Small Dense LDL (sdLDL)

As discussed previously, apoB-containing LDL particles exist as a heterogeneous collection of variable sized particles, from small to large. There are technologies that size or measure peak particle diameters (in Angstroms or nanometers).1,2

• Phenotype or Pattern A – Predominant LDL species is large. This is the one you want!
• Phenotype or Pattern B (not to be confused with apoB) – Predominant LDL species is small3,4

Small, dense LDL (sdLDL), or more accurately small, dense LDL-cholesterol (sdLDL-C), is the cholesterol mass trafficked within the small LDL particles. It takes 40-70% more smaller LDLs than larger ones to traffic a given cholesterol mass, hence increased sdLDL-C is usually associated with high numbers of small LDL particles and total LDL-P.5

By definition, smaller lipoproteins are denser than larger species as there is more protein relative to the lipid content. Hence, the redundant term small LDL need not be always written as small, dense LDL. As sdLDL often traffics lipoprotein associated phospholipase A2 (Lp-PLA2), it is more prone to oxidative forces than large buoyant LDL and thus is likely more atherogenic.6,7

Studies have shown that elevated sdLDL particle concentration is associated with increased risk for coronary heart disease (CHD) even in the presence of optimal LDL-C values.3,5,8-10 However, when sdLDL-P concentrations are high, so is total LDL-P (apoB). sdLDL mass (particle number) plays a more important role in the progression of CHD than the LDL size, and sdLDL concentration serves as a powerful surrogate marker for CHD risk.8 By using the ratio of sdLDL-C to total LDL-C, it is easy to estimate the percentage of the total LDL-C that is made up of small dense particles.

Clinical Impact

Small, dense LDL particles are more easily modified by reactive oxygen species than larger LDL particles. They are more susceptible to oxidation, have a reduced affinity for the LDL receptors, and have increased clearance by scavenger receptors resulting in increased foam cell formation.5-8,11

Small LDLs also have a longer half-life than larger LDL particles. That means they stick around longer. Plus, their very small size may permit easier penetration of the endothelial wall.11

Moreover, small LDL particles are thought to be more readily retained in the artery wall, having a higher affinity for the proteoglycans that reside in this area.12,13

sdLDL and Blood Sugar

Small LDL particles may be observed in association with insulin resistance (IR) disorders such as obesity, the metabolic syndrome and prediabetes, and type 2 diabetes mellitus (T2DM), or in patients with renal dysfunction.14-32 Plasma/serum sdLDL levels are highest in the morning before breakfast; postprandial sdLDL levels are lower than fasting sdLDL, in part due to CETP-mediated TG-enrichment.33 After glucose ingestion, sdLDL levels are decreased.34 Trans-fat intake has also been shown to increase sdLDL levels.35

In addition to cross-sectional studies that have demonstrated an association between a predominance of small LDLs and increased risk for cardiovascular disease and diabetes mellitus, a reduction in LDL size has also been reported in patients with acute myocardial infarction, with angina pectoris as well as in those with non-coronary forms of atherosclerosis.36-40

sdLDL & Cardiovascular disease

If unadjusted for particle number, LDL size appears to be an important predictor of cardiovascular events and progression of coronary artery disease. Indeed, the predominance of small LDL was (in 2001) accepted as an emerging cardiovascular risk factor by the National Cholesterol Education Program Adult Treatment Panel III.41

However, data emerging from more recent studies shows that once adjusted for total LDL-P, LDL size is no longer an independent predictor of risk.39,42,43

Nevertheless, high sdLDL values, with elevated triglyceride levels and low high density lipoprotein (HDL)-C concentrations (also defined as disorders of the TG/HDL-C axis), constitute the “atherogenic lipoprotein phenotype (ALP),”3,9,41 a form of atherogenic dyslipidemia that is a feature of Type-2 Diabetes and the metabolic syndrome.11,13,41

The most important role of sdLDL in drug-naïve patients is as a marker of insulin resistance. Because smaller LDLs are cholesterol depleted, LDL-C or total cholesterol may not be increased in patients with diabetes, except for a slight increase of LDL-C in women.17

Subjects with a predominance of sdLDL have a greater than two-fold increased risk for developing type-2 diabetes mellitus, independent of age, sex, glucose tolerance and body mass index. Increases of peak LDL size were associated with a 16% decrease in the risk of developing Type-2 Diabetes.19

It has also been shown that patients with the insulin resistance syndrome have an elevated prevalence of the LDL “pattern B” phenotype20 and this has been confirmed for diabetes, in both men and women.21,22,44 In addition, when individuals were categorized as insulin-sensitive, insulin-resistant, or type 2 diabetic, more severe states of insulin resistance were associated with smaller LDL particle size.23,45 The reduction in LDL size occurs long before any glucose perturbation.

