A.D.; Mikhailidis, D.P.; Elisaf, M.S. The effect of orlistat and ezetimibe, alone or in combination, on serum LDL and small dense LDL cholesterol levels in overweight and obese patients with hypercholesterolaemia. Curr. Med. Res. Opin. 2008, 24, 1919–1929, doi:10.1185/03007990802177150.
- Florentin, M.; Tselepis, A.D.; Elisaf, M.S.; Rizos, C.V.; Mikhailidis, D.P.; Liberopoulos, E.N. Effect of non-statin lipid lowering and anti-obesity drugs on LDL subfractions in patients with mixed dyslipidaemia. Curr. Vasc. Pharmacol. 2010, 8, 820–830.
- Hainer, V.; Hainerova, I.A. Do we need anti-obesity drugs? Diabetes Metab. Res. Rev. 2012, 28, 8–20, doi:10.1002/dmrr.2349.
- Zambon, A.; Marchiori, M.; Manzato, E. Dyslipidemia in visceral obesity: Pathophysiological mechanisms, clinical implications and therapy. G. Ital. Cardiol. (Rome) 2008, 9, 29S–39S.
- Gouni-Berthold, I.; Mikhailidis, D.P.; Rizzo, M. Clinical benefits of ezetimibe use: Is absence of proof, proof of absence? Expert Opin. Pharmacother. 2012, 13, 1985–1988, doi:10.1517/14656566.2012.720974.
- McKeage, K.; Keating, G.M. Fenofibrate: A review of its use in dyslipidaemia. Drugs 2011, 71, 1917–1946, doi:10.2165/11208090-000000000-00000.
- Superko, H.R.; Berneis, K.K.; Williams, P.T.; Rizzo, M.; Wood, P.D. Gemfibrozil reduces small low-density lipoprotein more in normolipemic subjects classified as low-density lipoprotein pattern B compared with pattern A. Am. J. Cardiol. 2005, 96, 1266–1272, doi:10.1016/j.amjcard.2005.06.069.
- Siri-Tarino, P.W.; Williams, P.T.; Fernstrom, H.S.; Rawlings, R.S.; Krauss, R.M. Reversal of small, dense LDL subclass phenotype by normalization of adiposity. Obesity (Silver Spring) 2009, 17, 1768–1775.
- Morgan, L.M.; Griffin, B.A.; Millward, D.J.; DeLooy, A.; Fox, K.R.; Baic, S.; Bonham, M.P.; Wallace, J.M.; MacDonald, I.; Taylor, M.A.; Truby, H. Comparison of the effects of four commercially available weight-loss programmes on lipid-based cardiovascular risk factors. Public Health Nutr. 2009, 12, 799–807, doi:10.1017/S1368980008003236.
- Didangelos, T.P.; Thanopoulou, A.K.; Bousboulas, S.H.; Sambanis, C.L.; Athyros, V.G.; Spanou, E.A.; Dimitriou, K.C.; Pappas, S.I.; Karamanos, B.G.; Karamitsos, D.T. The ORLIstat and CArdiovascular risk profile in patients with metabolic syndrome and type 2 DIAbetes (ORLICARDIA) Study. Curr. Med. Res. Opin. 2004, 20, 1393–1401, doi:10.1185/030079904125004466.
- Fontaine, K.R.; Redden, D.T.; Wang, C.; Westfall, A.O.; Allison, D.B. Years of life lost due to obesity. JAMA 2003, 289, 187–193.
- Waseem, T.; Mogensen, K.M.; Lautz, D.B.; Robinson, M.K. Pathophysiology of obesity: Why surgery remains the most effective treatment. Obes. Surg. 2007, 17, 1389–1398, doi:10.1007/s11695-007-9220-1.
- Garcia-Marirrodriga, I.; Amaya-Romero, C.; Ruiz-Diaz, G.P.; Fernandez, S.; Ballesta-Lopez, C.; Pou, J.M.; Romeo, J.H.; Vilahur, G.; Vilhur, G.; Badimon, L.; Ybarra, J. Evolution of lipid profiles after bariatric surgery. Obes. Surg. 2012, 22, 609–616, doi:10.1007/s11695-011-0534-7.
