New developments in cardiovascular risk factors concerning cholesterol show that small dense low-density lipoprotein (sd-LDL) is a most potent inductor of atherogenesis and is a better predictor than LDL.[1][2].
LDL consists of several subclasses of particles with different sizes and densities like the large buoyant “fluffy” LDL, mid-band LDL, and small dense LDL. In contrast to the small dense LDL, large buoyant LDL lowers cardiovascular risk.
Distinguishing the LDL particles is essential. The LDL in a Lipid Profile blood test includes all the LDL subclasses. One may have a low LDL and look like they have a low cardiovascular risk, but in actuality, the LDL may be mostly sd-LDL with a higher risk.
The reverse may also happen. A high LDL level may be mostly large buoyant LDLs that lowers cardiovascular risk. A statin may be started in this situation, or the statin dose may be increased unnecessarily.
Unfortunately, testing for LDL particle size is uncommon, and not many are aware of it. According to Labcorp, the American College of Cardiology and American Heart Association do not recommend routine subfraction testing.
People with diabetes are at high risk for heart disease. Accordingly, lipid profiles assess risk and guide treatment to prevent future heart attacks and strokes.
Lipid Profiles and what they mean
Lipid profiles include Triglyceride, HDL, LDL, mid-band, and very-low-density lipoprotein (VLDL). The values from them are used to stratify cardiovascular risk.
The latest European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) guidelines recommended LDL-C as the primary lipid analysis followed by Triglyceride (TG) and HDL.[5]
Non- HDL-Cholesterol or non-HDL-C is total cholesterol minus the HDL. Non-HDL-C is used to estimate the total amount of atherogenic lipoproteins in plasma. The National Institute of Health and Care Excellence recommends non-HDL-C as a better risk indicator than LDL-C.
The featured study aims to know if using information from the lipid profile may be a better predictor of small dense LDL. [4]
The Research
The study’s title, Triglyceride/low-density-lipoprotein cholesterol ratio, is the most valuable predictor for increased small, dense LDL in type 2 diabetes patients gives away its findings.
The Japanese research was peer-reviewed and published in January 2022 on Lipids in Health and Disease.
Study Participants
The study recruited one hundred ten patients with type 2 diabetes and hypertriglyceridemia from Okinawa, Japan. Forty-seven patients were taking statins, and 63 were not. No patients were treated with fibrates.
The study participants’ mean body mass index (BMI) was 26.7 kg/m2 (overweight range). The average glycated hemoglobin or hemoglobin A1C was 7.3 (1.4)% (diabetes range). The average kidney function or estimated Glomerular Filtration Rate GFR was 72.4 (18.8) mL/min/1.73 m2 (Stage 2 kidney disease).
Hypertension and CVD/stroke complications were reported for 67.3 and 19.1% of patients, respectively.
Method
A new test has to be compared against a standard to know the accuracy. In this research, the LDL cholesterol of all study subjects was measured by the direct method. Likewise, lipoprotein electrophoresis was conducted in all patients to reveal four lipoprotein fractions (HDL, LDL, mid-band, and very-low-density lipoprotein [VLDL]).
Small dense LDL (sd-LDL) was calculated from electrophoresis as LDL migration Index (LDL MI). LDL MI is an indicator of small dense LDL. A value ≥0.400 indicates an increase in sd-LDL. [7]
Nine lipid markers were statistically tested against the expected results to identify which of them or their ratios can accurately identify sd-LDL levels. The nine lipid markers are composed of results from direct testing and electrophoresis.
- Triglyceride – direct
- LDL-C – measured directly
- Non-HDL-C – direct
- LDL fraction – measured by electrophoresis
- Midband fraction – electrophoresis
- TG/LDL-C ratio
- TG/HDL-C ratio
- LDL-C/HDL-C ratio
- non–HDL-C/HDL-C ratio
Statistical analysis was done with Receiver Operating Characteristic or ROC curves. ROC curves compare the specificity (true negative) and sensitivity (true positive) of each nine lipid parameters against the standards, and the Area under the Curve (AUCs) was calculated.
As a sidenote, electrical engineers and radar engineers first developed ROC curves during World War II for detecting enemy objects on battlefields which explains the name.
Findings
The best test with the highest sensitivity and specificity for detecting small LDL is the TG/LDL-C ratio in the study. The ROC curves below compare the TG/LDL-C ratio and non–HDL-C for predicting small dense LDL (≥ 0.400) among all patients in (A) and those not treated with statins (B).
The Area Under the Curve AUCs is the red line for TG/LDL-C ratio and a blue line for non–HDL-C among all patients (A) and those not treated with statins (B).
The figures above show that the AUC of the TG/LDL-C ratio was significantly greater than that of non–HDL-C among all patients and those not treated with statins. This means that the TG/LDL-C ratio has a higher specificity (true negative) and sensitivity (true positive) than non-HDL-C. TG/LDL-C is the best predictor of small dense LDL among the nine lipid markers in the study.
I did not include the statistical results for the other lipid markers. However, the figure below from the study summarizes their main findings.
The right lower box shows TG/LDL-C ratio ≥1.1 is positively correlated with the triglyceride (TG) and small, dense LDL and non-HDL C is shown by the ⇑ arrow. An ⇓ arrow means a lower large, buoyant LDL, directly measured LDL cholesterol, and LDL measured by electrophoresis.
Summary
The TG/LDL-C ratio is a simple and reliable lipid marker of small, dense-LDL and superior to non–HDL-C in type 2 diabetes patients not treated with statins. According to the authors,
Even if LDL-C is low or within the normal range, it is possible to predict high values of sd-LDL by calculating the relative ratio with TGs.
The fact that the cut-off point for the TG/LDL-C ratio was constant irrespective of statin treatment suggests that the TG/LDL-C ratio is universal and reliable for the prediction of sd-LDL increase.
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References:
- Ikezaki et al. Small Dense Low‐Density Lipoprotein Cholesterol Is the Most Atherogenic Lipoprotein Parameter in the Prospective Framingham Offspring Study. Journal of the American Heart Association. 2021;10:e019140
- Hoogeveen RC et al. Small dense low-density lipoprotein-cholesterol concentrations predict risk for coronary heart disease: the Atherosclerosis Risk In Communities (ARIC) study. Arterioscler Thromb Vasc Biol. 2014;34:1069–77.
- Ivanova EA, et al. Small Dense Low-Density Lipoprotein as Biomarker for Atherosclerotic Diseases. Oxid Med Cell Longev. 2017;2017:1273042. doi:10.1155/2017/1273042
- Ouchi G, Komiya I, Taira S, Wakugami T, Ohya Y. Triglyceride/low-density-lipoprotein cholesterol ratio is the most valuable predictor for increased small, dense LDL in type 2 diabetes patients. Lipids Health Dis. 2022;21(1):4. Published 2022 Jan 7. doi:10.1186/s12944-021-01612-8
- Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H,
et al. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J. 2016;37:2999–3058. https://doi.org/10.1093/eurheartj/ehw272. - Imajo K et al. LDLmigration index (LDL-MI), an indicator of small dense low-density lipoprotein (sdLDL), is higher in nonalcoholic steatohepatitis than in nonalcoholic fatty liver: a multicenter cross-sectional study. PLoS One. 2014.
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