Therefore, the presence of both small LDL size and small LDL-P can be predictors of future T2DM.46

When Hulthe et al.47 assessed the prevalence of metabolic syndrome (using the World Health Organization definition) in a population-based sample of 58-year-old healthy men, the researchers found that LDL size was significantly smaller in subjects with the metabolic syndrome, compared to those without it.

In addition, subjects with pattern B had significantly higher mean values for body mass index, blood pressure, heart rate, serum cholesterol, triglyceride levels, and plasma insulin, and lower HDL levels compared with subjects with pattern A.

Subjects with pattern B also had a higher prevalence of moderate to large plaques in the carotid artery compared with subjects with pattern A. Decreasing LDL peak particle size was significantly associated with increasing carotid intima media thickening (CIMT) of the common carotid artery, the carotid artery bulb, and the common femoral artery. There was a statistically significant association between plaque occurrence and size and the LDL peak particle diameter in both the carotid and femoral arteries.45

Increased carotid intima media thickness (CIMT) is considered a reliable surrogate marker of early atherosclerosis and has been shown to correlate significantly with the presence of CHD and to predict coronary events.24,48,49 Berneis et al. (2005) found that LDL size was significantly associated with carotid IMT in patients with T2DM. LDL size was the second strongest predictor of IMT, after smoking, when compared with nine other cardiovascular risk factors, and was the strongest of all lipid parameters that were evaluated.50

However, this study was not adjusted for apoB or LDL-P. In another study, increased sdLDL-C level was a significant predictor of acute ischemic stroke (AIS) and in-hospital short-term mortality after AIS, a finding that persisted after adjustment for conventional risk factors (but not apoB). These results indicate that sdLDL predicts both AIS onset and consecutive short-term mortality, independent of traditional risk factors.51

Studies have demonstrated independent associations of both hepatic steatosis (HS) and the metabolic syndrome with LDL particle size, even after adjustment for apoB.12 LDL particle size is closely related with serum levels of TG, HDL cholesterol, and insulin resistance.45

Cholesterol Particles

Large amounts of plasma TG are carried or transported by very low-density lipoprotein (VLDL) from liver or chylomicrons from the gut. These particles typically undergo delayed catabolism in insulin resistant patients, which allows cholesteryl ester transfer protein (CETP) to exchange the TG for cholesteryl ester (CE) in intermediate-density lipoproteins (IDLs), LDLs and HDLs.52

These latter particles thus become TG-rich and CE-poor. TG-rich HDL and LDL then undergo additional hydrolysis by hepatic lipase (a form of lipoprotein lipase or LPL), creating smaller HDL and LDL species. The very small HDL is further degraded and its structural apoA-I is excreted by the kidney, leading to decreased serum apoA-I, HDL-P and HDL-C.30 As for cardiovascular risk, both quality (i.e., LDL peak particle size) and quantity (apoB or LDL-P) of LDL were reported to be important equally and additively.53 It should also be noted that CETP activity results in CE enrichment of VLDL and postprandial chylomicron remnants.

The smaller LDL particle size in the subjects with hepatic steatosis alone could be explained by the concept of hepatic insulin resistance, which occurred primarily31 and more evidently54 than peripheral insulin resistance. Hepatic fat accumulation in HepG2 cells was found to induce serine phosphorylation of insulin receptor substrate (IRS)-1 and endoplasmic reticulum (ER) stress, as previously reported by the authors.32 The ER stress, in turn, led to the suppression of insulin receptor signaling, causing hepatic insulin resistance with no evident peripheral insulin resistance.

How To Reduce sdLDL

Although not specified as a goal of therapy in any guidelines, sdLDL levels may be reduced through a variety of different treatment options:

• Diet (reducing intake of simple sugars and refined carbohydrates),11,35,43 exercise, and lifestyle modification (weight loss, smoking cessation).
• Statin therapy, the standard first line drug for elevated apoB or sdLDL-C, can effectively reduce the number of LDL particles (the primary goal) but does not generally influence their size distribution. Although statins may increase sdLDL levels when triglycerides are low, this is likely of no concern if apoB and LDL-P reductions are substantial.
• Other medications such as niacin, fenofibrate, high-dose omega-3 fatty acids, or a combination of medications (niacin + statin, fenofibrate + statin, or omega-3 + statin) can decrease sdLDL levels; however, only statin plus niacin reduces LDL-P beyond statin monotherapy.55,56
• Treating glycemic abnormalities in diabetes and insulin resistance patients with insulin therapy can decrease sdLDL particles by reducing triglycerides in TG-rich lipoproteins. Thiazolidinedione insulin sensitizers, such as pioglitazone (off-label use) may have a similar action.

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