- Zambon, S.; Romanato, G.; Sartore, G.; Marin, R.; Busetto, L.; Zanoni, S.; Favretti, F.; Sergi, G.; Fioretto, P.; Manzato, E. Bariatric surgery improves atherogenic LDL profile by triglyceride reduction. Obes. Surg. 2009, 19, 190–195, doi:10.1007/s11695-008-9644-2.
- Athyros, V.G.; Tziomalos, K.; Karagiannis, A.; Mikhailidis, D.P. Cardiovascular benefits of bariatric surgery in morbidly obese patients. Obes. Rev. 2011, 12, 515–524, doi:10.1111/j.1467-789X.2010.00831.x.
- Despres, J.P.; Golay, A.; Sjostrom, L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N. Engl. J. Med. 2005, 353, 2121–2134, doi:10.1056/NEJMoa044537.
- Despres, J.P.; Ross, R.; Boka, G.; Almeras, N.; Lemieux, I. Effect of rimonabant on the high-triglyceride/low-HDL-cholesterol dyslipidemia, intraabdominal adiposity, and liver fat: The ADAGIO-Lipids trial. Arterioscler. Thromb. Vasc. Biol. 2009, 29, 416–423, doi:10.1161/ATVBAHA.108.176362.
- Zhou, Y.H.; Ma, X.Q.; Wu, C.; Lu, J.; Zhang, S.S.; Guo, J.; Wu, S.Q.; Ye, X.F.; Xu, J.F.; He, J. Effect of anti-obesity drug on cardiovascular risk factors: A systematic review and meta-analysis of randomized controlled trials. PLoS One 2012, 7, e39062.
- FDA U.S. Food and Drug Administration. FDA approves Belviq to treat some overweight or obese adults. Available online: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm309993.htm (accessed on 13 March 2013).
- FDA U.S. Food and Drug Administration. FDA approves weight-management drug Qsymia. Available online: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm312468.htm (accessed on 13 March 2013).
- Bhattacharyya, S.; Schapira, A.H.; Mikhailidis, D.P.; Davar, J. Drug-induced fibrotic valvular heart disease. Lancet 2009, 374, 577–585.
- Drugs Contrave. Orexigen and FDA Identify a Clear and Feasible Path to Approval for Contrave. Available online: http://www.drugs.com/nda/contrave_110920.html (accessed on 13 March 2013).
- Katsiki, N.; Hatzitolios, A.I.; Mikhailidis, D.P. Naltrexone sustained-release (SR) + bupropion SR combination therapy for the treatment of obesity: “A new kid on the block”? Ann. Med. 2011, 43, 249–258.
- Bays, H.E. Lorcaserin: Drug profile and illustrative model of the regulatory challenges of weight-loss drug development. Expert Rev. Cardiovasc. Ther. 2011, 9, 265–277.
- Allison, D.B.; Gadde, K.M.; Garvey, W.T.; Peterson, C.A.; Schwiers, M.L.; Najarian, T.; Tam, P.Y.; Troupin, B.; Day, W.W. Controlled-release phentermine/topiramate in severely obese adults: A randomized controlled trial (EQUIP). Obesity (Silver Spring) 2012, 20, 330–342.
- Martin, C.K.; Redman, L.M.; Zhang, J.; Sanchez, M.; Anderson, C.M.; Smith, S.R.; Ravussin, E. Lorcaserin, a 5-HT(2C) receptor agonist, reduces body weight by decreasing energy intake without influencing energy expenditure. J. Clin. Endocrinol. Metab. 2011, 96, 837–845.
- Fidler, M.C.; Sanchez, M.; Raether, B.; Weissman, N.J.; Smith, S.R.; Shanahan, W.R.; Anderson, C.M. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: The BLOSSOM trial. J. Clin. Endocrinol. Metab. 2011, 96, 3067–3077.
- Asztalos, B.F.; Tani, M.; Schaefer, E.J. Metabolic and functional relevance of HDL subspecies. Curr. Opin. Lipidol. 2011, 22, 176–185.
- Calabresi, L.; Gomaraschi, M.; Franceschini, G. High-density lipoprotein quantity or quality for cardiovascular prevention? Curr. Pharm. Des. 2010, 16, 1494–1503.
- Otocka-Kmiecik, A.; Mikhailidis, D.P.; Nicholls, S.J.; Davidson, M.; Rysz, J.; Banach, M. Dysfunctional HDL: A novel important diagnostic and therapeutic target in cardiovascular disease? Prog. Lipid Res. 2012, 51, 314–324.
- Florentin, M.; Liberopoulos, E.N.; Wierzbicki, A.S.; Mikhailidis, D.P. Multiple actions of high-density lipoprotein. Curr. Opin. Cardiol. 2008, 23, 370–378.
- Krauss, R.M. Lipoprotein subfractions and cardiovascular disease risk. Curr. Opin. Lipidol. 2010, 21, 305–311.
- Superko, H.R.; Pendyala, L.; Williams, P.T.; Momary, K.M.; King, S.B., III; Garrett, B.C. High-density lipoprotein subclasses and their relationship to cardiovascular disease. J. Clin. Lipidol. 2012, 6, 496–523.
- Lagos, K.G.; Filippatos, T.D.; Tsimihodimos, V.; Gazi, I.F.; Rizos, C.; Tselepis, A.D.; Mikhailidis, D.P.; Elisaf, M.S. Alterations in the high density lipoprotein phenotype and HDL-associated enzymes in subjects with metabolic syndrome. Lipids 2009, 44, 9–16.
- Zeljkovic, A.; Vekic, J.; Spasojevic-Kalimanovska, V.; Jelic-Ivanovic, Z.; Bogavac-Stanojevic, N.; Gulan, B.; Spasic, S. LDL and HDL subclasses in acute ischemic stroke: Prediction of risk and short-term mortality. Atherosclerosis 2010, 210, 548–554.
- Ikewaki, K.; Terao, Y.; Ozasa, H.; Nakada, Y.; Tohyama, J.; Inoue, Y.; Yoshimura, M. Effects of atorvastatin on nuclear magnetic resonance-defined lipoprotein subclasses and inflammatory markers in patients with hypercholesterolemia. J. Atheroscler. Thromb. 2009, 16, 51–56.
- Agouridis, A.P.; Kostapanos, M.S.; Tsimihodimos, V.; Kostara, C.; Mikhailidis, D.P.; Bairaktari, E.T.; Tselepis, A.D.; Elisaf, M.S. Effect of rosuvastatin monotherapy or in combination with fenofibrate or omega-3 fatty acids on lipoprotein subfraction profile in patients with mixed dyslipidaemia and metabolic syndrome. Int. J. Clin. Pract. 2012, 66, 843–853.
- Otvos, J.D.; Collins, D.; Freedman, D.S.; Shalaurova, I.; Schaefer, E.J.; McNamara, J.R.; Bloomfield, H.E.; Robins, S.J. Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial. Circulation 2006, 113, 1556–1563.
- Superko, H.R.; Garrett, B.C.; King, S.B., III; Momary, K.M.; Chronos, N.A.; Wood, P.D. Effect of combination nicotinic acid and gemfibrozil treatment on intermediate density lipoprotein, and subclasses of low density lipoprotein and high density lipoprotein in patients with combined hyperlipidemia. Am. J. Cardiol. 2009, 103, 387–392.
- Bays, H.; Giezek, H.; McKenney, J.M.; O’Neill, E.A.; Tershakovec, A.M. Extended-release niacin/laropiprant effects on lipoprotein subfractions in patients with type 2 diabetes mellitus. Metab. Syndr. Relat. Disord. 2012, 10, 260–266.
- Toth, P.P.; Thakker, K.M.; Jiang, P.; Padley, R.J. Niacin extended-release/simvastatin combination therapy produces larger favorable changes in high-density lipoprotein particles than atorvastatin monotherapy. Vasc. Health Risk Manag. 2012, 8, 39–44.
- Ballantyne, C.; Gleim, G.; Liu, N.; Sisk, C.M.; Johnson-Levonas, A.O.; Mitchel, Y. Effects of coadministered extended-release niacin/laropiprant and simvastatin on lipoprotein subclasses in patients with dyslipidemia. J. Clin. Lipidol. 2012, 6, 235–243.
- Lawrence, J.M.; Reid, J.; Taylor, G.J.; Stirling, C.; Reckless, J.P. Favorable effects of pioglitazone and metformin compared with gliclazide on lipoprotein subfractions in overweight patients with early type 2 diabetes. Diabetes Care 2004, 27, 41–46.
- Berneis, K.; Rizzo, M.; Stettler, C.; Chappuis, B.; Braun, M.; Diem, P.; Christ, E.R. Comparative effects of rosiglitazone and pioglitazone on fasting and postprandial low-density lipoprotein size and subclasses in patients with Type 2 diabetes. Expert Opin. Pharmacother. 2008, 9, 343–349.
- Rizzo, M.; Vekic, J.; Koulouris, S.; Zeljkovic, A.; Jelic-Ivanovic, Z.; Spasojevic-Kalimanovska, V.; Rini, G.B.; Sakellariou, D.; Pastromas, S.; Mikhailidis, D.P.; Manolis, A.S. Effects of rosiglitazone on fasting and postprandial low- and high-density lipoproteins size and subclasses in type 2 diabetes. Angiology 2010, 61, 584–590.
- Ovalle, F.; Bell, D.S. Effect of thiazolidinediones on high-density lipoprotein subfractions. Endocr. Pract. 2002, 8, 102–104.
- Rizzo, M.; Corrado, E.; Patti, A.M.; Rini, G.B.; Mikhailidis, D.P. Cilostazol and atherogenic dyslipidemia: A clinically relevant effect? Expert Opin. Pharmacother. 2011, 12, 647–655.
- Nakou, E.S.; Filippatos, T.D.; Kiortsis, D.N.; Derdemezis, C.S.; Tselepis, A.D.; Mikhailidis, D.P.; Elisaf, M.S. The effects of ezetimibe and orlistat, alone or in combination, on high-density lipoprotein (HDL) subclasses and HDL-associated enzyme activities in overweight and obese patients with hyperlipidaemia. Expert Opin. Pharmacother. 2008, 9, 3151–3158.
- Filippatos, T.D.; Liberopoulos, E.N.; Kostapanos, M.; Gazi, I.F.; Papavasiliou, E.C.; Kiortsis, D.N.; Tselepis, A.D.; Elisaf, M.S. The effects of orlistat and fenofibrate, alone or in combination, on high-density lipoprotein subfractions and pre-beta1-HDL levels in obese patients with metabolic syndrome. Diabetes Obes. Metab. 2008, 10, 476–483.
- Kalogirou, M.; Tsimihodimos, V.; Gazi, I.; Filippatos, T.; Saougos, V.; Tselepis, A.D.; Mikhailidis, D.P.; Elisaf, M. Effect of ezetimibe monotherapy on the concentration of lipoprotein subfractions in patients with primary dyslipidaemia. Curr. Med. Res. Opin. 2007, 23, 1169–1176.
- De Souza, J.A.; Vindis, C.; Hansel, B.; Negre-Salvayre, A.; Therond, P.; Serrano, C.V., Jr.; Chantepie, S.; Salvayre, R.; Bruckert, E.; Chapman, M.J.; Kontush, A. Metabolic syndrome features small, apolipoprotein A-I-poor, triglyceride-rich HDL3 particles with defective anti-apoptotic activity. Atherosclerosis 2008, 197, 84–94.
- Shige, H.; Nestel, P.; Sviridov, D.; Noakes, M.; Clifton, P. Effect of weight reduction on the distribution of apolipoprotein A–I in high-density lipoprotein subfractions in obese non-insulin-dependent diabetic subjects. Metabolism 2000, 49, 1453–1459.
- Rashid, S.; Genest, J. Effect of obesity on high-density lipoprotein metabolism. Obesity (Silver Spring) 2007, 15, 2875–2888.
- Bhutani, S.; Klempel, M.C.; Kroeger, C.M.; Trepanowski, J.F.; Varady, K.A. Alternate day fasting and endurance exercise combine to reduce body weight and favorably alter plasma lipids in obese humans. Obesity (Silver Spring) 2013. in press.
- Pattyn, N.; Cornelissen, V.A.; Eshghi, S.R.; Vanhees, L. The effect of exercise on the cardiovascular risk factors constituting the metabolic syndrome: A meta-analysis of controlled trials. Sports Med. 2013, 43, 121–133.
- Anderssen, S.A.; Carroll, S.; Urdal, P.; Holme, I. Combined diet and exercise intervention reverses the metabolic syndrome in middle-aged males: Results from the Oslo Diet and Exercise Study. Scand. J. Med. Sci. Sports 2007, 17, 687–695.
- Kelley, G.A.; Kelley, K.S.; Tran, Z.V. Exercise, lipids, and lipoproteins in older adults: A meta-analysis. Prev. Cardiol. 2005, 8, 206–214.
- Jane, M.L.; Ho, C.C.; Chen, S.C.; Huang, Y.C.; Lai, C.H.; Liaw, Y.P. A simple method for increasing high-density lipoprotein cholesterol levels: A pilot study of combination aerobic and resistance exercise training. Int. J. Sport Nutr. Exerc. Metab. 2012. in press.
- Katzmarzyk, P.T.; Leon, A.S.; Wilmore, J.H.; Skinner, J.S.; Rao, D.C.; Rankinen, T.; Bouchard, C. Targeting the metabolic syndrome with exercise: Evidence from the HERITAGE Family Study. Med. Sci. Sports Exerc. 2003, 35, 1703–1709.
- Sui, X.; LaMonte, M.J.; Laditka, J.N.; Hardin, J.W.; Chase, N.; Hooker, S.P.; Blair, S.N. Cardiorespiratory fitness and adiposity as mortality predictors in older adults. JAMA 2007, 298, 2507–2516.
- Wei, M.; Kampert, J.B.; Barlow, C.E.; Nichaman, M.Z.; Gibbons, L.W.; Paffenbarger, R.S., Jr.; Blair, S.N. Relationship between low cardiorespiratory fitness and mortality in normal-weight, overweight, and obese men. JAMA 1999, 282, 1547–1553.
- Lee, C.D.; Blair, S.N.; Jackson, A.S. Cardiorespiratory fitness, body composition, and all-cause and cardiovascular disease mortality in men. Am. J. Clin. Nutr. 1999, 69, 373–380.
- Seshadri, P.; Iqbal, N.; Stern, L.; Williams, M.; Chicano, K.L.; Daily, D.A.; McGrory, J.; Gracely, E.J.; Rader, D.J.; Samaha, F.F. A randomized study comparing the effects of a low-carbohydrate diet and a conventional diet on lipoprotein subfractions and C-reactive protein levels in patients with severe obesity. Am. J. Med. 2004, 117, 398–405.
- Volek, J.S.; Sharman, M.J.; Gomez, A.L.; DiPasquale, C.; Roti, M.; Pumerantz, A.; Kraemer, W.J. Comparison of a very low-carbohydrate and low-fat diet on fasting lipids, LDL subclasses, insulin resistance, and postprandial lipemic responses in overweight women. J. Am. Coll. Nutr. 2004, 23, 177–184.
- LeCheminant, J.D.; Smith, B.K.; Westman, E.C.; Vernon, M.C.; Donnelly, J.E. Comparison of a reduced carbohydrate and reduced fat diet for LDL, HDL, and VLDL subclasses during 9-months of weight maintenance subsequent to weight loss. Lipids Health Dis. 2010, 9, 54.
- Shadid, S.; LaForge, R.; Otvos, J.D.; Jensen, M.D. Treatment of obesity with diet/exercise versus pioglitazone has distinct effects on lipoprotein particle size. Atherosclerosis 2006, 188, 370–376.
- Bos, M.B.; de Vries, J.H.; Feskens, E.J.; van Dijk, S.J.; Hoelen, D.W.; Siebelink, E.; Heijligenberg, R.; de Groot, L.C. Effect of a high monounsaturated fatty acids diet and a Mediterranean diet on serum lipids and insulin sensitivity in adults with mild abdominal obesity. Nutr. Metab. Cardiovasc. Dis. 2010, 20, 591–598.
- Kotani, K.; Tsuzaki, K.; Sakane, N.; Taniguchi, N. The correlation between small dense LDL and reactive oxygen metabolites in a physical activity intervention in hyperlipidemic subjects. J. Clin. Med. Res. 2012, 4, 161–166.
- Gouni-Berthold, I.; Bruning, J.C.; Berthold, H.K. Novel approaches to the pharmacotherapy of obesity. Curr. Pharm. Des. 2012. in press.
- Bhatt, K.N.; Wells, B.J.; Sperling, L.S.; Baer, J.T. High-density lipoprotein therapy: Is there hope? Curr. Treat. Opt. Cardiovasc. Med. 2010, 12, 315–328.
© 2013 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).